Mechanism of the pressor response to tetradecapeptide renin substrate in the rat.
The synthetic tetradecapeptide renin substrate (TDP; Asp-arg-val-tyr-ile-his-pro-phe-his-leu-leu-val-tyr-ser) has been employed frequently to elucidate the enzymatic action of renin in vitro and, to a lesser extent, in vivo. We assessed the utility of TDP as a renin substrate in vivo using conscious spontaneously hypertensive rats. Intravenous injection of TDP (1 and 3 micrograms/kg) increased diastolic pressure by 45 +r2 and 67 +/- 2 mmHg, respectively. The pressor response to TDP was significantly inhibited by captopril (3 mg/kg, po), indicating its dependence on conversion by ACE to some active molecule. Pressor responses to TDP also were less in animals subjected to bilateral nephrectomy 18-24 hr before study. However, responses to angiotensin I and II also were reduced, implying a non-specific effect of nephrectomy. Intravenous infusion of the renin inhibitor pepstatin (200 micrograms/min) inhibited pressor responses to hog renin by approximately 60%, but did not affect those to TDP. Intravenous infusion of the water soluble renin inhibitor, pepstatinyl-arginine-o-methyl ester (500 micrograms/min), also inhibited pressor responses to renin (approx. 80%) and did not affect those of TDP. Incubation to TDP (5 microM) with rabbit lung ACE resulted in generation of AI that was blocked by captopril (1 microM). These data suggest that TDP is a substrate for ACE and that the increase in blood pressure produced by TDP is due to its sequential cleavage by ACE to AII and can be independent of renin.
D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002216:Captopril / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D009392:Nephrectomy; D010436:Pepstatins / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000494:pharmacology; D000092502:Renin Inhibitors
D000803:Angiotensin I; D000804:Angiotensin II; D000806:Angiotensin-Converting Enzyme Inhibitors; D002216:Captopril; D010436:Pepstatins; D010455:Peptides; D010656:Phenylephrine; D012083:Renin; D000092502:Renin Inhibitors