Functional contribution of voltage-dependent and Ca2+ activated K+ (BK(Ca)) channels to the relaxation of guinea-pig aorta in response to natriuretic peptides.
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 Ca2+-activated KS (BK(Ca)) 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 > or = BNP >> CNP. Although the relaxations elicited by these three natriuretic peptide ligands were significantly diminished by iberiotoxin (IbTx, 10(-7) M), a selective BK(Ca) 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 BK(Ca) channel contribution to the total relaxant response was approximately 60% for CNP > approximately 20% for either ANP or BNP. Supporting the substantial role of BK(Ca) 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 BK(Ca) 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 BK(Ca) 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.
Otsuka
Kazuoki
K
Department of Pharmacology, Toho University School of Pharmaceutical Sciences, 2-2-1 Miyama, Funabashi City, Chiba 274-8510, Japan.
Tanaka
Hikaru
H
Horinouchi
Takahiro
T
Koike
Katsuo
K
Shigenobu
Koki
K
Tanaka
Yoshio
Y
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology*; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008297:Male; D009131:Muscle, Smooth, Vascular; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology*; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology; D011189:Potassium Chloride / Q000008:administration & dosage; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000502:physiology
D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; C016276:8-bromocyclic GMP; D011189:Potassium Chloride; D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP