The Effect of Dopamine on Pulmonary Diffusion and Capillary Blood Volume During Exercise

1. Study Objectives The primary objective of this study is to examine the effect of dopamine infusion and dopamine-2 receptor blockade on pulmonary capillary blood volume, diffusion, and the hemodynamic variables of pulmonary artery pressure, cardiac output, and pulmonary vascular resistance during exercise. Secondarily, this study will examine the effect of dopamine infusion and dopamine-2 receptor blockade on exercise tolerance.
2. Background To meet the increased oxygen demand required for exercise, pulmonary diffusing capacity (DLCO) must increase in order to avoid a drop in arterial oxygenation and early exercise termination. Enhanced DLCO during exercise is achieved by expanding pulmonary capillary blood volume (Vc) and diffusing membrane capacity (Dm) through recruitment and distention of the pulmonary capillaries, effectively increasing the surface area for diffusion. Recruitment and distention of the pulmonary capillaries decreases pulmonary vascular resistance (PVR), increasing pulmonary blood flow (Q) while limiting the rise in pulmonary artery pressure (PAP) with exercise. In health, pharmacological interventions are not believed to affect PAP during exercise. However, dopamine, a pulmonary vasodilator, may help to regulate PAP during exercise. Specifically, dopamine appears important for a normal cardiovascular exercise response, as Metoclopramide (pulmonary dopamine-2-receptor antagonist) decreases maximal Q and exercise tolerance (1). These results suggest that dopamine may modulate Vc during exercise via pulmonary smooth muscle regulation, subsequently affecting PVR, PAP, Q and exercise tolerance. However, how dopamine regulates DLCO, Vc, Q, and exercise tolerance is unknown. Purpose: The purpose of this study is to examine the effect of a dopamine agonist and a dopamine-2-receptor antagonist on DLCO, Vc, PAP, PVR, Q, and exercise tolerance. Hypothesis: It is hypothesized that dopamine will increase Vc, leading to a reduction in PVR and a corresponding decrease in PAP. This response will allow an increase in DLCO, Q, and exercise tolerance relative to control. Conversely, Metoclopramide (dopamine-2-receptor antagonist) will attenuate the increase in Vc as well as the reduction in PVR, leading to an increase in PAP. In this condition, DLCO, Q, and exercise tolerance will be reduced.
3. Methods

Study Overview: This study will utilize a randomized, double-blind crossover design where healthy subjects will have measurements performed at rest and 2 workloads (60% and 85% of previously determined VO2peak) with either intravenous dopamine (2µg/kg/min), dopamine receptor blockade (20mg oral Metoclopramide), or placebo (order randomized). Data will be collected across 5 different days over a 2-3 week period. Day 1: Pulmonary function and graded exercise testing to exhaustion. Day 2-4: Vc determination at rest and exercise with either intravenous dopamine, dopamine receptor blockade, or placebo (order randomized). Following a brief period of rest, time to exhaustion trials at 85% of VO2peak will be performed to characterize exercise tolerance. Day 5: Evaluation of PAP via cardiac ultrasound at rest and during exercise with either intravenous dopamine, dopamine receptor blockade, or placebo (order randomized).

Pulmonary Function \& Cardiopulmonary Exercise Test: Subjects will undergo a graded exercise test to volitional exhaustion to characterize aerobic fitness (VO2peak) and a standard pulmonary function test to characterize lung function parameters.

DLCO and Vc measurement during exercise: DLCO and Vc will be measured using the multiple oxygen tension DLCO breath-hold method (2) at rest and during cycling exercise at 60% and 85% of VO2peak. Over different three days, participants will be randomized to each of the following conditions: 1) dopamine (2 μg/kg/min intravenous) and a placebo pill, 2) metoclopramide (20 mg oral) and intravenous saline, or 3) intravenous saline and a placebo pill. During each workload, subjects will perform a DLCO breath-hold maneuver for six seconds, repeated three times during exercise at differing oxygen tensions (0.21, 0.40, 0.60; workload and oxygen tension randomized) allowing for calculation of Vc and Dm. Trials will be spread over several days to ensure no CO buildup. DLCO will be corrected for hemoglobin, and we have considerable experience in performing these tests.

Pulmonary Artery Systolic Pressure (PASP), PVR, and Q: Doppler echocardiography (PASP) will be used as a non-invasive estimate of PAP in all dopamine conditions. PASP will be evaluated at rest and during exercise, and this method has been used successfully by our group and others in previous investigations(3,4). Total PVR will be evaluated by dividing PASP by Q at any given workload. Q will be evaluated using the Physioflow® Impedance Cardiography (Manatec® Biomedical). When compared to direct Fick methods, impedance cardiography provides an accurate determination of Q at rest and during exercise.

Hemoglobin: Since DLCO will be corrected for hemoglobin concentration, a small sample of blood will be collected via finger prick at rest and during exercise and analyzed for hemoglobin concentration using a hand-held Hemoglobin measurement device (HemoCue 201+, HemoCue AB, Angelholm, Sweden).