Acute Effect of Endothelin AB Antagonist on Sympathetic Outflow in Conscious Rats With Heart Failure.

Abstract

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...

Increased Cardiac Sympathetic Drive and Reduced Vagal Modulation Following Endothelin Receptor Antagonism in Healthy Conscious Rats

“…Bosentan treatment caused a marked decrease in cardiac baroreflex sensitivity and this indicates the important contribution of ET‐1 in the autonomic reflex control of HR. This contribution had already been suggested by previous studies, 14–21 even though the effects of ET on autonomic reflex control were divergent. A possible explanation for these divergent findings is the different site of actions of ET within the baroreflex arc of cardiovascular control.…”

“…In anaesthetized rats, injection of low doses of ET‐1 into the cisterna magna increases renal sympathetic nerve activity (RSNA), HR and arterial pressure, but injection of high doses of ET‐1 has the opposite effect 15 . Conversely, acute and systemic blockade of ET‐1 receptors with the non‐selective antagonist TAK044 causes a decrease in RSNA in rats with cardiac failure 20 . A further study has shown that bolus injection of bosentan does not alter the sympathetic–vagal balance in rats with renal denervation or in sham‐operated rats 12 .…”

“…First, we used only one dose of bosentan and this prevented the quantification of any dose–response effects. However, this dose of bosentan was selected because it had been shown previously to inhibit pressor responses to big‐ET‐1 for up to 24 h after a single oral dose in control rats 20 . Therefore, it was considered appropriate for use in a once‐daily treatment protocol.…”

“…It has been reported that ET‐1 modulates baroreflex function by acting at several sites of the reflex arc (afferent pathways, central integration processes and efferent pathways) 14–21 . Accordingly, we hypothesized that chronically administered bosentan should have marked effects on autonomic control of the cardiovascular reflex.…”

Role of endothelin-1 in mediating changes in cardiac sympathetic nerve activity in heart failure

“…Inhibition of the ET-1 receptor in dogs with pacing-induced HF reduced plasma NE levels compared with placebo infusion (21). Interestingly, infusion of an ET-1 receptor antagonist reduced directly recorded renal sympathetic nerve activity (RSNA) in pacing-induced HF in rabbits (16) and in the myocardial infarction model of HF in rats (38).…”