Acta pharmacol. et toxicol. 1979. 44, 91-94.

From the Department of Pharmacology, AB Hassle, Molndal, Sweden

Haemodynamic Effects of the Quaternary Ammonium Compound Q X 572 in Anaesthetized Cats. I. Cardiac Chronotropic Effects BY G . .&berg,U. Kopp and L. R y d h

(Received May 9, 1978; Accepted August I , 1978)

Abstract: The haemodynamic effects of the antiarrhythmic compound, QX 572, have been studied in anaesthetized cats. I t was found that QX 572 increased the heart rate and decreased the blood pressure of the cats during the infusion of the drug. A slight increase in blood pressure was seen after the infusion was terminated. The same results have been obtained in patients. Experiments on cats pretreated with propranolol or reserpine showed that infusions of QX 572 caused an increase in heart rate by increasing the sympatheticactivity in the cats. I t is also shown that changes in vagal tone may contribute to the effects of QX 572 on the heart rate. Key-word.~Antiarrhythmic compound - quaternary ammonium compound - haemodynamic effect -

chronotropic effect - anaesthetized cats.

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Fig. 1. Structural formula of QX 572. Q X 572 is a quaternary lidocaine-like compound (fig. 1). It has been shown to possess antiarrhythrnic properties both in animals (Covino 1962; Katz 1964) a n d in man ( R y d i n 1974). However, in human studies some investigators (Katz 1965; Schwartz et at. 1967; R y d i n et al. 1974, 1975a. 1975b & 1 9 7 5 ~ )have found cardiovascular sideeffects of Q X 572. Thus, R y d h et at. have reported a n increased heart rate in man during intravenous infusion of 8 m g k g body-weight of Q X 572 ( A H R = 3 2 f 10 beats/min.). They also found that Q X 572 induced a concomitant a n d transient decrease in the brachial artery pressure followed by a n increase in the brachial artery blood pressure. To

study the cardiovascular side-effects of Q X 572 greater in detail experiments have been performed in animals. In this communication we describe studies o n the positive chronotropic effects of Q X 572 in cats a n d the possible role of neural mechanisms involved in these effects.

Materials and Methods All experiments were performed on cats of either sex, weighing 2.5 - 4.0 kg. They were anaesthetized with chloralose 60 m d k g body-weight intravenously during a slight ether anaesthesia. A tracheal cannula was inserted and the animals were artificially ventilated with room air. The body temperature of the animals was kept constant by a heat lamp, connected to a thermometer in the oesophagus. Arterial blood gases were continously checked and kept within the following values: PO2 pC02 PH

60-120 mmHg 25- 35 mmHg 7.35-7.45

Heart rate was recorded via a cardiotachometer from the

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ECG and systemic blood pressure was recorded from the femoral artery. In all experiments QX 572 9 mg/kg bodyweight was infused intravenously over 30 min.

Experimental series 1. Effects on heart rate and blood pressure were studied by recording these parameters before, during and after the intravenous infusion of QX 572. The experiments were performed on 5 cats; each cat was given one infusion of QX 572. Series 2. A surgical parasympathectomy of the heart was performed by bilaterally cutting the vagal nerves in the neck before the infusion ofQX 572. Experiments were performed on 5 cats. Series 3. A blockade of cardiac sympathetic effects was performed in these cats by treatment with propranolol, 0.5 mg/kg body-weight, 10 min. before the infusion of QX 572 was started. In separate experiments in anaesthetized cats, this dose of propranolol has been found to block the cardiac chronotropic effect of isoprenaline 0.01 p d k g to more than 80 per cent for 60 rnin. (unpublished results). Experiments were performed on 5 cats. Series 4. The cats were vagotomized like those in series 1 and in addition they were pretreated with propranolol as in series 2 before the infusion of QX 572. Experiments were performed on 5 cats. In addition, 2 vagotomized cats received the dextro-isomer of propranolol. Series 5. The cats were pretreated with reserpine 2.5 m d k g body-weight, intramuscularly, 18 hours before the experiment. The efficacy of the reserpinization was checked prior to the experiment and the heart rate of these cats was not increased by electrical stimulation of their cardiac sympathetic nerve fibres. Vagotomy and ligation of the adrenal glands were also performed. QX 572 was infused as in the other series. Experiments were performed o n 3 cats.

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Results Series 1. When 9 m d k g of QX 572 was given intravenously over 30 min. the heart rate was increased in all the 5 cats tested. The mean heart rate was increased by 2 5 + 4 beatdmin. S.E.M.); see fig. 2A. As shown in fig. 2B there was no significant effect of QX 572 on the mean blood pressure during the infusion of the drug. A slight tendency to a decrease of the mean blood pressure was however seen during the infusion of QX 572 and a slight increase was seen after the infusion had been terminated. Series 2. The heart rate of the cats in response to QX 572 was significantly increased although their vagal nerves had been cut (fig. 3A). In these experiments on cats with “normal” sympathetic tone, the basal heart rate was not changed by vagotomy. However, the heart rate was increased

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Fig. 2A and B. Effects of QX 5 7 2 , 9 mg/kg on the mean heart rate (fig. 2A) and the mean blood pressure (fig. 2 8 ) in anaesthetized cats. The drug was given intravenously during 30 min. Mean values f S . E . M . from 5 cats. The statistical significance of the effects, as compared to predrug values, is shown in the figures, where x means