Effect of Ca2+/calmodulin-dependent protein kinase II inhibitors on the neurogenic cerebroarterial relaxation.
In canine cerebral artery strips contracted with prostaglandin F2alpha, transmural electrical stimulation (5 Hz for 40 s) produced a relaxation which was abolished by tetrodotoxin. The neurogenic response was inhibited moderately by [S]-5-isoquinolinesulfonic acid,4-[2-[(5-isoquinolinyl-sulfonyl)methylamino]-3-oxo-(4-phenyl-1-piperazinyl)-propyl] phenyl ester (KN62), an inhibitor of Ca2+ /calmodulin-dependent protein kinase II, which however did not alter or only slightly reduced the relaxant response to electrical nerve stimulation in canine coronary arterial strips that is mediated via beta-adrenoceptors stimulated by norepinephrine. Nicotine-induced relaxation, mediated by nitric oxide (NO) derived from perivascular nerves, was also attenuated by KN62, whereas the response to exogenous NO was unaffected. The nicotine-induced increase in the cyclic GMP content in cerebral arteries was depressed by KN62. The neurogenic relaxation was not influenced by phorbol 12-myristate 13-acetate, an activator of protein kinase C. 8-Bromo-cyclic GMP and 8-bromo-cyclic AMP did not significantly alter the response to nerve stimulation. It is concluded that the phosphorylation pathway involving Ca2+/calmodulin-dependent protein kinase II, but not other protein kinases so far tested, appears to be involved in the function of vasodilator nerves innervating the cerebral artery.
Toda
N
N
Department of Pharmacology, Shiga University of Medical Sciences, Seta, Ohtsu, Japan. toda@bellebsd.shiga-med.ac.jp
Ayajiki
K
K
Okamura
T
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002536:Cerebral Arteries / Q000187:drug effects* / Q000294:innervation; D003331:Coronary Vessels / Q000187:drug effects / Q000294:innervation; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000032:analysis / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D004285:Dogs; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010120:Oxytocics / Q000494:pharmacology; D010766:Phosphorylation; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018722:Nicotinic Agonists; D010120:Oxytocics; D011943:Receptors, Adrenergic, beta; D014662:Vasoconstrictor Agents; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; D013779:Tetrodotoxin; C063302:KN 62; D009538:Nicotine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015237:Dinoprost; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D006152:Cyclic GMP; D013755:Tetradecanoylphorbol Acetate; D009638:Norepinephrine