Urotensin II Acts Centrally to Increase Epinephrine and ACTH Release and Cause Potent Inotropic and Chronotropic Actions

Abstract

Abstract-Urotensin II is a small peptide whose receptor was recently identified in mammals as the orphan G protein-coupled receptor-14. The reported cardiovascular responses to systemic urotensin II administration are variable, and there is little detailed information on its central cardiovascular actions. We examined the cardiovascular and humoral actions of intracerebroventricular urotensin II (0.02 and 0.2 nmol/kg and vehicle) and intravenous urotensin II (2, 20, and 40 nmol/kg and vehicle) in conscious ewes previously surgically implanted with flow probes and intracerebroventricular guide tubes. Two hours after intracerebroventricular infusion of urotensin II (0.2 nmol/kg over 1 hour; nϭ5), heart rate (ϩ56Ϯ13 beats per minute, and cardiac output (ϩ3.4Ϯ0.4 L/min) increased significantly compared with vehicle, as did renal, mesenteric, and iliac blood flows and conductances. Plasma epinephrine, adrenocorticotropic hormone, and glucose levels also increased dramatically (ϩ753Ϯ166 pg/mL, ϩ14.3Ϯ3.5 pmol/L, and ϩ7.0Ϯ1.4 mmol/L, respectively). All of these variables remained elevated for up to 4 hours after infusion. In contrast, 1 hour after intravenous urotensin II (40 nmol/kg bolus; nϭ6), a sustained tachycardia (ϩ25Ϯ8 bpm) ensued, but cardiac output, cardiac contractility, total peripheral conductance, and plasma glucose levels did not change significantly. In summary, this is the first study to show that urotensin II acts centrally to stimulate sympathoadrenal and pituitary-adrenal pathways, resulting in increased adrenocorticotropic hormone and epinephrine release and potent chronotropic and inotropic actions. In contrast, tachycardia was the only major response to intravenous urotensin II. These findings suggest that urotensin II is a novel stimulator of central pathways that mediate responses to alerting stimuli or stress.

Role of urotensin II in health and disease

“…Intravenous UII administration in ewes caused a sustained tachycardia with no significant effect on cardiac output, contractility, or total peripheral conductance (140). In a recent human forearm blood flow experiment, administration of UII yielded no effect on forearm blood flow in both normal subjects and subjects with cardiovascular disease (23).…”

“…For example, corticosterone secretion was decreased by UII in cultured rat adrenocortical cells, an effect abolished by the UII antagonist palosuran (4). Upon intracerebroventricular infusion of UII in conscious ewes, plasma levels of epinephrine and ACTH increased, remaining elevated for up to 4 h after infusion (140). Thus, UII appears to play an important regulatory role in adrenal steroidogenesis and in adrenal hormonal release.…”

“…UII is also implicated in digestive behavior. UII increases mesenteric, iliac, and renal blood flow (140) and contracts strips of isolated ileum from the guinea pig via mesenteric neuron activation (52).…”

“…These effects were proposed to be mediated by sympathetic activation, as the observed effects were significantly attenuated by preinfusion of the ganglionic-blocking agent pentolinium (73). Intracerebroventricular administration of UII to conscious ewes caused an increase in heart rate, contractility, and cardiac output (140). These effects were blocked upon administration of propranolol (30 mg bolus followed by 0.5 mg·kg Ϫ1 ·h Ϫ1 iv) in a subsequent experiment in sheep, implicating the importance of ␤-adrenoceptor activity in central UII cardiac control (51).…”

The Importence of Urotensin and Urotensin Receptors in Cardiovascular System

“…Sağlıklı insandaki infüzyon çalışmalarında ÜT 2'nin çok küçük bir role sahip olduğunun gösterildiği belirtilmiş, hastalık durumlarında ise nispeten rolunun daha belirgin olduğuna değinilmiş-tir [25]. ÜT 2 potent hemodinamik olaylarda [25], pozitif inotrop ve kronotrop yanıtlarda [26], osmoregulatuar olaylarda [27], kollajen ve fibronektin birikimini indüklemede [28,29], inflamatuar yanıt modülasyonunda [30], kardiyak ve vasküler hipertrofide [31] rol oynar. ÜT 2 aynı zamanda güçlü anjiojenik etkiye neden olur [32,33].…”