Rendig S V, Amsterdam E A, Henderson G L, Mason D T
J Pharmacol Exp Ther. 1980 Oct;215(1):259-65.
Cardiac muscle contractile responses to six narcotic analgesics (morphine, meperidine, pentazocine, fentanyl, methadone and l-alpha-acetylmethadol), at concentrations from 10(-8) to 10(-4) M, both in the presence and absence of the narcotic antagonist, naloxone, were studied in the isolated, isometric cat right ventricular papillary muscle preparation. Measurements of maximum developed tension (T), maximum rate of tension development (dT/dt) and time to peak tension indicated that no major changes in contractile function occurred with any narcotic at concentrations of 10(-8) to 10(-6) M except for small but significant (P < .05) increases in all three parameters at 10(-6) M fentanyl, and small but significant increases in dT/dt at 10(-8) to 10(-6) M meperidine. At 10(-5) M narcotic, dT/dt was significantly elevated in meperidine-treated muscles (+7%), but significantly reduced in muscles exposed to pentazocine (-8%) or l-alpha-acetylmethadol (-11%). For all six narcotics, the 10(-4) M drug concentration resulted in depression of contractile function that was often associated with nonresponsiveness to electrical stimulation. Pretreatment of muscles with naloxone (10(-4) M) did not prevent this reduction of contractile performance except at the highest concentration (10(-4) M) of meperidine. Following removal of drug, contractile performance improved to varying degrees (recovery to 72-97% of control T), except in l-alpha-acetylmethadol-treated muscles, in which there was no recovery of T. Isoproterenol (0.8 X 10(-7) M) elicited a positive inotropic response whether administered in the presence of 10(-4) M narcotic or following narcotic removal. We conclude that narcotic analgesics in high concentrations exert a direct myocardial depressant effect which is not prevented by naloxone and therefore is not mediated by interaction with opiate receptors. Rather, several effects, including myocardial depression, its reversibility by both drug removal and isoproterenol and decreased muscle excitability are consistent with the hypothesis that narcotic analgesics in high concentrations exert nonspecific, local anesthetic effect on the myocardium.
在离体等长收缩的猫右心室乳头肌标本中，研究了六种麻醉性镇痛药（吗啡、哌替啶、喷他佐辛、芬太尼、美沙酮和左旋 - α - 乙酰美沙朵）在浓度为10^(-8)至10^(-4)M时，在有和没有麻醉拮抗剂纳洛酮存在的情况下对心肌收缩反应的影响。最大张力（T）、最大张力发展速率（dT/dt）和达到峰值张力的时间的测量结果表明，在浓度为10^(-8)至10^(-6)M时，除了在10^(-6)M芬太尼时所有三个参数有小但显著（P < 0.05）的增加，以及在10^(-8)至10^(-6)M哌替啶时dT/dt有小但显著的增加外，任何麻醉药对收缩功能都没有重大影响。在10^(-5)M麻醉药浓度下，哌替啶处理的肌肉中dT/dt显著升高（+7%），但暴露于喷他佐辛（-8%）或左旋 - α - 乙酰美沙朵（-11%）的肌肉中dT/dt显著降低。对于所有六种麻醉药，10^(-4)M的药物浓度导致收缩功能抑制，这通常与对电刺激无反应相关。用纳洛酮（10^(-4)M）预处理肌肉并不能防止这种收缩性能的降低，除了哌替啶的最高浓度（10^(-4)M）时。去除药物后，收缩性能有不同程度的改善（恢复到对照T的72 - 97%），但左旋 - α - 乙酰美沙朵处理的肌肉除外，其中T没有恢复。异丙肾上腺素（0.8×10^(-7)M）无论在10^(-4)M麻醉药存在时给药还是在去除麻醉药后给药，都会引起正性肌力反应。我们得出结论，高浓度的麻醉性镇痛药具有直接的心肌抑制作用，这种作用不能被纳洛酮阻止，因此不是通过与阿片受体相互作用介导的。相反，包括心肌抑制、通过去除药物和异丙肾上腺素均可逆转以及肌肉兴奋性降低等几种效应，与高浓度麻醉性镇痛药对心肌发挥非特异性局部麻醉作用的假设一致。
