INHIBITION OF CGMP MEDIATED RELAXATION IN SMALL RAT CORONARY-ARTERIESBY BLOCK OF CA++ ACTIVATED K+ CHANNELS

The functional importance of Ca++ activated K+ (K-Ca) channels in cGMP mediated relaxation ofpressurized septal arteries (internal basal dia meter 213 +/- 4 mu m) was investigated. Vascular tone was increased by the thromboxane A(2) analogue, U46619 and internal pressure was maint ained at 60 mmHg. Vessels were tested with an endothelium independent agonist (nitroprusside) and endothelium dependent agonist (acetylcholi ne) of nitric oxide which activates soluble guanylate cydase. Receptor activation of particulate guanylate cyclase was tested by atrial natr iuretic peptide. Direct changes in intracellular cGMP concentration we re done with the cell permeable analog, 8-Bromo-cGMP. Tetraethylammoni um ion (TEA(+)), 1 mM, significantly inhibited relaxation to nitroprus side from 10(-7) to 10(-3)M with a maximal inhibition of 53 +/- 8% at 10(-3)M. Relaxation to acetylcholine from 10(-9)M to 10(-5)M was signi ficantly inhibited by TEA(+) with a maximal inhibition of 52 +/- 13% a t 10(-7)M. TEA(+) significantly inhibited relaxation to 8-Bromo-cGMP f rom 10(-6)M to 10(-3)M with a maximal inhibition of 59 +/- 14% at 10(- 4)M. The relaxation response to atrial natriuretic peptide from 10(-12 )M to 10(-7)M was significantly inhibited by TEA(+) with a maximal inh ibition of 84 +/- 5% at 10(-11)M. The large conductance K-Ca channel b locker, iberiotoxin, eliminated the relaxation response to 8-Bromo-cGM P (10(-3)M). The results suggest that a large portion of the dilator a ction of cGMP is mediated by effects on K+ membrane channels.