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

Abstract

Emerging evidence suggests that the urocortin (UCN) peptides contribute to pressure and volume regulation with possible involvement in the pathophysiology of cardiovascular disease. We have recently reported that i.v. UCN1 potently inhibits 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 i.v. UCN2 on CSNA, hemodynamics, and plasma catecholamines in normal conscious sheep. Bolus i.v. administration of UCN2 (25 and 100 mg) resulted in the expected hemodynamic actions including transient falls in arterial pressure (PZ0 . 016) and 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. CSNA burst area and incidence showed prolonged, dose-dependent falls in response to UCN2 administration (all P!0 . 001). UCN2 also induced a short-lived rise in plasma norepinephrine levels (PZ0 . 006).The marked rise in heart rate in response to UCN2 is preserved in sheep undergoing pharmacological ganglionic blockade with hexamethonium. In conclusion, this is the first study to report the effects of UCN2 on SNA and indicates potent inhibition of sympathetic traffic to the heart despite a generalized 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.

Prolonged Urocortin 2 Administration in Experimental Heart Failure

“…The impressive and persistent improvements in CO observed in the HF animals in the current study likely reflect Ucn2's potent inotropic activity 5,17 given the concomitant rise in dP/dt(max), as well as falls in cardiac afterload (CTPR). The CO increase presumably contributed to the marked decline in LAP (Ͼ15 mm Hg drop by day 4), although the lusitropic 5 and venodilator actions of the peptide (the latter decreasing circulatory filling pressures) 18 may also have participated.…”

Cardiovascular effects of urocortin 2 and urocortin 3 in patients with chronic heart failure

“…Effects of urocortin 2 (red) and urocortin 3 (blue) last 40-60 min after cessation of dose 3 (D3) before returning to baseline. At the doses used, urocortin 3 caused a greater increase in cardiac output compared with urocortin 2 in patients with heart failure (P < 0.0001) but not healthy subjects (P = 0.48) of cardiac sympathetic nerve activity [SNA] [27,28], often overactive in patients with heart failure. Although Ucn2 has been reported to increase skeletal muscle SNA in humans [29], this should not necessarily be seen as a discrepant finding as SNA responses typically are regionally differentiated.…”

Clinical Perspectives of Urocortin and Related Agents for the Treatment of Cardiovascular Disease

“…On the other hand, several trials in which Ucns are being used to treat experimental [59–64] and human cardiac failure [65] are ongoing and have provided some potentially beneficial results, because Ucn I may exert inotropic actions that may play a key role in the treatment of cardiac failure. And Ucn II may also improve the renal function [66], and sympathetic activity in heart failure [30], synthetic Ucns, or nonpeptide CRF receptor agonists may prove useful for the treatment of cardiac failure.…”

“…[22, 26, 27]. The other reported beneficial actions of Ucn I on the heart is to reduce infarct size in vivo, improve intracellular calcium handling [28], increase the ventricular fibrillation threshold [29], reduce the occurrence of arrhythmias [28], and inhibit efferent cardiac sympathetic nerve activity [30]. These facts indicated that Ucn I and its analogs may have beneficial actions in the treatment of cardiac diseases as well as play certain roles in cardiac diseases.…”