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Original Articles – Cardiovascular

Investigation of the relaxant effects of pancuronium, rocuronium, vecuronium and mivacurium on rat thoracic aorta

Gursoy, Sinana; Bagcivan, Ihsanb; Durmus, Nedimb; Kaygusuz, Kenana; Kol, Iclal Ozdemira; Yildirim, Sahinb; Mimaroglu, Canera

Author Information
European Journal of Anaesthesiology: February 2009 - Volume 26 - Issue 2 - p 155-159
doi: 10.1097/EJA.0b013e32831a461f

Abstract

Introduction

Pancuronium, vecuronium, mivacurium and rocuronium are nondepolarizing neuromuscular blocking agents. Although neuromuscular blocking drugs are designed to specifically block nicotinic cholinergic receptors at the neuromuscular junction, many bind to muscarinic cholinergic receptors on ganglia, nerve endings and smooth muscle [1]. The principal action of nondepolarizing muscle relaxants is competitive antagonism against acetylcholine at nicotinic receptors in the neuromuscular junction and these agents are considered to have no direct actions on vascular smooth muscle [2].

Although they have a similar amino steroidal three-dimensional structure, experimental studies performed in different species have shown that these compounds affect the cardiovascular system with different potencies [3,4]. Pancuronium, which has been reported to have more sympathomimetic properties than vecuronium [5], is reported to increase heart rate and arterial blood pressure (BP) [6,7] by its positive inotropic and chronotropic effects [3,4]. Although rocuronium did not produce significant cardiac effects [7] except minor haemodynamic changes [8], vecuronium has been reported to induce bradycardia [9–11]. Mivacurium injection caused transient tachycardia and hypotension in healthy individuals [12]. The mechanisms of action of these compounds have been explained by cardiac antimuscarinic effects, noradrenaline release and inhibition of noradrenaline reuptake [13–16].

The aim of this study was to investigate the relaxant effects and possible underlying mechanisms of pancuronium, vecuronium, mivacurium and rocuronium on isolated rat thoracic aorta along with their effects on the BP in clinical doses and compare their vascular actions with each other.

Methods

All experimental procedures were performed in accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals and the experiments were approved by Cumhuriyet University Medical Faculty, Animal Care Committee. Twenty male albino Wistar rats (weighing 180–220 g) were injected with pentobarbital sodium (100 mg kg−1) and sodium heparin (5000 IU kg−1) intraperitoneally. The thoracic aorta was removed carefully and cleaned of fat and adherent connective tissues. It was cut into segments of 2–3 mm in length and mounted onto two stainless-steel stirrups immersed in a 10 ml organ chamber, containing Krebs–Henseleit solution (composition in mmol l−1: NaCl 120.0, KCl 4.6, CaCl2 2.5, MgSO4 1.2, NaHCO3 22.0, NaH2PO4 1.2, CaCl2 2.5, glucose 11.5) that was gassed continuously with 95% O2 and 5% CO2 and maintained at 37°C. The upper ends of the preparations were tied to an isometric transducer (Grass FT 03, Quincy, Massachusetts, USA) and preloaded with 1.5 g resting tension. They were allowed to achieve equilibrium for 60 min with the bath fluid being changed every 15 min. In some rings (n = 5), the endothelium was removed mechanically by inserting a polyethylene tube (PE50) into the lumen of the ring and rolling the vessel with the tube gently onto moistened gauze.

The aortic rings were precontracted with prostaglandin F2α (PGF) (10−7 mol l−1) and pancuronium (10−7–10−4 mol l−1), rocuronium (10−7–10−4 mol l−1), vecuronium (10−7–10−4 mol l−1) and mivacurium (10−7–10−4 mol l−1) were added to organ baths at cumulative concentrations in the presence or absence of a prostaglandin synthesis inhibitor, indomethacin (10−6 mol l−1), and a nitric oxide synthesis inhibitor, N(omega)-nitro-L-arginine methylester (L-NAME, 3 × 10−5) [17]. The same protocol was applied to both endothelia (+) and endothelia (−) aortic rings.

Preparations precontracted with PGF (10−7 mol l−1) were stimulated with two parallel platinum electrodes at a frequency of 10 Hz as square-wave pulses of 50 V (0.2 ms) delivered by a current amplifier and a stimulator. Before electrical field stimulation (EFS), the tissues were treated with a noradrenaline reuptake inhibitor, desipramine (10−7 mol l−1), and a nonselective beta-blocker, propranolol (10−6 mol l−1) [17]. Pancuronium, rocuronium, vecuronium and mivacurium were added to the organ bath at ineffective concentration of 10−7 mol l−1. Tetrodotoxin (10−7 mol l−1) was added to test whether the changes were depending on the neuronal response.

The drugs used were PGF, indomethacin, L-NAME, desipramine, propranolol, tetrodotoxin (Sigma Chemical, St Louis, Missouri, USA); vecuronium, rocuronium (N.W. Organon, Oss, Holland); mivacurium (Glaxo Smith Kline, Farma, Italy) and Pancuronium (Organon Teknika, Istanbul, Turkey). All drugs were prepared by dissolving in deionized water and were prepared freshly on the day of the experiment. The stock solutions were stored at −20°C.

Statistical analysis

All data are expressed as means ± SEM. Groups were compared statistically using general linear models of analysis of variance (ANOVA) followed by the Newman–Keuls test and t test when appropriate. A P value of less than 0.05 was considered significant. All analyses were performed with Statistica for Windows 6.0. (Statsoft, Inc., Tulsa, USA).

Results

Pancuronium (10−7–10−4 mol l−1) and rocuronium (10−7–10−4 mol l−1) relaxed the preparations precontracted with PGF (10−7 M) in a dose-dependent manner but vecuronium and mivacurium did not. The relaxation effect of pancuronium was statistically more than rocuronium (P < 0.05) (Fig. 1a). There was no significant difference between their relaxation effects in the endothelium-denuded preparations (Fig. 1b). L-NAME (3 × 10−5) did not change the pancuronium (10−7–10−4 mol l−1) or rocuronium (10−7–10−4 mol l−1) effects but indomethacin (10−6 mol l−1) decreased their effect significantly (P < 0.05) (Fig. 2a and b).

Fig. 1
Fig. 1
Fig. 2
Fig. 2

EFS (10 Hz, 50 V, 0.2 ms) relaxed the preparations precontracted with PGF2αa (10−7 mol l−1); this relaxation effect was increased significantly by pancuronium (10−7 mol l−1), vecuronium (10−7 mol l−1), mivacurium (10−7 mol l−1) and rocuronium (10−7 mol l−1) (P < 0.05). Although desipramine, at a concentration sufficient to inhibit the uptake of catecholamine (10−7 M) by sympathetic nerve terminals [18], did not change EFS-induced relaxations, a nonselective beta-blocker, propranolol (10−6 mol l−1), decreased them significantly (P < 0.05). Tetrodotoxin (10−7 mol l−1), which blocks voltage-dependent Na+ channels, abolished EFS-induced relaxations (Fig. 3). Emax and pD2 values of pancuronium and rocuronium were calculated and are shown in Table 1.

Fig. 3
Fig. 3
Table 1
Table 1:
Emax and pD2 values of pancuronium, rocuronium, vecuronium and mivacurium

Discussion

The vasomotor effects of anaesthetics have been widely evaluated by the isolated vessel ring model. Various animal preparations have been used (rat aorta, canine mesenteric artery, porcine coronary artery and others). There are some studies with intravenous anaesthetics (propofol, thiopental and others) using this model [19].

Although neuromuscular blocking drugs are widely used with general anaesthetics, there are few studies evaluating the effects of them on vascular tone. Sai et al. [17] found that pancuronium caused relaxations in canine coronary and renal arteries partially contracted with PGF, whereas these arteries did not significantly respond to vecuronium.

The relaxant responses were independent of endothelium and abolished by treatment with indomethacin, a cyclooxygenase inhibitor, or tranylcypromine, a prostaglandin I2 (PGI2) synthesis inhibitor [20,21]. Among available prostanoids, only PGI2 relaxes canine coronary and renal arteries [21,22]. They concluded that these results might indicate that pancuronium releases vasodilator prostaglandins, possibly PGI2, from subendothelial tissues.

It has been reported that pancuronium stimulates the release of norepinephrine from nerves and simultaneously inhibits the neural uptake in canine-isolated saphenous veins [23] and in anesthetized dogs [24]. Sai et al. [17] thought that the potentiation by pancuronium and vecuronium of the response to adrenergic stimulation appears to be due to the inhibition of the neural uptake of noradrenaline rather than the increased release of noradrenaline. In some studies, it was reported that, although vecuronium in clinical doses does not have the vascular action that pancuronium does [25,26], high doses of vecuronium may work as a sympathomimetic agent [17]. Because of the endothelium-independent action, pancuronium might have some beneficial clinical effect, especially under pathologic conditions such as atherosclerosis and hypertension, in which the synthesis or action of nitric oxide [27,28] and endothelium-derived hyperpolarizing factor (EDHF) [28–30] are reduced. Sai et al. [17] reported that, in patients with heightened sympathetic activity, pancuronium and vecuronium also might elicit coronary vasodilatation through a potentiated action of noradrenaline on beta-adrenoceptors, whereas renal vascular resistance may be increased.

In another study [31], pancuronium produced a positive chronotropic effect. Vecuronium and rocuronium induced a positive inotropic effect; furthermore, vecuronium shortened the effective refractory period. All the changes in cardiac activity observed were induced by relatively high concentrations of the drugs.

There is only one study on the cardiovascular effects of mivacurium and in that study the authors reported that a slow injection rate of mivacurium (>30 s) might be used in hypertensive patients.

The plasma concentration of pancuronium administered to humans during the first 3 h is reportedly [32] 500–100 ng ml−1 (about 90% free form [33], which is equivalent to 7 × 10−7 and 1.4 × 10−7 mol l−1, respectively). According to these data in this study, we used all of neuromuscular blocking drugs at concentrations similar to those in the study of Sai et al. [17]. In this study, pancuronium and rocuronium relaxed aortic rings precontracted by PGF in a dose-dependent manner, but vecuronium and mivacurium did not. The relaxation effect of pancuronium and rocuronium was endothelium independent because there was not a significant response difference from the endothelium-denuded group. Their relaxation effects may be due to an increase in prostaglandin synthesis. The increased relaxation effect of pancuronium, rocuronium, vecuronium and mivacurium at EFS may be by decreasing the effect of noradrenaline reuptake from nerve endings because a noradrenaline reuptake inhibitor, desipramine, did not change this effect. Also, these neuromuscular agents may affect beta-receptors, because a nonselective beta-blocker agent, propranolol, decreased their EFS-induced relaxations.

In conclusion, pancuronium and rocuronium may have some clinical effect, especially under pathologic conditions such as atherosclerosis and hypertension in which endothelium is damaged. The mediation of prostaglandins in the relaxation effect of pancuronium and rocuronium may decrease their effect before surgical operations in the presence of prostaglandin synthesis inhibitors.

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Keywords:

drug interactions; mivacurium; neuromuscular nondepolarizing agents; pancuronium; rat aorta; rocuronium; thoracic; vecuronium

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