Combination therapy with olmesartan and azelnidipine improves EDHF-mediated responses in diabetic apolipoprotein E-deficient mice.
BACKGROUND
The endothelium modulates vascular tone by synthesizing and releasing several vasodilating factors, including vasodilator prostaglandins, nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). In the present study, we examined whether an angiotensin-receptor blocker, a calcium-channel blocker or their combination improved EDHF-mediated responses in diabetic apolipoprotein E-deficient (ApoE(-/-)) mice.


RESULTS
We used male C57BL/6N (control) and streptozocin-induced diabetic ApoE(-/-) mice. The diabetic ApoE(-/-) mice were administered oral vehicle (untreated), olmesartan (OLM, 30 mgxkg(-1)xday(-1)), azelnidipine (AZL, 10 mgxkg(-1)xday(-1)), their combination (OLM + AZL), or hydralazine (HYD 5 mgxkg(-1)xday(-1)) for 5 weeks. In the untreated group, systolic blood pressure was significantly higher and both EDHF-mediated relaxation and endothelium-dependent hyperpolarization were markedly reduced as compared with the control group. Although EDHF-mediated relaxation was not significantly improved in the HYD, OLM and AZL groups, it was significantly improved in the OLM + AZL group, as was also the case with phosphorylation of Akt and endothelial NO synthase (eNOS). In contrast, the endothelium-independent relaxation response to sodium nitroprusside or NS-1619 (a direct opener of K(Ca) channels) was unaltered in any group.


CONCLUSIONS
OLM + AZL may improve the severely impaired EDHF-mediated responses in diabetic ApoE(-/-) mice, in which activation of the endothelial Akt - eNOS pathway may be involved.
Hosoya
Maki
M
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
Ohashi
Junko
J
Sawada
Ayuko
A
Takaki
Aya
A
Shimokawa
Hiroaki
H
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001685:Biological Factors / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D004095:Dihydropyridines / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013311:Streptozocin; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D001685:Biological Factors; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007093:Imidazoles; D013777:Tetrazoles; C067410:endothelium-dependent hyperpolarization factor; D001383:Azetidinecarboxylic Acid; D013311:Streptozocin; C437965:olmesartan; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; C061679:azelnidipine