Vasodilator mechanisms and the intracellular control of renin secretion

The renin angiotensin system forms an integral part of the regulation of blood pressure and fluid balance. Secretion of renin is under the control of stimulatory and inhibitory influences. In vitro preparations available to study the intracellular control of renin secretion retain intact nerve endings and fragments of tubule and blood vessel. These will indirectly influence renin release, and make interpretation of results difficult. While previous studies have implicated a stimulatory role for intracellular cyclic adenosine monophosphate (cAMP) and an inhibitory role for intracellular calcium (Ca2+) in renin secretion, the role of cyclic guanosine monophosphate (cGMP) remains unresolved. The experiments described in this thesis set out to evaluate the use of a recently developed superfused disaggregated rat renal cortical cell preparation which is free from haemodynamic and tubular influences. Sensitivity to stimulation by catecholamines was found to be high. The prepartion was consequently used to investigate the roles of cGMP and guanine nucleotide regulatory protein (G-proteins) in the control of renin release. Manipulations to elevate cellular levels of cGMP using nitrovasodilators, atrial natriuretic peptide, a cGMP phosphodeiesterase inhibitor and a cGMP analogue, all stimulated renin release. In the higher concentration range, responses were diminished. Decreasing cellular cGMP using methylene blue or LY83583 decreased basal and, in some cases, agonist-stimulated renin release. The data suggest that cGMP is a stimulatory second messenger for renin release. Activation of G-proteins using sodium fluoride (NaF) stimulated renin release in the low concentration range and inhibited renin release at the highest concentration used (10-2mol/l). NaF potentiated the response to isoprenaline. The results suggest involvement of a G-protein in renin secretion. In other experiments, the vasodilator drug cromakalim, a potassium channel activator, increased plasma renin levels in both anaesthetised rats and conscious chronically cannulated sheep. This drug also stimulated renin release in vitro. The data suggest that the renin response to cromakalim in vivo is mediated, in part, by activation of renal juxtaglomerular cells and partly by reflex sympathetic control. The main hypothesis put forward in this thesis is that cGMP is a stimulatory intracellular messenger for renin secretion. This is consistent with the notion that dilators of vascular smooth muscle also stimulate renin secretion.