omapatrilat and Insulin-Resistance

Mortality peri-myocardial infarction (MI) is increased with insulin resistance. As the vasopeptidase inhibitor (VPI) omapatrilat improves insulin sensitivity, it may be beneficial peri-MI in Zucker Insulin Resistant rats (ZIR). ZIR rats (n = 228) received omapatrilat 10 mg/kg/day, 7 days pre-MI, to 38 days post-MI, or control. Twenty-four protocol (n = 72): a subgroup of rats received the kinin receptor antagonist icatibant. Ambulatory ECG recordings, and MI size were evaluated. Thirty-eight-day protocol (n = 156): left ventricular (LV) remodeling, cardiac hemodynamics, morphology, infarct size, and RT-PCR for GLUT-4 and fetal genes were measured. Omapatrilat improved post-MI survival 24 h (62% vs 38%, P = 0.0007) which was maintained 38 days. There was a kinin-induced reduction of ventricular arrhythmias and there appeared to be a kinin-independent reduction in MI size (23.5 +/- 2.4% vs 17.0 +/- 2.2%, P = 0.053) for 24-h post-MI. Omapatrilat reduced but did not prevent LV dilatation, dysfunction, and fetal gene expression 38 days post-MI. Omapatrilat did not prevent reduced cardiac GLUT-4 expression. In ZIR rats, mortality post-MI is reduced by omapatrilat, due and a kinin-dependent reduction in ventricular arrhythmias and possibly a kinin-independent reduction in MI size. Ventricular dilatation, dysfunction, and fetal gene expression are variably attenuated but not prevented.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Arrhythmias, Cardiac; Disease Models, Animal; Drug Administration Schedule; Gene Expression; Heart Ventricles; Insulin Resistance; Myocardial Infarction; Myosin Heavy Chains; Protease Inhibitors; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Zucker; Survival Analysis; Thiazepines; Ultrasonography; Ventricular Dysfunction, Left; Ventricular Remodeling

ACE inhibitors (ACEIs) improve insulin resistance and prevent type 2 diabetes, possibly mediated by inhibition of bradykinin (BK) degradation. The vasopeptidase inhibitor omapatrilat (OMA) raises BK to a greater extent than ACEIs by dual enzyme inhibition, whereas its insulin-sensitizing effects and mechanisms have not been investigated.. We compared the insulin-sensitizing effects of OMA, ramipril (an ACEI), losartan (an angiotensin II type 1 receptor blocker), and placebo by 2-step euglycemic hyperinsulinemic clamp in insulin-resistant Zucker fatty rats (n=6 to 7 in each group). OMA resulted in a lower rate of endogenous glucose production than placebo at baseline (35+/-5 versus 54+/-4 mmol x kg(-1) x min(-1), P<0.01), greater suppression of endogenous glucose production by low-dose insulin (73+/-11% versus 27+/-18%, P<0.05), and greater glucose disposal at high-dose insulin (135+/-5 versus 92+/-4 mmol x kg(-1) x min(-1), P<0.01). Ramipril tended to improve insulin sensitivity, but losartan did not. OMA significantly increased 2-deoxyglucose uptake by myocardium, fat, and skeletal muscle. Ramipril increased 2-deoxyglucose uptake only by some skeletal muscles, but losartan did not. The insulin-sensitizing effects of OMA were blocked significantly by HOE-140 (a BK, B2 receptor antagonist) and NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor) in all tissues except myocardium.. OMA induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats. This effect is greater than that of ramipril and probably occurs at least in part via stimulation of the B2 receptor. OMA has the potential for greater type 2 diabetes prevention than ACEI.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biological Transport; Blood Glucose; Bradykinin; Bradykinin Receptor Antagonists; Drug Synergism; Enzyme Inhibitors; Glucose; Glucose Clamp Technique; Insulin; Insulin Resistance; Losartan; Male; Myocardium; Neprilysin; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Protease Inhibitors; Pyridines; Ramipril; Rats; Rats, Zucker; Receptor, Angiotensin, Type 1; Receptor, Bradykinin B2; Thiazepines

To assess the effects of omapatrilat, fosinopril and placebo on blood pressure, plasma insulin, glucose and triglycerides concentrations in Zucker rats, a model for insulin resistance.. Double blind, parallel, prospective trial.. Forty-two male obese Zucker (falfa) rats (aged 13-18 week) initially weighing 400-600 g were used for the experiments. Omapatrilat (n = 14), placebo (n = 14) or fosinopril (n = 14) were administrated once daily at 10 micromol/kg oral for 15 days. At baseline and at the end of the study, a tail-cuff blood pressure measurement was performed; an oral glucose tolerance test was done at the end of the study.. Omapatrilat and fosinopril resulted in significant lower systolic blood pressure compared to the placebo group (p < 0.001). This parameter was significantly lower in the omapatrilat group compared with fosinopril-treated rats (116+/-9 vs 125+/-4 mmHg, p < 0.05). After an overnight fast, there was no difference in the fasting glucose concentrations among treatment groups. The basal and post-glucose challenge insulin concentrations were lower in the omapatrilat group compared to the placebo group. No difference was observed in the fasting triglycerides concentrations between the treatment groups.. Compared to placebo and fosinopril treatment, omapatrilat results in lower arterial blood pressure in an animal model of insulin resistance. The results suggest that omapatrilat may have a positive effect on insulin sensitivity.

Topics: Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Double-Blind Method; Fosinopril; Glucose Tolerance Test; Insulin; Insulin Resistance; Male; Models, Animal; Obesity; Pyridines; Rats; Rats, Zucker; Thiazepines; Triglycerides