12 An Approach to the Study of the Pulmonary Circulation

Albert L. Hyman, M.D.

Professor , Department of Surgery, Medicine, and Pharmacology , Tu­ lane University School of Medicine, New Orleans, Louisiana

Thou shalt have no false gods before with his classical concepts of faith, moral ­ thee! Some of mine have been godlike, ity , and justice . Here, I first came to be some stern, some even cruel, but none electrified by ideas and abstractions. In have been false. Although , like the great college came a standard platter of Ameri ­ lawgiver , none actually walked upon the can education, food but no feast - some Canaan of the pulmonary circulation, classics , some literature, a bit of science. whether wittingly or not, they led me step Then I was off to medical school. by step in an uninterrupted path to that The war with Japan and Germany had study. First was my father , a Tulane ­ just commenced , and the pace of medical educated general practitioner, who was education quickened, leaving little time wont to remind me of my great disappoint ­ for concepts to germinate . Nonetheless, ment with kindergarten "because they those 36 uninterrupted months were am­ don't teach no doctor stuff there. " Then ple time to elevate new gods. Dr. Richard there was his father, an old-world Hebraic Ashman, chairman of physiology, deliv­ scholar , litterateur, and moralist , who , ered the first 20 of the daily physiology with my father, had miraculously escaped lectures. Electrophysiology was his major the Odessa pogroms. He spent most of my interest , and on e of the several phenome­ childhood attempting to inculcate me nan he described still bears his name. From: Wagner WW, Jr, Weir EK (eds): The Pulmonary Circulation and Gas Ex change. ©1994, Futur a Publishing Co Inc, Armonk, NY.

235 236 • THE PULMONARY CIRCULATION AND GAS EXCHANGE

Sitting in on those lectures were Dr. patient back to his family and work as George Burch, himself soon to become quickly as possible. He had an enduring widely published in electrocardiography, but quiet concern for his house staff mem­ and Dr. Sam Levine's nephew, Harold bers , not only during their training at Levine from Boston, a well -known cardi­ Charity Hospital, but also throughout their ologist in his own right. The curriculum careers. He once postponed an important was rushed, and for many reasons these staff meeting because, as I learned years electrophysiology lectures were complex. later, he had gone to northern Louisiana to Moreover, we had not even studied car­ help reconcile a former cardiac fellow and diac anatomy. In one of Dr. Ashman's his wife . His student examinations were lectures I had failed to identify correctly always oral, straight from Cecil's textbook, the electrocardiographic appearance of and he enjoyed "helping you out a bit" atrial flutter. In a subsequent discussion, when you faltered. There was also Dr. the great electrophysiologist was far more Robert Bayley, a former cardiac fellow concerned with goading his errant student under Dr. Frank N. Wilson of Ann Arbor. into formulating a concept that would ex­ He, like Wilson, had a remarkable talent plain how continuous atrial electrical ac­ for mathematics and applied it skillfully tivity could usurp sinus node function . and often to electrocardiology. He had With my guess that a faster irritable focus devised what has come to be known as the depolarizing at 250-300 times a minute triaxial reference system. Medicine could do it, Dr. Ashman was off with a "porch conferences" (porches had ceiling host of experiments he and I could do to fans) were vibrant with clinical cardiol­ further test this widely accepted concept . ogy, electrocardiology, cardiovascular He suggested that we go off to his labora­ physiology , and the invariable "let's see tory-"Never mind the exam, there will be your data" or "can you give us the mathe­ others and you'll do well ." Many years matical proof." Somehow the other areas later my wife pointed out that the intensity of medicine got much less attention. and dedication I learned as a child had not Undoubtedly the foremost figure in altered, but I had substituted medical sci­ my early progress was Dr. John Samuel La ence for theosophy and humanism, and Due. He had done medicine at Harvard, the former had become my new "reli­ internal medicine at Mayo, and a Ph.D. at gion." Electrophysiology , electrocardiol­ Minnesota. He had only recently turned ogy, and cardiac arrhythmias were chal­ all of his enormous energy to cardiology, lenges that came along in rapid succession joining with Drs. Ashman, Hull, and Bay­ while working with Dr. Ashman . ley. With the fortunes of alphabetic stu­ Further along, my time at medical dent assignments and a high class failure school was largely consumed with new rate , John La Due was my rounding man icons, each with special cardiovascular all through medical school. One soon skills. Dr. Edgar Hull, the medicine chair­ came to emulate his penchant for thor­ man, was an unquestioned master of bed­ ough historical inquiry, complete physical side medicine and cardiac auscultation. exam, and an unabridged write-up . Before At Charity Hospital in New Orleans, pa­ case presentation, it was wise to spend the tients took to him immediately because he evening in the medical library acquainting knew their hometown physicians. In fact, oneself with current literature related to he seemed to know every physician who the patient's illness. If all went well, the practiced in every parish in Louisiana. He ultimate question was always, "Well, had taught most of them. His was a practi­ what have you read about this illness cal approach. He sought the correct diag­ lately?" He wasn't one to let you off the nosis to the extent possible but got the hook easily. Two examples are memora - An Approach to the Study of Pulmonary Circulation • 237 ble . As a second semester student visiting cation was with Dr. Ashman , demonstra­ the wards for the first time, I was asked ting that the anatomic axis of the heart , as what the "Robinson -Power-Kelper test" seen fluoroscopically, could be predicted was. "I would have to go to the library; it from the ECG taken in the same position. 1 wasn't yet in Cecil's text. " La Due smiled, La Due went on to New York , where , with "Yes, that's a good idea." As we com ­ Wroblewski and Karmen, he was the first menced discussion of another patient, he to publish the use of the cardiac enzyme looked up at me rather surprised and (SGOT) in the diagnosis of acute myocard­ shouted "Now!" On another occasion, Dr. ial infarction. La Due prodded a less than ardent medical Shortly before I received my medical student to study more and more thor ­ degree, my father's brother, a colorful gy­ oughly the blood of a patient with unex ­ necologist at Cedars of Lebanon (now Ce­ plained anemia . On the great day, Dr. La dars-Sinai), Los Angeles, suggested I learn Due finally received all the hematologic his specialty and join him in his practice. data and asked for the student's appraisal This digression was short-lived. My pro ­ of the anemia. "I don't know, Dr. La Due, fessor of obstetrics knew me well, having but you've had me take an awful lot of delivered me about twenty-one years be ­ blood out of her." This was one of the few fore . He agreed to give me an obstetrics times John La Due was ruffled. residency if I would first do a rotating The experience I acquired over three internship at Charity Hospital. His condi ­ academic years with John La Due left an tions were clear: take as many specialty indelible mark on my approach to medi ­ blocks as I could, except obstetrics, and if cine and science. "If you don't know and I still wanted the obstetrics residency at it's not in the library, you have a golden the end of that year, it would be mine. My research opportunity," he would say. Al­ first assignment was internal medicine, though I worked with him on the wards, in with Drs . Hull, La Due, and Bayley as my the clinics, and in his research laboratory, clinical staff and Louis Levy, another ar­ it was only years later that he expressed dent follower of Dr. Ashman, as my resi­ any appraisal of my work or productivity . dent physician. Professor Graffagino, Un­ Some seven or eight years later, I saw John cle Earl, Cedars, and Los Angeles became in the lobby of the Los Angeles hotel host­ a pipe dream (and we used pipe cleaners ing the American College of Cardiology in those days to project vectorcardiogra­ meeting. He insisted that I come immedi ­ phic loops) . It was clear, however , that ately to a private reception honoring him before embarking on a training program in upon his election to the presidency of that cardiology, it was necessary to complete group. At that reception, I was introduced that rotating internship and three more to the cognoscenti of cardiology and the years of general internal medicine . My new specialty of cardiovascular surgery as second rotation was onto Dr. Alton "one of the best damn medical students I Ochsner's surgical ward with a young resi­ ever contended with." The libations and dent from Philadelphia, Oscar Creech . atherogenic refreshments were lavish, and There was a new surgery , tying off a patent John had probably partaken heavily of ductus , or turning down a subclavian ar­ both. With Dr. Ashman and Robert Bayley, tery, to the pulmonary artery for Fallot's La Due perfected the concept of electro ­ tetralogy. Oscar was disappointed, seeing cardiographic vector analysis, developed that I was much more interested in the the ventricu lar gradient of F. N. Wilson, cardiovascular and hemodynamic de­ and from the QRS loops identified the rangements than in the mechanics of sur­ effects of anatomic rotation of the heart on gical repairs. I did the forbidden obstetrics the standard ECG. Indeed, my first publi - month, for the most part to see first hand 238 • THE PULMONARY CIRCULATION AND GAS EXCHANGE how a physiologic volume overload af­ pital! The cultures were negative, but we fects healthy people as well as thos e with established the diagnosis of pulmonary rheumatic and congenital heart disease. stenosis with the catheter and kymograph. Alcohol was the only pharmacologic diu­ Somehow this seemingly minor event retic known then. did not pass unnoticed in the staid com­ The next year was spent at the Univer­ munity of Charity Hospital. I got a strain sity of Cincinnati. Dr. La Due had urged gauge! What's more, on his retirement, Dr. me to spend a year with Professor Marion Ashman gave me his prized double­ Blankenhorn to learn a more disciplined channel Cambridge string galvanometer approach to internal medicine. Dr. Blank­ with the two quartz spare strings and rap­ enhorn had made many early observations idly moving photographic paper. He had on beriberi heart disease. His son, David, had it uniquely designed to take not one, was an excellent fourth-year student on but two ECG leads concurrently. One our wards, and we have been friends over channel was converted to use with the the years. He went to the University of strain gauge, permitting measurement of Southern California and became inter­ one pressure change concurrently with ested in atherosclerosis. About halfway one ECG lead . One channel was standard­ through the first-year residency, I was in­ ized against a column of mercury and the vited to give a cardiology seminar on this other with a DC voltmeter each day. It was new business of vectorcardiography. Dur­ large, about the size of the fluoroscopic ing the year-end holida ys in New Orleans, table, but was a distinct improvement over Richard Ashman took me into his labora­ the smoked kymographic drum and rub­ tory and his home and amply prepared me ber tambour. On the other hand, its quartz for the seminar. Noble Fowler, a senior strings broke easily, were difficult to insert resident, attended and showed interest. between the magnet heads, and were ex­ We talked many times during that year. pensive. My assignment in the internal Indeed, after a short visit to Bellevue, he medicine residency program somehow be­ started this "new thing," cardiac catheter­ came concentrated on the cardiology ization in the heart station at the General. clinic with the new bright-line fluoro­ Soon I had learned what little was known scope (only 5.0 m.a.!), the ECG reading about it in 1946. I returned to Charity room with Dr. Ashman, and, of course, the Hospital for two more years of internal catheterization procedure on selected pa­ medicine residency. Shortly into that sec­ tients seen in cardiac consultations or ond year, a patient thought to have bacte­ clinics . Dr. George Burch became inter­ rial endocarditis on the pulmonary valve ested, and soon we were occasionally appeared. It seemed best in those days studying Tulane patients as well. Dr. Nel­ (1947) to culture blood drawn from the son Ordway joined the Louisiana State pulmonary artery. A cardiac catheter University's pediatrics service and intro­ somehow appeared quickly. Since the duced the Roughton-Scholander glass pi­ only horizontal fluoroscope available was pette to measure blood-oxygen content. in the tuberculosis hospital unit, the cath­ Pediatric patients from both schools came eterization procedure was done there. along, and we grew busy. There were no There were no strain gauges in those days. standards, no procedural texts , no ECG One of Dr. Ashman's jerry-rigged smoked­ oscilloscope, no defibrillation, no surgery kymographs with a calibrated rubber tam­ standby . We flew by the seat of our pants, bour measured pressures as the fluoro­ but fortune smiled, and no one was in­ scope guided the catheter up . This was the jured. Perhaps the exception was the hair first heart catheterization at Charity Hos- on my hands, which was lost . I was able to An Approach to the Study of Pulmonary Circulation • 239 get a "bright-line" fluoroscopic screen. Arts and Science at Michigan to the one at Still 5 m.a. T.V. screens, remote or other­ Tulane. His wife, who had Fallot's wise were unknown! tetralogy, was under the care of Franklin In the heart station there were new Johnson and F. N. Wilson at Ann Arbor. and exciting sessions. Dr. Frank N. Dr. Burch showed me the rather complete Wilson, who first described the precordial letter he had received from Ann Arbor and electrocardiogram, began coming quar­ asked me to examine his patient in the terly to visit his daughter in New Orleans. elite doctor's infirmary at Charity. I was Dr. Franklin Johnson, his close associate, impressed with this attractive young sometimes accompanied him. Wilson's blonde, lying in bed, sparsely clothed, student, Dr. Demetrius Sodi-Pallares, now reading Tolstoy's book. After my examina­ chief of electrocardiography at the Na­ tion, I returned to Dr. Burch's office armed tional Institute of Cardiology, Mexico with Taussig's new text. I confidently as­ City, also came. Sodi's New Basis of Elec­ sured him I would put a catheter retro­ trocardiography in 1956 was a classic. He gradely through a patent ductus. "A was later to advocate glucose, potassium, tetralogy has equal distribution of extre­ and insulin for acute myocardial infarc­ mity cyanosis, but this young woman has tion. With Dr. Ashman reading ECG's in differential cyanosis with pink fingers and the Charity Heart Station and Drs. Wilson, blue toes." Burch cautioned that x-ray Johnson, Sodi-Pallares, Bayley, La Due documentation of the catheter in the duc­ and Hull doing commentary, those were tus would be required. "But Dr. Burch, some heady sessions for a medicine resi­ I've never seen such an attractive young dent. Nonetheless , the new potential for blonde so scantily clothed in Charity Hos­ hemodynamic studies began to occupy pital." The Catholic nuns have always more and more time. Dr. George Burch, maintained strict decorum. "What's more, who had also embarked on a notable ca­ she was lying there reading Peace and reer in electrocardiography, invited me to War." "Al," he replied, "Tolstoy's book is the Tulane cardiology functions, and I called War and Peace." I paled, but his came to know his cardiology staff. On the consummate smile told me a new icon Tulane surgery service , Dr. Michael De would arise from an unlikely source, Tu­ Bakey and his resident Oscar Creech lane. The x-ray was dutifully brought to showed great interest in these cardiovas­ his office; he thanked me and kept it. cular conferences. The Taussig-Blalock Years later I came to learn that he had sent procedure for Fallot's tetralogy had been the film to Ann Arbor and gently chided described at Hopkins, and eventually the the doctors there about bedside examina­ first edition of Helen Taussig's book on tion and the need for a university catheter­ congenital heart disease appeared. Maude ization lab! Years after that I came to truly Abbott's book was largel y a pathologic understand that the judge and the execu­ anatomy treatise. Cournaud's short book tioner never dine together. hadn't appeared yet. After the rotating internship and three I came to know Dr. Burch even more years of "internal medicine," I was now in the third year of the LSU internal medi­ preparing to undertake a cardiology fel­ cine residency. Once his secretary called lowship. Dr. Ashman had me placed with me from Charity Hospital to see to him in Dr. Louis Katz at Michael Reese Hospital, his Tulane medicine department office. Chicago, but he wanted most that I set up Something was surely wrong! He ex­ a catheterization laboratory, not a new plained to me that a young instructor in experience for me. Drs. Langendorf and English had transferred from the School of Pick were superb students of arrhythmia, 240 • THE PULMONARY CIRCULATION AND GAS EXCHANGE but that didn't seem right. Dr. Hull wanted perspective. He was eager for me to visit me to go with his friend Sodi-Pallaris in his own Edinburgh and other British and Mexico City, but there was a language continental hospitals . "One doesn 't come barrier. I'd only learned Cajun French at to Europe every day," he was fond of Charity. Dr. Burch had another idea. He saying. At 8:00 a.m. on the first day, I went had a great interest in systemic veins, to the hospital, only to learn that the Brit ­ because "that's where most of the blood ish start their laboratory at about 10 a.m. is." He 'd written one of his famous prim­ and carry on until 8 p.m . Professor Mc­ ers on venous function , which had been Michael took me from firm to firm (sub ­ well received. I had studied some of Pro­ speciality sections) introducing me to the fessor John McMichael 's papers dealing people with whom I'd be working, a re­ with the concepts of digitalis affecting pri­ markably talented group, each of whom marily the systemic veins but knew little was destined for greater tasks. Professor about how veins controlled heart func­ Paul Wood, an Australian, was the round­ tion. I asked Dr. Burch about this work, ing man on the largest cardiac ward at and he immediately suggested I go to Lon­ Hammersmith. He was an excellent clini­ don and study with Professor McMichael. cal cardiologist, a good teacher, somewhat In June 1948, Dr. Burch and I composed dogmatic, and very self-assured. He was letters to him. About November, I had friendly from the outset and showed me taken a week to cruise to Havana , and, the chapter dealing with electrocardio­ while there, visited Dr. Castillano's new graphy in his forthcoming book Diseases angiocardiographic laboratory, one of the of the Heart and Circulation. He was well earliest in this hemisphere . As my boat acquainted with the work of F. N. Wilson, moored on the bank of the Mississippi Richard Ashman, Robert Bailey, and the River, Dr. Burch's secretary pulled me off other vectorcardiology group. John Good­ and into his office. Professor McMichael win came the same year I did. He was had come to Tulane to deliver the John interested in cardiomyopathy and devised Musser Memorial Lecture and was sitting a manual compression system to deliver at Dr. Burch 's desk waiting to interview radio-opaque material down a cardiac me . He explained that he had place for one catheter . His publications on cardiomy­ American, and Dr. Epstein from Yale had opathy are widely known. He and Paul Yu been appointed. A problem arose re­ edited an annual Progress in Cardiology, garding American Board oflnternal Medi­ for many years. John grew in stature and cine credits for studying in London, and became one of Britain's renowned senior Dr. Epstein was going to stay in the States cardiologists. He was often an invited in­ to complete those requirements. IfI had no ternational speaker at the American Heart such constraints, he would accept me. Dr. Association and the American College Burch arranged one of the first NIH Trav­ meetings . Professor E. P. Sharpey-Schafer eling Fellowships for me. I was on my way was one of the most clever and at times the to London in June 1949. most acerbic member of the Hammersmith London may be part of the Old World group. He and Professor McMichael had to Americans, but to me Hammersmith studied heart failure, cor pulmonale , and Hospital was an exciting new world. Pro­ the effects of ouabain during the late war fessor McMichael was surely an icon who years. strived to reach a balance between man Richard Bayliss, with whom I worked and his instruments, who leaned heavily closely, was a very able clinician and close on experience and less on statistics, and to the professor. One of Hammersmith's who had the skill to use bedside medicine greatest raconteurs, he was fond of the and keep advanced technology in proper apocryphal tale of Sharpey and the chair An Approach to the Study of Pulmonary Circulation • 241 in medicine at Thomas 's. He was short­ He was interested in going to the United listed, but a second round was announced. States to do pediatric cardiology and even­ The story has it that Sharpey and Richard tually in setting up such a subsection. I were at a pub on Duncane Road near the urged him to look at Cincinnati, which White Castle, having a beer before going offered many academic and intellectual home. Richard suggested that if Sharpey advantages, including a marvelous chil­ would obtain a fresh new suit and shirt dren 's hospital, heavily support ed by and present himself as a candidate the Proctor and Gamble. Besides, the meals second time, he would get the chair . Rich ­ there were superb. As a junior house­ ard suggested a suit like the blue serge the officer at the General, I arranged to read man next to them was wearing. Sharpey, their ECG's in the lunch hour because of always direct, commenced a conversation the food differential. In later years , I was to with the man. Soon the two went upstairs interview quite a few candidates for the and Sharpey emerged with the suit. Some pediatric cardiology job at Tulane and two say he bought it; others say he convinced for the Established Investigatorship award the man to enter Hammersmith Hospital of the AHA who had trained with Sam at for treatment of his cough. No one will Cincinnati Childrens. More recently, Bill ever know how the transaction occurred, Friedman , who joined the AHA Research but a few days later, Lancet had an an­ Committee as my term was ending , told nouncement that Professor E. P. Sharpey­ me he had lured Sam out to the pediatric Schafer had assumed the chair at Tho­ department at UCLA. The professor was mas ' s. rightfully proud of the bright young peo­ Sheila Sherlock was one of the most ple he brought together at the Ham­ colorful, clever young women at Ham­ mersmith-not only British physicians, mersmith. She was interested in liver dis­ but also those from the provinces, South ease and studied hepatic metabolism each Africa, Australia , India , New Zealand, and afternoon using a catheter passed into a Canada . (In spite of reminding him about a hepatic vein. She always commenced her certain melee in 1776, I was always intro­ catheter lab studies promptly at 2 p .m. If duced as being from the American prov­ Professor McMichaels 's firm- which in­ ince!) cluded Dick Bayliss, Morris Ethridge, Finally I was conducted to a labora­ from Adelaide, and me-hadn 't finished tory where thoracic blood volume was in the catheterization laboratory by that being measured by the blue-dye tech­ time, we experienced the full spectrum of nique . There I met Harry Kopelman and a Sheila's colorful nature. She has revised tall young physician who was introduced her book Liver Disease for many editions. as "Grant Lee." I smiled at the professor, She became a Dame, and Professor Mc­ who had me explain, "In my country , Michael and Dick Bayliss were eventually nobody is called both Grant and Lee." knighted by the British queen. Sheila is There began a long and still cherished now chairperson at the Royal Free. She is friendship that has lasted even through married to Jerry James, a pulmonary phy­ this most recent pulmonar y conf erence sician who was with Professor John Scad ­ outside of Denver. ding at Hammersmith. Working with Hammersmith Hospital was always Sheila was Alex Beam, who later studied frenetic with excitement - new ideas , new copper metabolism in Wilson's disease research initiatives , cardinal seminars , while at the Rockefeller in New York . He and penetrating , and at times, acerbic had the medicine chair at Cornell in later grand rounds. The professor was th e obvi­ years . Sam Kaplan was a South African ous leader and the arbitrator among working in cardiolog y at Hammersmith. sharply circumscribed opinions from the 242 • THE PULMONARY CIRCULATION AND GAS EXCHANGE

diverse firms. Hammersmith had newly were not sure of the mechanism of the been designated the Postgraduate Medical enhanced pulmonary hypertension. The School of the University of London and hypertension didn't seem to be due to was considered by British medicine to be enhanced flow, and the patient's oxygena ­ a heterodox, not one that taught the skilled tion improved. I've concerned myself with orthodox British tradition of clinical ex­ it for many years and am still not sure . cellence. At Hammersmith , the position Ironically , last year in my laboratory we was that one had acquired those skills spent much time characterizing the elec­ before coming. Nonetheless , as late as trogenic Na-K-ATPase pump in the pul­ 1949 the other great teaching hospitals monary vascular bed of healthy cats. were not sure about this Hammersmith There is no doubt that, at elevated tone, place. activation of the pump induces vasodila­ This was only four years after the tion. When the pump is blocked with second Great War, and London had only ouabain, a sizeable pulmonary hyperten­ begun to rebuild. The single catheteriza­ sion quickly appears. When we go about tion laboratory was in a galvanized hut writing up those experiments, we'll quote jerry-built onto the end of the hall. Dick that 1950 paper describing this strange Bayliss, Morris Ethridge, and I used it to aggravation of pulmonary hypertension study the effects of digoxin on the heart by ouabain in cor pulmonale. and circulation in different types of heart Many stimulating visitors came to failure . Sheila and her group were study­ Hammersmith. Werner Forsmann came ing liver function, and John Goodwin and from his small hospital practice in south ­ his group were doing angiocardiography, ern Germany. He had been a thoracic sur ­ looking at various forms of cardiomyopa­ geon who had studied with Adolph Fick. thy. When the London fog turned quite He had searched for Fick's mixed venous green, Hammersmith went out of control. sample with the zeal of Jason searching for The professor , Sharpey, Sheila Howath, the Golden Fleece. Alas , his one publica ­ and our group were looking at the effects tion on right heart catheterization for ob­ of ouabain on acute cor pulmonale in­ taining the sample was telling. He had duced by that thick, soupy green fog. Be­ used a ureteral catheter, which he had cause of the urgency and large number of passed upon himself with a system of patients, these catheters were floated in at mirrors and a fluoroscope. But the x-ray he the bedside with the help of a water ma­ published clearly indicated that the cathe­ nometer. Some nearby residents of East ter was too short and had stopped at the Acton actually came in to have the "arm­ superior vena cava- right atrial junction. tube with the digitalis." Watching the Nonetheless , he had come up with the pressure level and the oscillations of the idea, and he, with Cournaud and Dickin­ tip of the column of water was all that was son Richards, who did get the mixed ve­ needed. A mixed venous sample , a quick nous sample, were awarded the Nobel arterial sample, and , where possible , 3 prize. Forsmann had apparently done no min of collected exhaled air. A rapid Hal­ research since that x-ray was taken . He dane blood oxygen analysis and an 0 2 had had problems with other surgeons at meter and we had pressure and flow-no their hospital and seemed to have gone to balloons, no thermodilution, not even dye a small practice in a small German hospi ­ dilution. We were not sure of the salutary tal during and after the war. He told us that effects of ouabain in acute cor pulmonale , newspaper reporters had found him in as opposed to other types of failure , but it this small city and asked him how he felt often produced a remarkable pulmonary having just received the Nobel prize . He hypertension. We reported our data but said he thought for a moment and replied, An Approach to the Study of Pulmonary Circulation • 243

"Like a village priest who had just been lish. And one who had helped modernize elected pope. " Visiting the clinical re­ Hebrew had been my father's teacher search facilities at Hammersmith, he was Chiam Naham Bialik in Odessa. Several indeed a village priest. With the advent of Russian delegations came to Ham­ dye dilution , and now thermodilution, mersmith from time to time but left fairly one wonders , like Jason, about the value of promptly. The professor , like his prime the Golden Fleece after it served its pur­ minister, never trusted the Russians and pose. Indeed, no one knows its ultimate their brand of communism. Borst came disposition. from the Netherlands and showed the abil­ Dr. Sam Levine came from the ity of licorice to increase blood volume by Brigham. At grand rounds he demon­ a DOCA-like salt-retaining property. The strated his legendary auscultatory skill , value of the jugular venous pressure in correctly predicting the length of the PR accurately measuring right atrial pressure interval by listening to the intensity of the at the bedside was demonstrated , even if a first heart sound. I was elated at this dem­ tilt table was needed for low pressure . C. onstration that American physicians, too, Heymanns came from Ghent and lectured had great clinical skills and could reach a on the carotid sinus function. He also balance between the bedside and the labo­ received a Nobel prize. Andre Cournaud ratory. Sitting in the back of the room with gave a superb lecture on the pulmonary Paul Wood, I heard his quip, "Let him try blood flow and ventilation-perfusion that again." Well he didn't but he 'd shown matching. Bill Briscoe , who was in our it could be done. Von Euler from Stock­ Hammersmith group , eventually went to holm lectured on sympathetic control of work with him at Bellevue. He spent much cardiac inotrophy and attempted to relate of his time calculating the distribution of that to Starling curves. The family of ventilation and ventilation-perfusion ra­ curves came later, as did Von Euler's No­ tios. Bill was a heavy smoker, but these bel prize. Lenegre came from France and were the days before smoking became an described fibrosis in the cardiac conduct­ anathema. ing tissue and heart block. Somehow he One other perk appeared in London was rumored to have obtained his normal when postwar rationing was still neces­ control specimens at the guillotine. I erred sary. The first month, my NIH check badly , with my weak command of the hadn 't arrived, so I went to our embassy at Cajun-French patois, when the French Grovsner Square. No one had heard of this cardiologist Professor Heim de Balzac, a new NIH, but "if it has anything to do with nephew of Honore de Balzac visited us. the Public Health Service , you 're in luck Thinking in English but speaking the pat­ because the European chief is here. " He ois, I referred to Lenegre as "l'homme hadn't heard of the NIH either , but some­ guillotine .'' how I ended up with an embassy passport Then Sheba came from the new medi­ and Navy ship-store privileges. Like being cal school at Jerusalem and invited us to at Macy 's in a ration-ridden London! The visit him. He had just been appointed professor always enjoyed a wee bit of Israeli minister of health. Some of us took whisky (Scotch). To earn dollars , the him up on his invitation. The Hebrew Scotch was made in the U.K., shipped to University Hospital in 1950 was not the New York, and back to the U.S. Navy ship Hadassah Hospital of today. Nonetheless, stores in London by return flight. For er­ it was fascinating to read the patient charts rant young sailors preparing to visit the in a language untarnished by 3,000 years continent , ladies ' stockings were packed of history but suddenly transformed and in special boxes, a single stocking each. transliterated into scientific medical Eng- The professor was quite correct in his 244 • THE PULMONARY CIRCULATION AND GAS EXCHANGE appraisal of the remarkable effect of that excellent successor to their mentor, Dr. digitalis on systemic vessels. Much later it Ochsner. Soon after Oscar assumed the was shown to be related to its blocking surgery chair, he busied himself setting up action on the electrogenic pump. We were a combined cardiology-cardiovascular all convinced that much, if not most, of its surgery service. Dr. Burch asked me to effect was on the heart, but the two are come over to Tulane, set up the cardiol ­ closely intertwined, and sorting out the ogy-surgery catheterization laboratory in differences was difficult in intact man. the surgery department , and work closely Nonetheless , it fell to me to present the with the surgeons . Dr. Burch, who never group paper at the First World Heart Con­ quite trusted surgeons, felt that a well ­ gress in Paris, September 1950. It was to be trained cardiologist in their midst would presented in French; I protested that oth­ reduce their mortality rate . Neither he nor ers spoke fluent French. They explained any in his group had the time or penchant that the English and the French speak each for that work. The job carried a major other 's languages but won't. But my patois hazard. I would be working directly with was insular and far from contemporary the chairman of the surgery department, French; even my university cheering-song but my own chairman , Dr. Burch, had very was "Geaux Tigers." Sure enough, before little interest in surgery, much less cardio­ I had completed the presentation, my first vascular surgery. At later conferences, he ever, Dr. Cournaud was on his feet pre­ was wont to point out that the major cause senting a response in his staccato native of death from ventricular septal defect was French. I suggested that, because he was surgery . Nonetheless, he assured me that now an American, he would be good the need was great and my uneasiness enough to repeat his comments in English. ill-founded . Only later did English become the lingua When Oscar walked into his newly franca of science. At the meeting, I had an activated catheterization lab and saw me, interesting discussion with Bill Milnor he decried, "Lord, not you again!" Oscar from Johns Hopkins and Tom Mattingly. was one of the most princely men I've ever Bill was interested in the electrocardio­ had the pleasure to know. He was an graphic criteria for the diagnosis of ven­ accomplished cardiovascular physiologist tricular hypertrophy. Tom, a general in who happened to be a master surgeon. the U.S. Army Medical Corp, was study­ Work went well; new brooms sweep well. ing trauma to the heart. There were daily cardiac catheterizations, Working back at Charity Hospital, I attendance at surgery and the intensive told Dr. Burch that we had finally con­ care unit, and presenting or standing in for vinced Professor McMichael that the pri­ Dr. Burch at cardiology conferences and at mary effect of digitalis was on the heart . his student rounds during his important Without a hesitation, Burch replied "Well, visits to the NIH, to other universities, and I'm not so sure anymore!" He said that to Europe. The research seminars were Tulane was undergoing changes. The es­ replete with promising young people. teemed Dr. Ochsner was about to retire as Tom James was studying coronary arterial chairman of surgery, and Tulane wanted supply to specialized conducting tissue the cardiovascular surgeon Dr. Michael and electronmicroscopy of the sinoatrial DeBakey to succeed him. Mike was a Tu­ and atrioventricular node , Ralph Lazarro lane graduate and had been Dr. Ochsner's was doing early electrophysiologic experi­ finest before going to Baylor. But Mike ments, Lewis Thomas was involved in suggested that Tulane invite Oscar Creech cardiac pathology , Thorpe Ray was study ­ instead. He had done a superb job with Dr. ing sodium and tagged rubidium excretion DeBakey at Baylor and should make an induced with the new mercury diuretics. An Approach to the Study of Pulmonary Circulation • 245

Leo Horan was looking at mechanisms in Creech's patients. The catheter had gone atrial fibrillation. Victor Ferrans was fin­ across the atrial septum but entered the ishing clinical cardiology training on my left inferior pulmonary vein. A plastic 3F ward and doing his Ph.D. in cardiac elec­ was then passed out the transseptal cathe­ tronmicroscopy, and Bill Love was esti ­ ter into a peripheral pulmonary vein, and mating coronary blood volume by dye pressures in the left atrium and large and dilution. In physiology, Dr. Hyman May­ small pulmonary veins were recorded erson and Karlman Wasserman were concurrently as the patient lay comforta­ measuring pulmonary lymph protein . bly on the catheterization table . This ap­ The ivory-towered top floor of the proach simulated to a great extent the medical school was Burch's Bercht­ continuous measurements of systemic ve­ esgaden. Here his hemetically sealed tem­ nous pressure that Dr. Burch had studied. perature- and humidity-controlled rooms He had described the spontaneous fluctu­ had been constructed. In them, I did bed­ ations in pressure in these vessels. side cardiac catheterizations to measure At that moment Dr. Burch, who gener­ pulmonary vascular pressures and Fick ally wanted little to do with cardiac cathe­ outputs . We were studying the effects of terization, walked in and asked about the temperature and humidity on human car­ progress of the procedure. When I ex­ diovascular function. New Orleans could plained how readily one could measure get hot in the summer, and hospitals pulmonary venous pressure in a man rest­ weren't yet air-conditioned. Moving ing quietly, he was enthusiastic. He quickly to make measurements and keep watched the pressure tracings carefully as the instruments functioning in those rooms he asked the patient to undertake complex often caused incapacitating weakness mental tasks . After the diagnostic proce­ within 15 to 20 minutes. Dr. Burch himself dure was complete , he announced with had once experienced a syncopal episode great conviction, that I was to study pul­ in one of the rooms. Strangely, the volun­ monary circulation . There was no need for teer, who lay quietly on a couch, sweated me to do all of these diagnostic catheteri­ but had no real discomfort. Cardiac outputs zations; other people could be brought to were measured 35-40 L/min at the most Tulane to do that , but to study the intact humid and hottest temperatures. pulmonary vessels was a more important Work had proceeded quite well until undertaking. Responding to my reluctance an unlikely incident changed all that. I to undertake the study of a circulatory had visited John Ross at the NIH and system about which so little was known, received instructions in his newly intro­ he smiled again and said, "Can't think of a duced transseptal catheterization tech­ better reason to do it." After many years of nique. The transbronchial approach we clinical cardiology, electrophysiology, previously used to cross the mitral valve and about twenty-five hundred diagnostic was difficult for the patient, and twice the heart catheterizations, I was now into the PE- 50 tubing had knotted inside the left pulmonary circulation. atrium before it could be passed through Many months of long evenings were the mitral valve. Fortunately, both were in consumed in the medical library, reading patients with severe mitral stenosis . In what was not quite "so little." The relation each , the PE-50 was drawn tautly against of vascular flow to pressure, interstitial the patient's lips , and Oscar Creech caught lung pressure to lung volume , hypoxia , the errant loop during a finger fracture, gravitational effects , distention and re­ closed valvulotomy. Back at the Tulane cruitment , pulmonary capillary blood lab after the NIH visit, I was doing a trans­ flow, pulmonary venous pressure, and septal catheterization on one of Oscar pulmonary reflexes were among the major 246 • THE PULMONARY CIRCULATION AND GAS EXCHANGE topics of interest. Rewarding weekends monary vessel could induce reflex were spent with Bill Milnor at Hopkins bradycardia and hypotension, with possi ­ learning from his work on pulmonary ve­ bly reflex pulmonary arterial and venous nous and arterial pressures in open chest constriction. Dr. Greene, from the NIH, dogs. Bill had recently transferred from was visiting Tulane, and Oscar arranged a cardiology to physiology at Hopkins and meeting, where I learned for the first time was even then formulating plans for his how to apply and write a grant applica­ unique book, Hemodynamics, published tion. The application was submitted under in 1982. It wasn't that far from New Or­ Oscar's aegis, and, to my complete sur­ leans, and my sister was there with her prise, the study section funded my project. husband, who was on the child psychiatry Oscar was delighted, there was joy in faculty. Mudville, the first of this growing junior Dr. Burch advised me to make simple, faculty had gained indepe ndent support. direct measurements in intact dogs. I con­ There was, however, an unforeseen prob­ trasted the spontaneous changes in large lem, and my Icarian wings experienced and small vein pressures, after taking elab ­ the first rays of the sun's heat . A member orate pains to ensure that this was not of the medicine faculty only applies for pulmonary venous wedge pressure . Out ­ grant support from the medicine depart­ put and pulmonary blood volume were ment, not surgery. The careful instruc­ measured by dye dilution. We then looked tions from the NIH hadn't covered this at the effects of transfusion, of a cold point. They saw my laboratory in surgery, environment, and of balloon occlusion. A my close clinical and laboratory relation ­ pressure gradient between the large pul ­ ship with the surgeons, and said that's the monary vein and the left atrium was never way to go. In spite of the progress of the identified. We found no support for the research, I could not bring any of these concept of large vein throttling pulmonary studies to readily provide for a definitive venous flow in the left atrium. Interpreting experiment. One had to differentiate be ­ the data provoked interesting discussions. tween passively induced pulmonary hy ­ Measurements dealing with pulmonary pertension from mechanical obstruction hemodynamics are not interpretable in with embolization and actively induced terms commonly used in the systemic cir ­ vasoconstriction. Paul Yu from Rochester culation. I urged those near Dr. Burch who was chairing the American Heart Associa ­ were reviewing my data with me to re­ tion session at which Abe Rudolph was member that this is a high flow, low pres ­ presenting a paper suggesting that the pul ­ sure bed, modula ted by Starling -type re­ monary hypertension resulting from em­ sistors not seen in the systemic bed; that bolus was mechanically induced, and I flow and pressure are not always nearly followed with data suggesting reflex con­ linear; and that calculated resistance val­ tribution. I had known Paul for many ues must be inte rpreted with great cau ­ years. He was working in the American tion. Moreover, although changes in small Heart Association and was soon to be its vein pressure are valid, the more the vein president . He spoke to us before the ses­ constricted, the more likely the size of the sion and developed an excellent discus ­ catheter was to inte rfere with exact calcu­ sion during the session based on prior lations of absolute venous resistance. knowledge of the presentations. Abstracts Nonetheless, papers began to be pub­ were not published until later, if at all, in lished, and Oscar Creech urged me to those days. apply for my own NIH grant. By then I was The implications of all these studies looking at pulmonary embolism and the were becoming increasingly obvious. The possibility that sudden distention of a pul- pulmonary vascular bed could not be An Approach to the Study of Pulmonary Circulation • 247 studied by methods used in the systemic catheter with an extracorporal pump. I bed . Techniques were available to perfuse had the transseptal technique for lobar an excised lung or to perfuse it in situ at vein pressures. In those days, one simply constant pressure or constant flow, or went to Glens Fall, New York, and showed even in the intact chest to look at three U.S . Catheter and Instrument Company points on a pressure-flow curve. However, what was needed for research, and they what was needed was a technique permit­ developed the catheter. Marketability or ting the study of a hemodynamically iso ­ patent rights were not issues . The com ­ lated lung lobe perfused at constant flow, pany directed me to an unusual balloon and constant left atrial pressure, in an designer in New Jersey, just outside New intact, spontaneously breathing animal. York City. He devised the balloon and With such a preparation , the pharmacol­ showed me how to attach it and a length of ogic responses of pulmonary blood vessels PE- 50 tubing to the catheter with thread could be more closely studied with re­ and a quick-drying glue . spect to dose response curves , receptor After introducing this catheter with sites blocking agents , and , later , transduc ­ the attached balloon and side PE- 50 cath ­ tion mechanisms. Moreover, reflex re ­ eter into the dog 's left external jugular sponses of the pulmonary vessels are bet ­ vein , one could guide it, under fluoros ­ ter examined in intact chest animals. In copy , through the tricuspid and pulmo­ the clinical arena , this was the time of a nary valves by altering the distal catheter great thrust toward surgical pulmonary curve , simply changing the tension of the embolectomy . Working with Oscar Creech PE-50 on the distal curve . The left lobar and his surgical group, we had done some artery was entered with the standard but saw the unfortunate complication of a 0.035-inch guide wire. The left lobar vein successful embolectomy followed rapidly was easily entered transseptally with a by adult respiratory distress syndrome. Ross needle and sheath from the right Indeed, the sanguinous froth appeared in external jugular vein via the left atrium . the endotracheal tube less than an hour The Cope adaptor permitted concurrent after embolectomy in one memorable pa­ measurement of pressure in a large and tient. The concept of reperfusion injury small pulmonary vein in left lower lobe. was not yet developed. Along with many The surgeons had now abandoned iso ­ others, I was trying to devise a large car ­ lated coronary perfusion in favor of hypo­ diac catheter method to extract larger em­ thermia for bypass surgery. Those pumps boli without thoracotomy and bypass , and served well (and still do) for pumping then later to use thrombolysis with strep­ femoral arterial blood through the catheter tokinase . I soon learned that , with suction to the left lower lobe. The lobar artery was on the catheter, the pulmonary arterial hemodynamically isolated from the pul ­ wall quickly obstructed large catheters monary artery by balloon distension . The and that technique was not going to be transseptal technique was developed with effective . much trial and error. In man, the transsep ­ Serendipitously , I was surprised to tal catheterization is done from the right learn how large a catheter one could put femoral vein, but in the lower animals, the into a dog 's pulmonary artery without plane of the atrial septum is such that one causing any evidence of hemodynamic must approach it from the external jugular alteration, as long as one didn 't apply vein. Fortunately , in these animals the negative pressure . I could put a balloon on external jugulars are very large and ac­ that large catheter, isolate the left lower commodate these catheters easily . More­ lobe artery by balloon distension , and per­ over, for those trained in cardiac catheter ­ fuse the lobe with blood through the large iza ti on before the percutaneous trans- 248 • THE PULMONARY CIRCULATION AND GAS EXCHANGE venous technique appeared, catherter­ pressed wonder at "what Al Hyman was izing the pulmonary artery from the supe ­ going to talk about for forty-five minutes ." rior cava was easier than from the inferior Bloodied but unbowed, I expressed the cava. Positive pressure ventilation during angst of a relative novice in this subject catheter insertion prevented air embolus. but proceeded to present 45 minutes of The catheters and needles were im­ data. A lively exchange followed (the first proved and miniaturized for smaller ani­ of many over the years), which was finally mals as time went on. The cat is the sturdi­ interrupted by introduction of the third est animal, remaining hemodynamically speaker, Domingo Aviado. He was to stable for 6-8 hours of experimentation. speak on the pharmacology of the pulmo­ The dog is not as stable for long periods, nary system but spoke to the vascoactivity often has heart worms (with or without a of pulmonary veins, measurements he had negative microfilaria blood test), is expen­ made in his laboratory. Domingo was ob­ sive, and requires large catheters. The viously in pain, hobbling about the po­ sheep is too large, and its atrial septum is dium because the colchicine hadn't re ­ often very difficult to find fluoroscopi­ lieved his acute gout. His comments di­ cally. The rabbit is a flower than wilts rected toward the first speaker were more easily. It readily develops shock with pul­ trenchant, indicating pedagogically to the monary hypertension, both of which we lead speaker that "he hadn't done his found to be easily corrected with cycloox­ homework." ygenase blockers. Its septum is soft and Among the speakers the next day was often tricky to puncture. We have used Gil Blount from Denver, who spoke pigs and occasionally monkeys with some presciently on an interesting topic, "High success. Altitude Effects on the Pulmonary Circula­ The organizers of the Eighth National tion in Cattle and Man." Bob Grover and Symposium on the Pulmonary Circulation Jack Reeves worked in his cardiac cathe­ had invited a number of prominent inves­ terization laboratory, and their later con­ tigators of this vascular bed to the Phila­ tributions to our understanding of pulmo­ delphia meeting. Bill Rashkind had been nary hypertension are well known. Gil interested in congenital anomalies of pul­ was superb and showed us how things are monary veins, and he somehow asked me done in Denver. In the freezing Philadel ­ to show my data at the meeting. The con­ phia night, Gil came to Bookbinders with cept of active changes in pulmonary ve­ us wearing a light jacket, no vest, sweater, nous tone was not readily accepted in or top coat! Others in the group, Jesse those early days. Aviado 's group and Edwards, Art Sahshara, Ray Truex, Al Milnors' group had data in open chest Fishman, and Van Mierop, were more isolated perfused lungs, and now I had conventionally attired. data in intact dogs with constant lobar Having finally experienced relief the flow. That afternoon session had three next day, Domingo was more placid and speakers. The first speaker, an internation­ spent the afternoon with me in his labora­ ally known authority, spoke about the tory. Soon after that session, he moved on physiology of the pulmonary circulation. I to do toxicology for the army, a loss to the was chagrined to see his first slide, a com­ pulmonary circulation group. We waited parison of the histology of a pulmonary many years until Chris Dawson, John Li­ artery and a pulmonary vein. He stressed nehan, and their group in Milwaukee de­ the musculature of the pulmonary artery veloped a better technique to assess pul­ and by comparison the sparse muscula­ monary venous reactivity and in large ture of a pulmonary vein. He also ex- measure showed more clearly what we An Approach to the Study of Pulmonary Circulation • 249 were trying to demonstrate. Only recently striction, but when tone is increased , stim­ Chris was kind enough to have me to his ulation produces a transient alpha -1- laboratory . Their work is unique. induced vasoconstrictor response fol­ It seemed clear that a more detailed lowed by a longer vasodilator response, study of the pharmacology of the pulmo­ induced by beta-2 adrenoceptor stimula­ nary vessels was a fruitful area of study. tion. We also found the beta-2 adrenocep­ First the endogenous peptides. Bradyki­ tor activity was enhanced at elevated tone. nin actually constricted the dog's pulmo­ Moreover, agents such as epinephrine and nary veins at resting tone , a finding re­ phenylephrine, which have both alpha cently reported at the New York Academy and beta adrenoceptor activity, reverse of Science by Paul Guth. I was able to find from vasoconstrictors to vasodilators as him and discuss the data when I learned tone is increased. Several years later , I was he was a professor of pharmacology at giving a seminar on this topic at Sol Tulane. I began working more closely with Langer's laboratory in Paris. I pointed out the basic science groups, especially phar­ that the pulmonary bed was unusual, be­ macology. The pharmacology of pulmo­ cause in that bed , phenylephrine, which is nary vessels was apparently not a topical the paradigm of alpha-1 adrenoceptor ag­ research area. Although the grant renewal onists , has clear beta-2 activity in the lung was funded, one of the pink sheets con­ vessels. Both Sol and Icilio Cavern tained the query, "How many ways does beamed as they pointed out that they had this fellow intend to make the lung cry published similar data using right atrial ouch!" A cartoon framed in my lab shows muscle preparation several years before. a lung with a megaphone and the inscrip­ Our studies of hypoxia in the dog tion "ouch." Many years later, a promi­ revealed only a modest vasoconstrictor nent pulmonary vascular investigator vis­ response , quite similar to that reported ited my laborator y, saw the cartoon, and earlier by Al Fishman's group. The sheep laughed. "You know, years ago, I put that gave a somewhat more vigorous response, same remark on someone's NIH grant cri­ and we studied hypoxia in this species . tique," but he couldn't recall who the Bob Grover and Jack Reeves had reported applicant was. Well enough. He didn't a far more vigorous response in their dogs. believe in pulmonary veins either. We thought it might have been related to The Schuller Memorial Lecture is acclimatization to high altitude and ex­ sponsored annually by the pharmacology changed a group of dogs via air freight to department at Tulane. Sol Langer from and from Denver. Sure enough, the first Paris delivered a remarkable lecture deal­ two of his dogs were vigorous responders ing with subtypes of adrenoceptors and in my laboratory, and the first of mine their pre- and postjunctional activities in gave the weakest response they had ever the systemic vascular bed. But the pulmo­ encountered. The next was more respon­ nary vascular bed functions at a lower sive, and Bob asked me to check where the level of tone, and virtually none of this vendor got the dog. Probably a high­ data is available in the pulmonary bed . altitude area. "No , the only place flatter Following his lead, we looked at the neu­ than New Orleans is Mobile ." That theory ral control of the pulmonary bed as a faded . We are still not sure of the reason, short-term project. We found that the but the difference was real. problem was more complex in the lung In clinical cardiology , Tulane was vessels because of altered response at vari­ handicapped in those days. We used the ous levels of tone. At low tone, stellate huge and academically rewarding Charity stimulation induces pulmonary vasocon- Hospital, but there was no private Tulane 250 • THE PULMONARY CIRCULATION AND GAS EXCHANGE

Medical Center, which only came later. to stimulate opoid receptors to relieve More and more patients were being re­ chronic intractable pain . In the faculty ferred directly to Oscar Creech and placed parking garage we exchanged pleasant ­ in two large private hospitals. These hos­ ries, and he suddenly asked me how to pitals now had catheterization laborato­ treat ventricular tachycardia. He had in ­ ries, and Oscar asked me to study and serted this electrode and stimulated; in follow them outside the Tulane-Charity lieu of producing relief of pain, the re­ system. Only those referred patients with sponse was hypertension and ventricular more complex problems were admitted by tachycardia. "Don , there are 15 people in special arrangement to Charity for diagno­ the cardiology department who can help sis and treatment. As the university med­ you treat tachycardia as well as I, but ical and surgical groups became more and where did you put that electrode?" He more disunited, the inevitable happened . showed me in his cat model, in the su ­ A departmental reorganization resulted in praoptical diagonal band of Broca. I spent my faculty appointment being placed en­ the summer months that year relearning tirely in the surgery department, with the the neuroanatomy I'd forgotten since catheterization laboratory. My Icarian 1942. Function had been added to the wings had now completely melted, and I bland memorization of sites and tracts. We was now at sea, treading research alone. combined techniques in my laboratory, Friends, advisors, and coworkers came using stereotactic electrode insertion and from time to time, but, alas, the last icon cardiac fluoroscopy for pulmonary cathe­ had departed, and my approach to the ter insertion . Alas , the stimulation in­ pulmonary circulation became a complete duced the systemic effects he had already immersion in my own research laboratory, shown but no pulmonary responses. with my own model. For many years , I had been concerned I miniaturized the apparatus to study with the effects of pulmonary vascular the cat , an animal almost free of heart tone on responses. I had devised a tech­ worms (a nemesis in New Orleans). To do nique infusing a thromboxane A2 simula­ so, we lost the small pulmonary vein mea ­ tor U46619 which raised lobar pressure surements because the lung is too small. from 12 to 35 mmHg at constant flow with We gained in sturdiness, reproducibility a stable baseline. We repeated the stimula­ of responses, and ease of catheterization. tion, and now we saw a vigorous biphasic My coworkers and I have devised experi ­ response, a vasoconstrictor that com­ ments to study pulmonary vascular regu­ menced with 5-10 s of stimulation fol­ lation by the sympathetic and parasympa­ lowed shortly by a vasodilator response thetic nervous system, by the prosta­ that persisted 3-4 min. We were excited. glandins , by acid-base alterations, by Aubrey Taylor in Mobile suggested that hypoxic sensors in the arteries upstream the vasodilator response should be looked to gas-exchange vessels, and by adrenergic at more thoroughly . How did we know it and purinergic receptors. Most recently, a wasn 't mediated by a circulating vasodila­ unique opportunity was presented to look tor rather than directly by a neurogenic at central regulation of the pulmonary mechanism? Well, we didn't, but the in­ bed. About twenty years earlier, Donald troduction of a 4-min trap in the femoral Richardson, a young academic neurosur­ artery - lobar artery pump clearly identi ­ geon, had been studying pain and temper­ fied two separate vasodilator responses, ature fibers in cats in his laboratory next one before the perfused blood from the door to me. He grew in stature and eventu­ femoral artery reached the lung, and one 4 ally assumed the chair in neurosurgery. minutes later, when that blood arrived. He was now implanting electrodes in man Although the earlier constrictor and dila- An Approach to the Study of Pulmonary Circulation • 251 tor responses were not affected by stan ­ U46619 , hypoxia or selected vasoconstric­ dard blocking agents , the late dilator re­ tors, these agents become vasodilators. On sponse was clearly blocked by ICI 11855 1, the other hand , alpha-2 adrenoceptor ag­ a specific beta-2 adrenoceptor blocker , onists are greatly potentiated at high tone and by propranolol. Moreover, the serum but prostaglandin F2 alpha , Bay K 8644, epinephrine levels rose 5- to 10-fold with and angiotensin II are not potentiated as the stimulus. Our earlier work had demon­ vasoconstrictors at high tone. This re­ strated the tone dependency of responses mains one of our areas of intense study. In to some phenylethylamines. At low rest ­ the past three and a half years, since being ing tone, epinephrine is a vasoconstrictor, joined by my young colleague, Howard but a very active dilator with even small Lippton, a pulmonologist, we have re­ increases in pulmonary vascular tone. turned to looking at vasoactive peptides Jack Reeves was one of the referees se­ and their tone responses. Indeed, endothe­ lected by the journal editor. He wrote that lins are also vasodilators at high tone! he checked it out with the Colorado neu ­ Presently , I remain pleasantly at sea, rology department, and we were quite on paddling around in the pulmonary circu­ target - he even signed his name to the lation . I still do my own experiments at the reviewer's comments. bench, an old curmudgeon myself now, The effects of tone on the pulmonary but steadfastly refuse to be anyone's icon, vascular responses have continued to fas­ false or true. Moreover , I maintain an ac­ cinate and perplex us. At low resting tone, tive interest in clinical cardiology, doing epinephrine, acetylcholine, serotonin, consult ations and invasive procedures in phenylephrine, adenosine, ADP, ATP, the cardiac catheterization laboratory in and bradykinin , to name a few, are vaso­ the early morning hours , before going to constrictors, but at high tone , induced by my research laboratory .

References ventricles be estimated from the electro­ cardiogram? Am. Heart f. 36:906 - 910, 1. Hyman, A., R. B. Failey, and R. Ashman . 1948. Can the longitudinal anatomical axis of the