Urotensin II (UII) is a vasoactive peptide which binds to a G protein-coupled receptor, and is coexpressed with its receptor in the heart. Structure of somatostatin is similar to UII, and its receptors (SSTRs) are expressed in cardiomyocytes. Natriuretic peptides play an important role in regulating blood pressure and blood volume. However, the relationship between UII or somatostatin and atrial natriuretic peptide (ANP) and effect of UII on pathologic condition is still unknown. The purpose of the present study is: (1) to investigate the effect of UII or somatostatin on ANP secretion, and also determine its signaling pathways, (2) to check whether human UII (hUII)-mediated ANP secretion influences hypoxia-induced cardiac hypertrophy, and (3) to discover the effect of hUII on heart function against I/R injury. The isolated perfused beating rat atria model is used to check the effect of UII or somatostatin on ANP secretion and effect of hUII on hypoxia-induced cardiac hypertrophy. Global ischemia was performed using Langendorff hearts in rat. hUII stimulated high frequency-induced ANP secretion. An increase in ANP secretion by rat UII was similar to that by hUII; however, urotensin-related peptide showed no significant effect. Pretreatment with UII receptor (UTR) antagonist and inhibitors for PLC, PI3K, or PKC attenuated hUII-induced ANP secretion. Intravenous infusion of hUII increased plasma ANP level, along with increased heart rate and pulse pressure in anesthetized rats. Somatostatin decreased ANP secretion in a dose-dependent manner, and this was significantly attenuated by the pretreatment with SSTR 2 antagonist. SSTR 2 agonist reduced ANP secretion similar to that of somatostatin. The suppressive effect of somatostatin on ANP secretion was attenuated by the pretreatment with an inhibitor for adenylyl cyclase or PKA. In diabetic rat atria, the suppressive effect of somatostatin on ANP secretion and concentration was attenuated. Real time-PCR and western blot show the decreased levels of SSTR 2 mRNA and protein in diabetic rat atria. Hypoxia caused an increase in ANP secretion and a decrease in atrial contractility. hUII attenuated hypoxia-induced ANP secretion, and the effect was mediated by the UTR signaling involving PLC, IP3 and PKC. Rats treated with monocrotaline (MCT) showed right ventricular hypertrophy with increases in pulmonary arterial pressure and its diameter and plasma levels of UII and ANP that were attenuated by the pretreatment with urantide. An acute administration of hUII decreased the plasma ANP level in MCT-treated rats but increased the plasma ANP level in MCT plus urantide-treated and sham-operated rats. Pretreatment with hUII increased the recovery percentage of the post-ischemic left ventricular developed pressure and ?bdp/dt, and decreased post-ischemic left ventricular end-diastolic pressure as compared with I/R group. hUII markedly decreased the infarct size, increased the concentration of ANP, and attenuated the increased lactate dehydrogenase level in effluent during reperfusion. The expression of eNOS mRNA level and hydrogen peroxide activity were increased. Decreases on Mn-SOD, catalase, HO-1, and Bcl-2 levels and increases on Bax, caspase-3 and caspase-9 level by I/R were suppressed by hUII treatment. Pretreatment with urantide blocked all these effects of hUII. In conclusion, UII stimulates high stimulation frequency-induced ANP secretion partly through the UTR and the PLC/PI3K/PKC pathway. Somatostatin decreases ANP secretion through SSTR 2 and an attenuation of suppressive effect of somatostatin on ANP secretion in diabetic rat atria is due to a down-regulation of SSTR 2. hUII may deteriorate MCT-induced cardiac hypertrophy mainly through a vasoconstriction of the pulmonary artery and partly through the suppression of ANP secretion. hUII has protective effects on heart function which mediated through activating antioxidant enzymes and ROS.