PP.33.29

Abstract

Objective: Obesity is associated with development of cardiovascular risk factors such as arterial hypertension, dyslipidemia, atherosclerosis and metabolic syndrome. RhoA associated kinase has been identified to play an important role in modulating vascular effects. In arterial hypertension abnormalities in RhoA/Rho-kinase signalling lead to augmented contractile response on vasoconstrictors. The pleiotrophic effect of statins is linked to this by inhibition of RhoA isoprenylation. Our aim was to explore the vascular changes of diet induced obesity leading to hypertension and the effects of Pravastatin incubation on vascular contractility. Design and method: Aortas from mice, fed with high-fat-diet (HFD, 51% of energy from fat) for two weeks, were incubated either with Pravastatin (10 μM) or without for 1 or 24 hours. A second group was treated with HFD and Pravastatin 50 mg/kg/d in drinking water. To examine vasoconstrictor response, dose-response-curves to norepinephrine, high potassium and acetylcholine were performed on a wired myograph. Blood pressure was measured by determining the tail blood volume. Results: Mice fed with HFD developed an increased blood pressure compared to normal weight mice. A two weeks treatment of Pravastatin showed a significant decrease in blood pressure compared to mice treated only with HFD (systolic blood pressure control: 138.5 ± 3.3 mmHg vs. 2wks Pravastatin: 125.3 ± 2.3mmHg). In vitro treatment with Pravastatin for 24 h attenuated the contractile response to norepinephrine and high potassium whereas incubation for one hour had no significant effect on vascular contractility (obese control: logEC50 -7.650 vs. Pravastatin 24 h: logEC50 -7.315). In vivo, a two week treatment with Pravastatin showed a significant reduction of contractile response to vasoconstrictors (obese control: logEC50 -6.880 vs. Pravastatin 2wks: logEC50 -6.593). Dose-response curves showed a shift to the right depending on length of treatment. Sensitivity against vasoconstrictors was significantly decreased. Acetylcholine dependent dilatation was not affected by treatment. A two weeks HFD treatment did not lead to endothelial dysfunction. Conclusions: Our study shows that a Pravastatin treatment of obese mice for just two weeks has beneficial effects on the cardiovascular system. The treatment prevented an increase in blood pressure and vascular smooth muscle cell contractility in obese mice.