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Objectives: We sought to evaluate the effects of various doses of guanethidine, a sympathoinhibitory drug, on ventricular function and survival in chronic heart failure (CHF) after myocardial infarction (MI) in rats., Background: Direct inhibition of sympathetic outflow by a sympathoinhibitory drug might be an effective approach to therapy of CHF. However, recent clinical trials suggest that excessive suppression of sympathetic activity has an adverse effect on outcome. It remains unclear whether the beneficial effects of the sympathoinhibitory drug would be modified by its dosage., Methods: Three doses of guanethidine (low-dose [LG], 1 mg/kg/day; medium-dose, 3 mg/kg/day; high-dose, 10 mg/kg/day) were administered via an osmotic mini-pump for 4 weeks. Hemodynamics, left ventricular (LV) diameters, plasma and myocardial norepinephrine (NE) levels, and survival were determined for four weeks after MI., Results: As compared with MI rats receiving vehicle, LG suppressed LV dilation (9.2 +/- 0.9 mm vs. 11.0 +/- 0.8 mm, p < 0.05) and improved LV fractional shortening (25.0 +/- 4.5% vs. 16.4 +/- 4.7%, p < 0.05) in association with a reduction of plasma NE levels (520 +/- 250 pg/ml vs. 1,000 +/- 570 pg/ml, p < 0.05), but not with a significant reduction of noninfarcted myocardial NE levels (154 +/- 71 ng/g vs. 207 +/- 71 ng/g). Low-dose guanethidine reduced 24-h (6%) and 28-day mortality (6%), as compared with untreated MI rats (36% and 52%, respectively). High-dose guanethidine also reduced 24-h mortality (12%) but increased 28-day mortality (91%), in association with a depletion of myocardial NE. Medium-dose guanethidine had no beneficial effects on LV hemodynamics or long-term survival., Conclusions: These results indicate that the dosage of the sympathoinhibitory drug might be quite important for the treatment of CHF.

One of the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in the treatment of heart failure may derive from sympathoinhibition and the prevention of beta-adrenergic desensitization. However, the roles of these properties in the overall effects of ACE inhibitor are not clear. We studied the effects of chronic enalapril treatment (20 mg/L in drinking water for 12 weeks) on left ventricular (LV) function, cardiac norepinephrine (NE), sympathetic neuronal function assessed by 131I-metaiodobenzylguanidine (MIBG), beta-receptors, and isometric contraction of papillary muscle in rats with myocardial infarction (MI) induced by coronary artery ligation. Decreased LV function in the MI rats was associated with reduced cardiac NE content and MIBG uptake, and severely blunted responses of non-infarcted papillary muscle to isoproterenol, forskolin, and calcium. Enalapril attenuated LV remodeling in association with a reduction of the ventricular loading condition and restored baseline developed tension of non-infarcted papillary muscle to the level of sham-operated rats. However, enalapril did not improve cardiac NE content, MIBG uptake, or inotropic responsiveness to beta-agonists. These results suggest that the major effect of the ACE inhibitor enalapril in the treatment of heart failure is not due to sympathoinhibition or restoration of beta-adrenergic pathway in this model of heart failure.

The purpose of the present study was to investigate the effects of long-term renal denervation (RD) on heart failure due to myocardial infarction (MI). Wistar rats were anesthetized and the bilateral renal nerves were surgically denervated 2 days before MI was induced by coronary artery ligation. Four weeks later, left ventricular (LV) function and sodium excretion were determined. In MI rats, RD improved the reduced sodium excretion. MI + RD rats revealed lower LV end-diastolic pressure and greater maximum dP/dt as compared with those of MI+ innervation (INN) rats. LV end-diastolic and end-systolic dimensions were significantly smaller and LV fractional shortening was greater in MI + RD rats than in MI + INN rats (20.9% +/- 3.2% vs 14.9% +/- 3.0%). In rats without MI, RD did not affect either sodium excretion or LV function and dimensions. The present results suggest that the long-term RD reduces LV filling pressure and improves LV function after MI, probably due to a restoration of impaired natriuresis. Increased renal sympathetic nerve activity might contribute to the progression of heart failure after MI.

Abnormalities in energy metabolism may play an important role in the development of hypertensive heart failure. However, the transition from compensated hypertrophy to heart failure is not fully understood in terms of energy metabolism. In Dahl salt-sensitive (DS) and salt-resistant (DR) rats, myocardial fatty acid and glucose uptake values were determined using 131I- or 125I-labeled 9-methylpentadecanoic acid (131I- or 125I-9MPA), and [14C]deoxyglucose ([14C]DG), fatty acid β-oxidation was identified using thin-layer chromatography, and insulin-stimulated glucose-uptake was observed using a euglycemic hyperinsulinemic glucose clamp. Six-week-old rats were fed a diet that contained 8% NaC1, which resulted in development of compensated hypertrophy in DS rats at 12 wk of age and ultimately led to heart failure by 18 wk of age. Uptake of [14C]DG increased markedly with age in the DS rats, whereas 131I-9MPA uptake was marginally but significantly increased only in animals aged 12 wk. The ratio of 125I-9MPA β-oxidation metabolites to total uptake in the DS rats was significantly lower (P < 0.05) at 12 (37%) and 18 (34%) wk compared with at 6 (45%) wk. Insulin increased [14C]DG uptake more than twofold in the DS rats at 6 wk, although this increase was markedly attenuated at 12 and 18 wk (11 and 8%, respectively). Our data suggest that in a hypertrophied heart before heart failure, fatty acid oxidation is impaired and the capacity to increase glucose uptake during insulin stimulation is markedly reduced. These changes in both glucose and fatty acid metabolism that occur in association with myocardial hypertrophy may have a pathogenic role in the subsequent development of heart failure. [ABSTRACT FROM AUTHOR]