Effect of central administration of MK-422 (the diacid form of enalapril) on the development of hypertension in the spontaneously hypertensive rat.
Intracerebroventricular (i.c.v.) administration of captopril attenuates the development of hypertension in spontaneously hypertensive rats (SHR). To determine whether these effects are related to inhibition of angiotensin-converting enzyme we assessed the effects of chronic i.c.v. administration of MK-422 (a converting enzyme inhibitor chemically unrelated to captopril) on arterial pressure and vascular reactivity in young (seven-week-old) male SHR. MK-422 (0.2 or 1.0 microgram/h, osmotic mini pump) was infused into the lateral ventrical for 4 weeks. Control SHR received artificial CSF i.c.v., or 0.2 microgram/h MK-422 i.v. Vascular reactivity to phenylephrine, vasopressin and direct sympathetic nerve stimulation was assessed in renal and mesenteric vascular beds using miniaturized pulsed Doppler flow probes. MK-422 attenuated the development of hypertension. Arterial pressure at 4 weeks of treatment was: SHR-i.c.v. MK-422 (0.1 microgram/h): 137 +/- 3.4; (1.0 microgram/h): 138 +/- 2.9; SHR i.v. MK-422 176 +/- 4.5 and SHR control: 168 +/- 4.9 mmHg (P less than 0.01). SHR-i.c.v. MK-422 showed significantly attenuated increases in mesenteric vascular reactivity in response to vasoconstrictors, nerves and sympathetic nervous stimulation. Dose and frequency response curves were characterized by a shift to the right and a significant decrease in the slopes. In conclusion, both captopril and MK-422 prevent the development of hypertension in SHR, presumably by blocking angiotensin-converting enzyme, suggesting that the brain renin-angiotensin system contributes to the pathogenesis of hypertension in that model.
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004558:Electric Stimulation; D004656:Enalapril / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015773:Enalaprilat; D006973:Hypertension / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D011919:Rats, Inbred Strains / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects
D000959:Antihypertensive Agents; D004656:Enalapril; D002216:Captopril; D015773:Enalaprilat