Since the discovery of renin 80 years ago, there have been remarkable advances in our understanding of the renin-angiotensin system. The system as it is known today is summarized in Figure 1. Angiotensin III, the active component of the system, has several important physiological actions. The first of these to be identified was its pressor action, and for many years it was felt that the sole function of the renin-angiotensin system was regula­ tion of blood pressure. A new dimension was added in 1960 with the discovery that angiotensin II stimulates the secretion of aldosterone and is therefore in a position to exert important effects on salt and water balance. Several additional actions of angiotensin II were then discovered. It was found that the peptide can increase the secretion of catecholamines from the adrenal and facilitate adrenergic transmission. It also acts directly on the brain to increase blood pressure via sympathetic and parasympathetic path­ ways, to produce thirst, and to stimulate the secretion of vasopressin and ACTH. Through these actions, the renin-angiotensin system plays an im­ portant role in the regulation of blood pressure and of the volume and composition of the extracellular fluid. Major advances have also been made in our understanding of other aspects of the renin-angiotensin system. It has become clear that the hep­ tapeptide metabolite of angiotensin II, [des-Aspl] angiotensin II ("angio-

The Renin-Angiotensin System

Laser light scattered from tissue in vivo is broadened in line width as a result of the Doppler shift produced by moving red cells in the microcirculation. A feasibility study was carried out to demonstrate use of this effect to measure and monitor tissue blood flow. Light from a helium-neon laser illuminated a 1-mm area of tissue (human skin or rat renal cortex), and the backscattered light was detected with a photomultiplier. The spectrum of the Doppler beat notes was analyzed directly with a digital spectrum analyzer, or processed by analog circuitry to yield a flow parameter based on the root-mean-square Doppler line width. This parameter was compared with 133Xe washout in the skin of volunteers subjected to UV-induced erythema and the skin of volunteers subjected to UV-induced erythema and was found to vary in an approximately linear manner with skin blood flow. The laser instrument provided continuous monitoring of blood flow fluctuations, including the pulsatile component. The instrument was used to monitor flow in the outer cortex of the rat kidney during administration of norepinephrine, angiotensin, hydralazine, dextran, dopamine, nitroprusside, and angiotensin blocked by saralasin. Dynamic and steady-state responses were consistent with known pharmacology and renal physiology, and with the assumption that vasoconstrictor angiotensin II receptors in the kidney are accessible to blood-borne inhibitors. The laser-Doppler method is a promising tool for rapid monitoring of dynamic changes in tissue perfusion.

https://www.physiology.org/doi/pdf/10.1152/ajpheart.1977.232.4.H441

Continuous measurement of tissue blood flow by laser-Doppler spectroscopy.

Effect of aging on plasma renin and aldosterone in normal man

In 15 patients with severe chronic left ventricular failure, plasma renin activity (PRA) ranged widely, from 0.2--39 ng/ml/hr. The level of PRA was unrelated to cardiac output (CO) or pulmonary artery wedge pressure (PWP), but was slightly negatively correlated with mean arterial pressure (MAP) (r = -0.45) and systemic vascular resistance (SVR) (r = -0.40). After infusion of the angiotensin converting enzyme inhibitor teprotide (SQ 20,881) PWP fell from 26.3 +/- 1.3 (SEM) to 20.3 +/- 1.4 mm Hg (P less than 0.001), CO rose from 3.94 +/- 0.23 to 4.75 +/- 0.31 l/min (P less than 0.001), MAP fell from 87.5 +/- 3.8 to 77.9 +/- 4.1 mm Hg (P less than 0.001) and SVR from 1619 +/- 148 to 1252 +/- 137 dyne-sec-cm-5 (P less than 0.001). The fall in MAP and in SVR was significantly correlated with control PRA (r = 0.68 and r = 0.58, respectively). When subjects were divided on the basis of control PRA the hemodynamic response to teprotide was greatest in the high renin group. PRA rose after teprotide (8.7 +/- 3.4 to 37.9 +/- 7.7 ng/ml/hr, P less than 0.05) but plasma norepinephrine fell (619.1 +/- 103.6 to 449.7 +/- 75.7, P less than 0.05). The renin-angiotensin system thus appears to have an important role in the elevated SVR in some patients with heart failure. Chronic inhibition of converting enzyme should be explored as a possible therapeutic approach.

Role of the renin-angiotensin system in the systemic vasoconstriction of chronic congestive heart failure.

The adrenal glomerulosa cell and the renal vasculature respond to similar arterial angiotensin II (A II) levels We have assessed the effect of decreased sodium intake on their responses to A II in man Studies were performed in 42 normal subjects in balance on a daily intake of 100 meq potassium and either 200 or 10 meq sodium/day Renal blood flow was measured with 133Xe and arterial A II, renin and aldosterone concentrations by radioimmunoassay A II was infused intravenously (1, 3, or 10 ng/kg/min) for 40—60 min; 14 subjects received graded doses The A II level increased linearly with dose and plateaued within 3 min; blood pressure and renal vascular resistance showed a similar time-course Aldosterone rose within 10 and plateaued within 20 min Dose-response relationships were established between the rate of A II infusion and the adrenal, the renal vascular, and pressor responses Sodium restriction reduced the pressor (P < 001) and the renal vascular response (P < 001), but potentiated the adrenal response to A II (P < 001) An excellent correlation was found between the plasma A II and aldosterone levels, but the slope of their regression relationship on a high (y = 013x + 6) and low salt intake (y = 032x + 14) differed significantly (P < 00005) Thus, sodium intake reciprocally influences vascular and adrenal responses to A II: salt restriction blunts the vascular response and potentiates the adrenal's, a physiologically important influence in view of aldosterone's role in sodium conservation

https://dm5migu4zj3pb.cloudfront.net/manuscripts/107000/107748/JCI74107748.pdf

Reciprocal Influence of Salt Intake on Adrenal Glomerulosa and Renal Vascular Responses to Angiotensin II in Normal Man

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.

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

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 0.02, 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.

Intrarenal role of angiotensin II. Homeostatic regulation of renal blood flow in the dog.

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.

https://science.sciencemag.org/content/sci/179/4076/906.full.pdf

Angiotensin. II. Important role in the maintenance of arterial blood pressure.

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 ...

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

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.

J. Alan Johnson

Papers

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

Intrarenal role of angiotensin II. Homeostatic regulation of renal blood flow in the dog.

Angiotensin. II. Important role in the maintenance of arterial blood pressure.

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

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