1. The effects of combined inhibition of
neutral endopeptidase 24.11 and
angiotensin-converting enzyme, with the dual
metallopeptidase inhibitor,
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
peptides were studied in conscious Long Evans rats (350-450 g: n = 9) chronically instrumented for the assessment of regional haemodynamics. 2. The experiments ran over 4 consecutive days. On the first 2 days the animals received the vehicle for
MDL 100,240, and were given bolus i.v.
injections 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 pmol 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 order as before, but in the presence of
MDL 100,240. 3. Thirty minutes after onset of administration of vehicle, on the first or second experimental day, there were no consistent cardiovascular changes. However, at the same time following onset of
MDL 100,240 administration on the third experimental day, there was a significant, but slight, reduction in mean arterial blood pressure (MAP; -5 +/- 2 mmHg) together with
tachycardia (41 +/- 12 beats min-1) and increases in renal and mesenteric flows (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 administration of the
drug on that day, but otherwise the pattern of response to
MDL 100,240 was similar to that on the previous day. 4. In the presence 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, AII caused effects similar to those of AI.
MDL 100,240 did not affect the pressor, bradycardic or hindquarters
vasoconstrictor effects of AII. However, in the presence of
MDL 100,240, the overall renal and mesenteric
vasoconstrictor effects of AII were enhanced, probably because of the renal and mesenteric vasodilatation caused by
MDL 100,240. 6. In the presence of vehicle, BK had a slight pressor effect, accompanied by
tachycardia and transient increases in conductances in renal, mesenteric and hindquarters vascular beds. In the presence of
MDL 100,240 BK caused marked
hypotension, but an attenuated
tachycardia; renal, mesenteric and hindquarters
vasodilator responses were enhanced. 7. In the presence of vehicle,
ANP caused slight
hypotension and
tachycardia, together with reductions in renal and mesenteric vascular conductances, and transient increases in hindquarters conductance.
MDL 100,240 enhanced the hypotensive effect of
ANP and promoted a delayed hindquarters vasoconstriction. 8. Big ET-1, in the presence of vehicle, caused a marked and prolonged increase in MAP, accompanied by
bradycardia and reductions in renal, mesenteric and hindquarters vascular conductances. Although
MDL 100,240 significantly attenuated the magnitude of the pressor effect of big ET-1, its bradycardic and renal, mesenteric and hindquarters haemodynamic actions were not reduced significantly. 9. In the presence of vehicle, ET-1 caused an initial
hypotension,
tachycardia and vasodilatation in the hindquarters, but reductions in renal and mesenteric 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 hindquarters haemodynamic effects of ET-1. Moreover the subsequent pressor and bradycardic actions of ET-1 were unchanged, but its renal and mesenteric
vasoconstrictor effects were enhanced, possibly because of the dilatation