pepstatin and Hypertension

Although renin was identified as playing a part in cardiovascular homeostasis by the experiments of Goldblatt in the 1930s, neither its physiological role in organs other than the kidney nor its contribution to the genesis of essential hypertension have been defined. It is difficult to interpret studies with converting enzyme inhibitors because of their multiple pharmacological effects. Specific inhibitors of renin appropriate for clinical investigation would help to resolve many questions. Four classes of compounds have been shown to be renin inhibitors of high potency: specific antibody, general peptide inhibitors of acid proteases, analogues of angiotensinogens and peptides that are related to the amino-terminal sequence of prorenin. Of these, it is likely that angiotensinogen analogues will be the first applied in human studies. The minimal substrate for renin has the sequence: His-Pro-Phe-His-Leu-Val-Tyr. Variants of this sequence have yielded competitive inhibitors. Remarkably active compounds have recently been synthesized by reducing the peptide bond that is cleaved by renin, or by incorporating the amino acid statine, found in pepstatin. These compounds have been shown to be effective in dogs, rats and monkeys and, most recently, preliminary studies have reported their efficacy in man. Recent studies with one of these inhibitors, RIP, raise questions concerning both its specificity and site of action.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antibodies, Monoclonal; Antihypertensive Agents; Blood Pressure; Heart Rate; Humans; Hypertension; Oligopeptides; Pepstatins; Renin

The effect of prolonged intracerebroventricular (i.c.v.) infusion of N-acetyl-pepstatin in young and adult spontaneously hypertensive rats was studied. In young animals, pepstatin infusion resulted in a decrease in blood pressure and heart rate. Water intake and body weight were not affected. The depressor effect was accompanied by a slight increase in plasma renin activity and decreases in plasma vasopressin and plasma catecholamines. The blood pressure of adult rats with already established hypertension was not significantly affected. In addition, changes in plasma renin or catecholamines were not observed in these animals while vasopressin levels were slightly increased. The involvement of a possibly decreased sympathetic activity in the depressor effect of pepstatin is suggested. It is concluded that increased brain renin activity contributes to the development of hypertension of spontaneously hypertensive rats.

Topics: Aging; Angiotensin I; Animals; Blood Pressure; Cerebral Ventricles; Heart Rate; Hypertension; Injections, Intraventricular; Kinetics; Male; Oligopeptides; Pepstatins; Rats; Renin; Renin-Angiotensin System; Vasopressins

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antihypertensive Agents; Captopril; Enzyme Activation; Humans; Hypertension; Peptidyl-Dipeptidase A; Renin