Long-term treatment with Low-Dose, but not High-Dose, guanethidine improves ventricular function and survival of rats with heart failure after myocardial infarction

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.