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Effects of cyclic GMP elevation on isoprenaline‐induced increase in cyclic AMP and relaxation in rat aortic smooth muscle: role of phosphodiesterase 3
Author(s) -
Delpy Eric,
Coste Hervé,
Gouville AnneCharlotte le Monnier
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15696.x
Subject(s) - isoprenaline , phenylephrine , chemistry , endocrinology , sodium nitroprusside , forskolin , medicine , phosphodiesterase inhibitor , roxithromycin , soluble guanylyl cyclase , phosphodiesterase , cyclic guanosine monophosphate , guanosine , nitric oxide , adenosine , agonist , biochemistry , biology , cyclic gmp , receptor , enzyme , erythromycin , stimulation , blood pressure , antibiotics
1 In rat aortic rings precontracted with phenylephrine, the β‐adrenoceptor agonist isoprenaline (10 nM to 30 μ m ) produces greater relaxant effects in preparations with endothelium than in endothelium‐denuded preparations. The aim of this study was to determine the mechanisms involved in this effect and in particular investigate the possibility of a synergistic action between adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) and guanosine 3′:5′‐cyclic monophosphate (cyclic GMP). 2 Isoprenaline‐induced relaxation of rat aortic rings precontracted with phenylephrine was greatly reduced by the nitric oxide (NO) synthase inhibitor N ω ‐nitro‐L‐arginine methyl ester (L‐NAME, 300 μ m ) or the soluble guanylate cyclase inhibitors methylene blue (10 μ m ) or 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ, 10 μ m ) but unaffected by indomethacin (10 μ m ), a cyclo‐oxygenase inhibitor. Similarly, in intact rings, the concentration‐response curve of forskolin (10 nM to 1 μ m ) was shifted to the right upon endothelium removal or treatment with methylene blue. 3 In endothelium‐denuded rat aortic rings, isoprenaline‐induced relaxation was potentiated by the guanylate cyclase activators atrial natriuretic factor (ANF, 1 to 10 nM) and sodium nitroprusside (SNP, 1 to 10 nM), and to a greater extent in the presence of the cyclic GMP‐specific phosphodiesterase (PDE 5) inhibitor, 1,3dimethyl‐6‐(2‐propoxy‐5‐methane sulphonylamidophenyl) pyrazolo [3,4‐d] pyrimidin‐4‐(5H)‐one (DMPPO, 30 nM). Relaxation induced by isoprenaline was also potentiated by the cyclic GMP‐inhibited PDE (PDE 3) inhibitor cilostamide (100 nM). 4 Intracellular cyclic nucleotide levels were measured either in rat cultured aortic smooth muscle cells or in de‐endothelialized aortic rings. In both types of preparation, isoprenaline (5 nM and 10 μ m ) increased cyclic AMP levels and this effect was potentiated by cilostamide (10 μ m ), by rolipram, a cyclic AMP‐specific PDE (PDE 4) inhibitor (10 μ m ) and by cyclic GMP‐elevating agents (50 nM ANF or 30 nM SNP plus 100 nM DMPPO). In isoprenaline‐stimulated conditions, the increase in cyclic AMP induced by rolipram was further potentiated by cilostamide and by cyclic GMP‐elevating agents. Cilostamide and cyclic GMP‐elevating agents did not potentiate each other, suggesting a similar mechanism of action. 5 We conclude that in vascular smooth muscle (VSM) cells an increase in cyclic GMP levels may inhibit PDE 3 and, thereby, cyclic AMP catabolism. Under physiological conditions of constitutive NO release, and to a greater extent in the presence of the PDE 5 inhibitor DMPPO, cyclic GMP should act synergistically with adenylate cyclase activators to relax VSM.