Role of calcium-activated potassium channels and cyclic nucleotides on pulmonary vasoreactivity to serotonin

The role of Ca²⁺-activated K⁺ channel modulation and cyclic nucleotide second messenger signal transduction in the canine pulmonary vascular response to serotonin was determined in the isolated blood-perfused dog lung. Pulmonary vascular resistances and compliances were measured using vascular occlusion techniques. Serotonin (10^-5 M) significantly increased precapillary and postcapillary resistance and significantly decreased total vascular compliance by decreasing large vessel compliance and middle compartment compliance. Tetraethylammonium ions (TEA+; 1 mM), an inhibitor of Ca²⁺-activated K⁺ channels, significantly potentiated the presser effect to serotonin on both the pulmonary arteries and pulmonary veins. Pretreatment with the guanosine 3',5'-cyclic monophosphate (cGMP)/adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (10^-5 M), the cell membrane-permeable analog of cAMP, dibutyryl-cAMP (10^{- 5} M), or the cAMP-dependent vasodilator isoproterenol (10^-5 M) inhibited the serotonergic response on both the arteries and veins, which was reversed by TEA⁺. In contrast, the stable membrane-permeable analog of cGMP, 8- bromo-cGMP (10^-5 M), had no effect on serotonin. These results indicate that there is a basal level of vasorelaxation in canine pulmonary blood vessels that is mediated by Ca²⁺-activated K⁺ channel activity and that inhibition of these K⁺ channels increases pulmonary vascular tone and potentiates the pulmonary vasoactive response to serotonin. Also, these data suggest that cAMP-induced pulmonary vasodilation is mediated primarily by Ca²⁺-activated K⁺ channels and that activation of these specific K⁺ channels attenuates the presser response to serotonin. Thus an important relationship appears to exist between the cAMP second messenger system and Ca²⁺activated K⁺ channels in canine pulmonary vasoreactivity.