Antihypertensive effect of MK-421 in rats. Role of the renal kallikrein-kinin system.
To study the hypotensive mechanism of the new oral converting-enzyme inhibitor, MK-421, we evaluated the antihypertensive effect of MK-421 in rats with hypertension induced by chronic administration of norepinephrine (NE) or vasopressin and measured urinary kallikrein and kinin excretions as indices of the renal kallikrein-kinin system. When 6 mg/kg/day of MK-421 was administered simultaneously with 1.8 mg/kg/day of NE, the systolic blood pressure of conscious rats rose on Day 1 to only 122.6 +/- 3.4 mm Hg compared with the rise to 146.3 +/- 1.6 mm Hg when NE alone was infused (p less than 0.001). Similarly, when the same dose of MK-421 was administered simultaneously with 7.2 U/kg/day of vasopressin, the systolic blood pressure of conscious rats rose on Day 1 to only 117.4 +/- 3.8 mm Hg compared with the rise to 141.6 +/- 3.4 mm Hg when vasopressin alone was infused (p less than 0.01). The antihypertensive effect of MK-421 was sustained for 6 days in rats infused with NE or vasopressin. Infusion of NE alone resulted in a small but significant increase in urinary kallikrein excretion and no change in urinary kinin excretion. The combined administration of NE with MK-421 induced additional increases in urinary kallikrein and kinin excretions. Vasopressin alone resulted in marked decreases in urinary kallikrein and kinin excretions. The combined administration of vasopressin with MK-421 induced no additional changes in urinary kallikrein and kinin excretion. These results indicate that the hypotensive effect of MK-421 may depend on a reduced sensitivity of the peripheral arteries to vasoconstrictor substances.(ABSTRACT TRUNCATED AT 250 WORDS)
D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D004656:Enalapril; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy*; D007610:Kallikreins / Q000652:urine*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007705:Kinins / Q000652:urine*; D008297:Male; D009638:Norepinephrine; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014667:Vasopressins
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004151:Dipeptides; D007705:Kinins; D014667:Vasopressins; D004656:Enalapril; D007610:Kallikreins; D009638:Norepinephrine