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. 2023 Aug 31;24(17):13532.
doi: 10.3390/ijms241713532.

Improvement of Vascular Insulin Sensitivity by Ranolazine

Sol Guerra-Ojeda  1 , Adrian Jorda  1   2 , Constanza Aldasoro  1 , Jose M Vila  1 , Soraya L Valles  1 , Oscar J Arias-Mutis  1 , Martin Aldasoro  1
Affiliations

Improvement of Vascular Insulin Sensitivity by Ranolazine

Sol Guerra-Ojeda et al. Int J Mol Sci. .

Abstract

Ranolazine (RN) is a drug used in the treatment of chronic coronary ischemia. Different clinical trials have shown that RN behaves as an anti-diabetic drug by lowering blood glucose and glycosylated hemoglobin (HbA1c) levels. However, RN has not been shown to improve insulin (IN) sensitivity. Our study investigates the possible facilitating effects of RN on the actions of IN in the rabbit aorta. IN induced vasodilation of the abdominal aorta in a concentration-dependent manner, and this dilatory effect was due to the phosphorylation of endothelial nitric oxide synthase (eNOS) and the formation of nitric oxide (NO). On the other hand, IN facilitated the vasodilator effects of acetylcholine but not the vasodilation induced by sodium nitroprusside. RN facilitated all the vasodilatory effects of IN. In addition, IN decreased the vasoconstrictor effects of adrenergic nerve stimulation and exogenous noradrenaline. Both effects were in turn facilitated by RN. The joint effect of RN with IN induced a significant increase in the ratio of p-eNOS/eNOS and pAKT/AKT. In conclusion, RN facilitated the vasodilator effects of IN, both direct and induced, on the adrenergic system. Therefore, RN increases vascular sensitivity to IN, thus decreasing tissue resistance to the hormone, a key mechanism in the development of type II diabetes.

Keywords: adrenergic system; insulin; nitric oxide; ranolazine; vascular.

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Conflict of interest statement

The authors have declared that no competing interest exits.

Figures

Figure 1
Figure 1
Concentration-response curves to IN (10−12–10−8 M) in rabbit aorta. (A) Effect of S961 (10−6 M), IN receptor blocker. (B) Effect of L-NG-Nitro-L-arginine methyl ester (L-NAME) (10−4 M). (C) Effect of RN (10−5 M).
Figure 2
Figure 2
Concentration-response curves to IN (10−12–10−8 M) in rabbit aorta. A: Effect of tetraethylammonium (TEA) (10−4 M) or indomethacin (INDO) (10−6 M).
Figure 3
Figure 3
Concentration-response curves to acetylcholine (10−9–10−6 M). Facilitating effect of IN (10−9 M) and IN (10−9 M) + RN (10−5 M).
Figure 4
Figure 4
Concentration-response curves to sodium nitroprusside (NPS) (10−9–3 × 10−5 M). Effects of IN (10−9 M) and IN (10−9 M) + RN (10−5 M).
Figure 5
Figure 5
Contractile response induced by electrical field stimulation (EFS) (2, 4 and 8 Hz) in rabbit aorta in the presence of IN (10−9 M), IN (10−9 M) + RN (10−5 M) or PRZ (10−4 M). * p < 0.05 compared to control. # p < 0.05 compared to insulin treated group. n = 8 rabbits for each condition.
Figure 6
Figure 6
Concentration-response curves to noradrenaline (10−9–10−5 M) in rabbit aorta in the presence of IN (10−9 M), IN (10−9 M) + RN (10−5 M) or PRZ (10−4 M).
Figure 7
Figure 7
Protein expression levels of eNOS, p-eNOS, AKT and p-AKT in rabbit aorta from control, IN (10−9 M), IN + RN (10−6), IN + RN (10−5) were indicated. The ratio of p-eNOS/eNOS and pAKT/AKT was plotted. Representative western blots for each antibody are added and β-actina was used as internal control. Data are mean ± SD of 5 independent experiments. * p < 0.05 vs. control. # p < 0.05 vs. IN group.
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