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© Copyright 2004 The British Pharmacological Society

055P University of Bath
Summer Meeting July 2004

Contractile responses in vas deferens and mesenteric artery from alpha1D-adrenoceptor knockout mice

S. Bexis1, L. Cleary1, J.C. McGrath2, A. Tanoue3, G. Tsujimoto3 & J. R. Docherty1. 1Department of Physiology, Royal College of Surgeons in Ireland, Dublin 2, Ireland, 2Institute of Biomedical & Life Sciences, University of Glasgow, Scotland, 3Department of Molecular Cell Pharmacology, National Research Institute for Child Health and Development, 3-35-31, Taishi-do, Setagaya-ku, 154, Tokyo, Japan

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Bexis S
Cleary L
McGrath JC
Tanoue A
Tsujimoto G
Docherty JR

Alpha1D-adrenoceptors are involved in smooth muscle contractions in a number of tissues including rat and mouse aorta (see Docherty, 1998). To elucidate further the role of these receptors in contractions of vas deferens and blood vessels, we have employed receptor knock-out technology (Tanoue et al., 2002).

Vas deferens, aorta and mesenteric artery were obtained from male alpha1D-KO (129S/C57 background), 129S/C57 wildtype (WT) and C57 WT (C57) mice (24-34g). All tissues were set up for recording of isometric contractions to noradrenaline or phenylephrine. In addition, isometric contractions to a single electrical stimulus (supramaximal voltage, 0.5 ms pulses) were obtained at 5 min intervals in vas deferens. Studies in vas deferens were carried out in the presence of cocaine (3 µM).

In mouse vas deferens, single pulse stimulation produced contractions of 0.038±0.012g (n=4) and 0.072±0.014g (n=6) in tissues from alpha1D-KO and WT, respectively (no significant difference). The selective alpha1D-adrenoceptor antagonist BMY 7378 cumulatively inhibited contractions with a pIC50 (-log M) of 6.10±0.22 9 (n=4), 6.97±0.10 (n=5) and 7.05±0.10 (n=6) in tissues from alpha1D-KO, WT and C57 mice, respectively. Potency of BMY 7378 was significantly reduced in alpha1D-KO (P<0.01). The maximum contraction to noradrenaline was not significantly affected by deletion of alpha1D-adrenoceptors. However, lower concentrations of noradrenaline produced significantly larger contractions in WT (e.g. NA 1µM produced 38.3±9.8% and 74.0±7.6% of maximum in tissues from 1D-KO and WT, respectively).

In mouse aorta, phenylephrine was significantly more potent at producing contractions in tissues from WT and C57 mice than 1D-KO mice. In mouse mesenteric artery, there was no difference between 1D-KO and WT in maximum response to phenylephrine, but there were no contractions to low concentrations of phenylephrine in alpha1D-KO.

It is concluded that alpha1D-adrenoceptors are involved in contractions not only in tissues such as aorta where they dominate, but also in tissues such as vas deferens, where the predominant receptor is an alpha1A-adrenoceptor.

Docherty, J. R. (1998). Eur. J. Pharmacol. 361, 1-15
Tanoue A. et al. (2002). J Clin Invest. 109:765-75

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