Testosterone-induced relaxation of rat thoracic aorta: Structural specificity of androgen analog effects on vascular smooth muscle (VSM) and endothelium (ENDO)
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abstract
Previously, we reported that testosterone (T) produces vasorelaxation of the rat thoracic aorta, which is androgen receptor-independent and involves both ENDO-dependent (nitric oxide) and -independent (delayed rectifier VSM K+ channel) mechanisms of action. To determine the structural specificity of T effects on ENDO and VSM, the ability of various androgen analogs and metabolites to produce vasorelaxation was examined. Paired ENDO-intact (E+) and -denuded (E-) aortic rings from male Sprague-Dawley rats (12-16 wks age) were prepared for isometric tension recording (37C, 2.50 g passive tension). After equilibration (90 min), aortae were precontracted with phenylephrine (PE, 1 M) and a cumulative dose-response to T or an androgen analog (5.300 M) was obtained. Data are means SE (n = 6-8 rats per expmtl. group). In E+ aortae, T induced full relaxation (100% of PE contraction) at a sensitivity (EC50) of 36 4 M. Compared to T, the active metabolite 5-dihydrotestosterone (DHT) exhibited a significantly lower maximal response (69 4%) and sensitivity (80 7 M). Maximal relaxation was slightly lower while sensitivity was substantially lower with the major excretory metabolites androsterone (ANDS; 92 2%. 76 6 M) and etiocholanolone (ETIO; 94 1%, 128 6 M). The non-polar ester T-hemisuccmate (THS) exhibited a noticeably lower maximal response (74 2%) and sensitivity (68 10 M). Maximal relaxation was reduced drastically with the more non-polar ester T-enanthate (TEN; 25 2%). Conjugation of THS with bovine serum albumin (THS:BSA) enhanced both maximal response (90 4%) and sensitivity (30 4 M). Removal of ENDO reduced sensitivity to T (60 3 M) and ANDS (94 3 M). These data suggest that: 1) T-induced relaxation is a structurally-specific effect of the T molecule; and 2) Vasodilatory efficacy and potency are enhanced in more polar androgen analogs (T, ANDS, ETIO, or THS:BSA) that have a lower permeability to the VSM cell membrane.
