A high level of fatty acid delays the recovery of pH(i) during reperfusion of ischemic hearts because of an increased H(+) production from glycolysis uncoupled from glucose oxidation. Improving the coupling of glucose metabolism by stimulating glucose oxidation accelerates the recovery of pH(i) and improves both mechanical function and cardiac efficiency.

Abstract-We determined the effect of 24-hour aldosterone (100 nmol/L) treatment on hypertrophic responses in rat neonatal ventricular myocytes and the possible role of Na ϩ -H ϩ exchange isoform 1 (NHE-1). Aldosterone significantly increased cell size by 61% and expression of atrial natriuretic peptide by 2-fold. NHE-1 mRNA expression and protein abundance were significantly increased, and intracellular Na ϩ levels were elevated. Both hypertrophy and elevated Na ϩ levels were prevented by the NHE-1-specific inhibitor EMD87580 as well as the aldosterone antagonist spironolactone, although the increased NHE-1 levels were prevented only by spironolactone. Aldosterone transiently (within 5 minutes) stimulated p44/42 phosphorylation, which decreased thereafter for the remaining 24 hours, whereas p38 phosphorylation was reduced. Neither a p38 nor a p44/42 inhibitor had any effect on aldosterone-induced hypertrophy or NHE-1 regulation. Our results therefore demonstrate a direct hypertrophic effect of aldosterone on cultured myocytes, which is dependent on NHE-1 activity. (Hypertension. 2003;42:1171-1176.)Key Words: aldosterone Ⅲ sodium-proton exchange Ⅲ kinase Ⅲ rats Ⅲ hypertrophy, cardiac Ⅲ myocytes C ardiac hypertrophy represents a major component of myocardial remodeling contributing to heart failure. 1 Hypertrophy is mediated by endocrine, paracrine, and autocrine growth factors acting via complex cell-signaling processes. 2,3 Aldosterone might contribute to heart failure independently of its renal effects (reviewed in Slight et al 4 ). Aldosterone is produced in cardiac tissue, and aldosterone receptors have been identified in the cardiac cell. 5,6 The aldosterone antagonist spironolactone has been shown to reduce mortality in patients with severe heart failure, although the precise mechanism is unknown. 7 Aldosterone infusion into uninephrectomized rats produces cardiac hypertrophy, which is attenuated by the angiotensin II type 1 receptor antagonist losartan as well by 2 calcineurin inhibitors. 8 Moreover, aldosterone failed to directly produce hypertrophy in cultured neonatal rat ventricular myocytes, although a synergistic hypertrophic effect with endothelin-1 was reported. 9 The preceding 2 studies suggest an indirect cardiac hypertrophic influence of aldosterone. However, in view of the demonstration of cardiac aldosterone receptors, 5,6 we hypothesized that direct aldosterone receptor-mediated actions on the cardiac cell could be predicted and therefore, determined whether it exerts direct hypertrophic effects. We focused on the potential role of the Na ϩ -H ϩ exchanger isoform 1 (NHE-1) in this response, because inhibition of the antiporter has been shown to attenuate myocardial hypertrophy and heart failure. 10 -13 Moreover, aldosterone activates NHE-1, including that in cardiac cells, 14,15 although with respect to the latter, this occurred only after 9 days of treatment. 15 Patients with primary aldosteronism have increased erythrocyte NHE activity. 16 In the present study, we examined the direct e...

BackgroundAccumulating evidence suggests glucagon-like peptide-1 (GLP-1) exerts cardioprotective effects in animal models of myocardial infarction (MI). We hypothesized that chronic treatment with GLP-1 or the exenatide analog AC3174 would improve cardiac function, cardiac remodeling, insulin sensitivity, and exercise capacity (EC) in rats with MI-induced chronic heart failure (CHF) caused by coronary artery ligation.MethodsTwo weeks post-MI, male Sprague-Dawley rats were treated with GLP-1 (2.5 or 25 pmol/kg/min), AC3174 (1.7 or 5 pmol/kg/min) or vehicle via subcutaneous infusion for 11 weeks. Cardiac function and morphology were assessed by echocardiography during treatment. Metabolic, hemodynamic, exercise-capacity, and body composition measurements were made at study end.ResultsCompared with vehicle-treated rats with CHF, GLP-1 or AC3174 significantly improved cardiac function, including left ventricular (LV) ejection fraction, and end diastolic pressure. Cardiac dimensions also improved as evidenced by reduced LV end diastolic and systolic volumes and reduced left atrial volume. Vehicle-treated CHF rats exhibited fasting hyperglycemia and hyperinsulinemia. In contrast, GLP-1 or AC3174 normalized fasting plasma insulin and glucose levels. GLP-1 or AC3174 also significantly reduced body fat and fluid mass and improved exercise capacity and respiratory efficiency. Four of 16 vehicle control CHF rats died during the study compared with 1 of 44 rats treated with GLP-1 or AC3174. The cellular mechanism by which GLP-1 or AC3174 exert cardioprotective effects appears unrelated to changes in GLUT1 or GLUT4 translocation or expression.ConclusionsChronic treatment with either GLP-1 or AC3174 showed promising cardioprotective effects in a rat model of CHF. Hence, GLP-1 receptor agonists may represent a novel approach for the treatment of patients with CHF or cardiovascular disease associated with type 2 diabetes.

BackgroundActivation of glucagon-like peptide-1 (GLP-1) receptors improves insulin sensitivity and induces vasodilatation and diuresis. AC3174 is a peptide analogue with pharmacologic properties similar to the GLP-1 receptor agonist, exenatide. Hypothetically, chronic AC3174 treatment could attenuate salt-induced hypertension, cardiac morbidity, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS) rats.MethodsDSS rats were fed low salt (LS, 0.3% NaCl) or high salt (HS, 8% NaCl) diets. HS rats were treated with vehicle, AC3174 (1.7 pmol/kg/min), or GLP-1 (25 pmol/kg/min) for 4 weeks via subcutaneous infusion. Other HS rats received captopril (150 mg/kg/day) or AC3174 plus captopril.ResultsHS rat survival was improved by all treatments except GLP-1. Systolic blood pressure (SBP) was lower in LS rats and in GLP-1, AC3174, captopril, or AC3174 plus captopril HS rats than in vehicle HS rats (p < 0.05). AC3174 plus captopril attenuated the deleterious effects of high salt on posterior wall thickness, LV mass, and the ratio of LV mass to body weight (P ≤ 0.05). In contrast, GLP-1 had no effect on these cardiovascular parameters. All treatments reduced LV wall stress. GLP-1, AC3174, captopril, or AC3174 plus captopril normalized fasting insulin and HOMA-IR (P ≤ 0.05). AC3174, captopril, or AC3174 plus captopril improved renal function (P ≤ 0.05). Renal morphology in HS rats was associated with extensive sclerosis. Monotherapy with AC3174, captopril, or GLP-1 attenuated renal damage. However, AC3174 plus captopril produced the most effective improvement.ConclusionsThus, AC3174 had antihypertensive, cardioprotective, insulin-sensitizing, and renoprotective effects in the DSS hypertensive rat model. Furthermore, AC3174 improved animal survival, an effect not observed with GLP-1.