Central endothelin: effects on vasopressin and the arterial baroreflex in doxorubicin heart failure rats.

Endothelin 1 (ET-1) is increased in heart failure, both in plasma and within the central nervous system. Centrally, ET-1 induces sympathetic hyperactivity and arginine vasopressin (AVP) secretion. Both sympathetic activity and AVP secretion are regulated by the arterial baroreflex, which is typically impaired in heart failure. We hypothesized that central blockade of ETA receptors (ETAR) alters the baroreflex response of heart rate, renal sympathetic nerve activity (RSNA), and plasma AVP levels in a cardiomyopathic model of heart failure. Female Sprague-Dawley rats received weekly intraperitoneal injections of doxorubicin 2.5 mg x kg(-1) (doxorubicin heart failure, doxo-HF) or saline vehicle (control). After 8 weeks, they were instrumented, conditioned to the study environment, and then studied in the awake, non-restrained state. Baseline mean arterial pressure (MAP), RSNA, and plasma osmolality were similar in both groups, but heart rate (p<0.02), left ventricular pressure (p<0.001), and plasma AVP (p<0.01) were higher in the doxo-HF group. ET-1 dose dependently increased MAP, but the rise was significantly attenuated in doxo-HF rats at all doses. Baseline baroreflex control of heart rate and RSNA was similar in both groups. ETAR blockade with 4 nmol BQ123 i.c.v. significantly decreased both the upper plateau (p<0.05) and the range (p<0.05) of the baroreflex response of both heart rate and RSNA in doxo-HF but not in control rats. Despite higher basal plasma levels of AVP, ET-1 evoked a rise in plasma AVP of 13.6+/-3.2 pg x mL(-1) in doxo-HF compared with 0.4+/-0.4 pg x mL(-1) in control rats (p<0.001). To account for the blunted pressor response to ET-1 in the doxo-HF rats, gain of AVP release was calculated as DeltaAVP/DeltaMAP and was also found to be significantly greater in the doxo-HF rats (p<0.001). BQ123 prevented the rise in AVP and restored the gain in doxo-HF rats to that seen in controls. Thus, central ETAR contribute to the sympathoexcitation and AVP responses observed in heart failure due to doxorubicin cardiomyopathy.