ndothelin (ET) is a vasoconstrictor peptide thatgreatly increases the contractility of vascular smooth muscle in pathological and physiological states. 1,2 Recent studies have shown that myocardial and plasma ET concentrations are elevated in congestive heart failure (HF), and increased endogenous ET plays a role in the progression of HF by induction of hypertrophy in cardiomyocytes and left ventricular dilatation. 3 Furthermore, long-term inhibition by the administration of ET A and AB receptor antagonist improves the survival, hemodynamic parameters, and ventricular remodeling in animals with HF. [4][5][6] However, the role of this peptide acting on the autonomic nervous system in HF remains unknown. Sympathoexcitation is well documented in both clinical and experimental HF, and plasma norepinephrine is an entirely independent predictor of mortality in patients with HF. 7-9 It has been reported that exogenous ET promotes sympathetic activation at several loci, including the central nervous system, in the normal animal. 10,11 Thus, it is possible that increased endogenous ET also contributes to this abnormality in HF, and sympathoexcitation via increased ET may be associated with the harmful effect in the progression of HF. However, only 2 studies to our knowledge have shown this phenomenon in the HF state. 12,13 In a recent study, Liu et al Circulation Journal Vol.66, September 2002 showed that the chronic dual ET-1 blockade, L-754, 142, reduced sympathetic activity and normalized the desensitized arterial baroreflex function in another model of experimental HF induced by pacing in rabbits. 14 We hypothesized that ET blockade also reduces the sympathoexcitation in the HF associated with myocardial infarction (MI) and observed the effects of the ET AB dual antagonist, TAK044, on sympathetic outflow and arterial baroreflex sensitivity (BRS) in a conscious rat model of this condition.
Methods
SubjectsAll procedures were in accordance with institutional guidelines for animal research. Male Wistar rats (n=14, 8 weeks old) were used as the experimental subjects. MI rats were produced by left coronary artery ligation, using techniques similar to those described previously, under intraperitoneal sodium pentobarbital anesthesia. 5 Rats with autopsy-proven transmural MI of the left ventricle were designated as MI rats. The rats were allowed access to their respective drinking water and standard rat chow ad libitum. We used 7 rats with MI at autopsy and elevated left ventricular (LV) end-diastolic pressure (EDP) ≥10 mmHg as models of HF (n=7). We also prepared 7 sham-operated rats (Sham) to compare all data with the HF group. Shams received left side open chest surgery without coronary ligation. All experiments were carried out 6 weeks after ligation. Although ET-1 antagonists have been beneficial in the treatment of heart failure (HF), their involvement in the effect on the sympathetic nervous system in HF remains unknown. The present study investigated the role of endogenous endothelin (ET) in the sympathetic nervou...
