Possible Role of Renin in Hypertension as Suggested by Renin-Sodium Profiling and Inhibition of Converting Enzyme

Abstract

To block renin activity, a nonapeptide converting-enzyme inhibitor was given to 65 seated hypertensive patients. Depressor responses occurred only when control plasma renin activity exceeded 2 ng of angiotensin I per milliliter per hour and correlated directly in amplitude with control plasma renin activity and with induced increments in activity (P less than 0.001 for both). Depressor responses, like renin activity, were characteristic for renin subgroups as defined by renin-sodium profiling. Before and after sodium deprivation, the nonapeptide reduced diastolic pressure in all patients with high renin (by 17.3 and 19.8 per cent) and most patients with normal renin (by 9.1 and 17.7 per cent). Low-renin patients remained unresponsive. This enzyme blockade may cause bradykinin accumulation. But if, as seems likely, depressor responses are due to blockade of angiotensin II formation, the results indicate that, irrespective of sodium balance, measurements of plasma renin activity reflect its contribution to blood-pressure maintenance. The results suggest broad participation of the renin system in common forms of hypertension.

Effectiveness and metabolic effects of perindopril and diuretics combination in primary hypertension

“…15 In agreement with previously published data the drug's antihypertensive efficacy was related to the renin-angiotensin axis activation; that is, the BP fall was well correlated to the pretreatment PRA. 16,17 However, a considerable proportion of hypertensive patients exhibit an inadequate response to monotherapy with ACE inhibitors, as was the case in our patients. 3,18 In such cases, the addition of a diuretic to a standard dose of ACE inhibitor gives a better response than increasing the dose of ACE inhibitor.…”

Racing To Invest? The Dynamics of Competition in Ethical Drug Discovery

“…Although this peptide was synthesized by Ondetti and his colleagues (Ordetti et al, 1971), there continued to be widespread doubt as to its therapeutic potential, and despite a sequence of papers exploring its role in the treatment of hypertension (Gavras et al, 1974;Case et al, 1976Case et al, , 1977, there was little general interest in exploiting the discovery commercially. It was not until Cushman and Ondetti published their achievement in synthesizing an orally active enzyme inhibitor that research in the field took on something of the characteristics of the race, with several pharmaceutical companies attempting to synthesize compounds with similar properties .…”

Reversal of renovascular hypertension by antibodies specific for angiotensin-converting enzyme.

“…A pentapeptide (10) and a nonapeptide (11) were particularly potent inhibitors of the isolated enzyme (27), and though their duration of action was short, they were highly effective in suppressing the vasopressor response to angiotensin I, in potentiating the vasodepressor effect of bradykinin, and in reversing renin-dependent hypertension in animal models (13)(14)(15)(16). The nonapeptide (SQ 20881) was shown to diminish the vasopressor response to angiotensin I in normotensive humans (35), and clinical investigations with it originally suggested that converting enzyme blockade might prove beneficial in most human hypertensive disease (18). The recent remarkable development of an apparently specific and highly potent, orally effective inhibitor (12,17) has provided the necessary chemical agent to determine whether long-term blockade will be similarly effective.…”

“…The enzyme is a glycoprotein (5,6) that is localized on the luminal surface of vascular endothelial cells in anatomic juxtaposition to the circulation (7)(8)(9). Specific chemical inhibitors of its activity (10)(11)(12) can reverse experimental renovascular hypertension (13)(14)(15)(16)(17) and can reduce blood pressure in a substantial fraction of human hypertensive disease (18,19). These considerations suggest that converting enzyme provides an unusual opportunity for exploring the possibility that the activity of an enzyme can be inhibited by specific anticatalytic antibody in vivo and that a pathologic process can thus be immunologically controlled.…”