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Combination Therapy with Inhaled Nitric Oxide and Intravenous Dobutamine During Pulmonary Hypertension in the Rabbit

Bradford, Katherine Kilroy; Deb, Bhaskar*; Pearl, Ronald G.*

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Journal of Cardiovascular Pharmacology: August 2000 - Volume 36 - Issue 2 - p 146-151
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Abstract

Pulmonary hypertension is a serious clinical problem with significant morbidity and mortality (1,2). Elevated pulmonary vascular resistance (PVR) may occur in neonates with hypoxic respiratory failure and in children and adults with primary pulmonary hypertension, acute respiratory failure, chronic lung disease, congenital heart disease, and chronic left ventricular failure. Pulmonary hypertension may produce right heart failure and result in low cardiac output. Therapy of pulmonary hypertension is directed at decreasing PVR and improving right ventricular function (3).

Intravenous vasodilators such as sodium nitroprusside, prostacyclin, prostaglandin E1, hydralazine, and phentolamine can decrease PVR but also decrease systemic vascular resistance (SVR) (1-4). In patients with pulmonary hypertension, the use of these drugs as pulmonary vasodilators may be complicated by the development of systemic hypotension, which decreases coronary perfusion pressure and can result in right ventricular ischemia and failure.

In contrast to the intravenous nitrovasodilators, inhaled nitric oxide (NO) produces selective pulmonary vasodilation (5-8). Inhaled NO diffuses from the alveoli to the pulmonary vascular smooth muscle, where it activates guanylyl cyclase, thereby increasing cyclic guanosine monophosphate (GMP) and producing pulmonary vasodilation. Inhaled NO does not produce systemic vasodilation because any NO that is absorbed into the pulmonary bloodstream is inactivated by binding to hemoglobin. Endogenous NO release and effects appear to be decreased in pulmonary hypertension.

One approach to treating right ventricular dysfunction in patients with pulmonary hypertension is the use of pharmacologic agents with combined inotropic and pulmonary vasodilator activity (9,10). Dobutamine is a β-adrenergic agent that increases cyclic adenosine monophosphate (AMP) levels in both heart and vascular smooth muscle, resulting in inotropic, chronotropic, systemic vasodilator, and pulmonary vasodilator effects (11). Dobutamine decreases pulmonary vascular resistance in experimental pulmonary hypertension (12-14) and has been extensively used in patients with pulmonary hypertension after cardiopulmonary bypass (15-17) and for evaluation of pulmonary vascular reactivity before cardiac transplantation (18,19). However, dobutamine by itself frequently produces no change or only small decreases in pulmonary artery pressure.

Vasodilators that increase cyclic AMP and cyclic GMP may act additively or synergistically to produce vascular smooth muscle relaxation (20-22). Combination therapy has been effective in treating pulmonary hypertension (23-26). We have previously demonstrated that increasing cyclic AMP with intravenous prostacyclin or adenosine or with inhaled prostacyclin will potentiate the effects of inhaled NO (27,28). One approach to achieving selective but potent pulmonary vasodilation with increased inotropic support of the failing right ventricle would be the combination of dobutamine with inhaled NO. Our study was designed to examine the hypothesis that inhaled NO would potentiate the pulmonary vasodilator effects of dobutamine in vivo.

METHODS

The protocol was approved by the Stanford Administrative Panel on Laboratory Animal Care, and the care and handling of the animals were in accord with National Institutes of Health guidelines. Nine male New Zealand White rabbits (2.4-3.9 kg) were premedicated with ketamine (65 mg/kg, i.m.) and anesthetized with pentobarbital (15-25 mg/kg, i.v., followed by a continuous infusion of 5-10 mg/kg/h). After tracheostomy, rabbits were mechanically ventilated with 40% oxygen with a peak inspiratory pressure of 12-15 mm Hg, 2.5 cm H2O positive end-expiratory pressure (PEEP), and a rate adjusted to maintain PaCO2 at 35-45 mm Hg. Cannulae were inserted into both internal jugular veins for drug infusion. A carotid artery catheter was inserted for measurement of systemic mean arterial pressure (MAP). A 2.5F aortic thermodilution catheter (model 94-030-2.5F; Baxter Healthcare Corporation, Irvine, CA, U.S.A.) for cardiac output (CO) monitoring was inserted into the descending thoracic aorta via a femoral artery.

After median sternotomy, a 20-gauge catheter was inserted into the pulmonary artery via the right ventricle, and a 22-gauge catheter was inserted into the left atrium via the left ventricle. Left atrial pressure (LAP) was maintained at 2 mm Hg by infusion of 6% hydroxyethyl starch (Hespan). Baseline hemodynamic measurements included MAP, mean pulmonary arterial pressure (PAP), and CO (in triplicate by aortic thermodilution). Systemic (SVR) and pulmonary (PVR) vascular resistance were calculated by standard formulae.

After baseline measurements, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 30 mg/kg, i.v.) was administered over a 15-min period. Pulmonary hypertension was then produced by a continuous infusion of U46619 (9,11-dideoxy-11α, 9α-epoxymethano-prostaglandin F2α), a thromboxane A2 mimetic. The infusion rate was titrated to increase PAP to ∼25 mm Hg. During stable pulmonary hypertension, inhaled NO was added to the inspiratory limb of the circuit to produce an inspired concentration of 40 ppm. Inhaled NO was administered using a tank of 800 ppm in nitrogen (Liquid Carbonic), and inhaled NO and NO2 concentrations were continuously monitored by chemiluminesence (CLD 700 AL; ECO Physics, Durnten, Switzerland). NO2 concentrations were always <1 ppm. Hemodynamic measurements were obtained during and after inhaled NO administration (Fig. 1). Dobutamine was then infused at 2.5 μg/kg/min. After 15 min of stabilization, hemodynamic measurements were obtained before, during, and after inhaled NO administration. Data at dobutamine infusion rates of 5, 10, and 20 μg/kg/min were similarly obtained with and without inhaled NO.

FIG. 1
FIG. 1:
Overview of experimental design. After surgical interventions and stabilization, measurements were obtained before, during, and after administration of inhaled nitric oxide. These three sets of measurements were obtained before dobutamine infusion and during progressively increasing dobutamine infusion doses. Each arrow represents a measurement time point. The shaded bars represent administration of inhaled nitric oxide at 40 ppm.

Data are expressed as mean values ± SEM. The data before and after inhaled NO administration for each condition were averaged. Statistical analysis used two-way analysis of variance (ANOVA) followed by Newman-Keuls' test for multiple comparisons with p < 0.05 considered significant.

RESULTS

Before the production of pulmonary hypertension, administration of inhaled NO did not affect systemic or pulmonary hemodynamics. During U46619 administration, PAP increased from 15.8 ± 0.8 to 24.2 ± 1.0 mm Hg, MAP increased from 88 ± 6 to 98 ± 8 mm Hg, CO decreased from 0.56 ± 0.08 to 0.34 ± 0.05 L/min, PVR increased from 29 ± 4 to 77 ± 10 mm Hg/L/min, and SVR increased from 179 ± 23 to 317 ± 32 mm Hg/L/min. During U46619-induced pulmonary hypertension, inhaled NO decreased PAP and PVR and did not alter MAP, CO, or SVR (Figs. 2-6).

FIG. 2
FIG. 2:
Pulmonary artery pressure (PAP) with and without inhaled nitric oxide during U46619-induced pulmonary hypertension before and during administration of dobutamine. Values are expressed as mean ± SEM of nine subjects. *p < 0.05 versus corresponding condition without inhaled nitric oxide.
FIG. 3
FIG. 3:
Pulmonary vascular resistance (PVR) with and without inhaled nitric oxide during U46619-induced pulmonary hypertension before and during administration of dobutamine. Values are expressed as mean ± SEM of nine subjects. *p < 0.05 versus corresponding condition without inhaled nitric oxide. #p < 0.05 versus U46619 (no dobutamine).
FIG. 4
FIG. 4:
Cardiac output with and without inhaled nitric oxide during U46619-induced pulmonary hypertension before and during administration of dobutamine. Values are expressed as mean ± SEM of nine subjects. #p < 0.05 versus U46619 (no dobutamine).
FIG. 5
FIG. 5:
Systemic mean arterial pressure (MAP) with and without inhaled nitric oxide during U46619-induced pulmonary hypertension before and during administration of dobutamine. Values are expressed as mean ± SEM of nine subjects.
FIG. 6
FIG. 6:
Systemic vascular resistance (SVR) with and without inhaled nitric oxide during U46619-induced pulmonary hypertension before and during administration of dobutamine. Values are expressed as mean ± SEM of nine subjects. #p < 0.05 versus U46619 (no dobutamine).

Dobutamine produced dose-dependent decreases in PVR, MAP, and SVR and increases in CO, but did not change PAP (Figs. 2-6). The highest dose of dobutamine resulted in a 6% decrease in PAP, a 9% decrease in MAP, a 17% increase in CO, a 14% decrease in PVR, and an 11% decrease in SVR.

During dobutamine administration, inhaled NO had no effect on systemic hemodynamics. At each dose of dobutamine, inhaled NO decreased PAP and PVR. The effects of dobutamine and inhaled NO on PVR were additive. The combination of the highest dose of dobutamine and inhaled NO resulted in a 31% decrease in PVR.

DISCUSSION

Therapy for pulmonary hypertension with intravenous vasodilators is usually limited by systemic hypotension because of the systemic vasodilator effects of the available agents (1-4). Systemic hypotension may decrease right ventricular coronary blood flow and thereby worsen right ventricular failure. In contrast to the intravenous vasodilators, inhaled NO may produce selective pulmonary vasodilation (5-8). Although the effects of inhaled NO are selective for the pulmonary circulation, the magnitude of the pulmonary vasodilation may be less than required. In such cases, combination of inhaled NO with a drug that either enhances the effects of inhaled NO (29-31) or independently produces pulmonary vasodilation (23-28) may increase pulmonary vasodilation without producing excessive systemic vasodilation. Vasodilators that increase cyclic AMP and cyclic GMP may act additively or synergistically to produce vascular smooth muscle relaxation (20-22). Beneficial effects of combinations with inhaled NO have been described for adenosine (27), prostacyclin (24-27), and the prostacyclin analogue beraprost (23). Our study extends these findings to dobutamine.

In this study, dobutamine produced dose-dependent decreases in PVR and increases in CO with no significant change in MAP or PAP. This pattern has been seen in multiple clinical and experimental studies (11-17). Inhaled NO produced small but selective decreases in PAP and PVR with no significant change in MAP or SVR. The combination of dobutamine and inhaled NO had additive pulmonary vascular effects, resulting in pulmonary vasodilation but no decrease in MAP. The results from this study are consistent with the limited clinical reports available, which show additive decreases in PAP when two drugs having different mechanisms of action are used to alleviate pulmonary hypertension (23-28).

However, extrapolation of the results of this study to the clinical setting is limited by several factors. We studied acute pulmonary hypertension caused by U46619 infusion in the rabbit. U46619 is a thromboxane A2 mimetic that produces pulmonary hypertension due to acute pulmonary vasoconstriction. Thromboxane A2 is a mediator of pulmonary hypertension in a variety of clinical (32-34) and experimental settings (35-40). We have used this model in multiple species (sheep, pig, rabbit, rat) for studies of acute pulmonary hypertension (27,41-45). In addition, the model has been used by other investigators in these and other species (46-51). One of the advantages of the U46619 model is the ability to produce pulmonary hypertension severe enough to decrease right ventricular output without producing systemic hypotension; pulmonary artery pressure increased by 53%, whereas systemic arterial pressure increased by 11%. CO decreased as a result of the increased right ventricular afterload (PVR increased by 166%), allowing us to study the inovasodilator dobutamine without the complication of systemic hypotension. The decrease in cardiac output may also have been due to direct negative inotropic effects of U46619 or to coronary vasoconstriction and/or platelet aggregation from U46619. However, such effects should not have affected the ability to determine whether inhaled NO produced additive pulmonary vasodilation in combination with dobutamine. The hemodynamic response to U46619 is stable for the period of study. We have performed time controls and found that the effects of U46619 are stable for ≥90 min and have used this U46619 model for extended dose-response studies in rabbits (41,42). A recent article from another group (46) also emphasized the stability of the model over time. Furthermore, the major issue addressed in the study was whether the addition of inhaled NO to dobutamine produced additional pulmonary vasodilation; a small change in the stability of the model would not affect this determination because we measured hemodynamics before and after NO administration at each dobutamine dose. Responses to therapy could depend on the etiology and chronicity of pulmonary hypertension and on the species studied. We have previously demonstrated that the relative efficacy of different vasodilators is similar in U46619-induced pulmonary hypertension in the sheep and microembolic pulmonary hypertension in the pig (43-45). In addition, the effects of combinations of inhaled nitric oxide and either sodium nitroprusside or adenosine were similar during acute versus chronic pulmonary hypertension in the rat (27).

This study examined only a single 40-ppm dose of inhaled NO. We chose to use a dose of NO that produces maximal effects (the usual clinical practice). In humans, the maximal effect of inhaled NO is usually seen at concentrations of ≤10 ppm (5-8). Published data on NO doses suggest a similar dose-response curve in most species; there have been no formal studies in rabbits. Our use of 40 ppm (rather than a minimally effective dose) was designed to avoid the issue of whether a higher dose of NO would still have had additive effects with dobutamine if we had not achieved the potential full response available from NO.

In summary, our results demonstrate that the combination of dobutamine and inhaled NO had additive pulmonary vascular effects, resulting in pulmonary vasodilation but no decrease in MAP. The combination of inhaled nitric oxide and intravenous dobutamine may be a useful therapy in the management of patients with pulmonary hypertension and associated right ventricular dysfunction.

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Keywords:

Dobutamine; Inhaled nitric oxide; Pulmonary hypertension; Right ventricular failure; Vasodilator

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