Carbachol inhibition of Ca2+ currents in ventricular cells obtained from neonatal and adult rats.
We investigated the postnatal developmental changes produced by the muscarinic receptor agonist, carbachol, on the L-type Ca2+ current (ICa(L)) in neonatal (aged 5 to 7 days) and adult (aged 2 to 5 months) rat ventricular cells by using the whole-cell voltage clamp technique. Carbachol inhibited the isoproterenol-stimulated ICa(L). The maximal inhibition was 89.3 +/- 4.8% (n = 5) in neonatal cells and 17.7 +/- 7.7% (n = 9) in adult cells. Carbachol inhibited the forskolin-stimulated ICa(L) to almost same extent as the isoproterenol-stimulated ICa(L). In the cells pretreated with pertussis toxin, carbachol failed to inhibit the isoproterenol-stimulated ICa(L), indicating that carbachol produced its effect via a pertussis toxin-sensitive G-protein pathway. The effects of carbachol in adult cells became more pronounced, increasing from 17.7% to 54.8% (n = 11), with the addition of the synthetic inhibitory G-protein alpha subunit (Gi alpha) (1 microM) to the reaction. Conversely, the alpha subunit of another pertussis toxin-sensitive synthetic G-protein (G(o) alpha, 1 microM) failed to mimic the effect of Gi alpha. These results suggest that, in rat ventricular cells, (1) the action of carbachol on ICa(L) showed a marked decrease during development; (2) the decrease in the effect of carbachol in adult cells is in part due to a decrease in the activity of pertussis toxin-sensitive G protein, especially Gi alpha.
Katsube
Y
Y
Department of Pediatrics, Nippon Medical School Hospital, Tokyo, Japan.
Yokoshiki
H
H
Sunagawa
M
M
Seki
T
T
Yamamoto
M
M
Sperelakis
N
N
D000818:Animals; D000831:Animals, Newborn; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D019204:GTP-Binding Proteins / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects*; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D016276:Ventricular Function
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002316:Cardiotonic Agents; D018721:Muscarinic Agonists; D005576:Colforsin; D002217:Carbachol; D019204:GTP-Binding Proteins; D007545:Isoproterenol