Studies on bitolterol, di-p-toluate ester of N-tert.-butylarterenol: a new long-acting bronchodilator with reduced cardiovascular effects.

The bronchodilator activity of bitolterol, the di-p-toluate ester of N-tert.-butylarterenol (N-t-B) was evaluated by comparing it with the activity of the parent compound (N-t-B), isoproterenol and in some experiments with salbutamol in the anesthetized, open-chest dog maintained under artificial respiration. Bronchodilation was expressed as percent inhibition of the control bronchoconstriction induced by intravenous carbachol or histamine. At equiactive intravenous bronchodilator doses, the duration of action of bitolterol was 10 times that of N-t-B or isoproterenol. In the cardiovascular studies in anesthetized dogs, chronotropic, inotropic and blood pressure effects of bitolterol were markedly reduced relative to its bronchodilator effect. The bronchodilator/heart rate ratio for bitolterol was 22 times that of isoproterenol and 6 times that of N-t-B or salbutamol suggesting greater selectivity for beta2 adrenoreceptors for bitolterol. A good intraduodenal bronchodilator activity with a prolonged duration of action was obtained with bitolterol when compared with N-t-B and isoproterenol. The intraduodenal/intravenous bronchodilator dose ratio for bitolterol was 2 compared with 240 and 960 for N-t-B and isoproterenol, respectively. Bitolterol showed a significantly less (P less than .01) chronotropic effect than salbutamol at equibronchodilator doses (ED60) by intraduodenal or aerosol administration. A similar difference in chronotropic effect was observed in the unanesthetized dog. The prolonged bronchodilator effect of bitolterol was attributed to high concentration of the ester in lung tissues and to its slow hydrolysis, gradually releasing the active catecholamine, N-t-B.