Contribution of Ca(2+)-Dependent Cl(−) Channels to Norepinephrine-Induced Contraction of Femoral Artery Is Replaced by Increasing EDCF Contribution during Ageing

The activation of Ca(2+)-dependent Cl(−) channels during norepinephrine-induced contraction of vascular smooth muscle was suggested to depolarize cell membrane and to increase Ca(2+) entry. Hypertension and ageing are associated with altered Ca(2+) handling including possible activation of Ca(2+)-dependent Cl(−) channels. Our study was aimed to determine Ca(2+)-dependent Cl(−) channels contribution to norepinephrine-induced contraction during hypertension and ageing. Norepinephrine-induced concentration-response curves of femoral arteries from 6- and 12-month-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were recorded using wire myograph. Pretreatment with Ca(2+)-dependent Cl- channel inhibitor indanyloxyacetic acid 94 [R(+)-IAA-94](IAA) attenuated norepinephrine-induced contraction in all groups, but relatively more in WKY than SHR arteries. The attenuation of norepinephrine-induced contraction after Ca(2+)-dependent Cl(−) channels blockade was partially reduced in 12-month-old WKY rats, but substantially diminished in 12-month-old SHR. IAA effect was enhanced after NO synthase inhibition but decreased by ageing. In 20-month-old WKY rats norepinephrine-induced contraction was not affected by IAA but was almost abolished after cyclooxygenase inhibition by indomethacin or niflumic acid. In conclusion, contribution of Ca(2+)-dependent Cl(−) channels to norepinephrine-induced contraction diminished with age, hypertension development, and/or NO synthesis inhibition. Ca(2+)-dependent Cl(−) channels are important for maintenance of normal vascular tone while their inactivation/closing might be a pathological mechanism.