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 el ectrophysiological in vivo experiments. However, its pharmacological e ffects are poorly understood. Here, the effects of urethane on in vitr o contractile responses of the rat thoracic aortic ring preparation we re investigated. Bath application of 5-HT produced a concentration-dep endent 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-H T to the right (EC(50) = 1.7 x 10(-5) M) and decreased the maximal con traction by 30.8%. The CRC for NA (EC(50) = 7.2 x 10(-9) M) was also s hifted to the right by urethane (EC(50) = 1.4 x 10(-8) M), but the shi ft of the 5-HT-CRC was twice that of the NA-CRC (3.95 vs. 1.95). The C RC to KCl was shifted rightwards only slightly by urethane (ratio 1.27 ) and the maximal contraction to KCl was not affected. The CRC to repl acement of CaCl2 (0.1 - 10 mM) to KCl-depolarized vessels in a Ca2+-fr ee Krebs solution was unaffected by urethane. Ketanserin (10(-9) M) an tagonized the contraction to 5-HT, and a combination of ketanserin and urethane was markedly more effective than either drug alone, decreasi ng the maximal contraction by 58%. Antagonism of NA contraction by pra zosin (5 x 10(-8) M) was not increased by addition of urethane. The ur ethane dose used here approximates blood and brain concentrations requ ired to produce anesthetic effects in mammals. It is possible that red uctions in 5-HT transmission and, to a lesser extent, in NA transmissi on, but not blockade of Ca2+ or K+ channels, may contribute to the ane sthetic effect of urethane. In addition, the action of the selective 5 -HT2 antagonist ketanserin is clearly altered by urethane. These findi ngs are important to consider when urethane is used for in vivo neurop hysiological investigations, particularly when 5-HT mechanisms are inv olved.