Sm. Gardiner et al., EFFECTS OF THE DUAL METALLOPEPTIDASE INHIBITOR, MDL-100,240, ON REGIONAL HEMODYNAMIC-RESPONSES TO VASOACTIVE PEPTIDES IN CONSCIOUS RATS, British Journal of Pharmacology, 122(8), 1997, pp. 1687-1693
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.