Differential Impact of Atorvastatin vs Pravastatin on Progressive Insulin Resistance and Left Ventricular Diastolic Dysfunction in a Rat Model of Type II Diabetes

Abstract

iabetes mellitus (DM) and metabolic syndrome frequently result in congestive heart failure (CHF) with either preserved or unpreserved left ventricular (LV) systolic function, independent of coronary atherosclerosis. 1,2 This is because insulin resistance (IR) and impaired glucose metabolism facilitate not only coronary atherosclerosis leading to coronary events, but also myocardial interstitial fibrosis 3 and coronary microangiopathy, 4,5 at least partly through nitric oxide (NO)/superoxide imbalance. 2,4 In this regard, new-onset DM during medical treatment of hypertensive patients was reported to significantly increase the risk of cardiovascular events, including CHF, during a long-term follow-up period. 6 Therefore, attention should be paid to the influence of cardiovascular agents on glycemic control during prevention of cardiovascular diseases.The hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) have been widely prescribed to reduce cardiovascular events, based on the results of several clinical trials in which lower lipid levels were related to lower coronary event rates. 7-9 Intensive lipid-lowering therapy with atorvastatin (AS) can stop 10 or reverse 11 the further progression of coronary plaques and shows greater prevention of recurrent coronary events after acute coronary syndrome, compared with standard lipid lowering by pravastatin (PS). 9 Thus, the benefit of intensive lipid lowering to prevent coronary events by stabilizing coronary plaques has been established. However, the effects of statin therapy on glycemic control [12][13][14][15][16][17][18][19][20] or on the development of CHF have not been fully investigated and remain controversial. We have recently shown that early and long-term treatment with PS eliciting moderate lipid-lowering effects can retard the development of DM and progression of LV diastolic dysfunction, 15 a manifestation of diabetic cardiomyopathy, in a model of spontaneously developing type II DM, the Otsuka Long-Evans Tokushima Fatty (OLETF) rats. 21 However, whether intensive lipid lowering by other statins can exert greater or similar effects remains unknown. Moreover, although adipocytokines [22][23][24] have been emerging as factors affecting IR and should play an important role in the development of DM, the effects of statin therapy on them also remain to be studied.Therefore, in this study, we compared intensive lipid Background Controversy exists regarding the effects of statin therapy on progressive insulin resistance (IR) and its consequences, in the present study a rat model of spontaneously developing type II diabetes mellitus (DM) was used to examine the impact of atorvastatin (AS) vs pravastatin (PS). Methods and ResultsThe Otsuka Long-Evans Tokushima Fatty rats were either untreated or treated with 100 mg/kg per day of AS or PS from 6 weeks of age for 24 weeks. AS achieved much greater lipid lowering than PS. Serial oral glucose tolerance tests revealed new-onset diabetes was delayed by PS only. The untreated rats exhibited a progressive decrea...

Effects of combined olmesartan and pravastatin on glucose intolerance and cardiovascular remodeling in a metabolic-syndrome model

“…Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed with normal chow were treated with either OLM (3 mg kg À1 per day), PRA (30 mg kg À1 per day: 30% of the full dose tested in our earlier studies 10,11 ), or their combination (OLM+PRA) (n¼12 for each) from 5 weeks of age. Agents were suspended in drinking water at concentrations adjusted according to the amount of water consumed during the preceding 2 days, so that the total scheduled doses were administered.…”

“…At 30 weeks of age, blood was sampled from the right jugular vein after an overnight fast and the oral glucose (2 g kg À1 body weight) tolerance test (OGTT) was applied as described elsewhere. 10,11,17 Then, all the rats were killed after administering deep anesthesia with i.p. sodium pentobarbital (50 mg kg À1 ), and the heart, aorta and epididymal WAT were excised.…”

“…Insulin resistance was evaluated based on the product of fasting glucose and insulin concentrations. 10,11 Tissue processing Short-axis sections (3-mm thick) of the left ventricle at the mid-ventricular level and aorta samples were fixed with formalin or frozen in an optimal cutting temperature (OCT) compound and stored at À80 1C until histological assessment. The remaining tissue samples and WAT were immediately frozen in liquid nitrogen and stored at À80 1C before total RNA and/or protein extraction.…”

“…We determined the wall-to-lumen ratio (medial thickness compared with luminal diameter) and the ratio of the area of perivascular fibrosis to the vascular cross-sectional area in 5-10 cross-sections of arteries between 30 and 200 mm in diameter, as described earlier, 10,11,19 which were reported as percentage of the values for the normal LETO rats.…”

“…[6][7][8] We and others have shown that PRA upregulates adiponectin messenger RNA expression in adipose tissue 8 and in cultured adipocytes, 9 and prevents the development of DM in animal models. [9][10][11] Clinical studies have also shown that PRA treatment increases plasma adiponectin in patients with hypercholesterolemia and is associated with improved glucose metabolism. 8,9 As dyslipidemia often accompanies hypertension, such individuals are frequently treated with both reninangiotensin system inhibitors and statins.…”