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Role of cyclic nucleotides in vasodilations of the rat thoracic aorta induced by adenosine analogues
Author(s) -
Hourani Susanna M O,
Boon Katherine,
Fooks Helen M,
Prentice Deborah J
Publication year - 2001
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 - 10.1038/sj.bjp.0704140
Subject(s) - zaprinast , adenosine , acetylcholine , phosphodiesterase , medicine , endocrinology , cyclase , chemistry , ibmx , adenosine receptor , phosphodiesterase inhibitor , stimulation , adenylate kinase , receptor , pharmacology , biology , biochemistry , agonist , enzyme , forskolin
Although adenosine analogues such as 5′‐N‐ethylcarboxamidoadenosine (NECA) relax the rat thoracic aorta in a partially endothelium‐dependent manner via adenosine A 2A receptors, others such as N 6 ‐R‐phenylisopropyladenosine (R‐PIA) act via an endothelium‐independent, antagonist‐insensitive mechanism. The role of cyclic nucleotides in these relaxations was investigated in isolated aortic rings using inhibitors of adenylate and guanylate cyclases as well as subtype‐selective phosphodiesterase inhibitors. The adenylate cyclase inhibitor 9‐(tetrahydro‐2‐furanyl)‐9H‐purin‐6‐amine (SQ 22536; 100 μ M ) significantly inhibited responses to NECA, but not responses to R‐PIA. The type IV (cyclic AMP‐selective) phosphodiesterase inhibitor 4‐[(3‐butoxy‐4‐methoxyphenyl)methyl]‐2‐imidazolidinone (RO 20‐1724; 30 μ M ) significantly enhanced responses to NECA and to a lesser extent those to R‐PIA. The guanylate cyclase inhibitor 1H‐[1,2,4]oxadiazolo[4,3a]quinoxalin‐1‐one (ODQ; 100 μ M ) significantly inhibited responses to NECA and acetylcholine but not responses to R‐PIA. The selective phosphodiesterase V (cyclic GMP‐selective) inhibitors, zaprinast (10 μ M ) and 4‐{[3′,4′‐(methylenedioxy)benzyl]amino}‐6‐methoxyquinazoline (MMQ; 1 μ M ), had no significant effect on responses to either NECA or R‐PIA, but enhanced responses to acetylcholine. These results are consistent with the effects of NECA being via activation of endothelial receptors to release NO which stimulates guanylate cyclase, as well as smooth muscle receptors coupled to stimulation of adenylate cyclase. The lack of effect of zaprinast and MMQ on responses to NECA are likely to be due to simultaneous activation of both adenylate and guanylate cyclases in the smooth muscle, as cyclic AMP reduces the sensitivity of phosphodiesterase V to inhibitors. These results also suggest that the effects of R‐PIA are via neither of these mechanisms.British Journal of Pharmacology (2001) 133 , 833–840; doi: 10.1038/sj.bjp.0704140