Search

The role of cGMP as a second messenger for renin secretion is contentious. This was investigated using a superfused collagenase-dispersed rat kidney cortex cell preparation devoid of indirect influences on renin secretion. Nitroprusside, atriopeptin II and 8-Br-cGMP all increased renin release but the dose-response relationships were biphasic. At low dose ranges there was a positive correlation between increasing drug concentration and renin secretion, but at high drug concentrations, a negative correlation was apparent. Methylene blue, a guanylate cyclase inhibitor, also suppressed baseline renin release at 10(-5) and 10(-6) M, but stimulated release at 10(-3) M. Using mid-range drug concentrations, the cGMP specific phosphodiesterase inhibitor MB22948 potentiated renin release in response to nitroprusside and 8-Br-cGMP. Inhibition of guanylate cyclase with either methylene blue or LY83583 attenuated renin release in response to nitroprusside, but, as expected, had no effect on 8-Br-cGMP induced release. We conclude that, under physiological conditions, cGMP is a stimulatory second messenger for renin release. This activity is mimicked at low dose ranges by 8-Br-cGMP, nitroprusside and atriopeptin II. In response to high doses of these drugs an unknown inhibitory pathway is activated and this opposes, in a dose-related manner, the stimulatory actions of cGMP for renin release.

The renin-angiotensin-aldosterone system (RAAS) plays an important role in cardiovascular and electrolyte regulation in health and disease. Juxtaglomerular cells in the kidney regulate endocrine RAAS by physiologically controlling conversion of prorenin and secretion of renin. The classical baroceptor, neurogenic, and macula densa mechanisms regulate renin expression at the cellular level by Ca2+, adenosine 3',5'-cyclic monophosphate (cAMP), and chemiosmotic forces (K+, Cl-, and water flux coupled to H+ movement). The baroceptor mechanism (through Ca2+) activates K+ and Cl- channels in the surface membrane and deactivates a KCl-H+ exchange chemiosmotic transporter in the secretory granular membrane. The neurogenic mechanism (through cAMP) promotes prorenin processing to renin. The macula densa mechanism (through K+ and Cl-) involves the processing of prorenin to renin. Ca2+, by inhibiting the KCl-H+ exchange transporter, prevents secretory granules from engaging in chemiosmotically mediated exocytosis. cAMP, on the other hand, by stimulating H+ influx, provides the acidic granular environment for prorenin processing to renin. It is concluded that, in the presence of a favorable chemiosmotic environment, prorenin is processed to renin, which may then be secreted by regulative degranulation or divergence translocation, a novel secretory pathway used by several secretory proteins, including renin.

Recent experimental evidence has provided important clues as to the role of electrolytes, particularly Ca, in the regulation of blood flow, renin secretion, and blood pressure. The smooth muscle cells of arterioles in general and the juxtaglomerular cells in the renal afferent arterioles have been shown to have Ca channels sensitive to voltage, hormones, and stretch. This paper reviews a model that utilizes these features along with a fundamental law of physics to point to some plausible explanations for some interesting experimental observations on renal blood flow, renin secretion, and hypertension. The chief features of the model are that in the steady state the arteriole must achieve a stable physical equilibrium in which the forces tending to distend the vessel (transmural pressure) counterbalance the forces tending to prevent distension (wall tension); the wall tension consists of a passive and an active component, the latter of which is sensitive to stretch of the vessel; and stretch activates the opening of stretch-sensitive Ca permeability channels that promote the influx of Ca to trigger active tension development. Thus Ca is the signal that couples stretch to contraction. This latter feature is the so-called myogenic response. Altered equilibrium may be initiated either by a rise in perfusion or tissue pressure to alter the distending force or by a rise in cytosolic Ca to increase active tension development and the constricting force. Several factors may initiate disequilibrium, some of which are discussed. Equilibrium is soon reestablished, however, at a new steady state. The model predicts curves for renal blood flow autoregulation and renin secretion in response to changes in renal perfusion pressure, tissue pressure, extracellular Ca, and blockers and promoters of Ca influx and Ca efflux. These predictions agree well with existing experimental evidence and suggest new experiments. The model provides a theoretical basis for explaining the steady-state blood pressure profile observed in renovascular hypertension and perhaps in other forms of hypertension as well. The model also provides a theoretical basis for understanding the volume-vasoconstriction approach used by some workers and the autoregulation approach used by others in explaining the mechanisms of hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)

Trifluoperazine, an inhibitor of calmodulin and calmodulin-directed secretion, was used to examine a possible role of calmodulin in renin secretion from isolated perfused kidneys and renal cortical cells. In isolated perfused kidneys trifluoperazine stimulated basal renin secretion in a dose-dependent manner, with 10 microM causing no stimulation and 50 microM causing 167% increase. Trifluoperazine potentiated the elevated renin secretion induced by isoprenaline and low Ca in isolated kidneys. In renal cortical cells trifluoperazine increased basal renin secretion and potentiated the secretion induced by Ca omission. Cells homogenized immediately after 1 h exposure to trifluoperazine had a substantial reduction in soluble renin without any effect on the change in granular renin. In the absence of trifluoperazine, soluble renin increased with O Ca and decreased with 1.5 mM-Ca. It is concluded that trifluoperazine stimulates renin secretion by a cellular mechanism possibly at the level of the juxtaglomerular cell. It is suggested that the role of trifluoperazine, and by inference calmodulin, in the secretion of renin may be quite different from its role in secretion of several other substances.

Regulation of plasma levels of active and inactive renin was investigated using sheep with indwelling artery, vein and bladder catheters. Control and experimental studies were carried out in the same animals on different days. Volume depletion during any single experiment was limited to a maximum of 50 ml. Despite large changes in sodium and water excretion, the diuretic furosemide at two dose levels, 1 and 10 mg/kg, failed to alter plasma levels of either active or inactive renin in conscious sheep. Induction of pentobarbitone anaesthesia in the sheep did not, per se, alter either plasma active or inactive renin. Furosemide (10 mg/kg) in anaesthetized animals produced a similar diuresis and natriuresis response to conscious sheep, but plasma active renin increased by 270% and inactive renin decreased to zero. In conscious sheep given an infusion of papaverine, furosemide also produced an increase in plasma active renin and a concurrent decrease in the inactive form. In both anaesthetized animals and in conscious sheep infused with papaverine, furosemide-induced intrarenal vasodilation, as evidenced by changes in clearance of p-aminohippuric acid, was much reduced in comparison to the conscious animals. This may be significant in relation to the control of renin secretion. It appears that the macula densa sodium receptor, which is considered to regulate renin release, will only function after it has been primed by other intra- or extrarenal factors. This is discussed, particularly in relation to the possible role played by the prostaglandin system.

Renin secretion from the juxtaglomerular cell is controlled by numerous receptors, humoral agents, and ions. Recently, a stretch receptor hypothesis has been advanced to suggest that all of these diverse factors control renin secretion by a mechanism initiated by a fall in cytoplasmic Ca2+. This fall in Ca2+ may be achieved by lowering Ca2+ influx, raising Ca2+ efflux, or sequestering Ca2+ into cellular organelles and binding sites. The increased renin secretion observed with low arterial pressure, beta-adrenergic agonists, parathyroid hormone, glucagon, cyclic AMP, prostaglandins, low Ca2+ and Ca2+ ionophore, high Mg2+, and Na+ and Cl- may be explained in this context. On the other hand, the decreased renin secretion observed with high pressure, alpha-adrenergic agonists, some prostaglandins, angiotensin, vasopressin, and high K+ may be explained by a rise in cytoplasmic Ca2+ mediated by an opposite sequence of events. Recent observations suggest that the fall in cytoplasmic Ca2+ sets in motion the transport of renin from its site of storage (granules) or synthesis into the cytoplasmic space and finally across the plasma membrane. Thus although renin is stored in granules, its secretion occurs by a process quite different from exocytosis.

This paper presents a model of myogenic control of renal blood flow based on the proposition that steady-state flow occurs when the distending and constricting forces acting on the afferent arteriole are equal. The distending force is represented by the Laplace relationship. The opposing force is governed by the properties of the arterioles and has two components--a purely passive component and an "active" component resulting from vascular smooth muscle contraction. Within the myogenic model, vascular smooth muscle contraction is initiated by "stretch"-induced changes in calcium permeability. Terms are developed describing the effect of stretch on calcium permeability, intracellular calcium, and contractile activity. The model is adapted to describe the myogenic control of blood flow in the dog kidney. Sigmoidal relationships between stretch and calcium permeability and between intracellular calcium and muscle tension seem to account for the shape of the autoregulatory curve. The model predicts a shifting of the autoregulatory pressure-flow curve upward and to the right in response to increased tissue hydrostatic pressure. The model is also exquisitely sensitive to changes in the parameters governing intracellular calcium. These predictions agree well with experimental observations.

1. An inactive form of renin exists in rabbit plasma. This can be activated, and therefore measured, after acidification (pH 2.8). 2. The effect of frusemide diuresis, with replacement of volume losses, on plasma levels of active and inactive renin was studied over a 3 1/2 h time course. Plasma active renin increased during frusemide diuresis but inactive renin disappeared from the circulation. The time courses for the changes in the two forms of renin were similar. 3. The peak of the frusemide-induced changes in renal function (urine flow, sodium and potassium excretion and creatinine clearance) preceded the maximum changes in the two forms of renin by 90 min. 4. The response of plasma levels of inactive renin to physiological stimuli depends on the nature of the stimulus, as well as its duration. Some form of sodium-sensitive mechanism may control the activation of inactive renin.