Exercise-induced pulmonary vasoconstriction during combined blockade of nitric oxide synthase and beta adrenergic receptors.

Abstract

We studied the effects of inhibition of nitric oxide (NO) (endothelium-derived relaxation factor) synthase in combination with alpha and beta adrenergic receptor blockade on pulmonary vascular tone during exercise. In paired studies, we exercised sheep on a treadmill at a speed of 4 mph, and measured blood flow and pressures across the pulmonary circulation with and without inhibition of NO synthase (Nw-nitro-L-arginine 20 mg/kg intravenous Ii.v.I), alpha receptor blockade (phentolamine 5 mg i.v.), beta receptor blockade (propranolol 1 mg i.v.), and combined alpha and beta receptor blockade. Activation of both types of adrenergic receptors occurs with exercise, and because increased release in NO is hypothesized to occur during exercise, these studies were designed to determine the magnitude of effect and interactions of these competing dilator and constrictor influences. We found that inhibition of NO synthase raised pulmonary vascular resistance (PVR) at rest and that, although a reduction in PVR occurred with exercise from this new baseline, vasoconstriction persisted. Combined beta blockade and NO synthase inhibition unmasked unopposed alpha vasoconstriction; PVR rose at rest and continued to rise with exercise; and mean pulmonary arterial pressures approached very high levels, 43.8±4.4 cmH20. Using a distal wedged pulmonary artery catheter technique, most of the vasoconstriction was found to be in vessels upstream from small pulmonary veins. During exercise in sheep there appears to be a high degree of alpha and beta adrenergic-mediated tone in the pulmonary circulation. Endogenous production of NO actively dilates pulmonary vessels at rest and opposes potent alpha-mediated pulmonary vasoconstriction during exercise. (J. Clin.

Changes in pulmonary vascular tone during exercise. Effects of nitric oxide (NO) synthase inhibition, L-arginine infusion, and NO inhalation.

“…To raise CO, isoproterenol, 5 mg in 100 ml normal saline, was infused intravenously at different rates into each sheep at rest using a pump (Harvard Apparatus, Inc., South Natick, MA). Flow meter and thermodilution values were measured at multiple COs at steady state, and a correlation plot and regression equation were constructed for each animal (2,3,6). Arterial (19,20).…”

“…These changes are associated with a significant reduction in pulmonary vascular resistance (PVR) in animals (2,3) and in humans (4). The mechanisms for the decrease in PVR during exercise are not completely understood (3)(4)(5)(6).…”

“…Release of NO in response to increased flow across the endothelium has been demonstrated in vitro (11 ), and NO may contribute to the progressive rise in pulmonary blood flow at birth ( 12,13). Basal NO release is partly responsible for the low pulmonary vascular tone at rest in adult sheep, and NO synthase inhibition in sheep results in pulmonary hypertension during exercise (6). Furthermore, exogenous inhaled NO has been shown to be a pulmonary vasodilator in experimental models and human diseases ( 14).…”

Nitric oxide and exercise in the horse.

“…From their results, Kane et al (1994) and Koizumi et al (1994) suggested that NO has a basal vasodilator function that persists, but is not enhanced, during exercise to oppose a-mediated vasoconstriction. However, there are species differences in the activity of NO which preclude the extrapolation of effects between species.…”

“…Inhaled NO is also used therapeutically in human patients with severe lung diseases, such as adult respiratory distress syndrome (ARDS), to improve selectively the vascular perfusion of ventilated regions of the lung, thereby reducing intrapulmonary shunt 5479 863 P C. Mills and others and minimizing 02 toxicity (Bigatello, Hurford, Kacmarek, Roberts & Zapol, 1994;. Exercise will increase pulmonary artery pressure (PAP), despite inducing a reduction in the pulmonary vascular resistance (PVR; West et al 1993;Manohar, 1994;Kane, Tesauro, Koizumi, Gupta & Newman, 1994;West & Mathieu-Costello, 1995). The contribution of endogenous NO to the modulation of PVR during exercise is uncertain.…”