Mechanisms underlying postjunctional synergism between responses of the vas deferens to noradrenaline and ATP.
Mechanisms of postjunctional synergism between adenosine 5'-triphosphate (ATP) and noradrenaline were studied in isolated guinea pig vas deferens. Whereas prior exposure to ATP had no significant effect on noradrenaline-mediated contractions, noradrenaline concentration-dependently enhanced ATP-induced contractions. Similarly to noradrenaline, histamine, which also acts via phospholipase-coupled receptors, induced contractions of the vas deferens and enhanced subsequent responses to ATP. Although phorbol-12, 13-dibutyrate (PDBu), a stimulant of protein kinase C (PKC), failed to induce contractions, it significantly potentiated ATP-induced contractions. The PKC inhibitor, Calphostin C, prevented this effect and the noradrenaline-mediated enhancement of ATP-induced contractions. The phosphatase inhibitor cantharidin induced a time- and concentration-dependent tonic contraction and markedly increased subsequent contractions to ATP. It is suggested that noradrenaline potentiates the contractile response of the vas deferens to ATP via a PKC-mediated mechanism. This may involve the inhibition of myosin light chain phosphatase (MLCP) and subsequent calcium sensitisation.
Smith
Neil C E
NC
Autonomic Neuroscience Institute, Royal Free and University College Medical School, Rowland Hill Street, London, NW3 2PF, UK.
Burnstock
Geoffrey
G
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002193:Cantharidin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011224:Prazosin / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014649:Vas Deferens / Q000187:drug effects* / Q000502:physiology; D054460:rho-Associated Kinases
D000317:Adrenergic alpha-Antagonists; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D015240:Phorbol 12,13-Dibutyrate; D006632:Histamine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; C058819:calphostin C; D002193:Cantharidin; C049347:fasudil; D009638:Norepinephrine; D011224:Prazosin