The effects of the intravenous injection of isoprenaline on heart rate and arterial pressure has been studied in dogs artificially respired with room air or with 12% oxygen—88% nitrogen. In dogs breathing room air, isoprenaline in doses from 0.02 to 500 μg/kg increased heart rate and reduced arterial pressure. Ventricular fibrillation was produced in one out of three dogs given 250 μg/kg. This was the only dog breathing room air which was killed by isoprenaline. In dogs breathing room air the repeated intravenous injection at 5‐min intervals of 2.5 μg/kg increased heart rate and reduced arterial pressure. No ill effects were produced by six doses. In dogs respired with 12% oxygen—88% nitrogen the Pao2 was reduced from 84 to 38 mm Hg with no changes in Paco2. In these dogs death was produced by doses of isoprenaline which in dogs breathing room air produced normal responses. The fatal dose of isoprenaline (10–50 μg/kg) reduced heart rate and arterial and pulse pressures; sinus rhythm persisted until arterial pressure was less than 50 mm Hg. Ventricular fibrillation did not occur; death occurred from cardiac asystole. Death was produced in a similar way in dogs with hypoxaemia by giving four or five doses of isoprenaline (2.5 μg/kg) at 5‐min intervals or by two doses of 25 μg/kg. The final reduction in arterial pressure during a fatal response resulted from a reduction in cardiac contractility. These lethal effects of isoprenaline could be prevented by pretreatment with propranolol.

In dogs respired with 10% oxygen: 90% nitrogen, only five out of 16 dogs survived repeated intravenous doses of isoprenaline (either 0.5 or 1.0 μg/kg) and only one out of six dogs survived repeated isoprenaline inhalations from a pressurized aerosol. In dogs respired with 15% oxygen: 85% nitrogen, five out of six dogs survived repeated intravenous doses of isoprenaline (2.5 μg/kg). The fatal response in these animals consisted of a fall in heart rate, arterial and pulse pressures. Sinus rhythm persisted even after the arterial pressure had fallen, though occasionally a slow A‐V nodal rhythm or irregular ventricular ectopic beats occurred. Ventricular fibrillation did not occur. Eight out of 10 dogs brought to the verge of a fatal response with 10% oxygen: 90% nitrogen and repeated doses of isoprenaline (2.5 μg/kg) were resuscitated by the administration of 100% oxygen and, when necessary, cardiac massage. A group of five dogs survived the combined effects of repeated doses of isoprenaline (2.5 μg/kg) and respiration with 10% oxygen: 90% nitrogen when the time interval between doses was 11 min, instead of the usual 5 minutes. Control of pH by infusion of sodium bicarbonate did not protect the dogs from the combined effects of hypoxia and repeated isoprenaline challenge. After a 60 min period of continuous isoprenaline infusion in dogs breathing room air, only one of 10 dogs survived artificial respiration with 10% oxygen: 90% nitrogen and repeated challenge with intravenous isoprenaline (1.0 μg/kg) at 5 min intervals. At the higher infusion levels of isoprenaline (0.1 and 1.0 μg kg−1 min−1), two dogs out of four died after the hypoxic mixture was started but before any isoprenaline challenge was given. The possible relevance of these findings in dogs to the recently observed increase in mortality in young asthmatics is discussed.

Using the in situ perfused rat liver model, the effect of erythromycin (Ery) on the disposition of cyclosporin A (CyA) and the major human metabolite, AM1, was investigated. Prior to perfusion experiments, oral dosing was carried out for three days on three groups of male Sprague-Dawley rats (300-350 g), involving pretreatment with water (control and H2O/Ery groups) or erythromycin (Ery oral group). On the fourth day, perfusion experiments took place using standard techniques, with the addition of 20 mg Ery to the H2O/Ery and Ery oral groups, and 2.5 mg CyA to all groups. Perfusate and bile samples were collected and assayed for CyA and AM1 by HPLC. Results indicated that inhibition of CyA metabolism had occurred as the CyA concentration in perfusate was significantly higher in both Ery groups at all times compared to the control group, and the levels of AM1 in both perfusate and bile were significantly lower than in the control group. There was also a marked reduction in the apparent metabolic clearance of CyA in the Ery groups. It was concluded that AM1 production had been inhibited by Ery, the most likely mechanism being inhibition of the isoenzyme CYP3A with which Ery forms a stable complex.

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The in situ perfused rat liver model was used to investigate the effect of three H2 receptor antagonists on the disposition of cyclosporin A (CyA) and the major human metabolite, AM1. Perfusion experiments, using standard techniques, were carried out on four groups (one control and three H2-receptor antagonist-treated groups) of male Sprague-Dawley rats (300-350 g). All animals received CyA, 2.5 mg; the three treated groups received cimetidine (8 mg), ranitidine (3 mg), or famotidine (0.4 mg). Perfusate and bile samples were collected and assayed for CyA, AM1, and the H2 receptor antagonists by HPLC. Results indicated that CyA perfusate concentrations in the controls and cimetidine and ranitidine-treated groups were not significantly different, although levels in the famotidine group were significantly higher at all times (p < 0.05), except 30 min, compared to the controls. However, examination of the AM1 perfusate and bile data and the apparent metabolic clearance data indicated that CyA metabolism was still occurring, despite the presence of the H2 receptor antagonist. It is suggested that the absence of a interaction may be attributed to a lack of specificity of the H2 receptor antagonists for CYP3A, the isoenzyme responsible for CyA metabolism.