EFFECTS OF THE DUAL METALLOPEPTIDASE INHIBITOR, MDL-100,240, ON REGIONAL HEMODYNAMIC-RESPONSES TO VASOACTIVE PEPTIDES IN CONSCIOUS RATS

1 The effects of combined inhibition of neutral endopeptidase 24.11 an d angiotensin-converting enzyme, with the dual metallopeptidase inhibi tor, MDL 100,240 (3 mg kg(-1) bolus, 3 mg kg(-1), h(-1) infusion), on baseline haemodynamics and on responses to a variety of vasoactive pep tides were studied in conscious Long Evans rats (350-450 g: n=9) chron ically instrumented for the assessment of regional haemodynamics. 2 Th e experiments ran over 4 consecutive days. On the first 2 days the ani mals received the vehicle for MDL 100,240, and were given bolus i.v. i njections of angiotensin I (AI; 250 pmol kg(-1)), angiotensin II (AII; 125 pmol kg(-1)), bradykinin (BK: 3 nmol kg(-1)) and endothelin-1 (ET -1; 250 pmol kg(-1)) on one day and AI (as above), atrial natriuretic peptide (ANP: 500 pmol kg(-1)) and big endothelin-1 (big ET-1; 500 pmo l kg(-1)) on the other day in a random manner. On the third and fourth experimental days the vasoactive peptides were given in the same orde r as before, but in the presence of MDL 100,240. 3 Thirty minutes afte r onset of administration of vehicle, on the first or second experimen tal day, there were no consistent cardiovascular changes. However, at the same time following onset of MDL 100,240 administration on the thi rd experimental day, there was a significant, but slight, reduction in mean arterial blood pressure (MAP; -5+/-2 mmHg) together with tachyca rdia (41+/-12 beats min(-1)) and increases in renal and mesenteric flo ws (17+/-3 and 13+/-4, respectively) and vascular conductances (23+/-4 and 19+/-5%, respectively). The mesenteric vasodilator effect of MDL 100,240 was still present on the fourth experimental day before admini stration of the drug on that day, but otherwise the pattern of respons e to MDL 100,240 was similar to that on the previous day. 4 In the pre sence of vehicle, AI caused hypertension, bradycardia, and reductions in renal mesenteric and hindquarters vascular conductances; all these effects were abolished by MDL 100,240. 5 In the presence of vehicle, A II caused effects similar to those of AI. MDL 100,240 did not affect t he pressor, bradycardic or hindquarters vasoconstrictor effects of AII . However, in the presence of MDL 100,240, the overall renal and mesen teric vasoconstrictor effects of AII were enhanced, probably because o f the renal and mesenteric vasodilatation caused by MDL 100,240. 6 In the presence of vehicle, BK had a slight presser effect, accompanied b y tachycardia and transient increases in conductances in renal, mesent eric and hindquarters vascular beds. In the presence of MDL 100,240 BK caused marked hypotension, but an attenuated tachycardia; renal, mese nteric and hindquarters vasodilator responses were enhanced. 7 In the presence of vehicle, ANP caused slight hypotension and tachycardia, to gether with reductions in renal and mesenteric vascular conductances, and transient increases in hindquarters conductance. MDL 100,240 enhan ced the hypotensive effect of ANP and promoted a delayed hindquarters vasoconstriction. 8 Big ET-1, in the presence of vehicle, caused a mar ked and prolonged increase in MAP, accompanied by bradycardia and sedu ctions in renal, mesenteric and hindquarters vascular conductances. Al though MDL 100,240 significantly attenuated the magnitude of the press er effect of big ET-1, its bradycardic and renal, mesenteric and hindq uarters haemodynamic actions were not reduced significantly. 9 In the presence of vehicle, ET-1 caused an initial hypotension, tachycardia a nd vasodilatation in the hindquarters, but reductions in renal and mes enteric vascular conductances; thereafter there was a rise in MAP and bradycardia with vasoconstriction in all three vascular beds. MDL 100, 240 had no effect on the initial hypotensive, tachycardic or hindquart ers haemodynamic effects of ET-1. Moreover the subsequent presser and bradycardic actions of ET-1 were unchanged, but its renal and mesenter ic vasoconstrictor effects were enhanced, possibly because of the dila tation caused by MDL 100,240 in these vascular beds. 10 Overall, the r esults are consistent with MDL 100,240 exerting important haemodynamic actions in conscious rats through inhibition of angiotensin-convertin g enzyme and neutral endopeptidase.