Functional Contribution of Voltage-Dependent and Ca2+-Activated K+(BKCa) Channels to the Relaxation of Guinea-Pig Aorta in Response to Natriuretic Peptides.

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Abstract
We examined the relaxant effects of natriuretic peptide family on the isolated guinea-pig aorta to determine the receptor subtype which primarily mediates this vascular relaxation, with particular attention to the apparent contribution of voltage-dependent and Ca 2+-activated K+ (BKCa) channels to the response. Three endogenous natriuretic peptide ligands (natriuretic peptide, ANP; brain natriuretic peptide, BNP; C-type natriuretic peptide, CNP) produced a concentration-dependent relaxation in de-endothelialized guinea-pig aorta pre-contracted by noradrenaline (NA), with a potency order of ANP ≥ BNP >> CNP. Although the relaxations elicited by these three natriuretic peptide ligands were significantly diminished by iberiotoxin (IbTx, 10-7 M), a selective BKCa channel blocker, the inhibitory effect of IbTx was most pronounced for the CNP-induced relaxation; when estimated at 10-7 M of each peptide, the apparent extent of BKCa channel contribution to the total relaxant response was ≈ 60% for CNP > ≈ 20% for either ANP or BNP. Supporting the substantial role of BKCa channels in the vascular responses, high-KCl (80 mM) potently suppressed the relaxations induced by these natriuretic peptide ligands. The relaxant response to 8-Bromo-cyclic GMP, a membrane permeable cyclic GMP analogue, was also diminished by IbTx (10-7 M) and high-KCl (80 mM), which indicates the key role of cyclic GMP in the BKCa channel-mediated, natriuretic peptide-elicited vascular relaxation. These results indicate that the A-type receptor (NPR-A, which is more selective for ANP and BNP) rather than the B-type receptor (NPR-B, which is more selective for CNP) predominates in the guinea-pig aorta as the natriuretic peptide receptor which mediates this vascular smooth muscle relaxation. Although activation of BKCa channels substantially contributes to both NPR-A-and NPR-B-activated relaxations, particularly in the NPR-B-activated relaxation, this K+ channel may function as a primary relaxant mediator in this conduit artery.

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