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.