The mechanism of increasing Ca2+ responsiveness by alpha1-adrenoceptor stimulation in rat ventricular myocytes.
We investigated the mechanism of alpha(1)-adrenoceptor stimulation on the myofibrillar Ca(2+) responsiveness at steady-state in intact rat ventricular myocytes. We produced tetanus, and an instantaneous plot of [Ca(2+)](i) vs. cell length (Ca-L trajectory) was constructed to estimate the Ca(2+) responsiveness. An alpha(1)-agonist, phenylephrine, dose-dependently shifted the Ca-L trajectory to the left, corresponding to sensitization of the myofilaments. An alpha(1)-antagonist, prazosin, and inhibition of the Na/H exchange by ethylisopropylamiloride (EIPA) completely reversed the phenylephrine-induced shift. Phenylephrine increased pH(i) (DeltapH(i) = +0.1), which was reversed by prazosin and EIPA. Chelerythrine, an inhibitor of protein kinase C (PKC), completely blocked the effects of phenylephrine on Ca(2+) responsiveness and pH(i). When pH(i) was increased (DeltapH(i) = +0.1) without phenylephrine by changing pH(o), the Ca-L trajectory was shifted to the same extent as that observed with phenylephrine. We conclude that alpha(1)-adrenoceptor stimulation activates Na/H exchange through a PKC-mediated pathway and that an increase in pH(i) is mainly responsible for the increase in Ca(2+) responsiveness.
Kusakari
Yoichiro
Y
Department of Physiology II, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461 Japan. kusakari@jikei.ac.jp
Hongo
Kenichi
K
Kawai
Makoto
M
Konishi
Masato
M
Kurihara
Satoshi
S
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006352:Heart Ventricles / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009210:Myofibrils / Q000187:drug effects / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology*; D011493:Protein Kinase C; D051381:Rats; D017208:Rats, Wistar
D000316:Adrenergic alpha-Agonists; D010656:Phenylephrine; D011493:Protein Kinase C; D007545:Isoproterenol; D002118:Calcium