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Testosterone relaxes coronary arteries by opening the large-conductance, calcium-activated potassium channel
V P Deenadayalu1, R E White, J N Stallone
1Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, Ohio 45435-0927, USA.
Insights
Testosterone relaxes coronary arteries by opening large-conductance, calcium- and voltage-activated potassium (BK(Ca)) channels in smooth muscle cells. This mechanism, independent of the endothelium, involves potassium efflux and may relate to cGMP accumulation.
Area of Science:
- Cardiovascular Physiology
- Endocrinology
- Molecular Biology
Background:
- Cardiovascular diseases are perceived as a male health issue, with testosterone often implicated negatively.
- The precise cellular and molecular mechanisms of testosterone's vascular effects remain largely unknown.
- Existing research lacks robust experimental support for detrimental cardiovascular effects of testosterone.
Purpose of the Study:
- To investigate the acute effects of testosterone on porcine coronary artery smooth muscle.
- To elucidate the cellular and molecular mechanisms underlying testosterone-mediated vascular responses.
- To determine if testosterone directly impacts coronary artery function.
Main Methods:
- Tissue-level contractile studies on porcine coronary arteries.
- Cellular electrophysiology using patch-clamp techniques on single coronary myocytes.
- Pharmacological inhibition of specific ion channels to assess their role.
Main Results:
- Testosterone and dihydrotestosterone induced relaxation of coronary arteries via an endothelium-independent pathway.
- This relaxation was linked to potassium (K+) efflux from smooth muscle cells.
- Testosterone was found to directly open large-conductance, calcium- and voltage-activated potassium (BK(Ca)) channels in coronary myocytes.
- Inhibition of BK(Ca) channels significantly reduced testosterone-induced vasodilation.
Conclusions:
- Testosterone primarily relaxes porcine coronary arteries by activating BK(Ca) channels in coronary myocytes.
- This vasorelaxation mechanism is associated with potassium efflux and potentially cGMP accumulation.
- The findings offer a novel molecular explanation for testosterone-induced vasodilation observed in experimental and clinical studies.
Abstract:
Cardiovascular diseases are often considered to be a predominantly male health problem, and it has been suggested that testosterone exerts deleterious effects on cardiovascular function; however, few experimental studies support this suggestion. Moreover, the cellular and molecular mechanism(s) underlying vascular responses to testosterone is unknown. The present study has investigated the acute effects of testosterone on porcine coronary artery smooth muscle at the tissue and cellular levels. Contractile studies demonstrated that testosterone or dihydrotestosterone (a nonaromatizable metabolite) relaxed these arteries by an endothelium-independent mechanism involving potassium efflux. Direct evidence from patch-clamp studies confirmed that testosterone opened K(+) channels in single coronary myocytes, and further analysis identified this protein as the large-conductance, calcium- and voltage-activated potassium (BK(Ca)) channel. Moreover, inhibiting BK(Ca) channel activity significantly attenuated testosterone-induced coronary relaxation. These findings indicate that testosterone relaxes porcine coronary arteries predominantly by opening BK(Ca) channels in coronary myocytes, and this response may be associated with accumulation of cGMP. This novel mechanism may provide a better understanding of testosterone-induced vasorelaxation reported in recent experimental and early clinical studies.