The bronchodilatory effect of histamine was evaluated in a conscious guinea-pig model of cholinergically mediated bronchoconstriction. The H1, bronchoconstrictor, property of histamine was masked using high doses of the H1-antagonist chlorpheniramine (30 mg/kg), and the bronchodilatory activity evaluated by observing the increase in latency to collapse induced by aerosol methacholine. Under these conditions, histamine (1.0, 3.0 or 10.0 mg/kg, i.p.) delayed methacholine-induced collapse in a dose-dependent manner. Cimetidine, an H2-receptor antagonist (10 to 100 mg/kg), did not delay collapse either in the presence or absence of an H1-antagonist. However, when cimetidine was administered prior to histamine, the bronchodilatory activity of histamine was abolished. A similar abolition of histamine bronchodilation was observed if propranolol, a beta-adrenoceptor antagonist, was administered prior to histamine. Propranolol alone had no effect on methacholine-induced bronchospasm. These data suggest that the major bronchodilatory property of histamine may be mediated indirectly via catecholamine release through an H2-receptor mechanism.

The major elastase inhibitor of human serum, alpha-1 proteinase inhibitor (A1PI), is susceptible to oxidative inactivation by a variety of agents, including chloramine T. We have examined the effects of chloramine T on the catalytic activity of porcine pancreatic (PPE) and human leukocyte elastase (HLE) and on the elastase inhibitory capacity of hamster, rat, and human serum as well as pure human A1PI. Both PPE and HLE, but not trypsin, were inhibited in a concentration-dependent manner by concentrations of chloramine T greater than 0.1 mM. The abilities of rat and human serum and pure human A1PI to inhibit both PPE and HLE were inhibited in a concentration-dependent manner by chloramine T. In contrast only the ability of hamster serum to inhibit HLE was altered by exposure to chloramine T: inhibition of PPE was not effected. Gel exclusion chromatography disclosed the existence of two major peaks of elastase inhibitory activity in hamster plasma: one, with an approximate molecular weight of 55 K, eluting in the region of A1PI that was sensitive to chloramine T inactivation and one with a molecular weight of approximately 180 K which was chloramine T insensitive. The parenteral administration of chloramine T to hamsters resulted in a modest and transient diminution of the serum HLE inhibitory activity and an equally modest and transient elevation of PPE inhibitory activity.

The administration of trypsin 24 h before, admixed with, or 24 h after administration of an emphysema-inducing dose of porcine pancreatic elastase (PPE) to hamsters resulted in significantly enhanced destruction of lung tissue as evidenced by mean linear intercept values 4 weeks post PPE. The coadministration of trypsin with a nonemphysema-inducing dose of PPE resulted in a significant destructive lung lesion. Administration of trypsin 24 h before or admixed with human leukocyte elastase (HLE) resulted in a lesion that was significantly reduced relative to that produced by administration of HLE alone. When trypsin was administered 24 h after HLE, no effect on the lesion was observed. In vitro, coincubation of trypsin with PPE resulted in a slight enhancement of rate of hydrolysis of elastin, while coincubation of trypsin with HLE resulted in a significant reduction of the rate of hydrolysis. These results suggest that interaction with other proteases may offer an additional physiological control mechanism to prevent inappropriate tissue destruction.