Pharmacological characterization of mechanisms involved in the vasorelaxation produced by rosuvastatin in aortic rings from rats with a cafeteria‐style diet

Abstract

The present study aimed to investigate the possible influence of several inhibitors and blockers on the vascular effect produced by the acute in vitro application of rosuvastatin to phenylephrine-precontracted aortic rings from rats with a semi-solid, cafeteria-style (CAF) diet. It also aimed to examine the effects of rosuvastatin on the expression of endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase, constitutive cyclooxygenase, and inducible cyclooxygenase in aortic rings from rats with a CAF diet. From comparisons of the effect on phenylephrine-precontracted aortic rings extracted from rats with two different diets (a standard and a CAF diet), it was found that 10−9–10−5-mol/L rosuvastatin produced lower concentration-dependent vasorelaxation on rings from the CAF diet group. The vasorelaxant effect was unaffected by the vehicle, but it was significantly attenuated by 10−5-mol/L NG-nitro-l-arginine methyl ester, 10−2-mol/L tetraethylammonium, 10−3-mol/L 4-aminopyridine, 10−7-mol/L apamin plus 10−7-mol/L charybdotoxin, 10−5-mol/L indomethacin, or 10−5-mol/L cycloheximide. Moreover, in aortic rings from rats with a CAF diet, rosuvastatin enhanced the expression of eNOS, inducible nitric oxide synthase, constitutive cyclooxygenase, and inducible cyclooxygenase. The acute in vitro application of rosuvastatin to phenylephrine-precontracted aortic rings from rats with a CAF diet had a vasorelaxant effect. Overall, the present results suggest that the stimulation of eNOS, the opening of Ca2+-activated and voltage-activated K+ channels, the stimulation of prostaglandin synthesis and enhanced protein levels of eNOS, inducible nitric oxide synthase, constitutive cyclooxygenase, and inducible cyclooxygenase are involved in this relaxant effect.

Effects of Rosuvastatin in Experimentally-Induced Cardiac Ischemia and on Aortic Vascular Reactivity.

“…The vasorelaxant effect of rosuvastatin in the present study was partially attenuated in vessels pre-incubated with L-NAME, indomethacin or glipenclamide indicating that, endothelial nitric oxide (NO), prostaglandin and ATP-sensitive K channel are involved in its vasorelaxant effects. These results are in agreement with the study done by Lopez-Canales et al (2011) and Lopez-Canales et al (2015).…”

Possible mechanisms involved in the effect of the subchronic administration of rosuvastatin on endothelial function in rats with metabolic syndrome

“…The CAF-diet is a robust experimental model of metabolic syndrome that is capable of inducing obesity, glucose intolerance, and inflammation in rats (7,9), and is consistent with the results of our experiments, which showed that the 16-week CAFdiet significantly increased (Po0.05) body weight, serum insulin, glucose, total cholesterol, and triglycerides in Wistar rats (Table 1). These findings reinforced previous studies in which an 8-week CAF-diet increased the same metabolic parameters in Wistar rats (4) and are in line with previous reports linking a high-fat diet to increases in levels of glucose, cholesterol, triglycerides, and insulin (10,11).…”

“…Seventy-two male Wistar rats were purchased from the Escuela Superior de Medicina (Mexico), housed in plastic cages in a special temperature-controlled room (22 ± 2°C, 50% humidity), and kept on a 12-h light/dark cycle (lights on at 7 am). They were randomly distributed into three groups that received for 16 weeks: i) a standard diet (Rat chow 5012, Pet Foods Home, Mexico); ii) a CAF-diet containing 33% ground commercial rat chow, 33% full-fat sweetened condensed milk (Nestlé), 7% sucrose, and 27% water (n=36), as reported by López-Canales et al (4); or iii) a CAF-diet plus rosuvastatin administered orally (10 mg/kg) once per day. All animals had free access to drinking water throughout the experiments.…”

“…One of the pleiotropic cholesterol-lowering effects attributed to statins is the improvement in endothelial function resulting from an increase in the expression and activity of endothelial nitric oxide synthase (NOS) (2,3). There is evidence of mechanisms involved in the vasorelaxation produced by an acute in vitro application of rosuvastatin on aortic rings of rats fed with a cafeteria-style diet (CAF-diet: a model of metabolic syndrome and endothelial dysfunction) (4). However, regarding a subchronic treatment with rosuvastatin, the mechanisms involved in the improvement of endothelial function in rats subchronically fed with a CAF-diet, remain unknown.…”

“…The present study set out to analyze in aortic rings of rats subjected to the CAF-diet the possible mechanisms responsible for an improved vasodilator response caused by acetylcholine after subchronic treatment with rosuvastatin. To explore the mechanism of action of the relaxant response to acetylcholine, an evaluation was made of the effect on this response produced by various compounds: 10 -5 M N o -nitro-L-arginine methyl ester (L-NAME; a direct inhibitor of NO synthase), 10 -7 M 1H- (1,2,4) oxadiazolo [4,3-a] quinoxalin-1-one (ODQ; an inhibitor of soluble guanylyl cyclase enzyme), 10 -6 M (9S,10R,12R)-2,3,9,10, 11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo [1,2,3fg:3',2',1'-kl] pyrrolo [3,4-i] (1,6) benzodiazocine-10-carboxylic acid, methyl ester (KT 5823; an inhibitor of protein kinase G), 10 -3 M 4-aminopyridine (4-AP; a voltage-activated K + channel blocker), 10 -2 M tetraethylammonium (TEA; a Ca 2+ -activated K + channel blocker and non-specific voltage-activated K + channel blocker), 10 -7 M apamin plus 10 -7 M charybdotoxin (blockers of small-and large-conductance Ca 2+ -activated K + channels, respectively), 10 -7 M glibenclamide (an ATP sensitive K + channel blocker), 10 -5 M indomethacin (a prostaglandin synthesis inhibitor), 10 -5 M clotrimazole (a cytochrome P450 inhibitor), and 10 -5 M cycloheximide (a general protein synthesis inhibitor).…”