Inhibitory Effect Of Fentanyl Research Articles

Inhibitory Effect of Fentanyl on Phenylephrine-Induced Contraction on Rabbit Aorta

This in vitro study was designed to assess the effects of fentanyl on isolated rabbit thoracic aorta rings contracted with phenylephrine. Methods included contraction of aorta rings with phenylephrine (10–5 M) and recording the changes after increasing concentrations of fentanyl (10–9 M – 10–5 M). Similar experiments were done after incubation with Nω- nitro-L-arginine methyl ester (10–4 M), indomethacin (10-5 M), naloxone (10–5 M), ouabain (10–5 M), TEA (10–4 M) and glibenclamide (10–5 M). It was revealed that, fentanyl causes relaxation in rabbit aorta rings precontracted with phenylephrine. Removal of endothelium significantly reduces the relaxant response to fentanyl. Nitric oxide synthase inhibitor L-NAME, K+ channel blocker glibenclamide and Na+/K+ ATPase inhibitor ouabain inhibits the relaxant effect of fentanyl in endothelium intact aorta rings. These results suggest that fentanyl causes dose dependent vasodilatation in the rabbit aorta via activation of KATP channels and Na+-K+ -ATPase, and nitric oxide released from endothelium.

Inhibitory Effect of Fentanyl on Phenylephrine-Induced Contraction of the Rat Aorta

PurposeFentanyl was reported to inhibit the α1-adrenoceptor agonist-induced contraction. The goal of this in vitro study was to identify the α1-adrenoceptor subtype primarily involved in the fentanyl-induced attenuation of phenylephrine-induced contraction in isolated endothelium-denuded rat aorta.Materials and MethodsAortic rings were suspended in order to record isometric tension. Concentration-response curves for phenylephrine (10-9 to 10-5 M) were generated in the presence or absence of one of the following drugs: fentanyl (3×10-7, 10-6, 3×10-6 M), 5-methylurapidil (3×10-8, 10-7, 3×10-7 M), chloroethylclonidine (10-5 M) and BMY 7378 (3×10-9, 10-8, 3×10-8 M). Phenylephrine concentration-response curves were generated in the presence or absence of fentanyl in rings pretreated with either 3×10-9 M prazosin, 10-9 M 5-methylurapidil or 3×10-9 M BMY 7378.ResultsFentanyl (10-6, 3×10-6 M) attenuated phenylephrine-induced contraction in the rat aorta. 5-Methylurapidil and BMY 7378 produced a parallel rightward shift in the phenylephrine concentration-response curve. The pA2 values for 5-methylurapidil and BMY 7378 were estimated to be 7.71 ± 0.15 and 8.99 ± 0.24, respectively. Fentanyl (10-6 M) attenuated phenylephrine-induced contraction in rings pretreated with 10-9 M 5-methylurapidil, but did not alter the rings when pretreated with 3×10-9 M BMY 7378. Pretreatment of the rings with chloroethylclonidine showed a 72.9 ± 2.3% reduction in phenylephrine-induced maximal contraction.ConclusionThe results suggest that fentanyl attenuates phenylephrine-induced contraction by inhibiting the pathway involved in the α1D-adrenoceptor-mediated contraction of the rat aorta.

Inhibitory effect of fentanyl on acetylcholine-induced relaxation in rat aorta.

Previous study has shown that fentanyl attenuates acetylcholine-induced vasorelaxation. The goal of the current in vitro study was to identify the muscarinic receptor subtype that is mainly involved in the fentanyl-induced attenuation of endothelium-dependent relaxation elicited by acetylcholine. The effects of fentanyl and muscarinic receptor antagonists on the acetylcholine concentration-response curve were assessed in aortic vascular smooth muscle ring preparations precontracted with phenylephrine. In the rings pretreated independently with pirenzepine, 4-diphenylacetoxyl-N-methylpiperidine methiodide, and naloxone, acetylcholine concentration-response curves were generated in the presence and absence of fentanyl. The effect of fentanyl on the concentration-response curve for calcium ionophore A23187 was assessed. Fentanyl (0.297 x 10 0.785 x 10 m) attenuated acetylcholine-induced vasorelaxation in ring preparations with or without 10 m naloxone. Pirenzepine (10 to 10 m) and 4-diphenylacetoxyl-N-methylpiperidine methiodide (10 to 10 m) produced a parallel rightward shift in the acetylcholine concentration-response curve. The concentrations (-log M) of pirenzepine and 4-diphenylacetoxyl-N-methylpiperidine methiodide necessary to displace the concentration-response curve of an acetylcholine by twofold were estimated to be 6.886 +/- 0.070 and 9.256 +/- 0.087, respectively. Methoctramine, 10 m, did not alter the acetylcholine concentration-response curve. Fentanyl, 0.785 x 10 m, attenuated acetylcholine-induced vasorelaxation in the rings pretreated with 10 m pirenzepine but had no effect on vasorelaxation in the rings pretreated with 10 m 4-diphenylacetoxyl-N-methylpiperidine methiodide. Fentanyl, 0.785 x 10 m, did not significantly alter calcium ionophore A23187-induced vasorelaxation. These results indicate that fentanyl attenuates acetylcholine-induced vasorelaxation via an inhibitory effect at a level proximal to nitric oxide synthase activation on the pathway involving endothelial M3 muscarinic receptor activation in rat aorta.

Lipid peroxidation in rat lung induced by neuroleptanalgesia and its components.

The aim of the present work was to determine the likelihood of lipid peroxidation in the lungs of rats subjected to neuroleptanalgesia and its components. In particular, the effect of fentanyl, droperidol, a nitrous oxide/oxygen mixture when used separately or in combination, on the lung level of lipid peroxidation was investigated. The in vitro antioxidant properties of fentanyl and droperidol were also tested. Lipid peroxidation was evidenced by the endogenously generated conjugated dienes and fluorescent products of lipid peroxidation and the decrease in lung vitamin E content. It was found that fentanyl and droperidol, used separately or in combination, did not induce lipid peroxidation in the rat lung, while the exposure of rats for 120 min to a nitrous oxide/oxygen mixture (2:1 v/v) led to well-expressed peroxidation. The (N2O + O2)-pro-oxidant action was significantly inhibited in rats previously injected with fentanyl and/or droperidol. The results show that the application of fentanyl, droperidol and (N2O + O2), as in neuroleptanalgesia, ensures minimal lipid peroxidation in the lung. In addition, we found that fentanyl and droperidol were able to inhibit the Fe(2+)-catalysed lipid peroxidation in lung homogenate. We speculate that the inhibitory effect of fentanyl and/or droperidol on the (N2O + O2)-induced lipid peroxidation in the rat lung may be caused directly by their antioxidant properties. However, another explanation seems to be possible. The free radicals that are produced during the metabolism of fentanyl and droperidol may react with the radicals generated during the one-electron reduction of nitrous oxide. Such reactions will obviously reduce the free radical concentration in the organism and, hence, the likelihood of initiating lipid peroxidation.

Glucuronidation of Propofol in Microsomal Fractions from Various Tissues and Species Including Humans

This in vitro study was conducted to evaluate propofol glucuronidation and the effect of concomitantly administered drugs in various species.Propofol glucuronidation was studied in microsomal fractions from rat, rabbit, and human livers. Extrahepatic metabolism was investigated using lung and kidney microsomes. The propofol-uridine diphosphate-glucuronosyltransferase (UGT) activity measured in liver microsomes was higher in rabbit than in rat. Among the three tested species, human livers exhibited the highest activity, with only small variability in the three samples studied. Animal kidney, but not lung (animal or human), microsomes were able to glucuronidate propofol, meaning that extrahepatic metabolism of propofol exists, at least in the kidney, in the tested species (rat and rabbit). Since metabolic interactions are potential sources of prolonged drug effect or overdose, we screened the effect of 21 compounds (known substrates of various UGT or potentially coadministered drugs) on the glucuronidation of propofol by human liver microsomes. Inhibitions obtained with chemicals or drugs glucuronidated by either UGT1 or UGT2 families (1-naphtol, 4-hydroxybiphenyl, carvacrol, n-propylgallate, ketoprofen, chloramphenicol, acetylsalicylic acid) indicated that at least two UGT isoforms are involved in propofol glucuronidation. Inhibition was observed with several drugs potentially coadministered during pre-, per-, or postoperative periods (e.g., acetylsalicylic acid, ketoprofen, oxazepam, fentanyl). Although not directly transposable to the in vivo situation, these results indicate that such interactions are theoretically possible. Similarly, the inhibitory effect of fentanyl on propofol glucuronidation demonstrated by our in vitro study could explain the in vivo drug-drug interaction that has been described for this drug. Nine other widely used drugs had no effect on in vitro propofol glucuronidation. (Anesth Analg 1995;81:855-61)

SITE OF ACTION OF FENTANYL IN INHIBITING THE PITUITARY-ADRENAL RESPONSE TO SURGERY IN MAN

To determine the site of action of fentanyl in attenuating the pituitary-adrenal response to surgery, we have measured serum concentrations of cortisol and growth hormone during and after a standardized surgical procedure in two groups of patients. One group received fentanyl 15 micrograms kg-1 i.v. immediately before the start of surgery; a second group received fentanyl 15 micrograms kg-1 i.v. together with corticotrophin releasing factor 100 micrograms i.v., growth hormone releasing hormone 100 micrograms i.v. and arginine vasopressin 10 units i.m. The concomitant administration of the releasing factors with the opioid resulted in a significantly greater serum concentration of cortisol 30, 60, 120 and 240 min after surgery commenced, compared with the group which received fentanyl alone. Similarly, the growth hormone response in the combined group was significantly greater than in the fentanyl-alone group 30 min after the start of surgery. We conclude that the inhibitory effect of fentanyl on surgically-induced secretion of pituitary hormone was mediated directly or indirectly via the hypothalamus.

ALPHA-ADRENERGIC BLOCKING ACTION OF FENTANYL ON THE ISOLATED AORTA OF THE RABBIT

The contractile response of helically-cut strips of rabbit ascending aorta to transmural electrical stimulation was attenuated in a dose-dependent manner by treatment for 20 min with fentanyl, 10(-6) to 10(-5) M. Fentanyl also shifted the dose-response curve of the contractile response of aorta to norepinephrine to the right. The response to transmural stimulation was more resistant to fentanyl than was the response to an equipotent dose of norepinephrine. The inhibitory effect of fentanyl was neither prevented nor reversed by naloxone, but was partially reversed by repeated washing of the preparations. The contractile responses to histamine and serotonin were not significantly altered by fentanyl. Treatment with fentanyl as well as phentolamine protected alpha-adrenergic receptors from persistent blockade by phenoxybenzamine. Morphine to 10(-3) M failed to influence the dose-response curve of norepinephrine significantly. It may be concluded that fentanyl reversibly blocks alpha-adrenergic receptors in a competitive manner in vascular smooth muscle, and the potency of fentanyl is approximately 1/30 that of phentolamine.

INFLUENCE OF FENTANYL ON THE CHRONOTROPIC RESPONSE OF ISOLATED RABBIT ATRIA TO CHOLINERGIC AND ADRENERGIC STIMULATION

Effects of fentanyl and morphine on chronotropic responses to transmural stimulation applied to the S-A node were studied in isolated rabbit atria. The stimulation caused a frequency-dependent negative chronotropism followed by positive chronotropism, the former abolished by atropine and the latter suppressed by propranolol. The former response at 5 and 20/sec was attenuated in a dose-dependent manner by fentanyl and morphine. Potency ratio of fentanyl to morphine was approx. 50-100. The inhibitory effect of fentanyl and morphine on the response to stimulation of cholinergic nerves was partially prevented or reversed by both naloxone and levallorphan, and also partially reversed by repeated washing of the preparations. Antagonism by naloxone was appreciably greater than that of levallorphan. The negative chronotropic response to transmural stimulation was reduced by levallorphan but not by naloxone. Dose-chronotropic response curves of acetylcholine were unaffected by treatment with fentanyl and morphine. High concentrations of fentanyl and morphine attenuated the response to stimulation of adrenergic nerves, while dose-chronotropic response curves of noradrenaline were not influenced by these narcotics. Naloxone was ineffective in preventing or reversing the effect of fentanyl and morphine. It is therefore concluded that fentanyl and morphine activate opiate receptors located in cholinergic nerve terminals innervating the S-A node, thereby interfering with the release of acetylcholine. Further, it appears that high concentrations of fentanyl and morphine interfere with the release of noradrenaline from postganglionic adrenergic nerve terminals in rabbit atria; however, this action is not related to opiate receptors.

Alpha-adrenergic blocking action of fentanyl on the isolated aorta of the rabbit.

The contractile response of helically-cut strips of rabbit ascending aorta to transmural electrical stimulation was attenuated in a dose-dependent manner by treatment for 20 min with fentanyl, 10(-6) to 10(-5) M. Fentanyl also shifted the dose-response curve of the contractile response of aorta to norepinephrine to the right. The response to transmural stimulation was more resistant to fentanyl than was the response to an equipotent dose of norepinephrine. The inhibitory effect of fentanyl was neither prevented nor reversed by naloxone, but was partially reversed by repeated washing of the preparations. The contractile responses to histamine and serotonin were not significantly altered by fentanyl. Treatment with fentanyl as well as phentolamine protected alpha-adrenergic receptors from persistent blockade by phenoxybenzamine. Morphine to 10(-3) M failed to influence the dose-response curve of norepinephrine significantly. It may be concluded that fentanyl reversibly blocks alpha-adrenergic receptors in a competitive manner in vascular smooth muscle, and the potency of fentanyl is approximately 1/30 that of phentolamine.