Vascular hyperresponsiveness in perfused lungs from monocrotaline-treated rats.

Studies were conducted in isolated, buffer-perfused lungs to determine whether altered pulmonary vascular responsiveness could contribute to the evolution of monocrotaline (MCT)-induced pulmonary hypertension. Adult male rats were given a single subcutaneous injection of either 105 mg/kg MCT or its vehicle and vascular responsiveness to angiotensin II, ventilatory hypoxia (3% O2), and KCl was assessed in isolated, buffer-perfused lungs at 4, 7, and 14 days post-treatment. Relative to preparations derived from control animals, vasopressor responses induced by 0.1 microgram, but not 0.05 microgram angiotensin, were augmented at 4 and 7 days but not at 14 days post MCT. Pulmonary vasoconstriction evoked by hypoxic ventilation was enhanced at 4 days but not at 7 or 14 days posttreatment. Pressor responses induced by 30 and 45 mg KCl were not different in treated animals relative to controls at any time post-MCT administration. MCT provoked perivascular edema, but this factor did not seem to contribute to vascular hyperresponsiveness, since the time course of edema did not parallel the time course of augmented responsiveness. Results of the present study indicate that MCT, by an unknown mechanism, causes an early and transient increase in pulmonary vascular responsiveness to some but not all vasoconstrictors. Because the enhanced responsiveness occurred prior to development of pulmonary hypertension, it is unlikely that this alteration contributes to the sustained elevation in pulmonary arterial pressure.

Pulmonary disposition and pharmacodynamics of verapamil.

Verapamil, a calcium channel blocker, has received recent attention as a potential therapeutic agent in pulmonary hypertension. Accordingly, the pulmonary disposition and pharmacodynamics of verapamil were evaluated in isolated rat lungs perfused at a constant rate with a physiological salt solution. Isolated rat lungs sequestered but did not metabolize verapamil. The efflux of verapamil into drug-free perfusate occurred from two kinetically distinct pools with half-lives of 1.3 and 14.1 min. The theoretical amount of verapamil effluxed at infinite time was less than the amount taken up during the infusion, thereby suggesting that verapamil was also bound in a third "noneffluxable" pool. The time course for decline of verapamil inhibition of pulmonary vasoconstriction was compared with the rate of verapamil efflux. Inhibition of pulmonary vasoconstriction was related to the amount of verapamil in a pool exhibiting mono-exponential efflux of drug with a half-life of 12.6 min. This half-life suggests association of the inhibitory response with the efflux component having a half-life of 14.1 min. These findings indicate that the verapamil persists in the lungs in the form of a noneffluxable pool and that verapamil in the pool with half-life of 14.1 min is responsible for some of the vasoactivity in the pulmonary circulation.

Leu-enkephalin provokes naloxone-insensitive pulmonary vasoconstriction.

Leu-enkephalin evoked dose-dependent pulmonary vasoconstriction in isolated perfused rat lungs. The pressor responses were not attenuated by either naloxone or naltrexone nor were they mimicked by morphine. Blockade of histamine receptors with pyrilamine or blockade of serotonin receptors with methysergide also failed to antagonize leu-enkephalin-induced pulmonary vasoconstrictor responses. These results suggest that neither opiate, histamine, nor serotonin receptors are involved with the pressor effects of leu-enkephalin on the pulmonary circulation. We propose that leu-enkephalin may have direct vasoconstrictor effects on the pulmonary circulation of isolated perfused rat lungs that may not be mediated by conventional opiate receptors.

Pulmonary vasoactivity of lung endocrine cell-related peptides.

Lung endocrine-like cells are believed to contain three immunohistochemically distinct peptides: bombesin, calcitonin, and Leu-enkephalin. Because these peptides exhibit smooth muscle stimulatory or inhibitory activity in some tissues, it has been suggested that their release from endocrine-like cells may influence airway or pulmonary vascular smooth muscle tone. To determine whether lung endocrine cell-related peptides could exert a regulatory influence in the pulmonary circulation, we evaluated their ability to constrict or dilate the vasculature of isolated perfused rat lungs. Neither bombesin nor calcitonin exhibited any pulmonary vascular effects. However, Leu-enkephalin provoked dose-dependent pulmonary vasoconstriction. These results suggest that Leu-enkephalin released from lung endocrine-like cells could be involved with regulation of pulmonary vascular tone.