title: Alpha1-adrenoceptor-mediated negative inotropic effect caused by intracellular ionic activities in guinea-pig papillary muscle.
abstract: In guinea-pig papillary muscle, phenylephrine (PE), an agonist of alpha1-adrenoceptor (alpha1-AR), led to a transient negative inotropic effect (NIE) and a subsequent sustained positive inotropic effect (PIE). To clarify the ionic mechanisms underlying the NIE, we measured the [Na+]i or [pH]i by ion-selective microelectrodes. PE produced a decrease in the intracellular Na+ concentration ([Na+]i) and an increase in intracellular pH ([pH]i). During the phase of NIE, PE produced only a (-) change of [Na+]i (Delta[Na+]i). With a decrease in extracellular Na+ or an increase in extracellular Ca2+, the PE-induced NIE was attenuated and PE produced (+)Delta[Na+]i. The PE-induced NIE and (-)Delta[Na+]i were definitely strengthened by lowering the bath temperature or increasing the stimulation frequency. 2-(2,6-di-methoxyphenoxyethyl)amino-methyl-1,4-benzidioxane HCl, an antagonist of alpha1A-AR, completely abolished the PE-induced NIE and (-)Delta[Na+]i. Phorbol 12,13-dibutyrate, an activator of protein kinase C (PKC), decreased the baseline [Na+]i and twitch force and increased the baseline [pH]i in mimicry of PE. Pretreatment with 1-5(isoquinolinesulphonyl)-2-methylpiperazine, an inhibitor of PKC, abolished the PE-induced NIE and (-)Delta[Na+]i. During pretreatment with benzamil, an inhibitor of Na+/Ca2+ exchange, we found that the PE-induced NIE and (-)Delta[Na+]i were reversibly abolished. Our results indicate the PE-induced NIE may be elicited upon the activation of Na+/Ca2+ exchange which can be attributed to the (-)Delta[Na+]i. (-)Delta[Na+]i is mediated through a PKC-dependent pathway via an activation of alpha1A-AR subtype and its effect could be strengthened remarkably at high [Na+]i and [Ca2+]i values.
authors.affiliation: Department of Pharmacology, College of Veterinary Medicine, Chonbuk National University, 664-14 Duckjin-Dong, Jeonju 561-756, Korea.
authors.forename: J S
authors.initials: JS
authors.lastname: Kim
authors.forename: S-J
authors.initials: SJ
authors.lastname: Kim
authors.forename: H-S
authors.initials: HS
authors.lastname: Kang
authors.forename: J-S
authors.initials: JS
authors.lastname: Kim
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004576:Electromyography / Q000662:veterinary; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D007474:Ion Exchange; D008274:Magnesium / Q000378:metabolism; D008564:Membrane Potentials; D010210:Papillary Muscles / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D013696:Temperature; D013997:Time Factors; D046509:Tissue Culture Techniques / Q000662:veterinary
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D012964:Sodium; D008274:Magnesium