I. Porsti et al., DUAL-ACTION OF ANGIOTENSIN-II ON CORONARY RESISTANCE IN THE ISOLATED-PERFUSED RABBIT HEART, Naunyn-Schmiedeberg's archives of pharmacology, 348(6), 1993, pp. 650-658
We studied the functional role of angiotensin II (AII) receptor subtyp
es and vasodilatory endothelial autacoid release in response to AII in
isolated perfused rabbit hearts. AII infusion induced biphasic change
s in coronary perfusion pressure (CPP): an initial increase was follow
ed by a decrease until a plateau was reached. At higher concentrations
of AII (greater-than-or-equal-to 10 nmol/1) this plateau phase was lo
wer than the initial CPP level. AII infusion elicited inverse changes
in peak left ventricular pressure (LVP): coronary constriction was ass
ociated with a transient decline, and during the plateau phase LVP was
clearly increased. AII also moderately augmented prostacyclin (PGI2)
release from the coronary vascular bed. The AII-induced changes in CPP
, LVP, and PGI2 release were effectively inhibited by the AT1 receptor
subtype antagonist ICI D8731 (30 nmol/1), but not by the AT2 receptor
antagonist CGP 42112 (30 nmol/1). The adenosine A1 receptor antagonis
t 8-phenyltheophylline (0.1 mumol/l) attenuated the decline in CPP fol
lowing the constriction phase without affecting the changes in LVP dur
ing AII infusion. The cyclooxygenase inhibitor diclofenac (I mmol/1) h
ad no effect on the AII-induced changes in CPP, whereas the nitric oxi
de-synthase inhibitor N(G)-nitro-L-arginine (30 mumol/1) markedly pote
ntiated the vasoconstriction but was without effect on the plateau pha
se of the response. In contrast to AII, the thromboxane analogue U4661
9 elicited sustained increases in CPP which were associated with sligh
t decreases in LVP. In conclusion, AII induced a biphasic pressor resp
onse in the rabbit coronary vascular bed consisting of a transient vas
oconstriction followed by a dilatation especially at higher concentrat
ions of AII, an effect which was independent of the endothelial autaco
ids nitric oxide and PGI2. The AII-induced dilatation probably reflect
ed rapid desensitization of the coronary arterial smooth muscle to the
constrictor effect, and the concomitant accumulation of vasodilatory
metabolites such as adenosine, generated during the positive inotropic
action of AII. All the effects of AII in the rabbit heart appeared to
be mediated via the AT, receptor subtype localized on coronary endoth
elial and smooth muscle cells, as well as on cardiomyocytes.