Prostacyclin production by isolated rat adipocytes: evidence for cyclic adenosine 3',5'-monophosphate-dependent and independent mechanisms and for a selective effect of insulin.
The rat adipocyte contains two separate mechanisms for prostaglandin (PG) production. Norepinephrine stimulates prostacyclin (PGI2) and PGE2 production and triglyceride lipolysis in isolated rat adipocytes. In contrast, the vasoactive peptides angiotensin II, vasopressin, and bradykinin stimulate PGI2 production, but not PGE2 production or triglyceride lipolysis, in these cells. In this study, we characterized the two separate mechanisms of PG production with respect to the time course, the role of cAMP, the identity of the adrenergic receptor, and the effects of insulin and glucocorticoids. Angiotensin II stimulated PGI2 production rapidly (at 5 min) and independently of cAMP. beta-Adrenergic stimulation with isoproterenol produced a rapid 11-fold increase in the cAMP concentration and stimulated PGI2 production more slowly (at 120 min). The phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine (0.2 and 0.5 mM) and the adenylate cyclase activator forskolin (10 microM) also stimulated cAMP production rapidly and PGI2 production more slowly. 1-Methyl-3-isobutylxanthine (5.0 mM) further stimulated cAMP levels, but prevented the increase in PGI2 production and blunted the increase in glycerol release seen at lower concentrations. beta-Adrenergic blockade with propranolol or timolol completely inhibited the norepinephrine- or isoproterenol-stimulated production of PGI2 and triglyceride lipolysis, respectively. Insulin selectively inhibited isoproterenol-stimulated PGI2 production and triglyceride lipolysis at physiological concentrations, but had no effect on angiotensin II-stimulated PGI2 production. In contrast, dexamethasone inhibited PGI2 production induced by both isoproterenol and angiotensin II. We conclude that: angiotensin II stimulates PGI2 production rapidly and independently of cAMP, but isoproterenol stimulates PGI2 production more slowly, an effect that is cAMP dependent; insulin inhibits the cAMP-dependent beta-adrenergic stimulation of PGI2 production (and triglyceride lipolysis), but not the cAMP-independent angiotensin II-induced stimulation of PGI2 production (this suggests that the former effect is mediated by a decrease in cAMP levels in the adipocyte); and dexamethasone inhibits both mechanisms of PGI2 production. Both mechanisms of PGI2 production by rat adipocytes are exquisitely sensitive to hormonal regulation.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis*; D007328:Insulin / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D007328:Insulin; D000804:Angiotensin II; D005576:Colforsin; D015121:6-Ketoprostaglandin F1 alpha; D003907:Dexamethasone; D011464:Epoprostenol; D000242:Cyclic AMP; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine