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We investigated the effect of the putative beta 3 agonist BRL 35135 on non-adrenergic non-cholinergic (NANC) contractions in guinea-pig bronchial strips. BRL 35135 (10(-9) to 10(-6) M) did not alter the baseline tension but reduced NANC contractions induced by electrical field stimulation (EFS) in a concentration-dependent fashion without having a significant effect on the contraction induced by substance P (10(-6) M). BRL 35135 (10(-6) M) also reduced the contraction induced by capsaicin (10(-7) M). Likewise, BRL 37344 (10(-9) to 10(-6) M) reduced NANC contractions induced by EFS in a concentration-dependent fashion. While BRL 37344 up to concentrations of 10(-8) M did not alter the contraction induced by SP (10(-6) M), BRL 37344 (10(-8) M) significantly inhibited NANC contractions induced by EFS and capsaicin (10(-7) M), (P less than 0.01). The inhibitory effect of BRL 35135 (10(-6) M) on NANC contractions induced by EFS was not significantly altered by the non-selective beta-adrenoceptor antagonists, propranolol and pindolol (P greater than 0.10), by the beta 1-selective antagonists, atenolol and metoprolol (P greater than 0.20) (10(-8) to 10(-6) M), or by the alpha-adrenoceptor antagonist, phentolamine (10(-7) to 10(-5) M) (P greater than 0.50). These results suggest that beta 3 agonists exert a prejunctional inhibitory action on NANC contractions.

19 patients with premature ventricular complexes (PVCs) were administered disopyramide and mexiletine at 300 mg/day in a cross-over comparison of efficacy. The mean daily count of PVCs significantly decreased after both treatments. There was no significant difference between the 2 groups in terms of overall improvement or usefulness. In the global comparison, the usefulness was evaluated as having been higher with disopyramide in 9 patients (47.4%), equal for the 2 drugs in 5 patients (26.3%) and higher with mexiletine in 5 (26.3%). This suggests that these drugs exerted their efficacy by different mechanisms.

To examine the effect of hypoxia on pulmonary vascular smooth muscle, rabbit lobar pulmonary artery was suspended in a glucose free solution and both chronologic changes in tension and ATP content were determined together at 30 min intervals after repeated hypoxic challenge (PO2 = 11 ± 2 mm Hg). The pulmonary artery contracted and its ATP content decreased with hypoxia. This contraction was not inhibited by nifedipine, Ca++-free EGTA, procaine, phentolamine, isopreterenol, diphenhydramine, prostaglandin E1, atropine or nitroglycerine. Upon reoxygenation (PO2 = 104 ± 3 mm Hg), the elevated resting tension decreased in a biphasic fashion and the ATP content of the lobar pulmonary artery increased. When hypoxic challenges were repeated, the rate of constriction on hypoxia increased, while the relaxation rate on reoxygenation, tension developed by 30 min of hypoxia and the total amount of ATP decreased. These results suggest that the ATP content in the lobar pulmonary artery is very sensitive to in vitro acute hypoxia and that the Ca++ transport process is more easily impaired by reduction in ATP levels than is the contractile machinery.