J. Alan Johnson

Effects of Catecholamines and Renal Nerve Stimulation on Renin Release in the Nonfilterlng Kidney

The mechanisms whereby catecholamines and renal nerve stimulation increase renin secretion were studied in dogs with nonfiltering kidneys. In six dogs, epinephrine was infused into the renal artery at a rate that decreased renal blood flow to half of the control value. Papaverine was then infused into the renal artery to block the decrease in renal blood flow produced by the catecholamine, and the epinephrine infusion was resumed while the papaverine infusion was continued. In this experiment, renin release increased during infusion of epinephrine alone, but no change occurred with epinephrine during papaverine infusion. The protocol for the experiment on six other dogs was similar except that the infused catecholamine was norepinephrine. In this experiment, norepinephrine increased renin release both prior to and during papaverine infusion. In seven dogs, the effect of electrical stimulation of the renal nerves on renin secretion was studied both before and during the infusion of papaverine into the renal artery; renin release increased strikingly both before and during papaverine infusion. It is suggested that epinephrine increased renin secretion in the nonfiltering kidney by an action on the renal arterioles. In contrast, norepinephrine and renal nerve stimulation apparently increased renin secretion in the nonfiltering kidney by a direct effect on the juxtaglomerular cells. These data provide evidence for specific mechanisms of action of epinephrine, norepinephrine, and the renal nerves in renin release.

Intrarenal Role of Angiotensin II: HOMEOSTATIC REGULATION OF RENAL BLOOD FLOW IN THE DOG

The analogue, l-sarcosine-8-alanine-angiotensin II, a specific competitive antagonist of the vascular action of angiotensin II in the rat, blocked the decrease in renal blood flow after a single intrarenal injection of angiotensin II but not after an injection of norepinephrine in normal dogs, in a sodium-depleted dog, and in a dog with thoracic vena caval constriction. Infusion of the analogue at 0.2 μg/kg min−1 into the renal artery consistently increased renal blood flow and decreased renal resistance in both sodium-depleted dogs and dogs with vena caval constriction but did not alter these functions in normal dogs. In five sodium-depleted dogs, renal blood flow increased from an average control value of 196 ± 5 ml/min to 222 ± 11 and 246 ± 12 ml/min after 20 and 40 minutes of antagonist infusion (P < 0.01 and P < 0.005, respectively); renal resistance fell from 0.71 ± 0.03 mm Hg/ml min−1 to 0.62 ± 0.06 and 0.54 ± 0.03 mm Hg/ml min−1 (P < 0.005 for the 40-minute value). In five dogs with vena caval constriction, renal blood flow increased from 143 ± 16 ml/min to 178 ± 23 and 190 ± 19 ml/min after 20 and 40 minutes of analogue infusion (P < 0.02 and P < 0.005, respectively); renal resistance fell from 0.90 ± 0.14 mm Hg/ml min−1 to 0.73 ± 0.14 and 0.64 ± 0.10 mm Hg/ml min−1 (P < 0.01 and P > 0.02, respectively). Mean arterial blood pressure was not altered significantly by the analogue when it was infused at 0.2 μg/kg min−1. Infusion of the analogue at 2.0μ/kg min−1 decreased arterial blood pressure and renal resistance and increased renal blood flow in five sodium-depleted dogs and in three dogs with vena caval constriction. These observations suggest an important intrarenal role for angiotensin II in the homeostatic regulation of renal blood flow in sodium-depleted dogs and in dogs with vena caval constriction.

Angiotensin II: Important Role in the Maintenance of Arterial Blood Pressure

An angiotensin II antagonist, [1-sarcosine, 8-alanine]-angiotensin II, was given intravenously to anesthetized dogs with thoracic caval constriction and ascites to investigate the role of angiotensin II in the control of arterial pressure. The antagonist produced a striking fall in arterial pressure and in aldosterone secretion and an accompanying increase in plasma renin activity. In a control experiment, normal anesthetized dogs were given the angiotensin analog, but it failed to reduce arterial pressure or to influence plasma renin activity. In conscious dogs with caval constriction, the antagonist produced essentially the same drop in arterial pressure as observed in anesthetized animals. These results suggest an important role for angiotensin II in the maintenance of arterial pressure by its action on specific receptor sites in arteriolar smooth muscle and in the adrenal cortex.

Effects of Renal Arterial Infusion of Sodium and Potassium on Renin Secretion in the Dog

The nonfiltering kidney model was used to determine whether sodium or potassium inhibits renin secretion in the absence of a functional macula densa in dogs with thoracic inferior vena caval constriction. The control rate of renin secretion was high, and decreases were readily recognized. After control observations, hypertonic sodium chloride or hypertonic potassium chloride was infused into the renal artery for 1 hour, and renin secretion was measured at 15-minute intervals. An increase in renal venous plasma sodium concentration from 141 to 154−158 mEq/liter caused no change in renin secretion for the first 45 minutes of infusion in dogs with a nonfiltering kidney. In contrast, dogs with thoracic caval constriction but with a filtering kidney showed a striking decrease in renin secretion during intrarenal sodium infusion (3,097 to 1,061 ng angiotensin/min, P <0.02). An increase in renal venous plasma potassium concentration from 3.9 to 6.1 mEq/liter in one group of dogs and from 4.9 to 8.3 mEq/liter in a second group also caused no change in renin secretion in the nonfiltering kidney of dogs with thoracic caval constriction. However, in dogs with thoracic caval constriction and a filtering kidney, potassium infusion decreased renin secretion (1,952 to 984 ng angiotensin/min, P <0.05). In all experiments, infusion of sodium chloride or potassium chloride failed to produce a significant change in renal blood flow, arterial blood pressure, or inferior vena caval pressure. Therefore, no evidence was obtained for a vascular action or a direct effect of sodium or potassium on the juxtaglomerular cells, and the data are consistent with an action mediated by the renal tubular system.

Brief Reviews: Agents Which Block the Action of the Renin-Angiotensin System

• The role of the renin-angiotensin system in the control of arterial blood pressure and aldosterone secretion has been studied extensively in homeostasis, hypertensive disease, and edematous states. For many years it has been realized that the availability of effective blocking agents for renin or for angiotensin II might help greatly in the study of this system and might have important value in the treatment of conditions such as renal hypertension and heart failure. During the past few years, an increasing number of blocking agents for the reninangiotensin system have been developed. These agents act at one of three sites: (1) they block the action of renin in plasma, (2) they prevent converting enzyme from forming angiotensin II from angiotensin I, or (3) they block the receptor sites for angiotensin II in arteriolar smooth muscle and adrenal cortex. In addition, adrenergic blocking agents such as propranolol decrease the release of renin from the renal juxtaglomerular cells. This review is concerned only with the agents which block the action of the renin-angiotensin system, not with those that decrease the release of renin. The new observations with blocking agents have helped solve several specific problems under investigation, and, in addition, new important functions of the renin-angiotensin system have been uncovered. For example, it is now recognized (1-5) that in low output states angiotensin II acts directly on the peripheral arterioles including the renal vasculature to increase peripheral resistance, decrease renal blood flow, and maintain arterial blood pressure. In this review, the recent findings have been collated to present this new knowledge on the physiology of angiotensin II, to evaluate the present state of our knowledge on such important problems as the pathogenesis of experimental renal hypertension, and to stimulate additional research on the physiology of the renin-angiotensin system.

The Signal Perceived by the Macula Densa during Changes in Renin Release

Renin secretion was studied in acute experiments in dogs during occlusion of the ureter alone (experiment 1), ureteral occlusion with a superimposed intrarenal infusion of papaverine (experiment 2), or ureteral occlusion with a superimposed intravenous ethacrynic acid injection (experiment 3) and following release of the ureteral occlusion (all three experiments). In all three experiments, ureteral occlusion increased renin secretion four- to fivefold. In experiment 2, papaverine, an inhibitor of smooth muscle contractility, was infused intrarenally during the last 20 minutes of ureteral occlusion, but renin secretion was unchanged by the infusion. Renin secretion decreased rapidly and was at the control level 5, 12½, and 27½ minutes after release of the occlusion, but urinary sodium concentration and excretion rate increased markedly during this period. In experiment 3, a superimposed injection of ethacrynic acid failed to alter renin secretion during ureteral occlusion. After release of the ureter, renin secretion remained unchanged for the first 5 minutes. Although renin secretion had decreased 12½ and 27½ minutes after release of the occlusion, it was still elevated twofold above the control level. Again, sodium excretion increased markedly and urinary sodium concentration was high after ureteral release. These findings support the hypothesis that the rate of renin release is inversely related to the rate of sodium transport by the macula densa cells.

Mechanisms Regulating Renin Release in Dogs with Thoracic Caval Constriction

In dogs with chronic thoracic caval constriction, renal denervation was followed by a fall in plasma renin activity from an average of 82.1 ± 1.5 (SE) ng angiotensin/ml of plasma over a 9-day control period to 40.8 ± 2.3 ng/ml for a 13-day period after denervation (P < 0.001); normal value was 4.7 ± 0.7 ng/ml. There was no detectable effect of renal denervation on the marked sodium retention. Thus the renal nerves contributed to the high plasma renin activity during caval constriction, but renal innervation was not essential for hypersecretion of renin. In a second group of dogs with caval constriction, the nonfiltering kidney model with a nonfunctional macula densa was produced, and renin secretion was measured before and after papaverine infusion into the left renal artery. Papaverine decreased renin secretion from 1090 ± 185 ng angiotensin/min to 497 ± 140 ng/min (P < 0.005). This initial rate of renin secretion of 1090 ng/min was higher than that from a nonfiltering left kidney of 190 ± 50 ng/min in otherwise normal dogs (P < 0.001). In a third series of dogs with caval constriction but with filtering kidneys, papaverine produced a similar decrease in renin secretion and an associated increase in sodium excretion. Since papaverine dilated the renal arterioles and the macula densa was nonfunctional in dogs with a nonfiltering kidney, these data support the concept that an intrarenal vascular receptor mediates the elevation in renin secretion in this model with chronic ascites. The striking decrease in renin secretion in response to intrarenal propranolol in dogs with either a filtering or a nonfiltering kidney indicates that a beta receptor is also involved.

The role of the renin--angiotensin system in experimental renal hypertension in dogs.

Summary An angiotensin II antagonist, l-sarcosine-8-alanine-angiotensin II, was infused intravenously into conscious dogs with experimental hypertension produced by renal artery constriction and unilateral nephrectomy. In dogs with malignant hypertension and elevated plasma renin activity, a decrease in arterial pressure was observed during infusion of the angiotensin II analog. However, in dogs that developed chronic hypertension of 2–7 weeks duration no decreases in arterial pressure occurred during infusion of this angiotensin II antagonist. Similarly, infusion of this compound into normal conscious dogs did not decrease arterial pressure. It is suggested that angiotensin II acts on receptors in arteriolar smooth muscle to increase peripheral resistance and arterial pressure in dogs with malignant hypertension, but chronic hypertension in the dog is maintained by other mechanisms.

Arterial Pressure Regulation during Hemorrhage: Homeostatic Role of Angiotensin II:

Summary The role of the renin-angio-tensin system in the maintenance of arterial pressure following hemorrhage was studied in conscious dogs. Hemorrhage (20 ml/kg body wt) decreased the mean arterial pressure, but compensatory mechanisms partially restored the arterial pressure toward normal. Plasma renin activity increased more than twofold following hemorrhage. To evaluate the role of endogenous angiotensin II in this compensatory response, a specific competitive antagonist of angiotensin II, l-sarcosine-8-alanine-angiotensin II, was infused intravenously at 6.0 μgAg min-1 for 30 min; the mean posthemorrhage arterial pressure decreased from 102 ± 7 mmHg to 80 ± 6 mmHg after 15 and 30 min of analog infusion (P < 0.01 for both values). After a recovery period of 60 min, arterial pressure returned to pre-infusion levels. These results suggest that angiotensin II plays an important role in the short-term maintenance of arterial pressure following hemorrhage in the conscious animal.

Role of the renin-angiotensin system in dogs with perinephritis hypertension.

Summary Cellophane perinephritis hypertension was produced in four dogs, while five additional dogs served as normotensive controls. A competitive antagonist of angiotensin II, 1-sarcosine-8-alanine angiotensin II, was infused iv into these conscious dogs at a rate of 6 μg/min/kg of body weight for 45 min. Arterial pressure averaged 170 ± 11 (SEM) mm Hg in the dogs with perinephritic hypertension, and was not altered significantly during infusion of the angiotensin antagonist. In the normal dogs the arterial pressure averaged 100 ± 10 mm Hg and likewise, did not change during administration of the angiotensin analog. Plasma renin activity values were essentially the same in these two groups of dogs and did not change during infusion of the angiotensin antagonist. These studies provide strong evidence that the renin-angiotensin system is not involved in maintaining the elevated arterial pressure in dogs with chronic hypertension produced by cellophane perinephritis. The authors gratefully thank Dr. A. W. Castellion of Norwich Pharmacal Company for supplying the 1-sarcosine-8-alanine angiotensin II used in these studies. The cellophane used to produce perinephritis hypertension was supplied by E. I. DuPont de Nemours and Company. Mr. Charles Payne assisted in the surgical procedures and the assays for plasma renin activity were performed by Ms. Jane Green.