Intracellular alkalinization augments alpha(1)-adrenoceptor-mediated vasoconstriction by promotion of Ca(2+) entry through the non-L-type Ca(2+) channels.
Modulation by intracellular pH of the vasoconstriction induced by alpha-adrenoceptor agonists was investigated in isolated guinea pig aorta. NH(4)Cl (15 mM) increased intracellular pH of aortic smooth muscle cells by about 0.2 pH unit and significantly augmented KCl-induced contraction of aortic strips, whereas simultaneous administration of NH(4)Cl (15 mM) plus Na(+) propionate (30 mM) failed to affect intracellular pH or contractility. NH(4)Cl (15 mM) potentiated contractions induced by alpha-adrenoceptor agonists, norepinephrine, phenylephrine and clonidine. Contraction induced by alpha(1)-selective adrenoceptor agonist, phenylephrine, but not that induced by norepinephrine or clonidine, was insensitive to inhibition by verapamil (1 microM). Phenylephrine-induced contraction was not affected by NH(4)Cl in Ca(2+)-free medium whereas extracellular Ca(2+)-induced contraction of phenylephrine-stimulated aorta was significantly augmented by NH(4)Cl. Consistently, 45Ca(2+)uptake into phenylephrine 1 microM)-stimulated aortic strips was increased by incubation with NH(4)Cl. The potentiating effects of NH(4)Cl on both phenylephrine-induced Ca(2+) entry and contraction were antagonized by Na(+) propionate. These results suggest that intracellular alkalinization facilitates alpha(1)-adrenoceptor-mediated vasoconstriction by facilitation of an agonist-induced Ca(2+) entry pathway that is independent of L-type Ca(2+) channels.
Wakabayashi
I
I
Department of Hygiene and Preventive Medicine, School of Medicine, Yamagata University, Iida-Nishi 2-2-2, Yamagata 990-9585, Japan. wakabaya@med.id.yamagata-u.ac.jp
Masui
H
H
Groschner
K
K
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D003000:Clonidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014700:Verapamil / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D011422:Propionates; D018340:Receptors, Adrenergic, alpha-1; D000643:Ammonium Chloride; D010656:Phenylephrine; D015240:Phorbol 12,13-Dibutyrate; D011189:Potassium Chloride; D014700:Verapamil; D003000:Clonidine; D002118:Calcium; D009638:Norepinephrine