Functional changes in adenylyl cyclases and associated decreases in relaxation responses in mesenteric arteries from diabetic rats

Abstract

Matsumoto, Takayuki, Kentaro Wakabayashi, Tsuneo Kobayashi, and Katsuo Kamata. Functional changes in adenylyl cyclases and associated decreases in relaxation responses in mesenteric arteries from diabetic rats. Am J Physiol Heart Circ Physiol 289: H2234-H2243, 2005. First published May 13, 2005; doi:10.1152/ajpheart.00971.2004.-To assess the functional change in adenylyl cyclases (AC) associated with the diabetic state, we investigated AC-mediated relaxations and cAMP production in mesenteric arteries from rats with streptozotocin (STZ)-induced diabetes. The relaxations induced by the water-soluble forskolin (FSK) analog NKH477, which is a putative AC5 activator, but not by the ␤-adrenoceptor agonist isoproterenol (Iso) and the AC activator FSK, were reduced in intact diabetic mesenteric artery. In diabetic rats, however, Iso-, FSK-, and NKH477-induced relaxations were 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 SQ-22536, 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 FSK-nor A-23187 (a Ca 2ϩ ionophore)-induced cAMP production was significantly different between diabetics and controls. However, cAMP production induced by Iso or NKH477 was significantly impaired in diabetic mesenteric arteries. Expression of mRNAs and proteins for AC5/6 was lower in diabetic mesenteric arteries than in 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.

Physical activity maintains aortic endothelium-dependent relaxation in the obese type 2 diabetic OLETF rat

“…3F and 4, E and F) makes it difficult to establish the exact cause of this decline in aortic function. Studies have shown that molecular mechanisms such as diminished expression and/or activity of vascular smooth muscle cell guanylyl cyclase (1,26) or adenylyl cyclase (37,38) contribute to impaired vasodilatory responsiveness in a sedentary lifestyle and T2DM progression, similar to sedentary OLETF rats in this study.…”

Connexins and gap junctions in the EDHF phenomenon and conducted vasomotor responses

“…A single abnormality seems unlikely, however, because there may be increased cAMP hydrolysis by type 3 phosphodiesterase, reduced generation of cAMP secondary to impaired activity of adenylate cyclases types 5/6, and impaired PKA function, possibly resulting from altered catalytic and regulatory subunit expression [125][126][127][128]. Furthermore, abnormalities in other essential components of the EDHF pathway such as impaired SK Ca channel function and reduced Cx40 expression have also been described [20,208].…”

Increased Enzyme Activity and β-Adrenergic–Mediated Vasodilation in Subjects Expressing a Single-Nucleotide Variant of Human Adenylyl Cyclase 6

“…In a model of acquired diabetes, the defect in vascular relaxation responses have been linked to impaired adenylyl cyclase function and reduced protein expression of ADCY5/ ADCY6. 12 In mice with cardiomyopathy, cardiac expression of ADCY5 or ADCY6 improves cardiac function 13,14 and survival. 15 In transgenic mice, inhibition of adenylyl cyclase activity via activation of G i␣2 results in insulin resistance.…”