M. Kahonen et al., ARTERIAL CONTRACTIONS INDUCED BY CUMULATIVE ADDITION OF CALCIUM IN HYPERTENSIVE AND NORMOTENSIVE RATS - INFLUENCE OF ENDOTHELIUM, Naunyn-Schmiedeberg's archives of pharmacology, 349(6), 1994, pp. 627-636
Responses to cumulative addition of Ca2+ (0.2-2.5 mM) after precontrac
tion with potassium chloride (KCl) and noradrenaline in Ca2+-free medi
um were studied in isolated mesenteric arterial rings from spontaneous
ly hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The Ca2+ contr
actions in 125 mM KCl-stimulated endothelium-denuded rings in the pres
ence of atenolol (10 mu M) and phentolamine (10 mu M) were less marked
in SHR than WKY, although the contractions to high concentrations of
KCI in normal organ bath Ca2+ (1.6 mM) were similar in these strains.
The difference in Ca2+ contractions between SHR and WKY during KCl sti
mulation was also present after 10-min pretreatment with 1 mM ethylene
glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) i
n Ca2+-free medium. However, when noradrenaline (1 mu M) was used as t
he agonist the Ca2+ contractions of endothelium-denuded rings in the t
wo strains were comparable, while exposure to EGTA reduced these respo
nses more effectively in SHR than WKY. Nifedipine (0.5 nM and 10 nM in
KCl- and noradrenaline-stimulated rings, respectively) more efficient
ly inhibited the Ca2+ contractions in hypertensive than in normotensiv
e rats. The presence of intact vascular endothelium attenuated the con
tractions to Ca2+ addition comparably (during KCl stimulation) or even
more (during noradrenaline) in SHR when compared with WKY. N-G-nitro-
L-arginine methyl ester (L-NAME, 0.1 mM) counteracted this attenuation
correspondingly in WKY and SHR, and L arginine (1 mM) restored it in
both strains, whereas indomethacin (10 mM) was without effect on the r
esponse. However, mesenteric arterial relaxations induced by the endot
helium-dependent agonists acetylcholine and ADP in noradrenaline-preco
ntracted (1 mu M) rings were clearly impaired in SHR, and also L-NAME
(0.1 mM) reduced the responses to acetylcholine more efficiently in SH
R. In contrast, the relaxations to acetylcholine and ADP in KCl-precon
tracted (60 mM) rings in the absence and presence of L-NAME were compa
rable between the two strains. In conclusion, attenuated contractile r
esponse to cumulative Ca2+ addition during stimulation with KCl clearl
y differentiated arterial smooth muscle of hypertensive and normotensi
ve rats, suggesting altered function of cell membrane in SHR. The more
pronounced effect of nifedipine on the response indicates abnormal fu
nction of voltage-dependent Ca2+ channels, and higher diminishing effe
ct of EGTA on the contraction during noradrenaline suggests exaggerate
d action of the chelator on membrane-bound Ca2+ in SHR. Interestingly,
the depressant effect of intact endothelium on the Ca2+ con traction
response, mediated largely via nitric oxide, was not attenuated in SHR
. Furthermore, impaired endothelium-dependent agonist-induced relaxati
ons can be attributed to reduced release of endothelium-derived hyperp
olarizing factor in this type of genetic hypertension.