James O. Davis

Renin Release after Hemorrhage and after Suprarenal Aortic Constriction in Dogs without Sodium Delivery to the Macula Densa

To study the possible factors that control renin secretion by the kidney, a model has been developed to prevent glomerular filtration in the dog. Ureteral ligation was combined with a 2-hour period of total renal ischemia to induce tubular degeneration and cessation of glomerular filtration. After the surgical procedures, the dogs were maintained for 4 days by peritoneal dialysis. The absence of lissamine green dye in the renal tubules after an intra-aortic injection provided evidence that filtration had ceased. Plasma renin activity was significantly increased in six conscious dogs at 30, 60, and 90 minutes after hemorrhage of 20 ml/kg body weight. In another group of five conscious animals, suprarenal aortic constriction produced increases in plasma renin activity at 30, 60, and 90 minutes that were 3 to 4 times the control values before aortic constriction. Plasma renin substrate concentration did not change significantly after hemorrhage or after aortic constriction. In a third group of five dogs, only the left kidney was subjected to ureteral ligation and renal ischemia. These dogs were anesthetized and renal blood flow was measured with an electromagnetic flowmeter. After hemorrhage (20 ml/kg), renin secretion increased significantly above control levels at 30, 45, and 60 minutes. It is concluded that sodium delivery to the macula densa is not essential for renin secretion.

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.

Effects of intrarenal infusion of calcium entry blockers in anesthetized dogs.

Renal function and renin release were studied in anesthetized, uninephrectomized dogs during intrarenal infusions of the calcium influx blockers, verapamil and nifedipine. Verapamil increased renal blood flow by 20% (p less than 0.05) but did not alter glomerular filtration rate. Verapamil produced five-to-seven fold increases in urine flow and the rates of excretion of sodium and chloride (p less than 0.01). Significant increases in the rates of excretion of potassium, calcium and magnesium were also observed. Despite its striking effects on renal function, verapamil, in nonhypotensive doses, failed to alter renin secretion. Intrarenal infusion of nifedipine had no consistent effect on renal blood flow or the rate of glomerular filtration but increased urine flow and the rates of excretion of sodium and chloride by more than three fold (p less than 0.01). Nonhypotensive doses of nifedipine had no significant effect on renin release. In dogs with a denervated nonfiltering kidney, an intrarenal verapamil or nifedipine infusion did not produce a significant change in renin release. This study demonstrates a striking effect of calcium entry blockers on the reabsorption of sodium, chloride, and water by the renal tubules in intact dogs but renin release did not increase unless hypotension occurred.

Review: What Signals the Kidney to Release Renin?

• Much has been said and much has been written on the renin-angiotensin-aldosterqne system but one of the most important problems remains unresolved. The specific signals perceived by the renal juxtaglomerular (JG) cells to secrete renin are still unknown. In an editorial in 1964 (1), attention was called to the paucity of experimentation in this area. There is now no lack of interest in and pursuit of this important problem, and recently a number of innovative approaches have resulted in pertinent new data. This article is written to describe these new approaches and to stimulate interest and further research which might close this important gap in our knowledge. Early attempts at elucidation of this problem were aimed at testing either the baroreceptor hypothesis or the macula densa theory. Increasing evidence has accumulated to support the idea that the sympathetic nervous system is also involved. And, a number of humoral agents influence renin release, espedally in pharmacologic doses; these findings raise the question of the physiological roles of these substances in the control of renin secretion. The JG cells, the macula densa, and the renal sympathetic nerves are depicted diagrammatically in relation to the renal arterioles (Fig. 1). In homeostasis and in several experimental and clinical situations with secondary aldosteronism, the renin-angiotensin-aldosterone

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.

The Renin-Angiotensin System and Aldosterone Secretion during Sodium Depletion in the Rat

The role of the renin-angiotensin system in the control of aldosterone secretion was studied in the sodium-depleted rat. Administration of angiotensin II produced a significant increase in aldosterone secretion and arterial blood pressure in normal rats; simultaneous infusion of the angiotensin analogue. 1-sarcosine-8-alanine-angiotensin II, blocked both the pressor and the steroidogenic actions of angiotensin. Since the angiotensin II analogue was effective in blocking exogenous angiotensin II, an attempt was made to block endogenously formed angiotensin II in the sodium-depleted rat; infusions of large doses of the analogue produced a significant fall in arterial blood pressure, but aldosterone secretion failed to change. Bilateral nephrectomy also failed to decrease aldosterone secretion in the sodium-depleted rat even though arterial blood pressure fell. Since the secretion of corticosterone in these rats was high, it seemed likely that the failure of aldosterone secretion to fall resulted from an overriding influence of adrenocorticotropic hormone (ACTH). To test this hypothesis, the renin-angiotensin system was again blocked in sodium-depleted rats with three levels of anterior pituitary function. With high or intermediate rates of corticosterone secretion, a nonapeptide converting enzyme inhibitor (CEI) failed to influence aldosterone secretion. However, when the influence of ACTH was completely eliminated by hypophysectomy in sodium-depleted rats, the nonapeptide CEI produced a striking fall in aldosterone secretion. In contrast, arterial blood pressure was significantly reduced by CEI in rats with all three levels of anterior pituitary function. The data suggest a role for angiotensin II in the regulation of aldosterone secretion and the maintenance of arterial blood pressure in the sodium-depleted rat.

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.

Evidence for a Renal Vascular Mechanism in Renin Release: New Observations with Graded Stimulation by Aortic Constriction

To examine the possibility of a renal intravascular receptor for renin secretion, bilateral ureteral ligation and a two-hour period of renal ischemia were used to produce a nonfiltering kidney model in dogs. In conscious animals with both innervated and denervated, nonfiltering kidneys, hemorrhage and suprarenal aortic constriction produced significant increases in plasma renin activity. To measure renin secretion directly, a unilateral, nonfiltering kidney was produced, and renal blood flow was determined with a square-wave electromagnetic flowmeter in anesthetized dogs. Renin secretion was significantly elevated after a 20 ml/kg hemorrhage in these animals. In another group of dogs, adrenalectomy was combined with renal denervation in the unilateral, nonfiltering kidney model. In these animals hemorrhage produced significant increases in renin secretion. After a recovery period three of these dogs were subjected to graded constriction of the suprarenal aorta. Slight decreases in blood pressure with and without decreases in renal blood flow produced increases in renin secretion. Since increased renin secretion occurred in the absence of sodium delivery to the macula densa, from denervated kidneys, and without the major portion of circulating catecholamines, it is suggested that an intrinsic receptor for renin release is present within the renal vascular tree.