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EXPERIMENTAL STUDY

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

^* Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan

Manuscript received August 13, 2002; revised manuscript received January 7, 2003, accepted January 30, 2003.

^* Reprint requests and correspondence: Dr. Takashi Nozawa, Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
tnozawa{at}ms.toyama-mpu.ac.jp

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.

Abbreviations and Acronyms   BW   body weight   CHF   chronic heart failure   HG   high-dose guanethidine   LG   low-dose guanethidine   LV   left ventricle/ventricular   LVEDD   left ventricular end-diastolic dimension   LVESD   left ventricular end-systolic dimension   MG   medium-dose guanethidine   MI   myocardial infarction   MOXCON   Moxonidine Congestive Heart Failure trial   MOXSE   Moxonidine Safety and Efficacy study   NE   norepinephrine   RV   right ventricle/ventricular