Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation.
OBJECTIVE
Compared with other non-steroid anti-inflammatory drugs (NSAIDs), aspirin is not correlated to hypertension. It has been shown that aspirin has unique vasodilator action in vivo, offering an explanation for the unique blood pressure effect of aspirin. In the present study, we investigate the mechanism whereby salicylates (aspirin and sodium salicylate) dilate blood vessels.


RESULTS
Rat aortic or mesenteric arterial rings were used to test the vascular effect of salicylates and other NSAIDs. RhoA translocation and the phosphorylation of MYPT1, the regulatory subunit of myosin light chain phosphatase, were measured by western blot, as evidenced for RhoA/Rho-kinase activation. Salicylates, but not other NSAIDs, relaxed contraction induced by most tested constrictors except for calyculin A, indicating that RhoA/Rho-kinase-mediated calcium sensitization is involved. The involvement of RhoA/Rho kinase in vasodilation by salicylates was confirmed by measurements of RhoA translocation and MYPT1 phosphorylation. The calculated half maximal inhibitory concentration (IC(50)) of vasodilation was apparently higher than that of cyclooxygenase inhibition, but comparable to that of proline-rich tyrosine kinase 2 (PYK2) inhibition. Over-expression of PYK2 induced RhoA translocation and MYPT1 phosphorylation, and these effects were markedly inhibited by sodium salicylate treatment. Consistent with the ex vitro vascular effects, sodium salicylate acutely decreased blood pressure in spontaneous hypertensive rats but not in Wistar Kyoto rats.


CONCLUSIONS
Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation and thus lower blood pressure.
Ying
Zhekang
Z
Department of Physiology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA. zhekang.ying@osumc.edu
Giachini
Fernanda R C
FR
Tostes
Rita C
RC
Webb
Robert Clinton
RC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology; D001241:Aspirin / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012459:Salicylates; D051418:Focal Adhesion Kinase 2; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D001241:Aspirin