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Selective Inhibition of L-Type Ca²⁺ Channels in A7r5 Cells by Physiological Levels of Testosterone

Hormone and Vascular Biology Research Group (J.H., R.D.J., T.H.J.), Academic Unit of Endocrinology, Division of Genomic Medicine, University of Sheffield, Sheffield S10 2RX, United Kingdom; Department of Cardiology (K.S.C.), Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom; School of Medicine (C.P.), University of Leeds, Leeds LS2 9JT, United Kingdom; and Barnsley Hospital NHS Foundation Trust (T.H.J.), Barnsley S75 2EP, United Kingdom

Address all correspondence and requests for reprints to: Prof. Chris Peers, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom. E-mail: c.s.peers{at}leeds.ac.uk.

Testosterone has marked beneficial cardiovascular effects, many of which have been attributed to a vasodilatory action. However, the molecular target of testosterone underlying this effect is subject to debate. In this study, we have used microfluorimetry as a noninvasive means of examining whether testosterone could exert dilatory effects via inhibition of voltage-gated Ca²⁺ entry in the model vascular smooth muscle cell line, A7r5. Rises of [Ca²⁺]_i evoked by 50 mM K⁺-containing solution were suppressed in a concentration-dependent manner by testosterone (IC₅₀, 3.1 nM) and by the nonaromatizable analog, 5ß-dihydrotestosterone (IC₅₀, 6.9 nM). The effects of testosterone were apparent in the presence of pimozide (to block T-type Ca²⁺ channels) but not nifedipine (to block L-type Ca²⁺ channels). Testosterone did not alter Ca²⁺ mobilization from intracellular stores by the prostaglandin analog U46619 or capacitative Ca²⁺ entry in cells pretreated with thapsigargin. Our results indicate that testosterone, at physiological concentrations, can selectively suppress Ca²⁺ entry into A7r5 cells via L-type Ca²⁺ channels. We suggest this effect is a likely mechanism underlying its vasodilatory actions and beneficial cardiovascular effects.

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