Elsevier

Peptides

Volume 26, Issue 7, July 2005, Pages 1248-1256
Peptides

Cardiac actions of central but not peripheral urotensin II are prevented by β-adrenoceptor blockade

https://doi.org/10.1016/j.peptides.2005.01.005Get rights and content

Abstract

Urotensin II (UII) is a highly conserved peptide that has potent cardiovascular actions following central and systemic administration. To determine whether the cardiovascular actions of UII are mediated via β-adrenoceptors, we examined the effect of intravenous (IV) propranolol on the responses to intracerebroventricular (ICV) and IV administration of UII in conscious sheep. Sheep were surgically instrumented with ICV guide tubes and flow probes or cardiac sympathetic nerve recording electrodes. ICV UII (0.2 nmol/kg over 1 h) caused prolonged increases in heart rate (HR; 33 ± 11 beats/min; P < 0.01), dF/dt (581 ± 83 L/min/s; P < 0.001) and cardiac output (2.3 ± 0.4 L/min; P < 0.001), accompanied by increases in coronary (19.8 ± 5.4 mL/min; P < 0.01), mesenteric (211 ± 50 mL/min; P < 0.05) and iliac (162 ± 31 mL/min; P < 0.001) blood flows and plasma glucose (7.0 ± 2.6 mmol/L; P < 0.05). Propranolol (30 mg bolus followed by 0.5 mg/kg/h IV) prevented the cardiac responses to ICV UII and inhibited the mesenteric vasodilatation. At 2 h after ICV UII, when HR and mean arterial pressure (MAP) were increased, cardiac sympathetic nerve activity (CSNA) was unchanged and the relation between CSNA and diastolic pressure was shifted to the right (P < 0.05). The hyperglycemia following ICV UII was abolished by ganglion blockade but not propranolol. IV UII (20 nmol/kg) caused a transient increase in HR and fall in stroke volume; these effects were not blocked by propranolol. These results demonstrate that the cardiac actions of central UII depend on β-adrenoreceptor stimulation, secondary to increased CSNA and epinephrine release, whereas the cardiac actions of systemic UII are not mediated by β-adrenoreceptors and probably depend on a direct action of UII on the heart.

Introduction

Urotensin II (UII) is a cyclic peptide isolated initially from the caudal neurosecretory system of the goby fish [3]. Recently, UII isopeptides have been identified in a number of mammals, including mouse, rat, and human [4]. UII is thought to be the endogenous ligand for the orphan GPR14 receptor [2], now termed the UT receptor. The UT receptor is widely expressed, being found in the CNS and vasculature as well as heart and kidney [17], [19]. The wide distribution and the close species homologies of the C-terminal of UII and the UT receptor suggest that UII has important functions in both the brain and periphery.

The systemic cardiovascular actions of UII have been examined in vitro and in vivo, with diverse responses depending on the species and vessel studied. In mammals, UII was first reported to reduce blood pressure in anesthetized rats [12] and cause endothelium-dependent vasodilatation in rat aortic strips [11]. UII was recently shown to have potent vasoconstrictor actions in anesthetized cynomolgus monkeys [2]. In contrast, intravenous administration of UII reduced arterial pressure in conscious rats [9], [14], caused a transient increase followed by a prolonged reduction in arterial pressure in sheep [21] and failed to cause any cardiovascular changes in man [1].

Although UII and its receptor have been localized in the brain, there is little information on the central cardiovascular actions of UII. We found that in conscious sheep, intracerebroventricular (ICV) administration of UII caused prolonged increases in cardiac rate and contractility and cardiac output (CO), together with an increase in mean arterial pressure (MAP) and peripheral vasodilatation in all major vascular beds [21]. These changes were accompanied by large and prolonged increases in circulating levels of epinephrine, but not norepinephrine. Similarly, in conscious rats, ICV administration of UII significantly increased MAP, heart rate (HR) and plasma epinephrine [14].

In view of the finding that central, but not peripheral, UII increased epinephrine release, the current study investigated the extent to which the actions of UII are mediated by β-adrenoreceptors. We examined the effects of β-blockade with propranolol on the responses to ICV and intravenous (IV) administration of UII in conscious sheep. Furthermore, to determine whether an increase in cardiac sympathetic nerve activity (CSNA) also contributed to the cardiac actions of central UII, we examined the effect of UII on directly recorded cardiac sympathetic nerve activity.

Section snippets

Materials and methods

The experiments were performed on 12 adult Merino ewes (35–45 kg), 6 for the hemodynamic studies and 6 for the measurement of CSNA. Experiments were performed on sheep while they were standing in individual metabolism cages. Experiments were approved by the Animal Experimentation Ethics Committee of the Howard Florey Institute following guidelines from the National Health and Medical Research Council of Australia.

Effect of propranolol on the responses to ICV infusion of UII

ICV infusion of UII significantly increased HR (+33 ± 11 beats/min; P = 0.007), dF/dt (+581 ± 83 L/min/s; P < 0.001), Fmax (+8.3 ± 0.9 L/min; P < 0.001) and CO (+2.3 ± 0.4 L/min; P < 0.001) (Fig. 1). These variables remained significantly higher than control for at least 4 h post UII infusion. The cardiac activation was accompanied by a significant increase in TPC (P = 0.017) that lasted for 3.5 h after the end of the UII infusion. In individual vascular beds, UII induced an increase in mesenteric blood flow (P = 

Discussion

This study confirms our previous findings that centrally administered UII has potent cardiac actions, causing increases in heart rate, cardiac contractility and cardiac output, which were accompanied by peripheral vasodilatation [21]. The present study extends these findings by investigating the role that the sympathetic nervous system plays in mediating the actions of centrally and peripherally administered UII. The present finding that the cardiac effects of central UII were prevented by

Acknowledgements

The authors are grateful to Craig Thomson and Alan McDonald for excellent technical assistance. This work was funded by National Health and Medical Research Council, Project Grant 232313.

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  • Cited by (25)

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      In the CNS, some intracrines were found to act as neurotransmission modulators (Re, 2004). In this regard, it has been demonstrated that UII evokes norepinephrine, dopamine and serotonin release in noradrenergic neurons (Ono et al., 2008) and that intracerebroventricular UII administration produces cardiac system modulation (heart rate, cardiac output) via β-adrenoreceptor stimulation (Hood et al., 2005). These observations, correlated with the regulation by UII and URP of the membrane and nuclear receptors upon hypoxia, bring up the idea that the presence of nuclear UT receptors might be associated to excitatory neurotransmission.

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      In normotensive and hypertensive unanesthetized rats and in unanesthetized sheep, ICV administration of U-II causes pressor and tachycardic responses through activation of the sympathetic system (for review see [56]) suggesting that in these species the baroreflex response is also impaired. Studies conducted on unanesthetized sheep to test this hypothesis demonstrated that, after ICV infusion of U-II (0.2 nmol/kg for 1 h), the baroreflex response is effectively blunted since no changes occur in the cardiac sympathetic nerve activity in spite of an increase in blood pressure [23]. In trout, comparisons may also be made between the central cardiovascular actions of trout U-II and trout U-I.

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