Mechanisms Mediating Testosterone-Induced Vasodilation of Myogenic Tone in a Rat Mesenteric Resistance Microvessel
No abstract is available.
Background and purpose: Testosterone (TES) supplementation has increased dramatically over the past decade; however, the role of TES in cardiovascular function remains unclear. Very few studies have examined the role of TES in modulating myogenic tone (MT) in resistance microvessels. MT, a component of autoregulation, is the reflexive constriction of a blood vessel when intraluminal pressure increases. The aim of this study was to examine the vascular effects of TES on MT in a microvascular artery and to elucidate mechanisms mediating the TES-induced response. Experimental approach: Tertiary branches of rat mesenteric artery from male Sprague- Dawley rats were isolated, mounted, and pressurized in an arteriograph chamber (Living Systems Instrumentation, St. Albans, Vermont). A blind-sac procedure was used in all experiments. Results: Mesenteric resistance arteries exhibited a decrease in diameters at 5, 15, 30, 45, 60, 75, 90, and 105 mmHg when placed in HEPES physiological solution with calcium (1.8 mM). The vessels exhibited a significantly larger diameter at the same pressures when placed in HEPES calcium-free solution and ethylene glycol bis-(β-amino-ethyl ether)-NN’tetra acetic acid (EGTA) (2 mM). The pressurized mesenteric resistance vessels that were bathed in HEPES with calcium (1.8 mM) demonstrated a significant decrease in MT in response to acetylcholine (70 μM). In another series of experiments, following the development of MT at 75 mmHg, TES (20 nM) produced an increase in vessel diameter. Pretreatment with 10 μM flutamide (androgen receptor antagonist) iv completely inhibited this response to TES. Pretreatment with 10 μM finasteride (5α- reductase inhibitor) completely inhibited the vasodilation effect of TES on MT. Immunofluorescent studies indicated the presence of the enzyme 5α-reductase in the endothelium and smooth muscle of the tertiary branch of the rat mesenteric artery. Pretreatment with 10 μM ICI 182, 780 (estrogen receptor antagonist) did not block TESinduced vasodilation of MT. Functional removal of the endothelium (ENDO) eliminated the TES-induced vasodilation of MT. Conclusions: The data from this study suggest that physiological concentrations of TES have a vasodilating effect on MT in resistance microvessels in the rat mesenteric vascular bed. Estrogen appears to have no role in this TES-induced modulation of MT. However, the data suggest that the androgen receptor (AR) mediated endothelial-dependent vasodilation induced by TES is not a direct effect of TES, but is an indirect effect which requires the local vascular conversion of TES via the enzyme 5α-reductase to dihydrotestosterone (DHT). To our knowledge, this is the first report to suggest the total dependence of TES-induced vasodilation of MT on local conversion to DHT in a resistance microvessel. These findings strongly suggest a novel mechanism whereby androgens can modulate blood pressure and influence cardiovascular function.