M. Kahonen et al., ANGIOTENSIN-CONVERTING ENZYME-INHIBITION ATTENUATES ARTERIAL CONSTRICTOR RESPONSES IN EXPERIMENTAL-HYPERTENSION, The Journal of pharmacology and experimental therapeutics, 277(3), 1996, pp. 1701-1709
Angiotensin-converting enzyme inhibition has been shown to attenuate a
rterial contractions, but the underlying mechanisms have not been clar
ified in detail. Therefore, we investigated the effects of 10-week-lon
g quinapril therapy (10 mg kg(-1) day(-1)) on responses of mesenteric
arterial rings in vitro in spontaneously hypertensive rats (SHR) and n
ormotensive Wistar-Kyoto rats. The hypertrophy of cardiac muscle and m
esenteric arterial smooth muscle was effectively reduced in SHR by qui
napril treatment. Maximal contractile force generation to 5-hydroxytry
ptamine was reduced in endothelium-intact and -denuded rings of quinap
ril-treated SHR when compared with untreated SHR. Contractile sensitiv
ity of endothelium-intact rings to 5-hydroxytryptamine was also attenu
ated in SHR by quinapril, whereas no differences were found between th
e study groups in sensitivity of endothelium-denuded rings. Inhibition
of NO synthesis by N-G-nitro-L-arginine methyl ester increased the se
nsitivity and contractile force generation of endothelium-intact rings
to 5-hydroxytryptamine more effectively in quinapril treated than in
untreated SHR, whereas indomethacin had only minor effects on the resp
onses in the study groups. Maximal responses and sensitivity to norepi
nephrine were also reduced in SHR by quinapril and were more effective
ly increased by N-G-nitro-L-arginine in quinapril-treated than in untr
eated SHR. In addition, KCl-induced maximal contractions of endotheliu
m-denuded rings were attenuated in quinapril-treated SHR. However, whe
n the release of norepinephrine from vascular adrenergic nerve endings
was eliminated by sympathectomy, no differences were found in maximal
KCl-induced contractions between the study groups; this suggests that
diminished contractions to KCl in quinapril-treated SHR resulted from
reduced release of endogenous norepinephrine from vascular nerve endi
ngs during depolarization. The inhibitory effects of the calcium chann
el blocker nifedipine on arterial contractions in the Wistar-Kyoto rat
groups and the quinapril-treated SHR were similar and were lower than
in untreated SHR. In conclusion, the present findings suggest that ef
fective reversal of cardiovascular hypertrophy, normalization of the f
unction of voltage-dependent calcium channels, sympathoinhibitory acti
on and enhanced endothelium-derived NO release can explain the attenua
ted arterial constrictor responses that occur after the long-term inhi
bition of angiotensin-converting enzyme.