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1 Department of Pharmacology, National University of Singapore, Singapore, Singapore
2 Department of Physiology and Pathophysiology, Key Laboratory of Molecular Medicine of The Ministry of Education, Fudan University Shanghai Medical College, Shanghai, China
3 Department of Cardiac Surgery, National University Hospital, Singapore, Singapore
4 Drug Metabolism and Pharmacokinetics, Aventis Pharma, Paris, France
5 Disease Group Cardiovascular, Aventis Pharma, Frankfurt, Germany
6 Innere Medizin III, Universitaete des Saarlandes, Homburg/Saar, Germany
* To whom correspondence should be addressed. E-mail: phczhuyz{at}nus.edu.sg.
Urotensin II (UII) is a vasoactive peptide that has recently emerged as a likely contributor to cardiovascular physiology and pathology. Acute infusion of UII into nonhuman primates results in circulatory collapse and death, however, the exact cause of death is not well understood. This study was undertaken to elucidate the mechanism underlying the fatal cardiovascular event upon UII application in vivo in nonhuman primates. To this end, cynomolgus monkeys (n=4) were anaesthetized and tracheal intubation was performed. One internal jugular vein was cannulated for administration of drugs, and one femoral artery for recording of blood pressure and heart rate using a transonic pressure transducer. Cardiac parameters were not significantly changed after administration of 0.003 nmol/kg human UII. 0.03 nmol/kg of bolus human UII caused a decrease of heart rate (HR) (13%), mean blood pressure (MBP) (18%), and dP/dt (11%). Carotid and coronary blood flow were reduced by 9% and 7%, respectively. 0.3 nmol/kg of human UII resulted in a further reduction of HR (50.3%), MBP (65%), dp/dt (45%), carotid (38%) and coronary blood flow (30%), ultimately leading to cardiovascular breakdown and death. Pulmonary pressure, however, was increased by 30%. Plasma histamine levels were found to be unaffected by administration of UII. Our results indicate that systemic administration of human UII has negative inotropic and chronotropic effects and reduces total peripheral resistance ultimately leading to severe myocardial depression, pulmonary hypertension and fatal circulation collapse in nonhuman primates. We suggest that successful design of UII antagonists might offer a new therapeutic principle in treating cardiovascular diseases.
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