Influence of diabetes mellitus, hypercholesterolemia, and their combination on EDHF-mediated responses in mice.

Abstract

The endothelium synthesizes and releases several vasodilator substances, including vasodilator prostaglandins, NO, and EDHF. NO-mediated relaxations are reduced by various risk factors, such as diabetes mellitus and hypercholesterolemia. However, it remains to be elucidated whether EDHF-mediated relaxations also are reduced by those factors and their combination. In this study, we addressed this point in mice. We used small mesenteric arteries from control, diabetic (streptozotocin-induced), apolipoprotein-E-deficient (ApoE-/-), and diabetic ApoE-/- mice. In control mice, endothelium-dependent relaxations to acetylcholine were largely mediated by EDHF. This EDHF-mediated component was slightly reduced in diabetic mice, preserved in ApoE-/- mice, and markedly reduced in diabetic ApoE-/- mice with an increase in NO-mediated component and a negative contribution of indomethacin-sensitive endothelium-derived contracting factor (EDCF). Endothelium-independent relaxations to sodium nitroprusside or NS1619, a direct opener of calcium-activated K channels, were attenuated in ApoE-/- and diabetic ApoE-/- mice. Endothelium-dependent hyperpolarizations were significantly reduced in diabetic mice, preserved in ApoE-/- mice, and again markedly reduced in diabetic ApoE-/- mice. These results indicate that hypercholesterolemia alone minimally affects the EDHF-mediated relaxations, and diabetes mellitus significantly attenuated the responses, whereas their combination markedly attenuates the responses with a compensatory involvement of NO and a negative contribution of EDCF.

• Authors: Keiko Morikawa, Tetsuya Matoba, Hiroshi Kubota, Makoto Hatanaka, Takako Fujiki, Shosuke Takahashi, Akira Takeshita, Hiroaki Shimokawa
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 45 Issue 5 Pg. 485-90 (May 2005) ISSN: 0160-2446 [Print] United States
• PMID: 15821445 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Benzimidazoles
• Biological Factors
• Blood Glucose
• Endothelium-Dependent Relaxing Factors
• Lipids
• Potassium Channels
• Vasodilator Agents
• endothelium-dependent hyperpolarization factor
• NS 1619
• Nitroprusside
• Nitric Oxide
• Acetylcholine

Topics

• Acetylcholine (pharmacology)
• Animals
• Apolipoproteins E (deficiency)
• Benzimidazoles (pharmacology)
• Biological Factors (physiology)
• Blood Glucose (analysis)
• Diabetes Mellitus, Experimental (physiopathology)
• Dose-Response Relationship, Drug
• Endothelium, Vascular (drug effects, physiology)
• Endothelium-Dependent Relaxing Factors (pharmacology)
• Hypercholesterolemia (physiopathology)
• Lipids (blood)
• Membrane Potentials (drug effects)
• Mesenteric Arteries (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide (pharmacology)
• Nitroprusside (pharmacology)
• Potassium Channels (physiology)
• Vasodilation (drug effects, physiology)
• Vasodilator Agents (pharmacology)