The Effects of Intravenously Infused Vasodilators on the Renal Plasma Flow and Renal Tubules

THE KURUME MEDICAL JOURNAL 1976 Vol.23, No.3, p.121-127

THE EFFECTS OF INTRAVENOUSLY INFUSED VASODILATORS ON THE RENAL PLASMA FLOW AND RENAL TUBULES

YOON-YOUNG KIM

Department of Pharmacology, Chung-ang University College of Medicine, Seoul, Korea

(Received for publication July 29, 1976, introduced by Dr. M. Shingu)

Nitroglycerin increased the renal plasma flow and altered electrolyte excretion. Perhexiline, i. v., caused an increase in sodium, chloride and osmolar clearance without the changes in the renal plasma flow. An elevation of the tubular sodium rejection fraction probably contributed to the increased solute clearance. I soproterenol caused retention of sodium, chloride potassium, and water without changing the renal plasma flow or the glomerular filtration rate. The tubular rejection fraction of sodium was decreased, indicating that isoproterenol was directly increasing the tubular reabsorption. The renal changes induced by isoproterenol were not altered by pretreatment with perhexiline.

INTRODUCTION In this study we selected two proto types of coronary vasodilators : nitro- Drugs which dilate the coronary glycerin and perhexiline HCl. The phar- arteries also affect other vascular beds. macological properties of perhexiline Since coronary vasodilators are pre- have been reported before (Cho et al., scribed for long periods of time, this 1970; Matsuo et al., 1970). Briefly, it effect on renal function and vasculature possess similar, as well as dissimilar, is an important consideration. We have pharmacological properties to that of reported previously on the unexpected nitroglycerin. Like nitroglycerin, per- effects of hexobendine on renal function hexiline is a coronary vasodilator and (Cho et al., 1973). Hexobendine is a its anti-anginal efficacy is currently portent coronary vasodilator whose bio-. being studied by others. It also has a chemical mechanism of action is by in- mild bronchodilatory action, but per- activation of adenosine deaminase and, haps much more so than nitroglycerin. hence, increases the circulatory adeno- Like nitroglycerin, while the systemic sine level. Hexobendine, thus, is phar- blood pressures were being minimally macologically similar to dipyridamole lowered, the heart rate was not in- (Persantin). creased but, rather, bradycardia was

1) Present Appointment : Assistant Professor , Department of Pharmacology, Chung-ang University College of Medicine, Seoul, Korea.

121 122 KIM observed (Cho et al., 1970). This latter given intravenously to each dog. After aspect of perhexiline is probably due to three 10 min urine collections, perhexi - its direct cardiac membrane action on line (0. 075 mg/kg dissolved in saline) the sinoatrial node and the atrial mem- was infused and the renal effects were brane, somewhat similar to that of studied for another 30 min. The possi- quinidine (Matsuo et al., 1970). bility of beta-adrenergic blocking activity of perhexiline was also studied. Isoproterenol was infused for 20 min METHODS AND MATERIALS at the rate of 0.1 ug/kg/min. Urine samples were collected every 10 min and A group of mongel dogs, weighing blood was drawn every 20 min. 18 to 20 kg each were anesthetized with A Buchler-Cotlove Chloridometer was morphine (20 mg/kg, subcutaneously) used to determine plasma and urine and chlora-abdominal midline incision chloride concentrations. The sodium and the cannulac were positioned ap- and potassium concentrations in both proximately .1/2 inch below the urotero- plasma and urine were determined using pelvic junction. The femoral vein and the internal lithium standard of Model artery were cannulated and the arterial 143 Instrumentation Laboratory Flame cannula was connected to a Stathum Photometer. A modification of the Transducer with a 3-way stopcock for Bonsnes and Taussky method (1945) was recordingg blood pressure with a Beck- used to determine plasma and urine man dynograph. Arterial blood samples creatinine and PHA determinations were obtained through the 3-way stop- were calculated using the technique of cock. Solutions containing creatinine Bratton and Marshall (1939). Plasma (1. 8 mg/ml) and p-aminohippurate (0. 5 and urine osmolalities were recorded by mg/ml) in normal saline were infused an Advanced Instruments osmometer. at the rate of 5 ml/min through the venous system by means of a dual- syringe constant-flow infusion pump. One to 2 hours were allowed for equili- RESULTS bration and then collections of 10 min urined samples from each kidney were The effects of systemically infused taken. Blood samples, drawn every 20 nitroglycerin and perhexiline, studied min, were heparinized, centrifuged and in two different groups of dogs, were the plasma immediately removed. At tabulated in Table 1. Nitroglycerin least three control urine samples were caused transient hypotension occurring collected before test agents were given. immediately after infusion of nitrogly- In 10 dogs, a bolus of nitroglycerin cerin. Perhexiline caused transient hy- with doses ranging between 0. 05, 0.1 potension of only 3 per cent of the con- and 0.2 mg/kg., was intravenously in- trol, 5 minutes following infusion. The fused through the femoral vein. An- hypotension induced by perhexiline (only other 10 dogs received an infusion of 3 %, which may not be a biologically 0.075, 0.150 and 0.300 mg/kg of per- significant change) and nitroglycerin (20 hexiline HCl dissolved in warm saline. to 36 % change in systolic and diastolic In another 18 dogs the additive renal blood pressures, which may not be a effects of perhexiline and nitroglycerin significant change) lasted briefly. The were studied. Nitroglycerin, 0.05 mg/kg systemic blood pressures returned to dissolved in 5 to 10 ml of saline, was the control values within 5 minutes. INTRAVENOUSLY INFUSES VASODILATORS 123

TABLE 1

Femoral arterial blood pressures before and after intravenous infusion of Nitroglycerin (GTM) and Perhexiline (Pexid) (Mean •} S. E. M.)

* = P less than 0.05 or less. % = The per cent change in blood pressure measured immediately following i. v. infusion of the drugs 5, 10 and 30 min after the drug infusion has been calculated against the control values.

The values obtained in the renal cle- (Table 2). At this dose level the renal arance studies are tabulated in Tables plasma flow rate was also increased. 2, 3 and 4. The control variables or Perhexiline, at a dose level of 0.075 renal plasma flow (ml/min), glomerular mg kg, caused no change in renal func- filtration rate (ml/min), osmolar cle- tion. However, perhexiline, at a dose arance (ml/min), urine volume (ml/min level of 0.300 mg/kg, caused a signifi- x 10-2), Sodium (mEq/min), potassium cant increase in urinary sodium and (mEq/min), chloride (mEq/min), the chloride excretion rates, as well as in- tubular rejection fraction of sodium, creases in osmolar clearance. Unlike and filtration fraction are compatible nitroglycerin, RPF was not altered at with published data (Bencasath et al., all dose levels (Table 3). 1971; Williams and Pearson, 1970). The results measured after 0.05 mg/ Nitroglycerin, 0.05 mg/kg, caused no kg of nitroglycerin showed an increase changes except a : minimal kaliuretic in renal plasma flow (+ 19.2 %) and action (Table 2). Marked natriuretic, glomerular filtration rate (+ 15.7%). All kali uretic and chloriuretic effects, as other variables were not significantly well as increases in the osmolar clearan- altered. ce rates, were observed in dogs receiv- When 0.075 mg/kg of perhexiline HCl ing 0.2 mg/kg of nitroglycerin, i. v. was added, there were significant in- 124 KIM

TABLE 2 The renal clearance studies after Nitroglycerin, I. V

TABLE 3 The renal clearance studies after Perhexiline HCl, I. V.

creases in renal plasma flow (+ 20.9 %), (+ 59.2 %), and tubular rejection frac- glomerular filtration rate (+ 17.8 %), tion of sodium (69.2 %). Perhexiline osmolar clearance (+ 20.7 %), sodium failed to block the renal effects of iso- clearance (+34.4 %), and chloride cle- proterenol. arance (+ 28.5 %). The infusion of isoproterenol at a rate of 0.1 ug/kg/min for 21 min caus- DISCUSSION ed a marked reduction in osmolar clearance (74.1%), urine volume (46. 3%), A pharmacologically active dose of sodium clearance (63.0%), potassium nitroglycerin (0.2 mg/kg) caused an clearance (54.5%), chloride clearance increase in the renal plasma flow and INTRAVENOUSLY INFUSES VASODILATORS 125

TABLE 4

The renal clearance studies after Nitroglycerin (0. 05 mg/kg) Perhexiline (0. 075 mg/kg) and Isoproterenol (0.1 mg/kg/min) (N=1s) (%= changes to the control) and absolute values (Mean •} S. E. M.)

* =(p 0.06 or less) # =(0.1 A 0.05) RPI = PAR clearance (renal plasma flow) in ml/min GFR = clomerular filtration rate in ml/min (Vol.) = brine volum in ml/min •~ 10•¬-2; U Na V = sodium excretion (uEq/min) •G U K V = potassium excretion (uEq/min) ; U Cl V = chloride excretion (uEq/min) ; C osm = osmolar clearance (ml/min) ; TRF Na = tubular rejection praction of sodium FF = filtration fraction

electrolyte excretion rate. Tubular so- hexiline may explain the clinical weight dium rejection fraction was not altered. loss in 69 patients receiving perhexiline Intravenous infusion of 0.3 mg/kg for 8 weeks (Unpublished data). The of perhexiline HCl did not increase renal weight loss has been noted by others plasma flow. There was an increase in (Hirshleifer, 1969) and is not due to sodium, chloride and osmolar clearance anorexia (Hudak et al., 1970). which would be attributed to an in- The additive renal effects of nitro- crease in renal flow. An elevation of glycerin (0.05 mg/kg) and perhexiline the tubular sodium rejection fraction 1101 (0.075 mg/kg) were interesting was not great enough to be statistical- findings. Nitroglycerin caused enhance- ly significant, but may well explain the ment of the perhexiline-induced renal saluretic effect of perhexiline which effects at an ineffective dose level. The was not accounted for by increased saluretic effects and osmolar clearance renal flow. This saluretic effect of per - rate were increased by perhexiline at 126 KIM the dose level of 0.075 mg/kg, which reabsorption and, therefore, a decrease was an ineffective dose of perhexiline in tubular rejection fraction of sodium. without the presence of nitroglycerin. However, other investigators have noted These additive renal effects of per- that a lower dose level infused slowly hexiline to nitroglycerin and the renal into the renal artery will induce diuresis action observed after nitroglycerin and natriuresis, while a higher dose at alone, or perhexilin alone, suggest that a faster rate will induce salt and water these two coronary vasodilators may retension (Mark et al., 1969). Apparent- act through two different mechanisms ly, high doses of isoproterenol stimulate in the kidney. Nitroglycerin, at effec- vasoconstriction in canine renal vascu- tive dose levels, may increase natri - lature. However, in clinical studies, uresis, kaliuresis and chloriuresis by isoproterenol was found to increase ef- changing the renal plasma flow rate, fective renal plasma flow in patients whereas perhexiline may be a mild di- with heart failure (Sandler et al., 1961) uretic agent acting directly upon the and pulmonary emphysema (Saltzman renal tubules at its effective dose levels. et al., 1961) Renal plasma flow was not altered by In conclusion, we have thus far perhexiline. studied three coronary vasodilators Perhexiline possesses certain pharma- whose pharmacological mechanisms of cological actions which mimic beta- action are different. Nitroglycerin, a adrenergic blocking agents. In canine prototype vasodilator of all the other heart-lung preparations (20 mg/kg) it nitrates and nitrates ; hexobendine reduced left ventricular work (Cho et (Cho et al., 1973), a prototype vasodila- al., 1970). Perhexiline will modify exer- tor of one whose action is by inactiva- cise - induced tachycardia in healthy tion of adenosine deaminase and in- volunteers (Bunde et al., 1969) and an- creasing coronary flow, such as dipyri- gina patients (Winsor, 1970). In isolat- damile (Persantin), prenylamine (Se- ed guinea pig atria a dose dependent gantin), etc. Finally, perhexiline HC1 increase in rate caused by histamine, may represent a totally new class of acetylcholine and isoproterenol can be antianginal drug. Perhexiline may in- blocked by perhexiline (Taxi, 1969). crease the coronary flow while it may However, in other areas, perhexiline not increase the heart rats in the face does not mimin beta-adrenergic block- of slightly lowered systemic blood pres- ing agents. In patients with bronchial sure (Cho et al., 1970). Also, perhexiline asthma perhexiline HC1 will cause bron- originally was thought to have some " chodilation. The data compiled in this sympatholytic" activities, such as in- study shows that perhexiline does not ducing a slight degree of bradycardia prevent or modify the renal effects in dogs (Cho et al., 1970) and causing induced by isoproterenol, a beta-stimu- a modification in tachycardia induced lant. by exercise in volunteers (Bunde et al., The infusion of isoproterenol after 1969). In isolated tissue preparations, perhexiline caused a decrease in urine perhexiline demonstrates certain anta- volume and osmolal, sodium, potassium gonistic effects to. those agonists such and chloride clearance without altering as isoproterenol, histamine and acetyl- renal plasma flow rate or glomerular choline (Unpublished data). Furthermore, filtration. The infusion of 0.1 ug/kg/ perhexiline possesses a cardiac mem- min in the f emoeral vein over a 20 min brane effect grossly similar to that of period caused an increase in tubular quinidine. For the time being, this INTRAVENOUSLY INFUSES VASODILATORS 127 agent may be classified as a "coronary Pharmacology of a new antianginal drug : vasodilator" acting directly upon the Perhexiline. I. Coronary circulation and ringed vascular smooth muscles. mvocardial metabolism. Chest. 58, 577. CHO, Y. W., PEARSON,J. E. and SAITO, S. (1973). Nitroglycerin, at a relatively higher The direct and systemic effects of hexo- dose level, may cause a slight degree bendine on renal function. Arch. Int. Phar" - of natriuretic action because of the macodyn, 201, 217. increased renal plasma flow rate. Per- FEINSILVER, O., CHO, Y.W. and AVIADO, D.M. hexiline, on the other hand, does not (1970). Pharmacology of a new antianginal increase the renal plasma flow but may drug : Perhexiline. III. Bronchopulmonary act directly upon the renal tubules to system in the dog and human. Chest, 58, reject the sodium. There are additive 448. renal effects between nitroglycerin and HUDAK, W. J., KUHN, W. L. and LEwIs, R. E. (1970). Cardiovascular activity of perhexi- perhexiline compensating one another. line. J. Pharmacol. Exp. Therap., 173, 364. Hexobendine apparently causes an HIRSHLEIFER, I. (1969). Perhexiline maleate antidiuretic activity, acting through in the treatment of angina pectoris. Curr. its direct effect on the renal tubules. Therap. Res., 11, 99. MATSUO, S., CHO, Y. W. and AVIADO,D. M. (1970). ACKNOWLEDGEMENT Pharmacology of a new antianginal drug : Perhexiline. II. Heart rate and transmem- I wish to thank Prof. Y. W. Cho •kProfessor brane potential of cardiac tissue. Chest, 58, and chairman, Department of Pharmacology, 581. Chung-ang University College of Medicine, MARK,A. L., ECKSTEIN, J. W., ABBOUD,F. M. and Seoul, Korea ; and University of North Caro- WENDLING, M. 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