Abstract
Individual vascular beds exhibit differences in vascular reactivity. The present study investigates the effects of streptozotocin-induced type I diabetes on endothelium-dependent responses of rat carotid, femoral, and mesenteric arteries. Rings with and without endothelium, suspended in organ chambers for isometric tension recording, were contracted with phenylephrine and exposed to increasing concentrations of acetylcholine. In carotid and femoral arteries, acetylcholine produced concentration- and endothelium-dependent relaxations that were abolished by Nω-nitro-l-arginine methyl ester (l-NAME; specific nitric-oxide synthase inhibitor) and were impaired slightly in preparations from streptozotocin-treated rats (STZ-rats). This impairment could be prevented by l-arginine. In femoral arteries incubated with l-NAME, acetylcholine caused endothelium-dependent contractions that were abolished by 3-[(6-amino-(4-chlorobenzensulfonyl)-2-methyl-5,6,7,8-tetrahydronapht]-1-yl) propionic acid (S18886) (antagonist of thromboxane A2/prostaglandins H2-receptors) and reversed to relaxation by indomethacin (inhibitor of cyclooxygenase). The latter relaxation was inhibited by charybdotoxin plus apamin, suggesting a role of endothelium-dependent hyperpolarizing factor (EDHF). This EDHF-mediated component was augmented slightly in arteries from STZ-rats. In mesenteric arteries, relaxations to acetylcholine were only partially inhibited by l-NAME, and the l-NAME-resistant component was abolished by charybdotoxin plus apamin. In the mesenteric arteries from STZ-rats, l-NAME-sensitive relaxations to acetylcholine were reduced and the EDHF-component was augmented. These findings demonstrate a marked heterogeneity in endothelium-dependent responses in rat arteries and their differential adaptation in the course of type I diabetes. In particular, the EDHF-mediated component not only compensates for the reduced bioavailability of nitric oxide in the femoral and mesenteric artery but also counteracts the augmented endothelium-dependent contractions in the former.
Footnotes
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This study was supported in part by Research Grants Council Grant HKU 7524.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.099739.
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ABBREVIATIONS: STZ, streptozotocin; EDCF, endothelium-derived contracting factor; EDHF, endothelium-dependent hyperpolarizing factor; l-NAME, Nω-nitro-l-arginine methyl ester; S18886, 3-[(6-amino-(4-chlorobenzensulfonyl)-2-methyl-5,6,7,8-tetrahydronapht]-1-yl) propionic acid; P450, cytochrome P450; TP, thromboxane A2/prostaglandins H2.
- Received December 12, 2005.
- Accepted March 23, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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