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1 Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia, USA
* To whom correspondence should be addressed. E-mail: sbarman{at}mail.mcg.edu.
Signaling mechanisms which elevate cyclic AMP (cAMP) activate largeconductance, calcium- and voltage-activated potassium (BKCa) channels in pulmonary vascular smooth muscle and cause pulmonary vasodilatation. BKCa channel modulation is important in the regulation of pulmonary arterial pressure and inhibition (closing) of the BKCa channel has been implicated in the development of pulmonary vasoconstriction. Protein kinase C (PKC) causes pulmonary vasoconstriction, but little is known about the effect of PKC on BKCa channel activity. Accordingly, studies were done to determine the effect of PKC activation on cAMP-induced BKCa channel activity using patch-clamp studies in pulmonary arterial smooth muscle (PASMC) cells of the fawn-hooded rat (FHR), a recognized animal model of pulmonary hypertension. Forskolin (10µM), a stimulator of adenylate cyclase, and an activator of cAMP, opened BKCa channels in single FHR PASMC which was blocked by the PKC activators phorbol myristate acetate (PMA; 100nM) and thymeleatoxin (100nM). The inhibitory response by thymeleatoxin on forskolin-induced BKCa channel activity was blocked by Go 6983, which selectively blocks the 
, 
, 
, 
and 
PKC isozymes and Go 6976, which selectively inhibits PKC, PKC, and PKCµ, but not by rottlerin, which selectively inhibits PKC. Collectively, these results indicate that activation of specific PKC isozymes inhibit cAMP-induced activation of the BKCa channel in pulmonary arterial smooth muscle, which suggests a unique signaling pathway to modulate BKCa channels and subsequently cAMP-induced pulmonary vasodilatation.
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