URETHANE REDUCES CONTRACTION TO 5-HYDROXYTRYPTAMINE (5-HT) AND ENHANCES THE ACTION OF THE 5-HT ANTAGONIST KETANSERIN ON THE RAT THORACIC AORTIC RING

The general anesthetic urethane (ethyl carbamate) is widely used in electrophysiological in vivo experiments. However, its pharmacological effects are poorly understood. Here, the effects of urethane on in vitro contractile responses of the rat thoracic aortic ring preparation were investigated. Bath application of 5-HT produced a concentration-dependent contractile response (EC(50) = 4.3 x 10(-6) M). Urethane (11.2 mM = 1 mg/ml) shifted the concentration - response curve (CRC) for 5-HT to the right (EC(50) = 1.7 x 10(-5) M) and decreased the maximal contraction by 30.8%. The CRC for NA (EC(50) = 7.2 x 10(-9) M) was also shifted to the right by urethane (EC(50) = 1.4 x 10(-8) M), but the shift of the 5-HT-CRC was twice that of the NA-CRC (3.95 vs. 1.95). The CRC to KCl was shifted rightwards only slightly by urethane (ratio 1.27) and the maximal contraction to KCl was not affected. The CRC to replacement of CaCl2 (0.1 - 10 mM) to KCl-depolarized vessels in a Ca2+-free Krebs solution was unaffected by urethane. Ketanserin (10(-9) M) antagonized the contraction to 5-HT, and a combination of ketanserin and urethane was markedly more effective than either drug alone, decreasing the maximal contraction by 58%. Antagonism of NA contraction by prazosin (5 x 10(-8) M) was not increased by addition of urethane. The urethane dose used here approximates blood and brain concentrations required to produce anesthetic effects in mammals. It is possible that reductions in 5-HT transmission and, to a lesser extent, in NA transmission, but not blockade of Ca2+ or K+ channels, may contribute to the anesthetic effect of urethane. In addition, the action of the selective 5-HT2 antagonist ketanserin is clearly altered by urethane. These findings are important to consider when urethane is used for in vivo neurophysiological investigations, particularly when 5-HT mechanisms are involved.