Urocortin 2 induces potent long-lasting inhibition of cardiac sympathetic drive despite baroreflex activation in conscious sheep

Emerging evidence suggests that the urocortin (Ucn) peptides are involved in pressure and volume regulation with possible involvement in the pathophysiology of cardiovascular disease. We have recently reported that Ucn1 exhibits potent inhibition of cardiac sympathetic nerve activity (CSNA) in normal sheep. However, little is known about possible interactions between Ucn2 and the sympathetic nervous system. Accordingly, we have examined the effects of Ucn2 on CSNA, hemodynamics and plasma catecholamines in normal conscious sheep. Bolus intravenous administration (25 and 100fÝg) of Ucn2 resulted in the expected hemodynamic actions of transient falls in arterial pressure (p = 0.016) with more sustained rises in heart rate (p < 0.001) and cardiac output (p < 0.001) and falls in peripheral resistance (p < 0.001). CSNA burst frequency showed a biphasic response (p < 0.001) with an acute rise followed by a more prolonged fall. All other indices of CSNA showed prolonged, dose-dependent falls in response to Ucn2 administration (all p < 0.001). Ucn2 induced a short-lived activation of plasma norepinephrine levels (p = 0.006). In conclusion, this is the first study to report actions of Ucn2 on SNA and indicates potent inhibition of sympathetic traffic to the heart despite a generalised baroreceptor-induced activation of sympathetic activity. These findings suggest an important role for Ucn2 in cardiovascular homeostasis and warrant further investigation for potential therapeutic applications in acute myocardial injury and heart disease.