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The Relationship of the Renal Vascular Activity of Angiotensin II to the Autonomic Nervous System * JOHN C

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The Relationship of the Renal Vascular Activity of Angiotensin II to the Autonomic Nervous System * JOHN C Journal of Clinical Investigation Vol. 44, No. 11, 1965 The Relationship of the Renal Vascular Activity of Angiotensin II to the Autonomic Nervous System * JOHN C. MCGIFF t AND THOMAS M. FASY (From the Departments of Pharmacology and Medicine, School of Medicine, University of Pennsylvania, and the Edward B. Robinette Foundation, Medical Clinic, Hospital of the University of Pennsylvania, Philadelphia, Pa.) The vasoconstrictor activity of angiotensin II vasoconstrictor activity of angiotensin II, similar was originally considered to be due to a direct ef- to that produced by renal ischemia (9). The fect on vascular smooth muscle (1, 2). Subse- present study reports on the role of the nervous quently, it has been suggested that the sympathetic system in determining the renal vascular reactivity nervous system participates in the vascular re- to angiotensin II. The renal vascular bed was sponse to angiotensin II (3-5). After acute selected for this study because it is the most sensi- denervation of the limb, the reactivity of the limb tive of the regional beds tested to the vasoconstric- vasculature to angiotensin II is reduced in the rat tor effect of angiotensin II (10). Blockade by (3) and dog (4). Bickerton and Buckley (5) autonomic drugs of the renal vasoconstriction pro- have described two elements in the pressor re- duced by angiotensin II was demonstrated. Au- sponse to angiotensin II: a centrally mediated ef- tonomic blocking agents selected were representa- fect, due to stimulation of central autonomic nerv- tive of several classes: ganglionic blockade (hexa- ous structures, and a peripheral action on the vas- methonium), alteration of the release of the neuro- cular smooth muscle. transmitter by either central (hydralazine) or Angiotensin II is not only influenced in its vas- peripheral activity (guanethidine and bretylium), cular activity by the autonomic nervous system, depletion of the transmitter (reserpine), and re- but itself will release or enhance the response to ceptor blockade (phentolamine). The capacity of stimuli releasing catecholamines. Thus, angio- autonomic blocking agents to oppose the effects of tensin II has been reported to enhance the pressor angiotensin II was related to the activity of the response to tyramine (6), to release catechola- drug at the neuroeffector site. Those blocking mines from the adrenal medulla (7), and to lower agents that reduced the release or depleted the the threshold to sympathetic nerve stimulation neurotransmitter were demonstrated to oppose the (8). renal vascular activity of angiotensin II. Renal ischemia was observed in this laboratory to alter the renal vascular response to angiotensin Methods II. While examining the role of the nervous sys- Dogs weighing 21 to 32 kg (mean, 24 kg) were anes- tem in the production of this effect, renal denerva- thetized with morphine sulfate (2 mg per kg, subcutane- tion was observed to produce a loss of the renal ously) and chloralose (70 mg per kg, intravenously). Heparin 1 (200 to 400 International U per kg) was ad- * Submitted for publication February 25, 1965; accepted ministered intravenously as the anticoagulant. The lungs August 5, 1965. were ventilated by a Starling Ideal pump through a Abstracts of this paper appeared in Circulation 1964, 30, Y-shaped glass tube inserted in the trachea. 124, and Clin. Res. 1965, 13, 214. Presented in part before A Sanborn multichannel direct writer recorded mean the American Heart Association, October 1964. arterial pressure and the venous outflow of one kidney. Supported by grants HE-08805 and HE-5239, general In one experiment the two renal blood flows were meas- research support grant 1S01-FR05115-01, and training ured simultaneously. The renal vein was cannulated with grant T5-GM-4-07 from the U.S. Public Health Service. a plastic cannula (4 mm, inside diameter). The time re- t Established Investigator, American Heart Associa- quired for cannulation, during which the arterial supply tion (July 1, 1964). was interrupted by a clamp, was less than 2 minutes. Address requests for reprints to Dr. John C. McGiff, The effluent was passed through a Shipley-Wilson ro- Dept. of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, Pa. 19104. 1 Panheprin, Abbott Laboratories, North Chicago, Ill. 1911 1912 JOHN C. McGIFF AND THOMAS M. FASY tameter (200 ml) that was placed below the cannulated nephrine and levarterenol (2 to 5 ug per kg per minute) vein. A common reservoir received the renal blood flow, were administered. The doses of hexamethonium, tyra- which was returned to the femoral vein by a Sigmamotor mine, and hydralazine are given in terms of the salt; for pump, automatically activated when 40 ml of blood was the other drugs, doses are expressed as the base. Intra- emptied into the reservoir. The amount of blood in the venous injections were made rapidly through a cannulated extracorporeal recording circuit was constant. The dead femoral vein in a fluid volume of less than 2 ml. In the space of the recording system was 120 ml; an equal volume experiments in which the kidney was denervated, renal of plasma expander (6% gelatin solution) was used to intra-arterial injections were made possible; 1 ml of the prime this system. drug in appropriate concentration was administered into In five experiments, acute denervation of the kidney was the cannula and tubing conducting the blood to the per- accomplished by transection of the renal artery. The fused kidney. Several schedules of reserpine 3 adminis- denervated kidney was then perfused with blood from tration were elected, for a usual dose of reserpine (e.g., the carotid artery through a cannula inserted into the 0.1 mg per kg per day intramuscularly for 2 days) proved distal end of the sectioned renal artery. insufficient in two experiments to alter the renal vascu- In four experiments the first cervical vertebra was ex- lar activity of angiotensin II. The dose of reserpine that posed and a laminectomy was performed. A 2-cm seg- effectively modified the renal vascular response to angio- ment of spinal cord was uncovered by removing the over- tensin II in four dogs was 0.1 mg per kg intramuscularly, lying dura mater. After the renal vascular responses to daily for 4 days, then 1 mg per kg intravenously, 24 hours the drugs were observed, the cord was transected. and 12 hours before the experiment. The following drugs were administered intravenously: To exclude tachyphylaxis or a time trend as a cause angiotensin II 2 (0.1 to 0.5 gg per kg), tyramine hydro- of the modified renal vascular response to angiotensin II, chloride (50 to 500 /Ag per kg), levarterenol bitartrate the following precautions were observed. a) In the con- (0.25 to 2.0 yg per kg), epinephrine bitartrate (0.4 to trol periods, i.e., before renal denervation, angiotensin II 2.0 /Ag per kg), phentolamine methanesulfonate (0.1 mg was administered only once. The only exception was that per kg), guanethidine sulfate (5 to 10 mg per kg), before spinal cord transection there were two injections bretylium tosylate (5 mg per kg), hexamethonium bro- of angiotensin II separated by an interval of 5 minutes. mide (5 to 10 mg per kg), nicotinic acid tartrate (30 to b) Successive injections of angiotensin II were separated 100 /Ag per kg), and hydralazine hydrochloride (2 mg per by an interval of at least 3 minutes, which was deter- kg). In several experiments intravenous infusions of epi- 3 Serpasil phosphate, Ciba Pharmaceutical Co., Summit, 2 Hypertensin, Ciba Pharmaceutical Co., Summit, N. J. N. J. TABLE I The renal vascular activity of angiotensin II as modified by acute denervation of the kidney (summary offive experiments) Mean change of renal blood flow from con- Blood pressure* Renal blood flow* trolt h SE of 4 SE of mean d SE of mean mean difference mm Hg mil/min ml/min Predenervation Controlt 116 :1 14t 175 ± 18: Angiotensin, iv, 0.1 ug/kg 165 ± 12§ 135 i 201 -42±10§ Control 126 4t 20 170 ± 17 Levarterenol, iv, 1.0 jug/kg 171 i1= 1911 94 i 23|| -76415 Postdenervation Controlt 95 ± 71: 123 ± 24t Angiotensin, iv, 0.1 ttg/kg 144 ± 11§ 143 ± 23§ +20 4 2§ Control 91±12 145± 8 Levarterenol, iv, 1.0 Mg/kg 136 ± 23 62 i 181 -80±15 Control 95 ± 11 115 ± 20 Angiotensin, renal intra-arterial, 0.05 M~g/kg 97 ± 9 58 ± 22§ -57± 9 * The mean values of the renal blood flows and blood pressures resulting from administration of angiotensin II and levarterenol were compared with the mean of the control values. Differences were statistically evaluated; unless other- wise indicated p > 0.05. t The mean changes of renal blood flow from control resulting from intravenous administration of angiotensin II and levarterenol were compared before and after denervation of the kidney. Differences were statistically evaluated; unless otherwise indicated p > 0.05. t The mean values for the angiotensin control periods, pre- and postdenervation, did not differ significantly. §p <0.01. II p <0.05. ANGIOTENSIN AND THE AUTONOMIC NERVOUS SYSTEM 1913 E0 _9 c R Mo0 E oi -- N A L on D z E N E R V A 0- T 0 N AENGONSIN ANGIOTENSIN ANGIOTENSIN ANGIOTENSIN O.Ipg/kg iv QOIug/ kg ia 0.2,ug/kg ivj 0.5kpg/kg iv ANGIOTENSIN O.O1ug/ kg ia 24 kg DOG 8-28-63 IImin I FIG. 1. EFFECT OF RENAL DENERVATION ON THE RENAL VASCULAR RESPONSE TO ANGIOTENSIN II IN A DOG UNDER MORPHINE-CHLORALOSE. Acute renal denervation abolished the constriction of the renal vasculature produced by angiotensin II intra- venously and reduced the response to intra-arterial (ia) angiotensin II. Ten min- utes elapsed between, the left and right panels.
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