Urotensin II causes fatal circulatory collapse in anesthesized monkeys in vivo: a "vasoconstrictor" with a unique hemodynamic profile.
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 on UII application in vivo in nonhuman primates. To this end, cynomolgus monkeys (n = 4) were anesthetized 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. A bolus of human UII (0.03 nmol/kg) caused a decrease of heart rate (HR) (13%), mean blood pressure (MBP) (18%), and first-order derivative of left ventricular pressure (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.
Zhu
Yi Zhun
YZ
Dept. of Pharmacology, Faculty of Medicine, National Univ. of Singapore, 18 Medical Dr., Singapore 117597. phczhuyz@nus.edu.sg
Wang
Zhong Jing
ZJ
Zhu
Yi Chun
YC
Zhang
Li
L
Oakley
Reida M E
RM
Chung
Chin Wee
CW
Lim
Kiat Wee
KW
Lee
How Sung
HS
Ozoux
Marie L
ML
Linz
Wolfgang
W
Böhm
Michael
M
Kostenis
Evi
E
D000707:Anaphylaxis / Q000139:chemically induced* / Q000503:physiopathology*; D000758:Anesthesia; D000818:Animals; D006632:Histamine / Q000097:blood; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D011863:Radioimmunoassay; D014579:Urotensins / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D014579:Urotensins; D014662:Vasoconstrictor Agents; D006632:Histamine; C029677:urotensin II