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1 Physiology and Morphology, Hoshi University, Shinagawa-ku, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: kamata{at}hoshi.ac.jp.
To assess the functional change in adenylyl cyclases (ACs) associated with the diabetic state, we investigated ACs-mediated relaxations and cAMP production in mesenteric arteries from streptozotocin (STZ)-induced diabetic rats. The relaxations induced by a water-soluble FSK analog NKH477, which is putative AC5 activator but not by 
-adrenoceptor agonist isoproterenol (ISO) and AC activator forskolin was reduced in intact diabetic mesenteric artery. In diabetic rats, however, ISO-, FSK-, and NKH477-induced relaxation was attenuated in the presence of inhibitors of nitric oxide synthase and cyclooxygenase. To exclude the influence of phosphodiesterase (PDE), we also examined the relaxations induced by several AC activators in the presence of 3-isobutyl-1-methylxanthine (IBMX; a PDE inhibitor). Under these conditions, the relaxation induced by ISO was greatly impaired in STZ-diabetic rats. This ISO-induced relaxation was significantly attenuated by pretreatment with SQ22536, an AC inhibitor, in mesenteric rings from age-matched controls, but not in those from STZ-diabetic rats. Under the same conditions, the relaxations induced by FSK or NKH477 were impaired in STZ-diabetic rats. Neither the, FSK- nor A23187 (a Ca2+ ionophore)-induced cAMP production was significantly different between diabetics and controls. However, the cAMP production induced by ISO and NKH477 were significantly impaired in diabetic mesenteric arteries. The expression of the mRNAs and proteins for AC5/6 were lower in diabetic mesenteric arteries than in the controls. These results suggest that AC-mediated relaxation is impaired in the STZ-diabetic rat mesenteric artery, perhaps reflecting a reduction in AC5/6 activity.
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