title: Nitric oxide modulation of endothelium-derived hyperpolarizing factor in agonist-induced depressor responses in anesthetized rats.
abstract: Vasodilators, such as prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF), released from the vascular endothelium are important in the maintenance of systemic blood pressure. Some studies have shown that NO affects EDHF-induced vasodilator responses in isolated perfused blood vessel segments. However, the effects of NO on EDHF-mediated dilation, and their contribution to systemic blood pressure, have not been clarified. Therefore, in the present study we investigated the mechanisms underlying acetylcholine- and bradykinin-induced depressor responses, as well as the interaction between NO and EDHF, by measuring systemic blood pressure in anesthetized rats. In the presence of indomethacin and N(G)-nitro-l-arginine (l-NA; an NO synthase inhibitor), apamin plus charybdotoxin significantly inhibited depressor responses to acetylcholine and bradykinin, whereas glibenclamide, iberiotoxin, quinacrine, catalase, and combination of ouabain plus BaCl2 failed to inhibit EDHF-induced depressor responses. 4-Aminopyridine significantly inhibited depressor responses to acetylcholine, but not to bradykinin. In the presence of indomethacin and l-NA, carbenoxolone, a gap junction inhibitor, significantly inhibited depressor responses to agonists. l-NA alone significantly potentiated agonist-induced depressor responses. In contrast, infusion of sodium nitroprusside, an NO donor, or 8-br-cGMP significantly inhibited depressor responses to agonist. The findings of the present study raise the possibility that agonist-induced depressor responses are elicited by propagation of endothelial hyperpolarization via apamin- plus charybdotoxin-sensitive K(+) channels to smooth muscle cells through gap junctions, but not by diffusible substance(s). It is suggested that, in anesthetized rats, the EDHF-induced depressor response is attenuated in the presence of endogenous and exogenous NO via an increment in cGMP.
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo 650-8530, Japan; Department of Pharmacology, Osaka City University Medical School, 1-4-3, Asahimachi, Abeno, Osaka 545-8585, Japan. Electronic address: kobuchi-s@huhs.ac.jp.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kobuchi
authors.affiliation: Applied Pharmacology and Therapeutics, Osaka City University Medical School, 1-4-3, Asahimachi, Abeno, Osaka 545-8585, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Miura
authors.affiliation: Department of Pharmacology, Osaka City University Medical School, 1-4-3, Asahimachi, Abeno, Osaka 545-8585, Japan; Department of Education, Shitennoji University, 3-2-1, Gakuenmae, Habikino, Osaka 583-8501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwao
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo 650-8530, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Ayajiki
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D004347:Drug Interactions; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001685:Biological Factors; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009599:Nitroprusside; D019335:Nitroarginine; D009569:Nitric Oxide; D000109:Acetylcholine; D000420:Albuterol; D001920:Bradykinin; D007213:Indomethacin
keywords: Ca(2+)-activated K(+) channel; Endothelium-derived hyperpolarizing factor (EDHF); Gap junction; Nitric oxide (NO); cGMP