Putative, selective inhibitors of sarcoplasmic reticulum Ca+(+)-pump ATPase inhibit relaxation by nitroglycerin and atrial natriuretic factor of the rabbit aorta contracted by phenylephrine.
Using three putative, selective inhibitors of the Ca+(+)-pump ATPase of sarcoplasmic reticulum (SR), cyclopiazonic acid, thapsigargin and 2,5-di-(tert-butyl)-1,4-benzohydroquinone, the mechanisms of relaxation of the arterial smooth muscle by cyclic GMP-generating vasodilators were studied in the ring preparations of the rabbit aorta. Nitroglycerin (NTG) and atrial natriuretic factor (ANF) were used as representative cyclic GMP-generating vasodilators. When the above three inhibitors of SR Ca+(+)-pump ATPase were present during the period of reloading of intracellular store sites with Ca++, the phasic contractions induced by phenylephrine or caffeine in the succeeding period in Ca+(+)-free media containing 2 mM EGTA were inhibited in a concentration-dependent manner. With 3 x 10(-5) M of cyclopiazonic acid the inhibition was almost complete for both agonists. NTG and ANF relaxed the aorta contracted by phenylephrine (10(-6) M) and produced an increase in cyclic GMP content. All the three SR Ca+(+)-pump ATPase inhibitors produced a concentration-dependent inhibition of the relaxation by NTG and ANF without affecting the increment of cyclic GMP content. These results indicate that the proper functioning of SR Ca+(+)-pump ATPase is necessary for elicitation of relaxation by NTG and ANF. Enhanced sequestration of Ca++ by SR may be an important mechanism by which these compounds induce relaxation in this type of smooth muscle.
Department of Pharmacology, Niigata University School of Medicine, Japan.
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Luo
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Nakazawa
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Ishibashi
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Kato
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Imai
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001011:Aorta; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000187:drug effects / Q000502:physiology*; D004110:Diltiazem / Q000494:pharmacology; D004347:Drug Interactions; D006873:Hydroquinones / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D005996:Nitroglycerin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin
D006873:Hydroquinones; D007211:Indoles; D013729:Terpenes; D010656:Phenylephrine; C019359:2,5-di-tert-butylhydroquinone; D019284:Thapsigargin; D009320:Atrial Natriuretic Factor; D000251:Adenosine Triphosphatases; D000252:Calcium-Transporting ATPases; D004110:Diltiazem; D005996:Nitroglycerin; D002118:Calcium; C000543:cyclopiazonic acid