Alpha 1-adrenergic and muscarinic cholinergic stimulation of phosphoinositide hydrolysis in adult rat cardiomyocytes.
Cardiac alpha-adrenergic receptors mediate cellular responses to norepinephrine through an undefined series of molecular events. We examined the possibility that phosphoinositide hydrolysis was stimulated through alpha-adrenergic receptors in cardiomyocytes purified from adult rat ventricle. Phosphoinositide stores were labeled with [3H]inositol, and [3H]inositol phosphate formation was assessed after the addition of lithium chloride and norepinephrine. Norepinephrine increased the accumulation of [3H]inositol phosphate by approximately 5-fold, giving a maximal response at approximately 30 microM and a half-maximal response at approximately 1 microM. There was a significant increase in [3H]inositol phosphate formation in response to norepinephrine at 5 minutes, and the response was linear over 40 minutes. Norepinephrine-stimulated [3H]inositol phosphate formation was not blocked by propranolol (1 microM) or yohimbine (0.1 microM) but was completely antagonized by the alpha 1-selective antagonist prazosin (0.1 microM). Muscarinic cholinergic receptor activation by carbachol also stimulated [3H]inositol phosphate formation in rat ventricular myocytes. The maximal effect of carbachol (approximately 2-fold) was always less than that of norepinephrine. The combined effects of norepinephrine and carbachol were additive, suggesting that the two hormones do not share a common rate-limiting step. Removal of extracellular calcium and addition of ethylene glycol bis(beta-amino ether)-N,N'-tetraacetic acid, attenuated, but did not abolish, norepinephrine- or carbachol-stimulated [3H]inositol phosphate formation. Neither the calcium ionophore A23187 nor the calcium channel blockers verapamil and nifedipine had any effect on basal or hormone-stimulated [3H]inositol phosphate formation. We suggest that some of the physiological and metabolic effects of adrenergic and cholinergic stimulation on the rat myocardium are secondary to receptor-mediated hydrolysis of phosphoinositides.
Brown
J H
JH
Buxton
I L
IL
Brunton
L L
LL
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006868:Hydrolysis; D007294:Inositol / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D007473:Ion Channels / Q000502:physiology; D007700:Kinetics; D008094:Lithium / Q000494:pharmacology; D018021:Lithium Chloride; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000502:physiology*
D002712:Chlorides; D007295:Inositol Phosphates; D007473:Ion Channels; D010716:Phosphatidylinositols; D011942:Receptors, Adrenergic, alpha; D011976:Receptors, Muscarinic; D000001:Calcimycin; D007294:Inositol; D011813:Quinuclidinyl Benzilate; D002217:Carbachol; D008094:Lithium; D018021:Lithium Chloride; D002118:Calcium; D009638:Norepinephrine