James W. Ziegler

Dipyridamole attenuates rebound pulmonary hypertension after inhaled nitric oxide withdrawal in postoperative congenital heart disease

OBJECTIVE Inhaled nitric oxide therapy causes selective and sustained pulmonary vasodilation in patients with pulmonary hypertension; however, attempts to discontinue inhaled nitric oxide therapy may be complicated by abrupt life-threatening events. Dipyridamole, a cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, blocks the hydrolysis of cyclic guanosine monophosphate in vascular smooth muscle cells. METHODS We studied 23 consecutive children who were treated with inhaled nitric oxide because of clinically significant pulmonary hypertension after surgery for congenital heart disease. Inhaled nitric oxide therapy was withdrawn before and after dipyridamole treatment of children in whom sustained elevations of pulmonary artery pressure developed for over 30 minutes. RESULTS In 7 of 23 children, inhaled nitric oxide withdrawal caused a 40% increase in pulmonary artery pressure, a 17% decrease in systemic venous oxygen saturation, and a 46% increase in the ratio of mean pulmonary artery pressure to aortic pressure. Compared with children who had no significant increase in pulmonary artery pressure, children who experienced the development of prolonged pulmonary hypertension after inhaled nitric oxide therapy withdrawal had higher mean pulmonary artery pressure immediately before inhaled nitric oxide withdrawal (22 +/- 1 mm Hg versus 27 +/- 2 mm Hg; p = 0.04) and received inhaled nitric oxide for a longer duration (2 +/- 1 days versus 4 +/- 1 days; p = 0.01). Dipyridamole therapy attenuated the rise in pulmonary artery pressure and fall in systemic venous oxygen saturation in all six patients studied with rebound pulmonary hypertension after withdrawal of inhaled nitric oxide. CONCLUSION We conclude that dipyridamole therapy acutely attenuates the adverse hemodynamic effects of rapid withdrawal of inhaled nitric oxide therapy. Children with higher pulmonary artery pressure and who are treated with inhaled nitric oxide for a longer duration may be at increased risk for adverse hemodynamic effects of inhaled nitric oxide therapy withdrawal. We speculate that dipyridamole therapy may sustain elevations of smooth muscle cyclic guanosine monophosphate induced by inhaled nitric oxide and that phosphodiesterase activity contributes to acute pulmonary hypertension after inhaled nitric oxide withdrawal.

Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity

An experimental ovine fetal model for perinatal pulmonary hypertension of the neonate (PPHN) was characterized by altered pulmonary vasoreactivity and structure. Because past studies had suggested impaired nitric oxide-cGMP cascade in this experimental model, we hypothesized that elevated phosphodiesterase (PDE) activity may contribute to altered vascular reactivity and structure in experimental PPHN. Therefore, we studied the effects of the PDE inhibitors zaprinast and dipyridamole on fetal pulmonary vascular resistance and PDE5 activity, protein, mRNA, and localization in normal and pulmonary hypertensive fetal lambs. Infusion of dipyridamole and zaprinast lowered pulmonary vascular resistance by 55 and 35%, respectively, in hypertensive animals. In comparison with control animals, lung cGMP PDE activity was elevated in hypertensive fetal lambs (150%). Increased PDE5 activity was not associated with either an increased PDE5 protein or mRNA level. Immunocytochemistry demonstrated that PDE5 was localized to vascular smooth muscle. We concluded that PDE5 activity was increased in experimental PPHN, possibly by posttranslational phosphorylation. We speculated that these increases in cGMP PDE activity contributed to altered pulmonary vasoreactivity in experimental perinatal pulmonary hypertension.An experimental ovine fetal model for perinatal pulmonary hypertension of the neonate (PPHN) was characterized by altered pulmonary vasoreactivity and structure. Because past studies had suggested impaired nitric oxide-cGMP cascade in this experimental model, we hypothesized that elevated phosphodiesterase (PDE) activity may contribute to altered vascular reactivity and structure in experimental PPHN. Therefore, we studied the effects of the PDE inhibitors zaprinast and dipyridamole on fetal pulmonary vascular resistance and PDE5 activity, protein, mRNA, and localization in normal and pulmonary hypertensive fetal lambs. Infusion of dipyridamole and zaprinast lowered pulmonary vascular resistance by 55 and 35%, respectively, in hypertensive animals. In comparison with control animals, lung cGMP PDE activity was elevated in hypertensive fetal lambs (150%). Increased PDE5 activity was not associated with either an increased PDE5 protein or mRNA level. Immunocytochemistry demonstrated that PDE5 was localized to vascular smooth muscle. We concluded that PDE5 activity was increased in experimental PPHN, possibly by posttranslational phosphorylation. We speculated that these increases in cGMP PDE activity contributed to altered pulmonary vasoreactivity in experimental perinatal pulmonary hypertension.

Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus.

Based on past studies of an experimental model of severe intrauterine pulmonary hypertension, we hypothesized that endothelin-1 (ET-1) contributes to high pulmonary vascular resistance (PVR), hypertensive lung structural changes, and right ventricular hypertrophy (RVH) caused by prolonged closure of the ductus arteriosus. To test this hypothesis, we studied the effects of BQ 123, a selective ET(A) receptor antagonist, after ligation of the ductus arteriosus in utero. In 19 late gestation fetal lambs (126+/-3 d; 147 d, term) we ligated the ductus arteriosus at surgery, and treated animals with either BQ 123 (1 mg/d) or vehicle (0.1% DMSO, HTN) in the pulmonary artery for 8 d. Chronic BQ 123 treatment attenuated the rise in mean pulmonary artery pressure (PAP) 8 d after ductus arteriosus ligation (78+/-2, HTN vs. 70+/-4 mmHg, BQ 123, P < 0.05). To study the effects of ET(A) blockade at birth, 15 animals were delivered by cesarean section and ventilated with 10% oxygen (O2), 100% O2 and inhaled nitric oxide (NO). Lambs treated with BQ 123 had lower PVR after delivery during ventilation with 10% O2, 100% O2, and inhaled NO (HTN vs. BQ 123, P < 0.05 for each intervention). Acute BQ 123 treatment (2 mg/30 min) lowered PVR in three HTN animals ventilated with 100% O2 and inhaled NO (P < 0.05). Chronic BQ 123 treatment prevented the development of RVH as determined by the ratio of the right ventricle/left ventricle + septum (0.79+/-0.03, HTN vs. 0.57+/-0.06, BQ 123, P < 0.05) and attenuated the increase in wall thickness of small pulmonary arteries (61+/-2, HTN vs. 50+/-2%, BQ 123, P < 0.05). In summary, chronic intrauterine ET(A) receptor blockade decreased PAP in utero, decreased RVH and distal muscularization of small pulmonary arteries, and increased the fall in PVR at delivery. We conclude that ET(A) receptor stimulation contributes to the pathogenesis and pathophysiology of experimental perinatal pulmonary hypertension.

Chronic intrauterine pulmonary hypertension alters endothelin receptor activity in the ovine fetal lung

Although endothelin (ET) contributes to the regulation of pulmonary vascular tone in the normal fetus, little is known about its role in pulmonary hypertension in the perinatal period. To examine the role of the ETB receptor in the normal ovine fetal lung, we studied the hemodynamic effects of ET-3 (a selective ETB receptor agonist) before and after RES-701 (a selective ETB receptor antagonist). RES-701 (10 μg/min for 10 min) did not change basal pulmonary tone and blocked pulmonary vasodilation to ET-3(500 ng/min for 10 min). To examine the effects of experimental perinatal pulmonary hypertension on activity of the ETA and ETB receptors, we studied the hemodynamic effects of ET-3, ET-1 (a nonselective ETA and ETB receptor agonist), and BQ 123 (a selective ETA receptor antagonist) in 12 chronically prepared late gestation fetal lambs after partial ligation of the ductus arteriosus. Serial changes in the pulmonary vascular effects of these agents were measured early (1-3 d) and late (7-10 d) after partial ductus arteriosus ligation. Left lung total pulmonary resistance in the normal late-gestation fetus was 0.62 ± 0.01 mm Hg/ml/min(n = 4). After partial ductus arteriosus ligation, total pulmonary resistance increased to 1.2 ± 0.3 (early; p < 0.05versus normal), and progressively rose to 1.9 ± 0.2 mm Hg/ml/min (late; p < 0.05 versus early). Intrapulmonary infusion of ET-3 (500 ng/min for 10 min) increased pulmonary blood flow from 94 ± 11 to 183 ± 17 mL/min in the normal fetus, but had no effect during late pulmonary hypertension. Infusions of ET-1 (50 ng/min for 30 min) caused transient pulmonary vasodilation followed by vasoconstriction during early pulmonary hypertension. During late pulmonary hypertension, however, infusion of ET-1 caused predominantly vasoconstriction. Pulmonary vasodilation to BQ 123 (100 μg/min for 10 min) was greater during late than early pulmonary hypertension (43 versus 21%; p < 0.05). After 10 d of ductus arteriosus ligation, immunoreactive ET-1 content in whole lung tissue was 3-fold higher in hypertensive (n = 7) than control(n = 10) lungs (p < 0.05). We conclude that the ETB receptor contributes little to regulation of basal vascular tone in the normal ovine fetal lung and that chronic intrauterine pulmonary hypertension causes the loss of ETB-mediated vasodilation, progressive ETA-mediated vasoconstriction, and increased lung ET-1 content. We speculate that diminished ETB receptor-mediated vasodilation in combination with enhanced ETA receptor-mediated vasoconstriction and increased ET-1 production contributes to high pulmonary vascular resistance in perinatal pulmonary hypertension.

Pediatric Myocardial Infarction After Racemic Epinephrine Administration

Myocardial infarction is a previously unreported complication of treatment with racemic epinephrine that is used commonly in the emergency department for severe respiratory distress in bronchiolitis or croup syndrome. We describe a pediatric patient who presented with the croup syndrome and severe respiratory distress that required multiple doses of nebulized racemic epinephrine in the emergency department. The patient developed ventricular tachycardia and mild chest discomfort during one treatment, which resolved spontaneously on discontinuation of the nebulization. Persistently abnormal electrocardiograms and elevated creatine phosphokinase MB isoenzyme (CPK–MB) levels suggested a myocardial infarction had occurred. Subsequent echocardiography, cardiac catheterization, and angiography revealed an anatomically normal heart with normal coronary circulation; however, a stress nuclear study showed a small myocardial infarct. The significance of this previously unreported complication of racemic epinephrine is discussed, along with recommendations for proper use in the emergency department.

PROLONGED ENDOTHELIN A RECEPTOR BLOCKADE ATTENUATES CHRONIC INTRAUTERINE PULMONARY HYPERTENSION • 1994

PROLONGED ENDOTHELIN A RECEPTOR BLOCKADE ATTENUATES CHRONIC INTRAUTERINE PULMONARY HYPERTENSION • 1994

Temporal Profile of Early Pulmonary Hypertension in Preterm Infants.

Objective The objective of this study was to study the temporal profile of pulmonary hypertension (PH) in preterm infants. Study Design Infants < 28 weeks were screened for early PH at 10 to 14 days of life. Infants with early PH (n = 10) and gestationally matched controls (n = 18) underwent serial echocardiography every 7 to 10 days until 36 weeks postmenstrual age. Results Groups with and without early PH were comparable except for higher Fio 2 by day 10 among infants with early PH. Early PH was moderate in extent and resolved in all infants with recurrence in one infant. Among infants without early PH, five infants developed late PH. In both groups, development of late PH occurred in association with important neonatal morbidities, such as patent ductus arteriosus, bronchopulmonary dysplasia, and infection. Conclusion Early moderate PH among preterm infants resolves over a variable time period but recurrence is possible. Late PH can appear during the course of hospitalization in association with other clinical morbidities.

HEMODYNAMIC EFFECTS OF DIPYRIDAMOLE AND INHALED NITRIC OXIDE IN PATIENTS WITH SEVERE PULMONARY HYPERTENSION. |[dagger]| 228

Inhaled nitric oxide (NO) causes pulmonary vasodilation by stimulating cGMP production in pulmonary vascular smooth muscle. One factor which might limit NO responsiveness is rapid cGMP degradation by cGMP phosphodiesterases (PDE5). To examine the clinical effects of PDE5 inhibition, we studied Dipyridamole(D), a potent PDE5 inhibitor, in 10 patients with severe pulmonary hypertension. Hemodynamic measurements including mean pulmonary, aortic, and pulmonary capillary wedge pressures (PAP, AoP, PCWP; mmHg), cardiac index (CI; liters/min/M2), and pulmonary and systemic vascular resistances (PVRI and SVRI; indexed units) were recorded on 100% oxygen (BL1 and BL2) and NO 20ppm, before and after D (0.6 mg/kg). Twelve studies were performed in 10 patients; 1 patient was excluded due to a marked fall in AoP after receiving D. NO caused a significant fall in PAP and PVRI without affecting systemic hemodynamics. D decreased PVRI to a similar degree as NO through its effect on CI; however systemic resistance fell proportionately. 4/9 (44%) patients had a≥ 20% augmentation of NO-induced pulmonary vasodilation with D. *p<0.05 vs respective BL. We conclude that D decreases PVRI to a similar degree as NO, but this response is primarily through increasing CI and is not selective for the pulmonary circulation. Although when analyzed as a group, D did not augment NO-induced pulmonary vasodilation, selected patients demonstrated potentiation of NO responsiveness with D. We speculate that lower doses of D might result in more selective pulmonary vasodilation in some patients with pulmonary hypertension. Table

DIPYRIDAMOLE ATTENUATES HYPOXIA-INDUCED PULMONARY HYPERTENSION. 227

Pulmonary hypertension is characterized by altered pulmonary vascular responsiveness to certain stimuli such as alveolar hypoxia. Although the mechanism of hypoxia-induced pulmonary vasoconstriction is not completely understood, recent evidence suggests that decreased production of endogenous nitric oxide (NO) and cGMP are partly responsible. We hypothesized that increasing pulmonary vascular cGMP concentration by inhibiting cGMP degradation might influence vasoreactivity in patients with heightened pulmonary responsiveness. To test this hypothesis, we studied the effects of dipyridamole (D), a potent cGMP phosphodiesterase (PDE5) inhibitor, in 4 patients with exaggerated hypoxia-induced pulmonary hypertension. Hemodynamic measurements including mean pulmonary, aortic, and pulmonary capillary wedge pressures (PAP, AoP, PCWP; mmHg), cardiac index (CI; liters/ min/M2), and pulmonary and systemic vascular resistances (PVRI and SVRI; indexed units) were recorded sequentially on room air (BL1 and BL2) and during hypoxic exposure (16% O2) before and after administration of D (0.6 mg/kg). D decreased baseline PAP and AoP (35 +/- 3 to 26 +/- 2 and 80 +/- 9 to 67 +/- 10 respectively; p<0.05). D attenuated the rise in PAP during hypoxic exposure keeping PAP and PVRI at subsystemic levels. Table

DIPYRIDAMOLE, A cGMP PHOSPHODIESTERASE INHIBITOR, ATTENUATES REBOUND PULMONARY HYPERTENSION AFTER WITHDRAWAL OF INHALED NITRIC OXIDE IN POSTOPERATIVE CONGENITAL HEART DISEASE. • 163

DIPYRIDAMOLE, A cGMP PHOSPHODIESTERASE INHIBITOR, ATTENUATES REBOUND PULMONARY HYPERTENSION AFTER WITHDRAWAL OF INHALED NITRIC OXIDE IN POSTOPERATIVE CONGENITAL HEART DISEASE. • 163