Atracurium besylate, 2,2′-(3,11-dioxo-4,10-dioxatridecylene)-bis-[6,7-dimethoxy-1-(3,4-dimethoxy-benzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolinium] dibenzenesulphonatc, is one of a new series of competitive neuromuscular blocking agents. An i.v. dose of 0.25 mg kg −1 produced complete paralysis in anaesthetized cats, dogs and rhesus monkeys; paralysis was of medium duration and was readily antagonized by neostigmine. Vagal blockade occurred only after doses 8–16 times greater than the full neuromuscular paralysing dose and effects on sympathetic mechanisms were minimal. Hypotension and bradycardia were evident after supramaximal doses of 4 mg kg −1 i.v. and these effects, together with circulatory depression, were probably attributable to histamine release. In vitro studies have shown that the non-enzymic decomposition of atracurium by "Hofmann Elimination" was enhanced by increasing pH. In vivo neuromuscular paralysis was significantly reduced when the arterial pH was increased. There were indications that neither the liver nor the kidney plays a major role in the metabolism and elimination of unchanged drug. These results are of sufficient interest to merit the evaluation of atracurium in anaesthetized man.

The pharmacology of atracurium: a new competitive neuromuscular blocking agent

Direct measurements of arterial pressure, stroke volume (SV), and cardiac output (CO) were obtained in ether-anesthetized rats with established spontaneous hypertension (SHR) treated with alpha-methyldopa and compared to both untreated hypertensive and normotensive Wistar-Kyoto (WKY) rats. Left ventricular pumping ability was determined by the maximum levels of SV and CO reached during rapid intravenous volume loading with blood. Treatment with methyldopa reduced the SHR arterial blood pressure (average 57 mm Hg) and reversed the cardiac hypertrophy toward normal. In comparison to untreated SHR, therapy increased heart rate and CO and decreased peripheral resistance. During volume-loading, the levels of SV and CO at matched left ventricular end-diastolic pressures were significantly higher in treated vs untreated SHR. To evaluate the role of blood pressure in the improved peak pumping ability observed in treated rats, a phenylephrine infusion was used to equalize pressures while repeating cardiac function studies. In normotensive WKY and untreated SHR, left ventricular pump function was not greatly affected. A pronounced depression in peak SV and peak CO was observed only in treated SHR. The data indicate that treatment with methyldopa is associated with improved ventricular function in part related to the reduction in arterial pressure.

Cardiac pumping ability following reversal of hypertrophy and hypertension in spontaneously hypertensive rats.

1 The aim of the study was to determine the mechanism of the hypotension and bradycardia produced by prostacyclin (PGI2). 2 Haemodynamic studies were carried out in nineteen open-chest beagle dogs anaesthetized with chloralose. PGI2 was infused intravenously or into the left atrium. 3 Infusions of PGI2 either intravenously or into the left atrium equally reduced arterial pressure and total peripheral resistance but bradycardia was greater after infusion into the left atrium. 4 Comparison of effects of PGI2 with those of prostaglandin E2 (PGE2) showed that although left atrial infusions both reduced aortic pressure and total peripheral resistance, PGE2 always increased heart rate, cardiac output and maximum acceleration. 5 Similar effects were observed with sodium nitroprusside except that it always caused tachycardia and reduced stroke volume. 6 Atropine (0.05 or 1 mg/kg i.v.) reduced or reversed the bradycardia induced by PGI2 but its hypotensive effects were reduced only after 1 mg/kg atropine. After vagotomy changes in cardiac output, stroke volume and maximum acceleration were increased, the hypotensive effects of PGI2 were reduced and the bradycardia was reversed; effects induced by PGE2 were not significantly altered. 7 The hypotension induced by prostacyclin is due to two components, a direct relaxation of vascular smooth muscle and a reflex, non-cholinergic vasodilatation. The bradycardia is reflex in nature and is partially mediated by the vagus pathway.

Some direct and reflex cardiovascular actions of prostacyclin (PGI2) and prostaglandin E2 in anaesthetized dogs.

The renal haemodynamic and excretory actions of prostacyclin and 6-oxo-PGF1 alpha in anaesthetized dogs.

SUMMARY Analogue techniques were applied to measurements of phasic aortic blood flow and pressure to obtain continuous recordings of peripheral vascular resistance and circulatory function in open-chest dogs during basal narcosis with chloralose. Whereas the hypotension following hexamethonium 1 and 3 mg/kg i.v. was associated with a marked fall in peripheral vascular resistance and some reduction of maximum acceleration and cardiac output, the hypotension during ventilation with 1 and 2% halothane was associated with a large reduction in maximum acceleration (i.e. cardiac depression) and cardiac output with a relatively small fall in peripheral vascular resistance. In closed-chest dogs 1–2% halothane caused falls in arterial blood pressure and heart rate similar to those after hexamethonium 1–3 mg/kg i.v. without comparable impairment of either vagally-induced bradycardia or the contractions of the nictitating membrane due to sympathetic nerve stimulation. Ganglion blockade did, however, become prominent with concentrations of 4% halothane. It is thought that diminished central vasomotor tone, a reduction of the effects of the sympathetic mediator on blood vessels and a direct relaxant effect of halothane on vascular smooth muscle also contribute importantly to the peripheral vascular depression.

The haemodynamic effects of halothane in dogs

Peripheral vascular resistance, stroke volume, cardiac output and maximum acceleration were computed in ‘real-time’ using aortic pressure and flow signals processed by simple analogue circuits incorporated into a multichannel recording system. The use of the system was exemplified by records of the haemodynamic effects of methoxamine and adrenaline in anaesthetized dogs and noradrenaline, isoprenaline and ephedrine in unanaesthetized dogs. These analogue techniques are applicable to circulatory studies in man.

Hughes R

Papers

Continuous measurement of peripheral vascular resistance and circulatory function.