Specific inhibition of the renin-angiotensin system: A key to understanding blood pressure regulation

Abstract The availability of specific inhibitors of the renin-angiotensin system has made it possible to evaluate precisely the contribution of this system to the maintenance of normal blood pressure and of various hypertensive situations encountered in animal models and in man. Furthermore, by combining the blockade of the renin system with accurate measurements of sodium balance, it is possible to expose and quantify latent or manifest abnormalities in renal sodium handling that operate directly or by interacting with the renin system. Experimental and clinical observations made with these inhibitors support the hypothesis that the level of blood pressure, normal or abnormal, is largely determined by two components: (1) the renin system (i.e., the angiotensin II-vasoconstrictor factor) and (2) the sodium extracellular and intravascular volume factor, which in the longer term may be indirectly supported by the renin system via angiotensin-induced aldosterone secretion. Normally, without threat to the homeostasis, the sodium volume component appears to be the main factor determining blood pressure and sustaining renal perfusion via adequate or—if necessary—increased blood pressure. However, whenever renal perfusion is compromised due to such events as hemorrhage, sodium depletion, upright posture, exercise, cardiac failure, cirrhosis, or renal vascular impairment, renin is secreted by the kidney. It seems that the renin-angiotensin system is the main vasoconstrictor system used by the body to support the sodium volume component to maintain or restore adequuate renal perfusion. There is little evidence that the catecholamines and the nervous system play any major or direct role in sustaining blood pressure, although indirectly they may be critically involved in monitoring renal renin release. Two models of renal hypertension have served as the experimental basis for development of this concept. Established two-kidney Goldblatt hypertension (one renal artery clipped, contralateral kidney intact) was found to be renin-dependent, since angiotensin II blockade induced a marked fall in blood pressure. Clinical counterparts to this predominantly “vasoconstrictor” type of hypertension are renovascular hypertension with unilateral renal artery stenosis, malignant and essential hypertension with high renin levels, and possibly normotensive situations with reduced “effective” blood volume such as cirrhosis and congestive heart failure. Chronic one-kidney Goldblatt hypertension (one renal artery clipped, contralateral nephrectomy) under conditions of unrestricted sodium intake appeared on the other hand to be predominantly sodium-volume-dependent, so that angiotensin II blockade did not alter the pressure level. However, sodium (and volume) depletion did not lower the blood pressure either in this model but resulted instead in a compensatory rise of renin release, and thus in a transition from a sodium-volume to vasoconstrictor-maintained type of hypertension. Accordingly, under conditions of sodium depletion, angiotensin II blockade did markedly reduce the blood pressure. Clinical counterparts to this model in which simultaneous sodium depletion plus blockade of the renin system are necessary to reduce blood pressure appear to be most patients with normal renin essential hypertension, chronic renal failure with normal or low renin levels, renovascular hypertension with bilateral renal artery stenoses, and possibly coarctation of the aorta. In contrast to these two model situations, low-renin essential hypertension as well as the hypertension induced by an excess of various mineralocorticoids appears to represent a pure volume type of hypertension, in which a diuretic-induced volume reduction does not result in a compensatory rise in renin release and a shift to vasoconstrictor support but instead results in a parallel reduction of blood pressure.