Submitted on December 1, 2004
Accepted on February 7, 2005
Permissive contributions of NO and prostacyclin in CO-induced cerebrovascular dilation in piglets
Charles W Leffler1*, Alexander L Fedinec1, Helena Parfenova1, and Jonathan H Jaggar1
1 Physiology, University of Tennessee Health Science Center, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: cleffler{at}physio1.utmem.edu.
Endogenously produced CO is an important dilator in newborn cerebrovascular circulation. CO dilates cerebral arterioles by activating KCa channels, but modulatory actions of other effectors and second messenger inputs are unclear. Specifically, the mechanisms behind the obligatory permissive roles of prostacyclin and NO are uncertain. Therefore, the present study was performed using acutely-implanted, closed cranial windows in newborn pigs to address the hypothesis that the permissive roles of NO and prostacyclin in cerebrovascular dilation to CO involve a common mechanism. The NO donor, sodium nitroprusside (SNP), restored dilation to CO following inhibition of that dilation with the prostaglandin cyclooxygenase inhibitor, indomethacin. The stable prostacyclin analog, iloprost, restored CO-induced dilation blocked by the nitric oxide synthase inhibitor, L-nitro-arginine (LNA). Restoration of dilation to CO by the cGMP-dependent phosphodiesterase inhibitor, zaprinast, and blockade of CO dilation by the guanylyl cyclase inhibitor, ODQ, suggest involvement of the cGMP/PKG pathway. Iloprost or the cAMP dependent dilator, isoproterenol, restored dilation to CO following ODQ. However, CO-induced dilation blocked by the cGMP dependent protein kinase (PKG) inhibitor, Rp-8-pCPT-cGMPs, could not be reversed by SNP, iloprost, or isoproterenol. Conversely, protein kinase A inhibition did not block dilation to CO. Overall, data indicate that activation of PKG is the predominant mechanism of the permissive actions of NO and prostacyclin for CO-induced pial arteiolar dilation.
