Role of nitric oxide and endothelin in endothelial maintenance of vasoconstrictor responses in aortas of diabetic female rats.

J Diabetes. 2013 Jun;5(2):197-206.

Simone M. Sartoretto1, Rosângela Santos-Eichler1, Rita de Cássia A. Tostes2, Maria Helena C. Carvalho1,Eliana H. Akamine1, Zuleica B. Fortes1

1 Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil

2 Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil



Zuleica B. Fortes

Dept. Pharmacology

Institute of Biomedical Sciences

University of São Paulo

05508-900 – São Paulo – SP


Phone/FAX: 55-11-3091-7317




BACKGROUND: Diabetes differentially affects the vascular system in males and females. Although various results have been reported, very few studies have focused on vascular reactivity in females. In the present study, we investigated contractile responses to norepinephrine in aortas of alloxan-diabetic female rats and evaluated endothelial modulation of these responses.

METHODS: Concentration-response curves were constructed to norepinephrine in the absence or presence of N(G) -nitro-l-arginine methyl ester (l-NAME), indomethacin, losartan, tezosentan, and calphostin C; pre-pro-endothelin mRNA expression was evaluated; and norepinephrine-stimulated expression of phosphorylated (p-) Akt Ser(473) , p-endothelial nitric oxide synthase (eNOS) Ser(1177) , and p-eNOS Ser(633) were determined in endothelial cells incubated in the presence of low (5 mmol/L) or high (25 mmol/L) glucose concentrations.

RESULTS: Similar maximal responses (Rmax ) to norepinephrine were seen in control and diabetic endothelium-intact aortas; however, Rmax was reduced in diabetic endothelium-denuded aortas. Incubation of endothelium-intact aortas with 100 μmol/L l-NAME increased Rmax in the control group only. Inhibition of cyclo-oxygenase (10 μmol/L indomethacin) and blockade of angiotensin II receptors (10 μmol/L losartan) reduced Rmax in endothelium-intact aortas in both the control and diabetic groups. Blockade of endothelin receptors (0.1 μmol/L tezosentan) and inhibition of protein kinase C (PKC; 0.1 μmol/L calphostin C) reduced Rmax only in endothelium-intact aortas from diabetic rats. Pre-pro-endothelin mRNA expression was increased in aortas from diabetic female rats. Finally, p-Akt Ser(473) , p-eNOS Ser(1177) , and p-eNOS Ser(633) levels were enhanced after norepinephrine stimulation only in low glucose-treated endothelial cells.

CONCLUSIONS: In aortas of diabetic female rats, reductions in smooth muscle contractile responses to norepinephrine are counterbalanced by the endothelium via reduced eNOS activation and increased endothelin release and PKC activation.

PMID: 23061464



Hyperglycemia negatively affects the vascular system, but results of vascular reactivity to vasoconstrictor agents in both animal models and in patients with type 1 diabetes mellitus are controversial. The gender, the type of artery, the vasoconstrictor agents, and the duration of diabetes are examples of experimental variables, which may contribute to the controversial results.13-15

Endothelial cells modulate the vascular tonus by releasing relaxing and constricting factors. Diabetes promotes a different balance of endothelium-derived relaxing and constricting factors in males and females, which could cause differential changes in the vascular contractile response in diabetic rats and contribute to the controversial data regarding contractile response in diabetes. However, diabetes-induced cardiovascular alterations are often studied in males, sex differences are not considered, and data regarding this issue are in general extrapolated from males to females.

The objective of the study was to evaluate the contractile response to noradrenaline in the aorta of diabetic female rats and its modulation by the endothelium; and the endothelium-derived factors involved in the modulation of noradrenaline response.

The main findings of the study are that, in female diabetic rats, the endothelium compensates for the reduction in smooth muscle vascular contractile response to noradrenaline through reduced negative modulation by nitric oxide and increased positive modulation by endothelin. PKC may be involved in the participation of endothelin in this compensatory process. Our findings suggest that the presence of the endothelium is a confounding factor and may contribute to the previously reported controversial data regarding vascular contraction in diabetes. In females, the endothelium may mask a reduced vascular contractile response.


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