Altered contractility of rabbit penile corpus cavernosum smooth muscle by hypoxia

Purpose: To investigate the effects of severe hypoxia on trabecular smooth muscle contractility. Materials and Methods: Strips of rabbit corpus cavernosum were mounted in organ chambers to measure isometric tension. In some experiments intracellular free Ca²⁺ concentration and tension were measured by the intracellular fluorescent dye FURA-2 and isometric tension recording simultaneously. Results: Contractions elicited by norepinephrine, endothelin-1 or potassium were attenuated under hypoxic conditions (pO₂ ~10 mm. Hg). Strips contracted with 20 mM, K⁺ under normoxic conditions and then exposed to hypoxia consistently lost the potassium-induced tone. The hypoxia- induced relaxation was not affected by the removal of the endothelium, by treatment with the cyclooxygenase blocker, indomethacin, or with the guanylate cyclase blocker, methylene blue. The potassium channel opener, cromakalim, and adenosine relaxed potassium contracted strips; however, the potassium channel blockers glibenclamide, apamin, barium chloride and charybdotoxin or the adenosine receptor antagonist 8-(p- sulfonyl)theophylline were unable to prevent hypoxia-induced relaxation. Tetraethylammonium, a potassium channel blocker, and the depolarizing agents ouabain and high potassium (80 mM.), partially prevented hypoxia-induced relaxation. The calcium ionophore, ionomycin, had no effect on hypoxia- induced relaxations. Hypoxia, within 2 to 6 minutes, caused a large accumulation in intracellular calcium, concomitant with a loss of trabecular smooth muscle tone. Both these effects could be reproduced by inhibiting oxidative phosphorylation with 2,4,dinitrophenol. Reoxygenation resulted in an immediate recovery of both tone and intracellular calcium levels. Tissues under hypoxic conditions for 30 minutes had a 24% and 67% decrease in the ATP/ADP ratio and in creatine phosphate concentrations, respectively. Conclusion: Hypoxia causes a simultaneous increase in intracellular calcium and relaxation which, we propose, is the consequence of inhibition of oxidative phosphorylation with loss of high energy phosphates, necessary for the homeostasis of Ca²⁺ and the contractile mechanism of the cavernosal smooth muscle.