Role for Tyrosine Kinases in Contraction of Rat Penile Small Arteries

Abstract

The devasting effect of cancer and treatment thereof contribute to sexual dysfunction. Recently, a series of tyrosine kinase inhibitors have been approved either as add-on or for targeted treatment of cancer. However, tyrosine kinases are not only important for cell growth and proliferation, but also in regulation of vascular tone. The present study investigated whether tyrosine kinases contribute to contractility in rat penile arteries, and addressed whether they are involved in calcium entry and/or related to the RhoA/Rho-kinase pathway. Segments of the rat dorsal penile artery were mounted in microvascular myographs for simultaneous measurements of intracellular calcium concentration ([Ca(2+)](i)) and tension, and tyrosine kinase activity, and phosphorylation of 20-kDa myosin light chain (MLC(20)) was measured in dorsal penile artery homogenates. In vitro evidence for contractility and changes in intracellular Ca(2+) in small penile arteries. Sodium vanadate (Na(3)VO(4), 1 mM), a tyrosine phosphatase inhibitor, increased [Ca(2+)](i) and tension. A l-type calcium channel blocker, nifedipine (1 µM), markedly reduced Na(3)VO(4)-evoked increases in [Ca(2+)](i) and tension. A thromboxane analog, U46619, increased TK activity. In contrast to the inactive analogue, genistein, a general TK inhibitor, concentration-dependently reduced both U46619-evoked contraction, and [Ca(2+)](i). U46619-induced contraction was markedly inhibited by tyrphostin A23 and bis-tyrphostin, whereas there was no effect of the tyrosine kinase c-Src inhibitor, herbimycin A. Tyrphostin A23 suppressed U46619-mediated phosphorylation of MLC(20). This study suggests that activation of tyrosine kinases is involved in contraction of rat penile smooth muscle probably by regulation of calcium entry through l-type calcium channels. These findings may have implications for the selections of novel add on anticancer treatments, e.g., inhibitors of tyrosine kinases, and for novel approaches to treat erectile dysfunction.