COMPARATIVE EFFECTS OF THE DUAL METALLOPEPTIDASE INHIBITOR, MDL-100,240 AND OF ENALAPRILAT ON REGIONAL AND ON CARDIAC HEMODYNAMICS IN CONSCIOUS, HYPERTENSIVE, TRANSGENIC ((MREN-2)27) RATS

1 Heterozygous, male, hypertensive, transgenic ((mRen-2)27) rats (350- 450 g) were instrumented for the measurement of regional or cardiac ha emodynamics (n = 16, in both groups). Animals were given continuous i. v. infusions of the angiotensin-converting enzyme inhibitor, enalapril at, or the dual metallopeptidase inhibitor, MDL 100,240 (both at 3 mg kg(-1), 3 mg kg(-1) h(-1); n = 8 for regional and cardiac haemodynamic s), for 32 h. Twenty four hours after the onset of infusion of enalapr ilat or MDL 100,240, the bradykinin (B-2)-receptor antagonist, Hoe 140 (1 mg kg(-1), i.v.), was given and measurements were continued for a further 8 h, to assess any possible involvement of bradykinin. 2 Over the first 8 h of infusion, both enalaprilat and MDL 100,240 had signif icant antihypertensive effects, accompanied by similar regional vasodi latations. However, the blood pressure lowering effect of MDL 100,240 (-54 +/- 9 mmHg) was greater than that of enalaprilat (-38 +/- 4 mmHg) , because the former caused a significantly greater reduction in cardi ac index. 3 Between 8-24 h after the onset of infusion, there was a re duction in the effect of enalaprilat on blood pressure, because cardia c index rose, with no further increase in total peripheral conductance . In contrast, the antihypertensive effect of MDL 100,240 persisted, i n spite of a recovery in cardiac index, because there was further vaso dilatation, particularly in the mesenteric and hindquarters vascular b eds. 4 There were no apparent haemodynamic changes associated with the injection of Hoe 140, and over the following 8 h, the difference betw een the haemodynamic effects of enalaprilat and MDL 100,240 persisted; there was little evidence of suppression of the effects of either dru g. 5 These results are more consistent with the antihypertensive effec ts of enalaprilat or MDL 100,240 in transgenic ((mRen-2)27) rats being due to suppression of angiotensin II production, than due to inhibiti on of bradykinin degradation. The additional effects of MDL 100,240 ma y be accounted for by inhibition of the degradation of natriuretic pep tides reducing cardiac output, initially, and decreasing vascular tone , subsequently. Alternatively, the additional increase in vascular con ductance following treatment with MDL 100,240 may represent an autoreg ulatory response to the reduced pressure.