The Effects of Anticholinesterases on the Bronchioles and Pulmonary Blood Vessels in Isolated Perfused Lungs of the Dog

Abstract

The effects of two potent inhibitors of cholinesterase, isopropylmethylphosphonofluoridate (sarin) and ethyl pyrophosphate (TEPP), were investigated on the bronchioles and pulmonary blood vessels in isolated dog lung preparations perfused with heparinized blood and ventilated artificially. These anticholinesterases caused gradual bronchoconstriction as indicated by a diminution in tidal air volume, a reduction in compliance and an increase in expiratory resistance. These effects were antagonized by atropine. An increase in pulmonary vascular resistance occurred which was enhanced by the addition of small quantities of acetylcholine to the perfusing blood. The pulmonary vascular effects of acetylcholine, sarin and TEPP were prevented and abolished by atropine. Evidence is presented which suggests that the site of action of these anticholinesterases is, at least in part, peripheral to the autonomic ganglia.The effects of anticholinesterases on the pulmonary circulation in the dog have been studied recently by Daly (1957) and by Daly and Wright (1957). Under conditions in which respiration, pulmonary blood flow and left atrial pressure were controlled to exclude passive effects on the pulmonary circulation, the intravenous administration of anticholinesterases caused an increase in pulmonary vascular resistance (Daly and Wright, 1957). It was suggested that several mechanisms probably contributed to this response, and evidence was presented that one of these was an alteration in alveolar gas tensions. Owing to the difficulty of controlling other variables it was not possible in these experiments to obtain evidence of a possible direct action of anticholinesterases on the pulmonary blood vessels. This problem has now been investigated and the results are presented in this paper. For the most part, isopropylmethylphosphonofluoridate (sarin) was used, but a few experiments were made with ethyl pyrophosphate (TEPP). METHODS Dogs, varying in weight from 6 to 14.7 kg., were given morphine hydrochloride (1 to 2 mg./kg. body weight, subcutaneously). Under local anaesthesia, a femoral artery was cannulated, and after intravenous injection of heparin (" Liquemin," Roche Products, 7 to 8 mg./kg.) to prevent intravascular clotting in later stages of making the preparation, the animal was bled to death. By means of a Dale-Schuster pump, the lungs were perfused in situ through the pulmonary artery at a constant blood volume inflow. Blood from the cannulated left atrium was collected in a reservoir, the bottom of which was connected to the input side of the pump. To prevent blood escaping from the pulmonary circulation by way of the bronchial vascular system, the superior and inferior venae cavae, the vena azygos, the aorta just above the level of the diaphragm and the oesophagus above and below the lung hilus were ligated. The ventricles were compressed by tying them tightly with tape just below the atrio-ventricular junction.Both the pump and reservoir were placed in a thermostatically controlled water-bath at 37'. The pulmon...

M1 and M3 muscarinic receptors in human pulmonary arteries

“…The in vivo effects of acetylcholine (ACh) on the pulmonary vascular bed are dependent on the state of the vascular tone. Under normal vascular tone, ACh increased the lobar arterial pressure (Daly, 1957;Rose, 1957;Nandiwada et al, 1983;El Kashef & Catravas, 1986;Matran et al, 1991) whereas under increased vascular tone, ACh caused a decrease of this pressure (Fritts et al, 1958;Nandiwada et al, 1983;Hyman & Kadowitz, 1988). Since both responses are blocked by atropine, these effects appear to be induced by stimulation of muscarinic receptors.…”

Degradation of acetylcholine in human airways: role of butyrylcholinesterase

“…Initial studies dealing with the effects of AChE activity in airway preparations have shown that inhibition of this enzyme by agents such as physostigmine and neostigmine increases the contractile response to exogenous ACh in airway preparations (Douglas, 1951;De Candole et al, 1953;Daly, 1957;Carlyle, 1963) or to electrical field stimulation (Kirkpatrick & Rooney, 1982;Ito et al, 1989). However, none of these reports distinguished between the relative contributions of the different cholinesterases involved in the contractions to cholinoceptor agonists in airway muscles.…”

The effects of anticholinesterases upon pulmonary vascular resistance in the dog

“…The lungs were artificially ventilated at a constant peak inflationary pressure which varied between 8 and 14 cm water in different experiments (Konzett & Rossler, 1940). The ventilation overflow volume, that is the volume of air not entering the lungs but spilling over the constant pressure device, was measured by means of a small Krogh spirometer or from the slope of the trace produced by collecting the air continuously in a 5 1. spirometer (Daly, 1957b). The lungs collapsed passively during the expiratory phase of respiration against a resistance of 2-3 cm water.…”

“…Experiments were carried out in which the whole of the left lung of a dog was isolated and perfused with venous blood from a donor animal. The method of perfusing the isolated lung was similar to that described by Daly (1957b) except that the cannula was inserted into the left pulmonary artery instead of into the main pulmonary trunk. The right lung was tied off at the hilum.…”