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S Nagahama, YF Chen, MD Lindheimer and S Oparil
Administration of LY171555 (1 mg/kg i.v.) decreased mean arterial pressure (MAP) and heart rate in both pentobarbital- and urethane- anesthesized Sprague-Dawley rats. The depressor response to LY171555 in pentobarbital-anesthetized rats was sustained for at least 30 min, but in urethane-anesthetized rats lasted only approximately 3 min after LY171555 injection. In pentobarbital-anesthetized rats, pretreatment with domperidone (0.5 mg/kg) or metoclopramide (5 mg/kg) attenuated the depressor action of LY171555, whereas pretreatment with d(CH2)5Tyr(Me)arginine vasopressin (AVP) (10 micrograms/kg) only delayed the recovery phase of the depressor response to LY171555. In contrast, LY171555 administered to urethane-anesthetized rats after domperidone pretreatment induced a pressor response which was blocked completely by d(CH2)5Tyr(Me)AVP. Metoclopramide pretreatment in urethane-anesthetized rats prevented the decreases in MAP and heart rate induced by LY171555, whereas pretreatment with d(CH2)5Tyr(Me)AVP delayed the recovery phase of the depressor response. Pretreatment with d(CH2)5Tyr(Me)AVP per se decreased basal MAP in the urethane- anesthetized group, but not in pentobarbital-anesthetized rats. Basal plasma norepinephrine, epinephrine and AVP levels were higher in urethane-anesthetized rats than in the pentobarbital-anesthetized group. LY171555 administration decreased plasma norepinephrine without altering plasma epinephrine in both groups and induced a significant increase in plasma AVP which was greater in the urethane-anesthetized rats than in pentobarbital-anesthetized animals. These results suggest that LY171555 decreases MAP and heart rate in anesthetized rats by inhibiting norepinephrine release from nerve endings through the peripheral dopamine D2 receptor and that the time course of the depressor response may be altered by LY171555-induced AVP release, the magnitude of which appears to be dependent on the anesthetic agent.
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