Inhibition of cGMP mediated relaxation in small rat coronary arteries by block of CA++ activated K+ channels.

The functional importance of Ca++ activated K+ (K(Ca)) channels in cGMP mediated relaxation of pressurized septal arteries (internal basal diameter 213 +/- 4 microm) was investigated. Vascular tone was increased by the thromboxane A2 analogue, U-46619 and internal pressure was maintained at 60 mmHg. Vessels were tested with an endothelium independent agonist (nitroprusside) and endothelium dependent agonist (acetylcholine) of nitric oxide which activates soluble guanylate cyclase. Receptor activation of particulate guanylate cyclase was tested by atrial natriuretic peptide. Direct changes in intracellular cGMP concentration were done with the cell permeable analog, 8-Bromo-cGMP. Tetraethylammonium ion (TEA+), 1 mM, significantly inhibited relaxation to nitroprusside 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 significantly inhibited by TEA+ with a maximal inhibition of 52 +/- 13% at 10(-7) M. TEA+ significantly inhibited relaxation to 8-Bromo-cGMP from 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 inhibition of 84 +/- 5% at 10(-11) M. The large conductance K(Ca) channel blocker, iberiotoxin, eliminated the relaxation response to 8-Bromo-cGMP (10(-3) M). The results suggest that a large portion of the dilator action of cGMP is mediated by effects on K+ membrane channels.