Role for tyrosine kinases in contraction of rat penile small arteries.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.
Villalba
Nuria
N
Department of Pharmacology, University of Aarhus, DK-8000 Aarhus C, Denmark; Department of Physiology, Universidad Complutense, Madrid, Spain.
Kun
Attila
A
Department of Pharmacology, University of Aarhus, DK-8000 Aarhus C, Denmark.
Stankevicius
Edgaras
E
Department of Pharmacology, University of Aarhus, DK-8000 Aarhus C, Denmark; Department of Physiology, Kaunas University of Medicine, Kaunas, Lithuania.
Simonsen
Ulf
U
Department of Pharmacology, University of Aarhus, DK-8000 Aarhus C, Denmark. Electronic address: us@farm.au.dk.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D019833:Genistein / Q000494:pharmacology; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology*; D010413:Penis / Q000098:blood supply*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020032:Tyrphostins / Q000494:pharmacology; D014638:Vanadates / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology*; D054460:rho-Associated Kinases / Q000502:physiology
D020746:Calcium Channels, L-Type; D020032:Tyrphostins; D014638:Vanadates; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D054460:rho-Associated Kinases; D017027:Protein Tyrosine Phosphatases; D002118:Calcium