THE NUTRITIONAL REQUIREMENTS FOR NITROGEN BALANCE IN SURGICAL PATIENTS DURING THE EARLY POSTOPERATIVE PERIOD.
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Journal Article↗
Biomedical subjects
J Boger
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Novel renin inhibitors containing the amino acid statine.
The proteolytic enzyme renin (EC3.4.99.19) cleaves the protein substrate angiotensinogen to yield angiotensin I, the decapeptide substrate transformed by converting enzyme into the pressor substance angiotensin II. Although the contribution of this pathway to the maintenance of normal blood pressure is unclear, it seems to be a major factor in various hypertensive states. Important progress in the control of hypertension has been achieved by development of the potent inhibitors SQ-14,225 (captopril) and MK-421 (enalapril maleate), which block the generation of angiotensin II by the inhibition of angiotensin converting enzyme. An attractive alternative to the inhibition of converting enzyme would be the blockade of the preceding step in the cascade, the renin reaction. We report here new highly potent (IC50 = 10(-9)-10(-8) M) competitive inhibitors of renin in which statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, is incorporated into analogues of the pig renin substrate (Fig. 1).
Amino Acid Sequence↗
Statine-containing renin inhibitor. Dissociation of blood pressure lowering and renin inhibition in sodium-deficient dogs.
Iva-His-Pro-Phe-His-Sta-Leu-Phe-NH2 is a new, potent, specific statine -containing renin inhibitor. In vitro, the ID50 needed to inhibit both dog and human plasma renin is approximately 10(-8)M. Injections into anesthetized rats receiving a continuous intravenous infusion of hog renin revealed a dose-related lowering of mean arterial blood pressure (MAP) with an ID50 of 0.04 mg/kg. In conscious Na-deficient dogs, infusion of the inhibitor for 48 hours resulted in a sustained lowering of MAP and suppression of plasma renin activity (PRA). To study the relationship between MAP lowering and inhibition of PRA, conscious Na-deficient dogs received continuous intravenous infusions for 1 to 3 hours. At doses of 20, 40, and 160 micrograms/kg X min, MAP was reduced 9 +/- 3, 15 +/- 0, and 22 +/- 4 mm Hg. No dose-related response was observed for PRA, which decreased from 7.8 +/- 0.9 to 0.4 +/- 0.3, 0.1 +/- 0.1, and 0.4 +/- 0.2 ng angiotensin I/ml X hr, respectively. Further studies using much-reduced infusion rates revealed a dose-related inhibition of PRA but not MAP. Doses of 0.1, 0.2, and 1.0 micrograms/kg X min inhibited PRA, 34% +/- 1%, 52% +/- 3%, and 82% +/- 4% while MAP decreased, 3 +/- 1, 4 +/- 1, and 2 +/- 1 mm Hg, respectively. These data reveal the potent blood-pressure-lowering effects of this new renin inhibitor and suggest that there may not be a direct relationship between inhibition of circulating renin and blood pressure lowering in Na-deficient dogs.
Animals↗
Comparison of renin and converting enzyme inhibition in sodium-deficient dogs.
While renin is a highly specific protease, converting enzyme has at least two principal substrates, angiotensin I and bradykinin. Changes in the rate of formation of angiotensin II or degradation of bradykinin can influence the hypotensive action of angiotensin converting enzyme inhibitors. The present study was designed to determine if there were differences in the maximal blood pressure reduction in Na-deficient dogs after angiotensin converting enzyme or renin inhibitor treatment. Five conscious dogs received 0.1, 0.5, and 1.0 mg/kg of i.v. enalaprilat, a potent angiotensin converting enzyme inhibitor, which reduced blood pressure to 75 +/- 4, 71 +/- 5, and 71 +/- 5 mm Hg. Plasma immunoreactive angiotensin II levels were reduced in a dose-related fashion to 35% of control level at the highest dose. Infusion of a maximally effective dose of a statine-containing renin inhibitor (SCRIP) with the high dose of enalaprilat produced no further fall in blood pressure (68 +/- 7 mm Hg), but immunoreactive angiotensin II levels fell to essentially zero in four of five dogs. The order of drug administration was reversed in another experiment in a group of nine dogs in which SCRIP reduced plasma immunoreactive angiotensin II to 25% of control at 0.04 mg/kg/minute (n = 5), with reduction to near zero levels at higher doses. Maximal blood pressure reduction was achieved at 0.32 to 0.64 mg/kg/minute (76 +/- 4 mm Hg); 1 mg/kg of enalaprilat lowered blood pressure an additional 11 +/- 2 mm Hg (p less than 0.01) while not further decreasing immunoreactive angiotensin II levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acids↗