Pulmonary vasodilatory action of testosterone: evidence of a calcium antagonistic action.

Recent evidence supports a beneficial effect of testosterone on the cardiovascular system. Testosterone acts as a coronary vasodilator and reduces myocardial ischemia in men with coronary heart disease. The aim of the current study was to determine whether testosterone has a similar vasodilatory action in the pulmonary circulation and to characterize the underlying mechanism of action. The vasodilatory action of testosterone was studied in pulmonary arteries (n = 132, mean internal diameter = 344 +/- 8 microm) isolated from male rats (n = 48, mass = 396 +/- 7 g) mounted in a small vessel wire myograph and loaded to a tension equivalent to 17.5 mm Hg. Micromolar concentrations of testosterone induced dilatation in pulmonary arteries preconstricted with prostaglandin F2alpha (100 microM) within seconds of application. Dilatation to testosterone was similar in vessels treated with N-gamma-nitro-l-arginine methyl ester (l-NAME) (10 microM) or vehicle (5 microl distilled water), -38.2 +/- 2.9%, and -38.1 +/- 3.4%, respectively, and in vessels treated with indomethacin (10 microM), flutamide (10 microM), or vehicle (5 microl ethanol), -35.5 +/- 2.8%, -43.2 +/- 3.6%, and -35.7 +/- 4.6%, respectively (all p > 0.05). Maximal dilatation to testosterone occurred following preconstriction with agents that activated voltage-gated calcium channels such as prostaglandin F2alpha (-34.6 +/- 5.0%), BAY K8644 (-32.9 +/- 8.7), or potassium chloride (-26.7 +/- 1.5%), compared with calcium-independent protein kinase C activation by phorbol dibutyrate (-14.7 +/- 1.6%) or capacitative calcium entry via thapsigargin (-5.1 +/- 0.9%). This study demonstrates that testosterone induces pulmonary dilatation via a mechanism that is independent of the classic androgen receptor and also of the release of nitric oxide or dilator prostaglandins. The data support a calcium antagonistic action for testosterone in the pulmonary circulation, primarily against voltage-gated calcium channels.