The Effects of Intravenously Infused Vasodilators on the Renal Plasma Flow and Renal Tubules
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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 eleva- tion 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 acti- vity 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 cle- arance (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.