Influence of diabetes mellitus, hypercholesterolemia, and their combination on EDHF-mediated responses in mice.
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.
Morikawa
Keiko
K
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Matoba
Tetsuya
T
Kubota
Hiroshi
H
Hatanaka
Makoto
M
Fujiki
Takako
T
Takahashi
Shosuke
S
Takeshita
Akira
A
Shimokawa
Hiroaki
H
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D001562:Benzimidazoles / Q000494:pharmacology; D001685:Biological Factors / Q000502:physiology*; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D045462:Endothelium-Dependent Relaxing Factors / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000503:physiopathology*; D008055:Lipids / Q000097:blood; D008564:Membrane Potentials / Q000187:drug effects; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D001057:Apolipoproteins E; D001562:Benzimidazoles; D001685:Biological Factors; D001786:Blood Glucose; D045462:Endothelium-Dependent Relaxing Factors; D008055:Lipids; D015221:Potassium Channels; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; C086491:NS 1619; D009599:Nitroprusside; D009569:Nitric Oxide; D000109:Acetylcholine