Rho kinase inhibitors reduce neurally evoked contraction of the rat tail artery in vitro.
The effects of Rho kinase inhibitors (Y27632, HA-1077) on contractions to electrical stimulation and to application of phenylephrine, clonidine or alpha,beta-methylene adenosine 5'-triphosphate (alpha,beta-mATP) were investigated in rat tail artery in vitro. In addition, continuous amperometry and intracellular recording were used to monitor the effects of Y27632 on noradrenaline (NA) release and postjunctional electrical activity, respectively. Y27632 (0.5 and 1 microM) and HA-1077 (5 microM) reduced neurally evoked contractions. In contrast, the protein kinase C inhibitor, Ro31-8220 (1 microM), had little effect on neurally evoked contraction. In the absence and the presence of Y27632 (0.5 microM), the reduction of neurally evoked contraction produced by the alpha-adrenoceptor antagonists prazosin (10 nM) and idazoxan (0.1 microM) was similar. The P2-purinoceptor antagonist, suramin (0.1 mM), had no inhibitory effect on neurally evoked contraction in the absence or the presence of Y27632 (1 microM). In the presence of Y27632, desensitization of P2X-purinoceptors with alpha,beta-mATP (10 microM) increased neurally evoked contractions.Y27632 (1 microM) and H-1077 (5 microM) reduced sensitivity to phenylephrine and clonidine. In addition, Y27632 reduced contractions to alpha,beta-mATP (10 microM). Y27632 (1 microM) had no effect on the NA-induced oxidation currents or the purinergic excitatory junction potentials and NA-induced slow depolarizations evoked by electrical stimulation. Rho kinase inhibitors reduce sympathetic nerve-mediated contractions of the tail artery. This effect is mediated at a postjunctional site, most likely by inhibition of Rho kinase-mediated 'Ca2+ sensitization' of the contractile apparatus.
Yeoh
Melanie
M
Prince of Wales Medical Research Institute, University of New South Wales, Barker St., Randwick, NSW 2031, Australia.
Brock
James A
JA
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D003000:Clonidine / Q000494:pharmacology; D004558:Electric Stimulation; D004594:Electrophysiology / Q000379:methods; D005260:Female; D019329:Idazoxan / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage; D047908:Intracellular Signaling Peptides and Proteins; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013498:Suramin / Q000494:pharmacology; D013623:Tail / Q000098:blood supply* / Q000294:innervation; D014661:Vasoconstriction / Q000187:drug effects*; D054460:rho-Associated Kinases
D000317:Adrenergic alpha-Antagonists; D000577:Amides; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D011725:Pyridines; C108830:Y 27632; D010656:Phenylephrine; D013498:Suramin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D003000:Clonidine; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; C049347:fasudil; C064758:Ro 31-8220; D011224:Prazosin; D019329:Idazoxan