ucn-1028-c and fasudil

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.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Adenosine Triphosphate; Adrenergic alpha-Antagonists; Animals; Cantharidin; Dose-Response Relationship, Drug; Drug Synergism; Electric Stimulation; Enzyme Inhibitors; Guinea Pigs; Histamine; Intracellular Signaling Peptides and Proteins; Male; Muscle Contraction; Muscle, Smooth; Naphthalenes; Norepinephrine; Phorbol 12,13-Dibutyrate; Phosphoprotein Phosphatases; Prazosin; Protein Kinase C; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; rho-Associated Kinases; Vas Deferens