Testosterone improves symptoms and exercise capacity in men with heart failure (Pugh et al., Heart, 2003, In Press), and has been demonstrated to lower peripheral vascular resistance in such individuals (Pugh et al., Eur.Heart J. 2003, 24, 909-15), consistent with a systemic vasodilatory activity. The vasodilatory mechanism of testosterone has yet to be investigated in the systemic vasculature. Mesenteric tissue was obtained from male patients (n=14, age=70+2), undergoing gastrointestinal surgery for removal of bowel cancer, who gave full informed consent. Mesenteric resistance arteries (n=28) were subsequently dissected, and the endothelium removed from half of the vessels (n=14, diameter=376+23um), by gently rubbing the intra-luminal surface. These and the endothelial intact vessels (n=14, diameter=393+31um) were then loaded in a wire myograph at a tension equivalent to 97.1+1.6mmHg, and maintained in oxygenated physiological saline at 37oC , pH 7.4. Vessel viability and reproducibility was confirmed by repeat exposure to potassium chloride (KCl, 70mM). Endothelial integrity was assessed by exposure to acetylcholine (ACh, 1uM) following preconstriction with noradrenaline (NA, 10uM). Vessels were then exposed to KCl (0.1-100mM) followed by cumulative additions of testosterone (1nM-100uM) or ethanol vehicle. Vessels were washed and then re-exposed to KCl followed by the alternative agent. Endothelial denudation was confirmed in the rubbed vessels by abolition of dilatation to ACh (Emax = 17.7+6.8%) compared to control vessels (Emax = -44.4+6.3%, P<0.0001). Denuded vessels also exhibited lower vasoconstriction to KCl; Emax = 3.49+0.69mN compared to 13.8+2.1mN, P<0.001. Vasodilatation to testosterone occurred at concentrations greater than 3uM and was statistically similar in both groups; Emax = -88.2+8.3% compared to -95.1+8.1%. Ethanol vehicle had no vasodilatory efficacy. Testosterone-induced vasodilatation, which may contribute to the clinical benefits offered by testosterone therapy to men with heart failure, is not mediated via endothelial-derived dilators.
03 - 05 Nov 2003
Society for Endocrinology