The Nature of the Peripheral Resistance in Arterial Hypertension with Special Reference to the Vasomotor System

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THE NATURE OF THE PERIPHERAL RESISTANCE IN ARTERIAL HYPERTENSION WITH SPECIAL REFERENCE TO THE VASOMOTOR SYSTEM

Myron Prinzmetal, Clifford Wilson

J Clin Invest. 1936;15(1):63-83. https://doi.org/10.1172/JCI100759.

Research Article

Find the latest version: https://jci.me/100759/pdf THE NATURE OF THE PERIPHERAL RESISTANCE IN ARTERIAL HYPERTENSION WITH SPECIAL REFERENCE TO THE VASOMOTOR SYSTEM By MYRON PRINZMETAL1 AND CLIFFORD WILSON 2 (From the Thorndike Memorial Laboratory, Second and Fourth Medical Services (Harvard), Boston City Hospital, and the Department of Medicine, Harvard Medical School, Boston) (Received for publication August 22, 1935)

From the physiological point of view elevation A. IS THE INCREASED PERIPHERAL RESISTANCB of blood pressure may be due to an increase in GENERALIZED THROUGHOUT THE BODY OR cardiac output, in the volume or viscosity of the LIMITED TO THE SPLANCHNIC AREA? blood or in the resistance of the peripheral vessels. Literature Since cardiac output is not increased in hyper- In view of the known physiological importance tension (1, 2, 3) and the viscosity (4) and volume of the splanchnic circulation it is essential to (5) of the circulating blood have been shown to determine whether the development of hyperten- be normal, there remains only the increased re- sion in man is especially due to abnormal behavior sistance in the peripheral circulation. of this vascular area. Various forms of evidence From an analysis of the literature it appears have been brought forward to support this pos- that investigations on the exact nature of this sibility. In the first place, pathological studies increase in peripheral resistance are compara- show that the arterial lesions in hypertension are tively few in number and have led to conflicting most intense in the splanchnic region, especially results. It is the purpose of this paper. to deal in the kidneys, adrenals, and pancreas. It ap- with the following questions. pears, however, that no constant relationship exists in A. Is the increased peripheral resistance gen- between the severity of arteriosclerosis the splanchnic area and high blood pressure. Long- eralized throughout the systemic circulation or cope and McClintock (7) obtained transitory ele- confined to the splanchnic area? vation of blood pressure by sudden occlusion of B. To what extent are the vessels responsible the splanchnic vessels in dogs. They attribute for the increased peripheral resistance capable of this effect to the increase in peripheral resistance, dilatation ? but find no evidence for regarding the splanchnic C. What part is played by the vasomotor nerves area as specifically important in the production of in the maintenance of the increased peripheral hypertension. Jansen, Tams and Achelis (8) resistance; i.e. if arterial hypertonus is present found in animals that obstruction of the circula- can it be attributed to an increase in sympathetic tion to a limb caused a greater rise in blood vasoconstrictor impulses? pressure if the splanchnic vessels were first oc- We have attempted to answer these questions cluded. In subjects with hypertension they state that an a and by studies on the blood flow in the arm under binding extremity produced higher more sustained elevation of blood pressure than various conditions, using the arm plethysmograph in normal individuals, and conclude from these as described by Lewis and Grant (6), and to results that hypertension is due to vasoconstric- determine whether the nature and distribution of tion in the splanchnic area. Splanchnic section the increased resistance is the same in the different has been performed (9, 10) in patients with hy- forms of hypertension, which have been desig- pertension on the basis of the same assumption, nated benign, malignant and secondary (" renal") and lowering of the blood pressure has been al- hypertension. leged to follow such operations. Critical examination of the above experiments, however, fails 1 National Research Council Fellow in Medicine. to furnish any conclusive evidence that the in- 2 Rockefeller Fellow in Medicine. creased vascular resistance is confined to the 63 64 MYRON PRINZMETAL AND CLIFFORD WILSON splanchnic area. Moreover, in certain forms of Method of determination high blood pressure, e.g. eclampsia and malignant Brodie (15) has shown that when an organ hypertension, vascular spasm may be observed in is placed in an oncometer connected to a volu- the retinal vessels. Volhard (11) has attributed metric recorder, obstruction of the venous outflow pallor of the skin in such patients to generalized causes an increase in size of the organ due to peripheral vascular spasm produced by a circu- inflow of unobstructed arterial blood. This in- lating pressor substance. There is, however, no flow can be measured for only a few seconds after conclusive evidence in support of this theory (12, venous occlusion, since congestion of the organ 13, 14). causes a rapid diminution of arterial flow. Hew- lett and van Zwaluwenburg (16) applied this Principle of method principle to man by enclosing the arm in a plethys- The cardiac output in patients with high blood mograph and occluding the venous return by a pressure is known to be within normal limits (loc. pneumatic cuff at a pressure just below diastolic. cit.). If, therefore, hypertension is due to in- From the increase in arm volume per unit time creased vascular resistance confined to the splanch- the blood flow may be determined. The arm nic area, the caliber of the vessels in the rest of volume is measured, and the blood flow expressed the body remaining normal, the blood flow in cubic centimeters per 100 cc. arm volume per through the latter must be increased. If, on the minute. Hewlett and van Zwaluwenburg found other hand, the increased resistance is generalized the blood flow to be somewhat above normal in and uniform, the blood flow in all parts of the patients with hypertension. Unfortunately, they systemic circulation will be the same as in normal paid no attention to the type of hypertension or individuals-the high blood pressure simply over- to the temperature of the arm during their experi- coming the increased resistance in all areas. This ments. is in accordance with Poiseuille's law that the The arm plethysmograph of Lewis and Grant is admirably adapted to our purpose. It has a blood flow in any cross section of the vascular great advantage in excluding the hand, which bed per unit time is directly proportional to the shows vasomotor responses of great intensity at- pressure and inversely proportional to the resist- tributable to the relatively large area of highly ance. may be expressed as a simple equa- This specialized skin (17). By means of the arm tion, Voo (P/R), where V is the volume of blood plethysmograph we can study a more representa- flowing through an organ per unit of time, P is tive segment consisting chiefly of striated muscle, the effective arterial pressure, and R the resistance. fat and fascia covered by a more " normal " skin We have therefore compared the blood flows area. In using the plethysmograph, the most im- in the arm in patients with hypertension and in portant practical point is to insure water-tight subjects with normal blood pressure. If the rest- junctions where the arm enters and leaves the ing blood flow in the arm in patients with hyper- plethysmograph, without producing appreciable tension is equal to that in normal individuals, the venous congestion. We were unable to obtain peripheral resistance in the vessels of the arm rubber tires of sufficient flexibility to follow must be increased to the same degree as the mean Lewis's method, and used instead the cuffs of peripheral resistance in the splanchnic area.3 If, surgical rubber gloves, which are available in all however, the peripheral resistance in the splanch- sizes. These are prevented from bulging in- nic area is greater than in other parts of the sys- wards or outwards by rings of hard rubber placed temic circulation, the blood flow in the arm in on either side, the whole being held in position hypertension will be greater than in normal indi- by a metal lid which fits tightly onto the end of viduals. the plethysmograph (Figure 1, inset). The arrangement of apparatus is shown in the 8 When referring to the mean peripheral resistance in accompanying diagram (Figure 1). The patient the splanchnic area we recognize the possibility that the in a wheel chair in a semi- increased peripheral resistance may not actually be uni- is seated comfortably form throughout the organs in this area. reclining position. The plethysmograph is fitted PERIPHERAL RESISTANCE IN ARTERIAL HYPERTENSION 65

METAL LID M/RUBBER DISCS RUBBER GLOVE

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FIG. 1. ARRANGEMENT OF APPARATUS. (After Lewis aind Grant (6).) onto the forearm, and filled with water at 240 C. until the blood flow becomes constant. All the Since the volume of the plethysmograph is known, experiments here reported were performed at the the arm volume can be readily obtained. The same room temperature (70 to 720 F.) since varia- arm is placed in a water bath at the same tem- tions in the latter cause alteration in flow. De- perature, and the plethysmograph connected to a terminations were made at approximately the same 35 cc. Brodie's bellows by means of which vol- time after the last meal (one to two hours) owing ume changes are recorded on a smoked drum. to the effect of digestion on the cardiac output Calibration is performed by the syringe as shown (18). Psychic factors exert a considerable in- in the diagram, a 5 cc. increment in volume giving fluence on the blood flow; hence such distractions approximately 1.5 cm. rise on the drum. A 6 cm. as reading and talking were avoided. Under these pneumatic cuff, connected with a mercury manom- uniform conditions average blood flows can be eter and pressure bottle, is fixed on the upper obtained on the same patient on different occa- arm. It is important to guard against constric- sions with an experimental error of not more than tion on the veins by the upper plethysmograph 15 per cent. Reference to the tables shows a cuff. Hence, at the outset, the venous pressure great individual variation. This is only to be is measured by determining the lowest pressure expected in view of the physiological nature of in the sphygmomanometer cuff which will cause the experiment and correspondingly wide varia- an increase in arm volume. This is usually about tions in cardiac output. These variations are no 5 to 10 mm. of mercury. Certain precautions are greater in patients with hypertension than in con- essential in order to obtain comparable results: trols. Four to ten blood flow determinations were after the plethysmograph is in position an interval made, the average of which is taken as the resting of at least half an hour should be allowed to elapse flow. Figure 2 shows typical blood flows. 66 MYRON PRINZMETAL AND CLIFFORD WILSON

B.RP O9Y70 (M.H) A.V. 700 c. . .5 C

4'8 A. V g2 rcc 5 F 1.3 cc B.P. i;'/oo50v . H). A-V. b50 cc B . 0

IP. 2o.~j1 AV ~00cc 15F 4 - .''/VB35 A V. 715 cc. 5. F. I. cc. B P. 2GOWD .& M A V. 000cc. BR. F. .4 ^

k *, 4r, , .. cr. F i 15 cc.:. n.Pi 5isro (L P A V 52 cc 1. Controls. Patients with Hypertension. FIG. 2. RESTING BLOOD FLOWS. B.P.--blood pressure. B.H.-benign hypertension. A.V.-arm volume. M.H.-inalignant hypertenision. B.F.-blood flow (cc. per 100 cc. arm volume per minute).

Classificationt of cases at autopsy in one of these subjects. In the group According to the prevailing classification, the of " secondary " hypertension were placed ten cases studied fall under the headings of benign, patients with chronic renal disease. Renal im- malignant, and secondary (renal) hypertension. pairment was present in all. Six were cases of The diagnosis of benign hypertension was made subacute or chronic glomerulonephritis, and in in fifteen patients on the basis of a slowly pro- one the diagnosis was confirmed at autopsy. One gressing hypertension of many years' duration. patient had acute glomerulonephritis, the diagnosis Kidney function tests were normal, and the being confirmed at autopsy. Of the remainder, previous history showed no evidence of renal dis- three were diagnosed as chronic pyelonephritis, ease. Hypertensive retinopathy of the type de- one originating in pregnancy and two associated scribed below was absent. A diagnosis of malig- with kidney stones and bilateral stenosis of the nant hypertension was made in seven cases. These ureters. Patients showing any evidence of cardiac patients were relatively young (12 to 47 years), failure were excluded from the investigation. a previous history of acute nephritis was absent, Results the blood pressure was comparatively high and the condition rapidly progressive. Clinical and 1. Patients with hypertension comlpared with con- laboratory evidence of renal impairment was pres- trols ent and hypertensive retinopathy was found in As indicated in Table I and Figure 2, the aver- all cases. The characteristic ophthalmoscopic age resting blood flow in eighteen normal sub- findings were papilledema and retinal edema, nar- jects was 1.65 cc. per 100 cc. arm volume per rowing of the arteries, and in all cases except one, minute. The average flow for 32 cases (all types) retinal exudates. The diagnosis was confirmed of hypertension was 1.52 cc. In benign hyper- PERIPHERAL RESISTANCE IN ARTERIAL HYPERTENSION 67

TABLE I tension (fifteen cases) 1.7 cc.; in malignant hy- Resting blood flow pertension (seven cases) 1.5 cc.; in secondary Case Blood Retng hypertension (ten cases) 1.3 cc. nun- Apgeex pres. blood Diagnosis ber sure flow 2. Effect on blood flow of variations in blood ce. pressure in the same individual years um. Hg per 100 cc. arm uet We were fortunate in obtaining blood flows in

CONTROLS two cases at considerably different levels of the blood pressure. 1 27 M 130/170 1.7 2 54 M 80/60 219 Case 1. Acute exacerbation of hypertension 3 26 M 130/70 2.2 4 33 M 140/85 1.2 (Number 7, Table IIA). This patient, a 43-year- 5 28 M 130/80 6.1 6 35 M 118/88 1.8 7 43 M 120/85 1.4 TABLE II 8 56 F 140/78 1.2 9 31 F 115/80 0.9 10 29 M 120/70 1.5 (A) 11 27 F 110/70 1.9 12 18 F 120/70 1.5 Resting blood flow in Case 7 during benign and malignant 13 47 F 110/70 1.5 14 44 F 120/70 1.3 phases of hypertension 15 22 F 110/60 0.65 16 39 M 120/80 0.6 17 39 M 120/80 0.71 Date Blood pressure Resting blood flow 18 41 F 0.61 cc. per 100 cc. arm Average 1.65 1935 mm. Hg volume per minute February 12 ...... 160/130 1.1 PATIET WrTH HYPTENWSON 1 ...... 1.05 (A) Benign hypertension May 245/185 1 58 M 185/115 1.8 (B) 2 42 F 200/120 1A7 3 37 M 165/130 1.9 Resting blood flow in patient with benign hypertension 4 49 M 250/150 1.45 5 55 F 250/110 4.7 and postural hypotension 6 44 M 238/160 2.2 7t 43 M 160/130 1.1 8 54 F 240/150 0.51 9 49 F 270/110 0.85 Position pressurl Cardiac output Resting blood flow 10 50 F 240/145 1.3 11 40 F 160/110 1.3 12 32 F 210/120 1.8 liters per minute cc. per 100 cc. 13 32 M 260/180 1.1 per square meter arm volume per 14 21 F 190/140 0.67 body surface minute 15 34 M 180/120 3.6 Horizontal..... 195/100 2.60 .37 Average (15 cas) 1.7 Upright ...... 1 100/75 2.64 .38 (B) Maligant hypeteion old man, on first admission had a history of 16 47 M 220/140 1.75 17 16 F 205/150 2.0 hypertension of three years' duration with no evi- 18 30 F 270/180 1.1 19I 12 F 210/170 1.5 dence of pre-existing kidney disease. Blood pres- 20 40 F 190/140 2.3 21 39 M 200/170 0.65 sure was 160/130 mm. Hg. Renal function tests 7t 44 M 245/185 1.05 were normal, and ophthalmoscopic examination Average (7 cases) 1.5 was negative. A diagnosis of benign hyperten- (C) Swondary hypertension sion was made. Three months later he was ad- 22 38 M 200/150 1.4 Chronic glomerulonephrltis mitted complaining of nocturia, headaches, and 23 40 M 170/105 1.05 Chronic glomerulonephritis 24 22 F 158/110 0.7 Subacute glomerulonephritl dimness of vision. Blood pressure was 245/185 25 60 F 170/105 0.7 Kidney stones. Pyelone,hritis 26 15 F 170/100 0.7 Subacute glomernlonephritis mm. Hg and renal impairment with nitrogen re- 27* 42 M 210/105 3.3 Chronic glomerulonephritis 28 27 F 200/110 1.3 Chronic glomerulonephritis tention was present. The fundi showed hyper- 29* 42 M 190/100 0.7 Acute glomerulonephritis 30 '43 F 250/150 1.1 Kidney stones. Pyelonephriti tensive retinopathy (papilledema and exudates). 31 23 F 210/140 1.8 Pyelonephrits The diagnosis of malignant hypertension was now Average (10 cases) 1.3 made. Blood flows measured on both occasions showed identical values. Average all types of hypertension (32 cas) 1.52 Case 2.' Benign hypertension weith postural * Died-Diagnosis confirmed at autopsy. 4We were permitted to study this case through the t Case 7 is included twice as explained in text. courtesy of Dr. L. B. Ellis and Dr. F. W. Haynes. 68 MYRON PRINZMETAL AND CLIFFORD WILSON hypotension (Table IIB). This patient, a 69- recumbent posture appears to be associated with year-old woman, complained of weakness and a generalized increase in peripheral resistance. dizziness on standing up. There was a history The results indicate also that the fall in blood of diabetes mellitus, high blood pressure, and pressure in this case of postural hypotension is a combined system disease of several years' duration. generalized phenomenon, i.e. is not produced by In the recumbent position the blood pressure was changes confined to the splanchnic area. 195/100, falling to 120/90 to 70/65 on standing. The cardiac output, determined by the acetylene B. TO WHAT EXTENT ARE THE VESSELS CAPABLE method, showed no change with position, in spite OF DILATATION IN SUBJECTS WITH of the variation in blood pressure. We have meas- HYPERTENSION? ured the resting blood flow in the arm in the re- Literature cumbent and in the erect posture and found identical values. In cases of acute hypertension (e.g. acute nephritis and eclampsia) where the blood pressure Discussion may fall rapidly to the normal level, and in cases These results demonstrated that the blood flow of fluctuant hypertension which returns to nor- in the arm of subjects with hypertension is no mal between the periods of exacerbation, the greater than in normal individuals. For the blood vessels are apparently capable of dilatation. reasons already given we must conclude that in- In the majority of cases, however, the pressure creased vascular resistance in hypertension is no is maintained above normal and may become greater in the splanchnic area than in the arm, " fixed " at a high level. Such a " fixation " has that is, we are dealing with a generalized increase been ascribed to organic changes in the blood in peripheral resistance throughout the systemic vessels (20). The histological evidence of dif- circulation. If this were not the case and the fuse arterial lesions in hypertension is, however, caliber of the arm vessels remained unaltered, an not conclusive and will be discussed later. Vol- increase of effective blood pressure by two-thirds hard (11) holds the somewhat different view the normal value would (according to Poiseuille's that arteriosclerosis of the renal vessels is respon- law) give a blood flow 1.5 times the normal, i.e. sible for the "reds" or benign form of hyper- approximately 2.65 cc. per 100 cc. arm volume. tension and refers to the increased peripheral Our deduction is valid only so long as there is resistance in these cases as " passive " in contrast no marked diminution in the cardiac output in to the " active " spasm in " white " hypertension. hypertension. Most observers are agreed on this Pal (21) maintains on clinical grounds that hy- point, though Weiss and Ellis (3) found that pertonus is present in the palpable arteries in in some cases the output is at the lower limit of hypertension, but furnishes no experimental proof normal. Weiss, Haynes and Shore (19) in this of this. clinic have recently reinvestigated the question by Brown and Alexander have recently shown the Grollman method (18). The results, which (22) that the percentage of patients with hyper- they have kindly placed at our disposal, show no tension who develop Duroziez's sign on placing diminution in cardiac output in hypertension. the arm in hot water is less than in subjects with The results in the two patients where it was normal blood pressure. They conclude from these possible to obtain blood flows at different levels findings that in hypertension the minute vessels of blood pressure confirm the above conclusions. are unable to dilate sufficiently to produce a dias- In both cases there was no increase in blood flow tolic murmur. Abnormal responses to heat, cold, when the blood pressure changed to a higher level. and arterial occlusion (23, 24) have been reported This indicates in Case 1 that the exacerbation of in hypertension, but the conflicting nature of the the hypertension was produced by a generalized results makes their interpretation difficult. There increase in peripheral resistance, the -distribution appears in fact to be no conclusive experimental of which was the same before and after the malig- evidence which demonstrates the capacity of the nant phase. Similarly, in Case 2 the increase in peripheral vessels to dilate in the different forms blood pressure on changing from the erect to the of hypertension compared with normal individuals. PERIPHERAL RESISTANCE IN ARTERIAL HYPERTENSION 69 Principle of method Results Vascular dilatation can be produced in normal The results are shown in Table III, A and B, individuals by two simple methods: (1) Direct and Figures 3 and 4. The ability of the vessels application of heat and (2) by reactive hyperemia to open up is expressed as the ratio of the flow at following arterial occlusion. Dilatation of the 450 C. to the flow at 240 C. Similarly, blood vessels by heat is probably a combined result of flows during reactive hyperemia are expressed as sympathetic vasodilatation and the direct effect ratios to the resting blood flows at the correspond- on the vessels of increase in temperature. In ing temperatures. Thus under the influence of reactive hyperemia Lewis and Grant (6) have heat the average ratio for normal individuals is shown that dilatation is caused by the action of 10.2; for cases of benign hypertension 11.6, ma- metabolites on the vessels, although it appears lignant hypertension 10.9, and secondary hyper- that vasomotor impulses may modify the response tension 14.0. Average for all cases of hyperten- (25). Thus, while both are physiological re- sion 12.0. sponses, the mechanism of production is different. Reactive hyperemia at 240 C. gives average We have compared the effects of these procedures ratios of 9.9 (controls); 13.5 (benign hyperten- on the blood flow in the arm in normal individuals sion); 13.7 (malignant hypertension); 11.6 (sec- and in patients with hypertension. ondary hypertension). The average of all cases of hypertension is 13.2. Methods of determination Reactive hyperemia at 400 C. gives ratios of After the resting blood flow in the arm at 240 1.97 (controls); 1.95 (benign); 2.1 (malignant); 1.8 (secondary). The average of all C. has been recorded, the temperature of the water cases of hypertension is 1.96. bath is gradually raised (50 in ten minutes). When the plethysmograph temperature reaches Discussion 450 C. the heater is turned off, and blood flows recorded until constant values are obtained (10 These results demonstrate that in all forms of to 20 minutes). hypertension the blood vessels of the arm are As an indication of the degree of vascular dila- capable of considerable dilatation, sufficient in tation produced by reactive hyperemia, the blood fact to cause an increase in blood flow equal to flow is determined in all cases ten seconds after that in normal individuals. Our findings do not circulatory release. The procedure is as follows: confirm the abnormal responses to heat and re- A pressure above the systolic is maintained in active hyperemia in hypertension reported else- the sphygmomanometer cuff for five minutes. A where (23, 24). The fact that the blood vessels slight increase in arm volume may occur during in hypertension are capable of opening up 15 to this period due to the collateral 20 times (as indicated by the ratio of the resting circulation in the flow bones (6). On releasing the pressure, is at 24° C. to the reactive hyperemic flow at there 400 C.) strongly suggests that the an increase in arm volume increased vas- which is recorded on a cular resistance in hypertension is not due to fast drum. Exactly ten seconds after release a organic changes of the vessel walls. If this were determination of blood flow' is made as previously the case, some diminution in the response to heat described, i.e. by throwing into the cuff a pressure and metabolites might be expected to occur. In just below diastolic. Although the blood flow fact, the physiological stimuli of heat and reactive may not be maximal at this time, a ten-second hyperemia produce the same increase in blood flow interval was arbitrarily chosen in order to permit in patients with hypertension as in normal indi- the initial increase in arm volume to reach its viduals. It follows that in patients with hyper- maximum. tension the blood vessels still exhibit a relatively Blood flows during reactive ryperemia were greater peripheral resistance than in normal sub- obtained at 240 C. and 40° C. Five-minute ar- jects even at the height of vascular dilatation. terial occlusion is usually too painful to allow This restriction of response to the limits of nor- determinations above the latter temperature. mal indicates the manner in which the vascular 70 MYRON PRINZMETAL AND CLIFFORD WILSON

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a I 04 00 o00 _ -4 " m v I* to t- w = = 1-4 eq " 144 K* I IA ______-4".. 4 " 11-4 " 1-4-4 PERIPHERAL RESISTANCE IN ARTERIAL HIYPERTENSION 71 mechanism, acting at a higher level of blood pressure, is adapted to physiological requirements. Such an efficient adaptation demonstrates the ability of the vessels to dilate, and makes it un- likely that any true organic rigidity is present. .0 From the physiological evidence we feel justi- Y fied, therefore, in attributing the increased peri- = pheral resistance in hypertension to a generalized 0 vascular hypertonus, rather than to organic

+ C 4+ C changes in the blood vessels. The histological 000200.01-t0= :+ 0)f000 0 , evidence bears out this conclusion. Thus several e observers have reported cases in which arterio- = sclerosis was minimal or absent even in the U,1 splanchnic area (41). Kernohan, Anderson and 000 -c -- 000 ' Keith (26) have described arteriolar lesions, . chiefly in the nature of medial hypertrophy, in H the voluntary muscles in hypertension, but state it)00 Ci eeq 4 00 I= 00 = that such lesions are usually absent in the benign es 4__ cli _ cli cs - form. More recently, it has been shown histo- logically (27) that there is no diminution in the mean internal diameter of the small arteries and arterioles in the voluntary muscles in hypertension. Cd A diminution in the arterial supply to the kidney

u: r has been found in advanced cases of hypertension c"o 000In0 t CID W q Ca : (42, 43). It is also known that organic changes 0 cz 4) ri7 found in the arterioles of certain abdominal eq D e o o eq uo organs .n are more marked than those found in the volun- ° tary muscles. It is theoretically possible that in Cd some of these cases organic changes may con- tribute to the increase in peripheral resistance. . However, these lesions are found in a small frac- : tion of the total arteriolar system, and should eq cause but a slight increase in the mean peripheral ro ooo_- _ Ce - - - resistance. The work of Goldblatt, et al. (37) x adds additional evidence to this viewpoint. In their animals, hypertension did not occur until - several hours after the renal arteries had been u0000 co 0000 00 u-0O 0o .S clamped. If obstruction of the renal arteries per e-i C es O-OOeD6 to Cco r. ci oq _'es q -4 q _ Q se causes a significant increase in the mean pe- 0. @ ripheral resistance, the blood pressure should have X risen immediately following the clamping pro- co W cedure. . . . . __00-t- 0-000000 -. 0. _0 Ei -ej r- C. RELATION OF THE VASOMOTOR NERVES TO 0000 0000 o Lo Loo 0 H YPERTENSION . - 0L) C -0e--q-0 00eses_-es es0 Cs -c I. BENIGN HYPERTENSION 0-0CD eq 000= (L U1) Literature bo cl _q _q _ e Ccqs Cs ca Cato C) eq Il 00 z t- 00 (M tc ¢-e ¢) Stimulation of the sympathetic nerves and of " 00 .. I ,I cq41c the vasomotor center is known to produce con- 72 MYRON PRINZMETAL AND CLIFFORD WILSON

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i,.1~50 cc B 9.0cc B. P. 20%j50502O~~ (C..G.N\ItC)}NA.'.' Bi5us>;lcK3 . Controls. Patients with Hypertension. FIG. 3. VASODILATATION PRODUCED BY HEAT (450 C.). B.P.-blood pressure. B.H.-benign hypertension. A.V.-arm volume. M.H.-malignant hypertension. B.F.-blood flow (cc. per 100 cc. arm volume per minute). C.G.N.-chronic glomerulonephritis. striction of the blood vessels and elevation of these results support the vasomotor theory of the blood pressure. Moreover, the results of hypertension. The significance of these findings nerve section indicate that the arterioles are usu- will be discussed later. On the basis of this ally in a state of tonus which is regulated in part neurogenic theory of hypertension certain surgical by the vasomotor nerves. It has naturally been procedures, e.g. splanchnic nerve section, dorsal widely assumed that the increased vascular re- and lumbar ganglionectomy and anterior root sec- sistance in hypertension is due to exaggerated tion, have been performed in an attempt to lower vasoconstrictor tone. We have, however, been the blood pressure. The poor therapeutic results unable to find any conclusive evidence in the which may follow such operations have been literature which supports such a hypothesis. attributed either to incomplete removal of the There are several experimental observations which vasomotor nerves or to fixation of the hyperten- suggest that in patients with hypertension the sion by organic changes in the blood vessels. react abnormally to certain stimuli. blood vessels Methods and results Thus, following immersion of the arm in ice water (20), inhalation of CO, (28), painful stimuli (29), We have attempted to demonstrate the r6le of and exercise (30), an exaggerated response in the the vasomotor nerves in hypertension by two blood pressure has been observed in subjects methods; namely by studying the increase in blood with hypertension. It has been assumed that flow in the arm following (1) vasomotor dilata- PERIPHERAL RESISTANCE. IN ARTERIAL HYPERT'ENSION 73

B. P. 9 AN. (25cc. BSF. 33.2cc. b P. 2 >

3 i;--)o A.V. 475rc. R.F 53.0cC. a P. 20fi5o(C.G.N4) AN. 825cc. F.E. 2Ii.`c.

150 ih) AN. 825s; A,5. cc Controls. Patients with Hypertension. FIG. 4. EFFECT ON BLOOD FLOW OF REACTIVE HYPERE-MIA AT 400 C. B.P.-blood pressure. B.H.-benign hypertension. A.V.-arm volume. M.H.-malignant hypertension. B.F.-blood flow (cc. per 100 cc. arm volume per minute). C.G.N.-chronic glomerulonephritis. tioni induced by heat and (2) blocking of vaso- is placed in water at 450 C., and the patient is motor impulses by novocain injection of the dorsal kept warm with blankets. The blood flow be- sympathetic ganglia. gins to increase in ten to fifteen minutes and reaches its maximum value in thirty to sixty min- 1. Vasoniiotor dilatation ittduiced by he(at utes, the nmaximum usually being attained about It is well known that when the body is heated ten minutes after the subject begins to perspire vasodilatation of the peripheral vessels occurs, as f reely. evidenced by increase in skin temperature. This In order to show that the above conclusions re- reaction is vasomotor in origin, since it is absent garding the nature of the heat test could be ap- when the sympathetic nerves are cut. Further- plied to the blood vessels of the arm, as well as to more, it has been shown that vasodilatation in the those of the skin, we performed the test in two skin is produced not only by inhibition of vaso- patients before and after sympathetic block for constrictors, but also by stimulation of vaso- Raynaud's disease of the fingers. dilators (31). Case 1. A 28-year-old woman with typical WVe have used the heat test devised by Gibbon Raynaud's disease of the fingers was admitted to and Landis (32). After the resting blood flow the Neurological Service of the Boston City Hos- in the arm has been determined, the opposite arm pital and alcohol injection of the upper dorsal 7474IYRON PRINZMETAL AND CLIFFORD WILSON sympathetic ganglia was performed by Dr. Walter mally innervated areas which causes a diversion Wegner. Before injection the resting blood flow of blood from sympathectomized segment. in the arm was .65 cc. per 100 cc. arm volume, Having shoxvn that the vascular dilatation in which increased to 1.75 cc. during the heat test. the arm induced by the heat test is vasomotor in After alcohol injection the lhand became hot and origin, we have performed this test on subjects dry, a typical Hormer's syndrome was present, with normal and with elevated blood pressure. If and perspiration was absent on the side of the in- the vascular hypertonus in hypertension is due to jection. The resting blood flow ten days later vasoconstrictor impulses, the release of these im- was 1.1 cc. and on performinig the heat test showed pulses by the heat test should result in a muclh not an increase but actually a slight decrease greater increase in blood flow thani in subjects (Table IV). with normal blood pressure. Cases of benign hypertension were compared TABLE IV with conitrols, as shown in Table V. In twelve Effect of sypnpalhectomy ont resting blood flow control subjects the degree of vascular (lilatation anid hcat test produced by the heat test, as given by the average

Unsympathectomized side After sympathectomy TABLE V

Case ntim- ber Resting Blood flow Resting Blood flow Vasomozotor dilatationt iudniccd by hcat test * blood following blood following flow heat test flow heat test Case Blood flow Ratio of cc. per 100 cc. cc. per 100 cc. cc. per 100 cc. cc. per 100 cc. ntnm- Age Sex Blood following increase over arm volume armn volume arm volume arm volume ber pressure leat test resting flow per minute per minutiie per minute per minute 32 0.61 1.75 1.2 0.75 cc. per 100 cc. 33 0.65 1.75 1.1 o.75 years mm. Hg arm volume per minuitte

Case 2. A 56-year-old woman with five years Controls of the fingers had history of Raynaud's disease 7 43 M 120/85 3.3 2.3 left-sided synmpathectomy performed by Dr. R. H. 8 56 F 140/78 5.5 4.24 9 31 F 115/80 2.6 2.9 Smithwick of the Massachusetts General Hospital, 10 29 M 120/70 4.6 3.1 with the typical results described in Case 1. One 11 27 F 110/70 3.5 1.85 12 18 F 120/70 3.2 2.1 month later resting blood flow determinations were 13 47 F 110/70 7.0 4.6 made and the heat test performed, comparing the 14 44 F 120/70 5.1 3.9 15 22 F 100/60 1.75 2.7 left arm with the right (non-sympathectomized) 16 39 M 120/80 2.2 3.7 si(le. As in the previous case the results (Table 17 39 M 120/80 3.0 4.2 18 41 F 1.75 2.9 IV) show an absence of vasodilatation in response to the heat test on the sympathectomized side. Average 3.63 3.2t The above findings confirm Lewis's observation Benign hypertension that vascular dilatation during the heat test is vasomotor in origin. They show also that active vaso- 6 44 M 238/160 4.35 2.2 dilatation occurs as well as vasoconstrictor inhibi- 7 43 M 160/130 5.0 4.5 8 54 F 240/150 2.4 4.7 tion. Thus if the vascular dilatation following 9 49 F 270/110 2.3 2.7 the heat test were due only to inhibition of vaso- 10 50 F 240/145 4.3 3.3 11 40 F 160/110 2.7 2.1 constrictors, the increase in blood flow during the 12 32 F 210/120 10.5 5.8 test xvould be the same as results from sympa- 13 32 M 200/180 2.8 2.5 14 21 F 190/140 3.5 5.2 thetic block. Actually it was much greater, as the 15 34 M 180/130 10.1 2.8 figures show (1.75:1.2 cc.). Average 4.8 3.58t In these experiments, as already noted, an on the actual diminution in blood flow occurs * Resting flow values for each case may be seen in sympathectomized side (luring the heat test. This Table I. is reaclily explained by the vasodilatation in nor- t This figure is the average of the ratios. PERIPHERAL RESISTANCE IN ARTERlAL HYPERTENSION 75 ratio of increased blood flow to the resting flow, is arctation of the aorta and found no difference in 3.2. In ten patients with benign hypertension the the histological appearance of the arterioles in the corresponding value is 3.58. two situations. The heat test after a severe exacerbation of We have studied four cases of coarctation of hypertension was studied in Case 7, already de- the aorta. In all, the blood pressure was increased scribed. It was possible to perform the heat test in the arms (Table VI) and decreased in the legs. on the same patient on different occasions at two Evidence of collateral circulation was present in different levels of blood pressure. When the the chest, and x-rays showed erosion of the lower blood pressure was 160/130 the test produced an borders of the ribs due to enlargement of the in- increase in blood flow from 1.1 cc. to 5.0 cc. tercostal arteries. During the exacerbation with change over to the malignant type and a blood pressure of 245/185, TABLE VI Coarctationt of aorta. Vasodilatation produced the flow increased during the heat test from 1.05 by heat test cc. to 2.2 cc. Discussion of the heat test includitng its appli- Case Blood Resting Blood flow num- Age Sex pressure blood following Ratio cation in coarctation of aorta. The fact that vaso- ber (Arm) flow heat test motor arterial dilatation induced by the heat test cc. per 100 cc. cc. per 100 cc. causes no greater increase in blood flow in pa- years mm. Hg arm volume arm volume per minute per minute tients with hypertension than in normal subjects 34 21 F 150/100 0.96 7.7 8.1 is strongly suggestive evidence against the vaso- 35 30 F 170/110 0.9 8.7 9.7 36 30 F 180/105 1.1 7.3 6.6 motor origin of the hypertonus in benign hyper- 37 27 F 160/100 0.6 6.4 10.6 tension. Similarly, in Case 7, if the exacerbation of the Average 0.9 7.5 8.8* hypertension were vasomotor in origin we should * This figure is the average of the ratios. have expected a greater increase in flow in response to the heat test with a blood pressure of As shown in Table VI and Figure 5, the aver- 245/185 mm. Hg than was obtained wnen the age resting blood flow in the arm in these pa- pressure was 160/130 mm. Hg. Actually, for un- tients was not increased but was definitely below explained reasons, a smaller increase was observed. normal (0.9 cc.). The heat test, however, pro- A possible criticism may be made of our induced in all cases a very great increase in blood terpretation of the results obtained from the heat flow with an average of 7.5 cc., i.e. a ratio of 8.8 test; namely, that the reaction is a physiological compared with ratios of 3.2 and 3.58 for normal response to heat resulting in an increase in blood subjects and patients with benign hypertension, flow to the periphery for the purpose of heat loss. respectively. The normal response in patients with hyperten- Since the resting flow in the arm is not increased sion might be explained in this way. The results in patients with coarctation of the aorta although of the heat test in cases of coarctation of the aorta the blood pressure is elevated, it follows on the may serve as an answer to this criticism. In this basis of our previous arguments that arterial condition there is congenital obstruction of the hypertonus is present in the upper limbs in this aorta below the point of origin of the arteries to condition. When, however, vasomotor arterial the upper extremities, resulting in hypertension in dilatation is produced in the arm by the heat test the upper and hypotension in the lower limbs. the increase in flow is far greater than that pro- Blumgart et al. (33) determined the arteriolar duced in controls and in patients with generalized pressure in the skin in such cases by the Weiss hypertension. The conclusion is that the vascular method, and found no difference in the upper and hypertonus in the upper extremities in coarctation lower extremities. This led them to the conclu- of the aorta is vasomotor in origin, in contradis- sion that arteriolar constriction is absent in the tinction to the hypertonus of generalized (benign) upper part of the body in coarctation of the aorta. hypertension. Graybiel, Allen and White (34) performed muscle The vasoconstriction in the upper part of the biopsies on the arm and leg in patients with co- body in coarctation acts as a compensatory 76 MYRON PRINZMETAL AND CLIFFORD WILSON

CT1-NT ROL B5P. 20/s B F. 1.4cC. B.F. 5.3c.Z RATlO 2.3

C.G. N. P. 170/105 a F. 1 05cc. B. S3.8 cc P,AT10 u

COARCTATION OF AORTA B.P 1'Ii9jo .F. .9cc. B.F 8.7cc RATIO 9.7 Resting Flow. Flow during Heat Test. FIG. 5. EFFECT OF HEAT TEST ON BLOOD FLOW. B.P.-blood pressure. C.G.N.-chronic glomerulonephritis. B.F.-blood flow (cc. per 100 cc. arm volume per minute). Ratio of blood flows indicates degree of vasodilatation produced by heat test.

mechanism and ensures the normal distribution of The skin is anesthetized with 2 per cent novo- blood. Were it not present, the areas supplied cain at two points 3 cm. laterally from the spines from above the coarctation would receive an ex- of the first and second dorsal vertebrae. At each cessive blood supply at the expense of the rest of point a lumbar puncture needle is introduced the body. vertically as far as the outer surface of the un- derlying rib. The needle is now withdrawn 2. Novocain injection of the vasontotor nerves slightly and reintroduced at an angle of 450 In view of the fundamental importance of this medially and caudally. At a depth of 4 to 6 cm., question, i.e. the r6le of the vasomotor nerves in according to the build of the patient, the side of hypertension, a more direct approach was made by the body of the vertebra is encountered. The comparing the increase in blood flow following needle is now introduced a further 1 cm. anteri- anesthetization of the vasomotor nerves to the arm orly and 5 to 10 cc. of 2 per cent novocain within patients with hypertension and in control sub- out epinephrine are slowly injected. At various jects. stages of the procedure suction is applied to en- Principle and details of method. The vaso- sure that the pleural cavity has not been entered. motor nerves to the arm emerge from the thoracic A small injection (% grain) morphia is gi-ven intervertebral foramina and join the sympathetic beforehand. chain as it lies along the sides of the bodies of the Before applying this method, injections with dorsal vertebrae. The upper dorsal sympathetic colored dyes were made on cadavers until a suc- ganglia can be anesthetized with relative ease by cessful technique was acquired. On opening the the method described by Labat (35) and White thorax the dyestuff is found below the pleura along and White (36). the sides of the vertebral bodies, i.e. surrounding PERIPHERAL RESISTANCE IN ARTERIAL HYPERTENSION 77 the sympathetic chain, and along the upper inter- This demonstrates that the injection was made at costal spaces. the correct site. The following are the criteria of a successful As a final check on the method, we compared injection. A Horner's syndrome appears on the the increase in flow produced in our two conitrol injected side within five to ten minutes. Anes- subjects who had novocain injections with that ob- thesia or hypo-esthesia is present over the first to served in the two cases of Raynaud's disease al- third dorsal segmental skin areas. If these signs ready described, where sympathetic block was are absent, the injection is considered unsuccess- produced by alcohol injection and sympathectomy, ful, and the experinment discarded. The blood respectively. The results are shown in Table flow in the arm begins to increase in five to ten VIIJA, and it is seen that the increase in flow is minutes, reaches its maximum in fifteen to twenty essentially the same in both groups. minutes and then gradually falls to its previous Injections were successfully made in four con- value. If the symnpathetic nerves are missed, no trols and five cases of hypertension. C)ne of these increase in blood flow is observed. was diagnosed as benign hypertension, two as ma- In one case iodized oil was injected with the lignant hypertension, one as secondary hyperten- needle in position. The x-ray (Figure 6) shows sion associated with chronic pyelonephritis, and the oil diffusely distributed along the sides of the one as acute glomerulonephritis. The last case bodies of the first to third dorsal vertebrae and in was particularly interesting, as acute nephritis de- the posterior mediastinum behind the trachea. veloped while the patient was under treatment for

FIG. 6. X-RAY TO SHOW SITE OF INJECTION OF NOVOCAIN. The bodies of the first and second dorsal vertebrae and the distribution of the iodized oil are outlined. 78 MYRON PRINZMETAL AND CLIFFORD WILSON

TABLE VII Effect of sympathetic block on blood flow

Resting flow 240 C. Case Age Sex Diagnosis pressure Before injection After injection Ratio cc. per 100 cc. cc. per 100 cc. years mm. Hg arm volume arm volume per minute per minute A. Controls 32 41 F Raynaud's disease Normal 0.61 1.2 2.0 33 22 F Raynaud's disease Normal 0.65 1.1 1.7 16 39 M Normal 0.70 1.1 1.6 17 39 M Normal 1.7 3.1 1.8 Average 0.91 1.6 1.8t B. Hypertension 21 39 M Malignant hypertension 200/170 0.5 0.9 1.8 (24.8)* 15 34 M Benign hypertension 180/130 0.96 1.6 1.7 (34.0) 29 42 M Acute glomerulonephritis 180/110 1.45 2.4 1.6 (20.0) 7 44 M Malignant hypertension 245/185 0.56 0.88 1.6 (17.3) 31 23 F Chronic pyelonephritis 230/140 1.3 1.9 1.5 (35.0) Average 0.95 1.5 1.6t * The figures in parenthesis are the maximum blood flows following reactive hyperemia. t This figure is the average of the ratios. chronic gonorrhea. The blood pressure rose dilatation on account of organic changes, since we acutely from 120/70 to 190/100, and the injection showed previously that they were capable of open- was made five days later. After three weeks' ill- ing up in response to heat and reactive hyperemia. ness the patient died in uremia. An autopsy was (These figures are given in parenthesis in Table performed and histological examination of the VIIB.) kidneys revealed an acute diffuse glomerulo- The statement has been made that patients with nephritis. hypertension often show " instability " or " irri- Results (Table VII and Figure 7). In four tability" of the vasomotor system. This is control subjects with normal blood pressure the brought forward as evidence for the vasomotor increase in blood flow produced by sympathetic origin of hypertension. It is well known, how- block was from 0.91 cc. to 1.6 cc., giving a ratio ever, that subjects with normal blood pressure of 1.8. In the five cases with hypertension the may exhibit the same symptoms of " vasomotor average blood flows before and after injection instability." It is true that certain stimuli, e.g. were 0.95 cc. and 1.5 cc., giving a ratio of 1.6. heat, cold, and pain, produce greater fluctuations The protocols of the five injection experiments in blood pressure in patients with hypertension are given in Table IX. than in normal individuals. Such findings, how- Discussion. The fact that anesthetization of ever, do not prove that the hypertonus of arterial the vasomotor nerves to the arm produces no hypertension is vasomotor in origin. In view of greater increase in blood flow in patients with our observations, a more probable explanation is hypertension than in control subjects demonstrates that the same stimulus produces an abnormal re- that the increased peripheral resistance in such action in patients with high blood pressure owing cases is not vasomotor in origin and is therefore to the local fault in the blood vessels themselves. to be considered as intrinsic hypertonus of the The results of the heat test and of sympathetic vessels themselves. It cannot be argued that the block demonstrate that both vasoconstrictor and blood vessels in these cases were incapable of vasodilator fibers innervate the blood vessels of PERIPHERAL RESISTANCE IN ARTERIAL HYPERTENSION 79

R'); f af- , N% Before Injection. After Injection. FIG. 7. EFFECT OF SYMPATHETIC BLOCK ON BLOOD FLOW. B.P.-blood pressure. C.P.N.-chronic pyelonephritis. B.F.-blood flow (cc. per 100 cc. arm volume per minute). A.G.N.-acute glomerulonephritis. B.H.-benign hypertension. M.H.-malignant hypertension. Ratio of blood flows indicates degree of vasodilatation produced by sympathetic block. the arm. A comparison of the increase in blood case in question (Table VIIB, Case 7) give fur- flow produced by the two methods indicates that ther confirmation. Hence the acute exacerbation in this segment of the arm a greater effect is pro- in this patient must be attributed to an increase in duced by vasodilator than by vasoconstrictor im- severity of the intrinsic vascular hypertonus and pulses, both in controls and in subjects with not to vasomotor hyperactivity. hypertension. In the types of hypertension we have studied it appears that normal vasomotor ac- II. MALIGNANT HYPERTENSION AND SECONDARY tivity is superimposed on an intrinsic vascular (RENAL) HYPERTENSION hypertonus which is independent of the vasomotor Literature nerves. It has been suggested that the exacerbations of Clinical experience and experimental evidence blood pressure or " vascular crises " occurring in both indicate that hypertension follows certain hypertensive subjects are vasomotor in origin. forms of renal damage. In particular, circulatory We have already brought evidence against such a obstruction to the kidney has been -shown to view, and the results of sympathetic block in the increase the blood pressure in animals (37). 80 MYRON PRINZMETAL AND CLIFFORD WILSON Volhard ( 11 ) attribtutes " red " hypertension to with 3.2 and 3.58 for control subjects and patients arteriosclerosis (elastosis) of the renal vessels, with benign hypertension. while Falhr (38) considers that endarteritis and XVe have previouslv stated that of the patients necrotizing arteriolitis in the kidney in malig- in whom the sympathetic nerves were successfully nant nephrosclerosis are responsible for the high injected with novocain two were cases of ma- blood pressure in this condition. The theories of lignant and two cases of secondary hypertension production of renal hypertension have been ably (acute glomerulonephritis and chronic pyelone- discussed elsewhere (39). One hypothesis as- phritis). The results (Table VIIB and Figure sumes that hypertension of renal origin is vaso- 7) show that the increase in blood flow after motor inl nature. Page (40) has recently shown sympathetic block is essentially the same as in that hypertension can be produced by clamping normal subjects and in benign hypertension. the renal artery in dogs even after removal of the There is, therefore, no evidence on the motor extrinsic nerves to the kidney. In order to test side for the vasomotor origin of " renal " or ma- the " reflex theory " on the motor side we have lignant hypertension. We must conclude that in investiogated cases of the malignant and secondary these cases, as in benign hypertension, the in- types by the methods outlined for benign hyper- creased peripheral resistance is attributable to tension. intrinsic hypertonus of the blood vessels them- Results selves. As shown in Table VIII and Figure 5, the heat DISCUSSION test in cases of malignant and secondary hyper- The above experiments have demonstrated that tension produces an increase in blood flow which hypertension is due to vascular hypertonus which gives ratios of 3.2 and 3.1 respectively, compared is generalized throughout the systemic circulation.

TABLE VIII Vasomotor dilatation induced by heat test

Case Blood Resting Blood flow Ratio of in- num- Age Sex pressure blood following crease over Diagnosis ber (Arm) flowv heat test resting flow cc. per 100 cc. cc. per 100 cc. years mm. Hg arm volume arm volume per mintute per minute

Malignant hypertension 18 30 F 270/180 1.1 4.9 4.45 19 12 F 210/170 1.5 2.1 1.4 20 40 F 190/140 2.3 2.75 1.2 21 39 M 200/170 0.65 4.6 7.0 7 44 M 245/185 1.05 2.2 2.1 A-verage 1.3 3.3 3.2t Secondary hypertension 22 38 M 200/150 1.4 3.8 2.7 Chronic glomerulonephritis 23 40 M 170/105 1.05 3.8 3.6 Chronic glomerulonephritis 24 22 F 150/110 0.7 1.4 2.0 Subacute glomerulonephritis 25 60 F 170/105 0.7 1.2 1.7 Pyelonephritis. Kidney stones 26 15 F 170/100 0.7 2.8 4.0 Subacute glomerulonephritis 27* 42 M 210/105 3.3 5.3 1.6 Chronic glomerulonephritis 28 27 F 200/110 1.3 7.4 5.7 Chronic glomerulonephritis 29* 42 M 190/110 0.7 3.0 4.3 Acute glomerulonephritis 30 43 F 250/150 1.1 3.5 3.2 Pyelonephritis. Kidney stones 31 23 F 210/140 1.8 3.7 2.1 Chronic pyelonephritis Average 1.3 3.6 3.1t * Diagnosis confirmed at autopsy. t This figure is the average of the ratios. PERIPHERAL RESISTANCE IN ARTERIAL HYPERTENSION 81

The hypertonus has been traced to a local dis- TABLE IX turbance in the blood vessels themselves, inde- Protocols pendent of the vasomotor nerves. Its nature and distribution are apparently the same in benign, Time Blood flow Comment malignant, and secondary (renal) hypertension, in both acute and chronic forms, and in acute cc. per 100 cc. arm volume exacerbations. The above evidence does not sup- per minute port Volhard's separation of hypertension asso- Case 31. Chronic pyelonephritis. Age 23. ciated with renal insufficiency ("pale" hyper- Blood pressure 230/140 tension) on the basis of generalized vascular hypertonus, since cases of "red" hypertension 2:10 1.4 Needle in position show the same phenomenon. Whatever the nature 2:11 1.3 5 cc. novocain injected 2:15 1.2 of hypertension of renal origin, we have shown 2:18 5 cc. novocain injected that on the motor side it is not produced by a 2:22 1.9 Horner's syndrome present. Anes- thesia 1st to 3rd intercostal spaces nervous reflex. This study does not exclude the and under arm possibility of a circulating pressor substance which 2:30 1.15 produces generalized peripheral vascular spasm but, as we have stated above, the existence of Case 7. Malignant hypertension (Exacerbation). Age 43. such a substance has not yet been satisfactorily Blood pressure 245/185 demonstrated. Among the surgical procedures which have 2:00 0.62 Needle in position been devised for the treatment of hypertension, 2:03 0.56 10 cc. novocain injected 2:08 1.35 Horner's syndrom present. Anes- section of the vasomotor nerves, particularly those thesia 1st to 3rd intercostal spaces to the splanchnic area, is amongst the most recent. and under arm The rationale of the operation is based on two 2:20 0.85 assumptions: (1) That hypertension is due to 2:30 0.63 excessive vasoconstriction in the splanchnic area; Case 29. Acute glomerulonephritis. Age 42. (2) that the vasoconstriction is brought about by Blood pressure 180/110 the vasomotor nerves. Since our results do not support either of these assumptions there would 2:15 1.7 Needle in position appear to be no rational basis for such operative 2:16 10 cc. novocain injected 2:22 1.9 Homer's syndrome present procedures. Theoretically, some fall in blood 2:25 2.4 Anesthesia 1st to 3rd intercostal pressure may follow sympathectomy in patients spaces and under arm with hypertension, since the normal vasoconstric- 2:30 2.5 tor tone is thereby abolished; but the intrinsic 2:45 2.35 vascular spasm responsible for the hypertension Case 15. Benign hypertension. Age 34. would be expected to persist after the vasomotor Blood pressure 180/130 nerves are cut. 2:00 0.88 Needles in position 2:02 0.83 Injection 10 cc. novocain SUMMARY AND CONCLUSIONS 2:05 0.96 Horner's syndrome present 2:15 1.6 Anesthesia 1st to 3rd intercostal 1. Determinations of resting blood flow in the spaces and under arm arm in various types of hypertension (benign, malignant, and secondary) give an average value Case 21. Malignant hypertension. Age 39. no greater than that obtained from subjects with Blood pressure 200/170 normal blood pressure. This indicates that in- 2:02 0.5 Needles in position creased vascular resistance in the different types 2:04 0.4 10 cc. novocain injected of hypertension is not confined to the splanchnic 2:19 0.9 Horner's syndrome present 2:30 0.6 Anesthesia 1st to 3rd intercostal area but is generalized throughout the systemic spaces and under arm circulation. 82 MYRON PRINZMETAL AND CLIFFORD WILSON 2. Patients with hypertension show increase in 8. It has been shown in both normal subjects blood flow in response to heat and reactive hy- and in patients with hypertension that there is peremia equal in degree to that produced in vasoconstrictor and vasodilator innervation to the normal individuals, showing that the blood vessels blood vessels of the arm. In this region greater in hypertension are capable of considerable dila- variations in blood flow are produced by vaso- tation and indicating that the increased peripheral dilator than by vasoconstrictor impulses. In the resistance is due to hypertonus and not to organic types of hypertension studied, it appears there- changes in the vessel walls. fore that normal vasomotor activity is superim- 3. Sympathetic vasodilatation produced by the posed on the intrinsic vascular hypertonus. "heat test " produces no greater increase in blood 9. Surgical procedures aiming at the relief of flow in subjects with high blood pressure than in high blood pressure by sympathectomy do not normal individuals, suggesting that the vascular abolish the vascular hypertonus which is funda- hypertonus is not vasomotor in origin. mentally responsible for the hypertension. 4. Patients with coarctation of the aorta, on the other hand, show a greater increase in blood flow We desire to thank Dr. Soma Weiss for his in the arm in response to the heat test than con- assistance and advice and Dr. James VVhite for trols or patients with generalized hypertension. his instruction in the method of novocain injec- This demonstrates that vasoconstriction of sympa- tion. We are indebted for cases of coarctation thetic origin is present in the upper extremities in of the aorta and Raynaud's disease to Dr. Paul D. coarctation of the aorta, and affords confirmatory White, Dr. F. C. Eppinger, Dr. R. H. Smithwick indirect evidence that the hypertonus in gener- and Dr. W. R. Wegner. alized hypertension is not of vasomotor origin. Sympathetic vasoconstriction in the upper ex- BIBLIOGRAPHY tremities in coarctation of the aorta may be 1. Lauter, S., and Baumann, H., Uber der Kreislauf regarded as a compensatory mechanism which bei Hochdruck, Arteriosklerose, und Apoplexie. maintains the normal distribution of blood Ztschr. f. klin. Med., 1928, 109, 415. throughout the body. 2. Burwell, C. S., and Smith, W. C., The output of the heart in patients with abnormal blood pressures. 5. Anesthetization with novocain of the vaso- J. Clin. Invest., 1929 7, 1. motor nerves to the arm produces the same in- 3. Weiss, S., and Ellis, L. B., The quantitative aspects crease in flow in normal subjects and patients with and dynamics of the circulatory mechanism in hypertension, proving that the vascular hypertonus arterial hypertension. Am. Heart J., 1929-30, 5. 448. is independent of the vasomotor nerves, and that 4. Austrian, C. R., The viscosity of the blood in health this hypertonus must therefore be regarded as and disease. Bull. Johns Hopkins Hosp., 1911. intrinsic spasm of the blood vessels themselves. 22, 9. 6. Acute exacerbation of hyper.tension with 5. Linder, G. C., Lundsgaard, C., Van Slyke, D. D., and change from the benign to the malignant type has Stillman, E., Changes in the volume of plasma and absolute amount of plasma proteins in nephri- been observed in one case. Such exacerbation is tis. J. Exper. Med., 1924, 39, 921. apparently not due to increased vasomotor activity 6. Lewis, T., and Grant, R., Observations upon reactive but must be attributed to an increase in the hyperaemia in man. Heart, 1925, 12, 73. intrinsic vascular hypertonus. 7. Longcope, W. T., and McClintock, A. T., The effect 7. The above conclusions apply to all types of of permanent constriction of the splanchnic arteries and the association of cardiac hypertrophy hypertension studied; namely, benign hyperten- with arteriosclerosis. *Arch. Int. Med., 1910, 6, sion, malignant hypertension, and " renal" hyper- 439. tension associated with acute and chronic glomeru- 8. Jansen, W. H., Tams, W., and Achelis, H., Blutdruck- lonephritis and chronic pyelonephritis; hence there studien. I. Zur dynamik des Blutdrucks. Deut- is no physiological evidence for the separation sches Arch. f. klin. Med., 1924, 144, 1. 9. Brown, G. E., Sympathectomy for early malignant into " organic" and " functional" types or for hypertension. M. Clin. North America, 1934, 18, the assumption that renal hypertension is due to 577. vasomotor hypertonus. 10. Craig, W. M., and Brown, G. E., Unilateral and PERIPHERAL RESISTANCE IN ARTERIAL HYPERTENSION 83

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