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Mechanisms underlying reduced P 2 Y 1 ‐receptor‐mediated relaxation in superior mesenteric arteries from long‐term streptozotocin‐induced diabetic rats
Author(s) -
Ishida K.,
Matsumoto T.,
Taguchi K.,
Kamata K.,
Kobayashi T.
Publication year - 2013
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/j.1748-1716.2012.02469.x
Subject(s) - streptozotocin , mesenteric arteries , receptor , term (time) , chemistry , endocrinology , medicine , microbiology and biotechnology , diabetes mellitus , biology , artery , physics , quantum mechanics
Abstract Aim Extracellular nucleotides activate cell‐surface purinergic ( P 2) receptors, contribute to the local regulation of vascular tone and play important roles in pathophysiological states. However, little is known about the vasodilator effects of P 2 Y 1 ‐receptor activation in diabetic states. We hypothesized that in a model of established type 1 diabetes, long‐term streptozotocin ( STZ )‐induced diabetic rats, the arterial relaxation elicited by a P 2 Y 1 ‐receptor agonist would be impaired. Methods Relaxations to adenosine 5′‐diphosphate sodium salt ( ADP ), 2‐ M e SADP (selective P 2 Y 1 ‐receptor agonist) and adenosine 5′‐triphosphate disodium salt ( ATP ) were examined in superior mesenteric artery rings from long‐term STZ ‐induced diabetic rats (at 50–57 weeks after STZ injection). ADP ‐stimulated nitric oxide ( NO ) production in the superior mesenteric artery was assessed by measuring the levels of NO metabolites. Mesenteric artery expressions of P 2 Y 1 receptor, and ADP ‐stimulated levels of phosphorylated endothelial NO synthase (e NOS ) (at S er 1177 and at T hr 495 ) and e NOS were detected by W estern blotting. Results Arteries from diabetic rats exhibited (vs. those from age‐matched control rats): (i) reduced ADP ‐induced relaxation, which was partly or completely inhibited by endothelial denudation, by NOS inhibitor treatment and by a selective P 2 Y 1 ‐receptor antagonist, (ii) reduced 2‐ M e SADP ‐induced relaxation, (iii) reduced ADP ‐stimulated release of NO metabolites and (iv) impaired ADP ‐induced stimulation of e NOS activity (as evidenced by reduced the fold increase in e NOS phosphorylation at S er 1177 with no difference in fold increase in e NOS phosphorylation at T hr 495 ). The protein expression of P 2 Y 1 receptor did not differ between diabetic and control arteries. Conclusions These results suggest that P 2 Y 1 ‐receptor‐mediated vasodilatation is impaired in superior mesenteric arteries from long‐term type 1 diabetic rats. This impairment is because of reduced P 2 Y 1 ‐receptor‐mediated NO signalling, rather than to reduced P 2 Y 1 ‐receptor expression.