Introduction: 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.
Aim: 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.
Methods: 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.
Main outcome measures: In vitro evidence for contractility and changes in intracellular Ca(2+) in small penile arteries.
Results: 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).
Conclusions: 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.