bq-123 and Hypertension--Pulmonary

The pulmonary endothelium modulates vascular tone by the release of endothelium-derived constricting (EDCF) and relaxing (EDRF) factors, among them endothelin-1, nitric oxide, prostacyclin, and putative endothelium-derived hyperpolarizing factors. Abnormalities in EDCF and EDRF generation have been demonstrated in a number of cardiopulmonary disease states, such as primary and secondary pulmonary hypertension, chronic obstructive lung disease, cardiopulmonary bypass, and congestive heart failure. An imbalance between EDCF and EDRF, termed "pulmonary endothelial dysfunction," may contribute to the alteration in vascular tone characteristic of pulmonary disease. The following review summarizes the present knowledge of the role of EDCF and EDRF in such processes with major focus on pulmonary endothelial dysfunction in hypoxia-induced pulmonary hypertension.

Topics: Animals; Antihypertensive Agents; Atrasentan; Bosentan; Controlled Clinical Trials as Topic; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Epoprostenol; Heart Failure; Humans; Hypertension, Pulmonary; Hypoxia; Lung Diseases, Obstructive; Nitric Oxide; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Circulation; Pyrrolidines; Receptors, Endothelin; RNA, Messenger; Sulfonamides; Time Factors; Vasoconstriction; Vasodilation

Ghrelin has cardioprotective properties and, recently, has been shown to improve endothelial function and reduce endothelin-1 (ET-1)-mediated vasoconstriction in peripheral vascular disease. Recently, we reported that ghrelin attenuates pulmonary hypertension (PH) caused by chronic hypoxia (CH), which we hypothesized in this study may be via suppression of the ET-1 pathway. We also aimed to determine whether ghrelin's ability to prevent alterations of the ET-1 pathway also prevented adverse changes in pulmonary blood flow distribution associated with PH. Sprague-Dawley rats were exposed to CH (10% O(2) for 2 weeks) with daily subcutaneous injections of ghrelin (150 μg/kg) or saline. Utilizing synchrotron radiation microangiography, we assessed pulmonary vessel branching structure, which is indicative of blood flow distribution, and dynamic changes in vascular responsiveness to (1) ET-1 (1 nmol/kg), (2) the ET-1(A) receptor antagonist, BQ-123 (1 mg/kg), and (3) ACh (3.0 μg kg⁻¹ min⁻¹). CH impaired blood flow distribution throughout the lung. However, this vessel "rarefaction" was attenuated in ghrelin-treated CH-rats. Moreover, ghrelin (1) reduced the magnitude of endothelial dysfunction, (2) prevented an increase in ET-1-mediated vasoconstriction, and (3) reduced pulmonary vascular remodeling and right ventricular hypertrophy-all adverse consequences associated with CH. These results highlight the beneficial effects of ghrelin for maintaining optimal lung perfusion in the face of a hypoxic insult. Further research is now required to establish whether ghrelin is also an effective therapy for restoring normal pulmonary hemodynamics in patients that already have established PH.

Topics: Acetylcholine; Angiography; Animals; Antihypertensive Agents; Endothelin-1; Ghrelin; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Synchrotrons; Vasoconstriction; Vasodilator Agents

The available treatment strategies against pulmonary hypertension include the administration of endothelin-1 (ET-1) receptor subtype blockers (ET(A) and ET(B) antagonists); vasoactive intestinal polypeptide (VIP) has recently been suggested as a potential new therapeutic agent. We set out to investigate the ability of these agents to protect against the vasoconstriction and impairment of lung function commonly observed in patients with pulmonary hypertension. An ET(A) blocker (BQ123), ET(B) blocker (BQ788), a combination of these selective blockers (ET(A) + ET(B) blockers) or VIP (V6130) was administered into the pulmonary circulation in four groups of perfused normal rat lungs. Pulmonary vascular resistance (PVR) and forced oscillatory lung input impedance (Z(L)) were measured in all groups under baseline conditions and at 1 min intervals following ET-1 administrations. The airway resistance, inertance, tissue damping and elastance were extracted from the Z(L) spectra. While VIP, ET(A) blocker and combined ET(A) and ET(B) blockers significantly prevented the pulmonary vasoconstriction induced by ET-1, ET(B) blockade enhanced the ET-1-induced increases in PVR. In contrast, the ET(A) and ET(B) blockers markedly elevated the ET-1-induced increases in airway resistance, while VIP blunted this constrictor response. Our results suggest that VIP potently acts against the airway and pulmonary vascular constriction mediated by endothelin-1, while the ET(A) and ET(B) blockers exert a differential effect between airway resistance and PVR.

Topics: Airway Resistance; Animals; Antihypertensive Agents; Bronchoconstriction; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Lung; Lung Compliance; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Respiratory Mechanics; Vascular Resistance; Vasoactive Intestinal Peptide; Vasoconstriction

Pulmonary hypertension is a kind of disease associated with a very high rate of mortality. There are not many effective drugs for the treatment of pulmonary hypertension. Treatment with ET-1 receptor antagonists was proved to be effective in the treatment of pulmonary hypertension. Aiming at developing new endothelin A receptor (ET(A)) antagonist for treatment of pulmonary hypertension, 242 peptide compounds were synthesized by structural optimization of a selective ET(A) receptor antagonist BQ-123. Among these, -azabicyclo[3,2,1]octane-1-yl-l-Leucyl-d-tryptophanyl-d-4-Cl-phenylalanine, named ETP-508, was selected for further harmacological characterization.. Radioligand binding assay was performed to study the binding affinity of ETP-508 for ET(A) and ET(B) receptors. The biological activity of ETP-508 was evaluated in isolated rat aortic ring experiment and in systemic arterial pressure experiment. In addition, hypotensive effect of ETP-508 was investigated on hypoxia-induced pulmonary hypertension.. ETP-508 binds to endothelin ET(A) receptor with >10,000-fold higher affinity than to endothelin B receptor in rat lung tissue preparation. ETP-508 inhibited endothelin-1 (ET-1)-induced contraction of isolated rat aortic ring and shifted the cumulative concentration-contraction response curve to ET-1 to right with no change in the maximal response. In vivo, ETP-508 inhibited the increased effect of ET-1 on mean systemic arterial pressure. Pre-treatment with ETP-508 by intravenous infusion significantly inhibited chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. ETP-508 also significantly inhibited the increase in lung ET-1 expression level, hemoglobin, red-cell count and red-cell hematocrit as induced by hypoxia. Furthermore, ETP-508 partially reversed pre-established pulmonary hypertension and right ventricle hypertrophy by chronic hypoxia.. These results indicated that ETP-508 is a novel highly selective ET(A) receptor antagonist and may have a great potential to be developed as a drug of anti-pulmonary hypertension.

Topics: Animals; Aorta, Thoracic; Azabicyclo Compounds; Azepines; Blood Pressure; Chronic Disease; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Lung; Male; Molecular Structure; Oligopeptides; Peptides, Cyclic; Rats; Rats, Wistar; Time Factors; Vasoconstriction

Endothelin 1 (ET-1) is a potent pulmonary vasoconstrictor and mediator of lung diseases. Antagonism of the ET-1-mediated effects has become an important therapeutic approach. ET-1 (A and B) receptors are differentially distributed in the lung vasculature. Whereas the ET(A) receptors mainly mediate vasoconstriction, the endothelial ET(B) receptor seems to have vasodilative properties. We sought to determine if antagonism of ET receptors can be achieved by inhalation of specific blockers in a model of ET-1-mediated pulmonary hypertension.

Topics: Administration, Inhalation; Antihypertensive Agents; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension, Pulmonary; Oligopeptides; Peptides, Cyclic; Piperidines; Pulmonary Artery; Pulmonary Edema; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Vascular remodeling, rather than vasoconstriction, is believed to account for high vascular resistance in severe pulmonary arterial hypertension (PAH). We have found previously that acute Rho kinase inhibition nearly normalizes PAH in chronically hypoxic rats that have no occlusive neointimal lesions. Here we examined whether Rho kinase-mediated vasoconstriction was also important in a rat model of severe occlusive PAH. Adult rats were exposed to chronic hypoxia ( approximately 10% O(2)) after subcutaneous injection of the vascular endothelial growth factor receptor inhibitor SUGEN 5416. Hemodynamic measurements were made in anesthetized rats after 2 weeks of hypoxia (early group) and 3 weeks of hypoxia plus 2 weeks of normoxia (late group). Both groups developed PAH, with greater severity in the late group. In the early group, intravenous fasudil was more effective than intravenous bradykinin, inhaled NO, or intravenous iloprost in reducing right ventricular systolic pressure. Despite more occlusive vascular lesions, fasudil also markedly reduced right ventricular systolic pressure in late-stage rats. Blood-perfused lungs from late-stage rats showed spontaneous vasoconstriction, which was reversed partially by the endothelin A receptor blocker BQ123 and completely by fasudil or Y-27632. Phosphorylation of MYPT1, a downstream target of Rho kinase, was increased in lungs from both groups of rats, and fasudil (intravenous) reversed the increased phosphorylation in the late group. Thus, in addition to structural occlusion, Rho kinase-mediated vasoconstriction is an important component of severe PAH in SUGEN 5416/hypoxia-exposed rats, and PAH can be significantly reduced in the setting of a severely remodeled lung circulation if an unconventional vasodilator is used.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Disease Models, Animal; Disease Progression; Endothelin A Receptor Antagonists; Hypertension, Pulmonary; Hypoxia; Indoles; Intracellular Signaling Peptides and Proteins; Male; Myosin-Light-Chain Phosphatase; Organ Culture Techniques; Peptides, Cyclic; Phosphorylation; Protein Serine-Threonine Kinases; Pulmonary Artery; Pyrroles; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Vascular Endothelial Growth Factor Receptor-2; Vasoconstriction; Vasodilator Agents

We have previously reported that vasoconstrictor sensitivity to KCl (a receptor-independent and voltage-gated Ca influx-mediated vasoconstrictor) is augmented in the chronically hypoxic hypertensive rat pulmonary circulation probably through increased Rho kinase-mediated Ca sensitization. However, the upstream mechanism by which the RhoA/Rho kinase signaling pathway is activated is unknown. This study examined if endogenous endothelin-1 (ET-1) and serotonin (5-HT) play roles in the Rho kinase-mediated augmented vasoconstrictor response to KCl and the activation of RhoA in chronically hypoxic hypertensive rat pulmonary arteries. The augmented KCl vasoconstriction in hypertensive lungs was reduced by the ETA receptor antagonist BQ123, while a dual ETA/B antagonist had no further effects. A combination of BQ123 and a 5-HT1B/1D receptor antagonist, GR127935, was more effective than either agent alone. The combined antagonists also reduced augmented contractile sensitivity to KCl in hypertensive intrapulmonary arteries. Membrane-to-cytosol ratio of RhoA expression in hypertensive arteries was greater than that in normotensive arteries and was reduced by BQ123 and GR127935. These results suggest that stimulation of ETA and 5-HT1B/1D receptors by endogenous ET-1 and 5-HT, respectively, is involved in RhoA/Rho kinase-mediated increased Ca sensitization in the chronically hypoxic hypertensive rat pulmonary circulation.

Topics: Amides; Animals; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Enzyme Activation; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Lung; Male; Peptides, Cyclic; Perfusion; Potassium Chloride; Pulmonary Artery; Pulmonary Circulation; Pyridines; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; rhoA GTP-Binding Protein; Serotonin; Signal Transduction; Vasoconstriction

In monocrotaline (MCT)-induced pulmonary hypertension (PH), only the right ventricle (RV) endures overload, but both ventricles are exposed to enhanced neuroendocrine stimulation. To assess whether in long-standing PH the left ventricular (LV) myocardium molecular/contractile phenotype can be disturbed, we evaluated myocardial function, histology, and gene expression of autocrine/paracrine systems in rats with severe PH 6 wk after subcutaneous injection of 60 mg/kg MCT. The overloaded RV underwent myocardial hypertrophy (P < 0.001) and fibrosis (P = 0.014) as well as increased expression of angiotensin-converting enzyme (ACE) (8-fold; P < 0.001), endothelin-1 (ET-1) (6-fold; P < 0.001), and type B natriuretic peptide (BNP) (15-fold; P < 0.001). Despite the similar upregulation of ET-1 (8-fold; P < 0.001) and overexpression of ACE (4-fold; P < 0.001) without BNP elevation, the nonoverloaded LV myocardium was neither hypertrophic nor fibrotic. LV indexes of contractility (P < 0.001) and relaxation (P = 0.03) were abnormal, however, and LV muscle strips from MCT-treated compared with sham rats presented negative (P = 0.003) force-frequency relationships (FFR). Despite higher ET-1 production, BQ-123 (ET(A) antagonist) did not alter LV MCT-treated muscle strip contractility distinctly (P = 0.005) from the negative inotropic effect exerted on shams. Chronic daily therapy with 250 mg/kg bosentan (dual endothelin receptor antagonist) after MCT injection not only attenuated RV hypertrophy and local neuroendocrine activation but also completely reverted FFR of LV muscle strips to positive values. In conclusion, the LV myocardium is altered in advanced MCT-induced PH, undergoing neuroendocrine activation and contractile dysfunction in the absence of hypertrophy or fibrosis. Neuroendocrine mediators, particularly ET-1, may participate in this functional deterioration.

Topics: Angiotensinogen; Animals; Antihypertensive Agents; Bosentan; Cytochrome P-450 CYP11B2; Endothelin-1; Gene Expression Regulation; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Male; Monocrotaline; Myocardial Contraction; Natriuretic Peptide, Brain; Neurotransmitter Agents; Peptides, Cyclic; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; RNA, Messenger; Sulfonamides; Ventricular Function; Ventricular Remodeling

Evidence has indicated that endothelin-1 is related to the pathogenesis of hypertension. To characterize the role of endothelin-1 (ET-1) in the development of pulmonary hypertension syndrome in broilers, the blockade effect of ETA receptor (ET(A)) antagonist, BQ123, on blood pressure in experimental models of pulmonary hypertension was examined. Birds were locally anesthetized and instrumented with venous catheters for pulmonary arterial pressure (PAP) and right ventricular pressure (RVP), followed by packed cell volume (PCV) and Ascites heart index (AHI) measured, after exposed to low ambient temperature for 7 or 14 d. In treated groups, BQ123 (0.4 or 2.0 microg each time, 2 times a day), administered in abdominal cavities for 7 or 14 d during birds kept in low ambient temperature, prevented both PAP and RVP increasing, especially the high dose BQ123 lowered PAP and RVP to normotensive levels as that in control under normal temperature, whereas significant increases (p<0.05) were found in the two parameters of broilers in both untreated and saline treated group under low ambient temperature compared with those of birds in control. Furthermore, there was also a reduction in low ambient temperature-induced right ventricular hypertrophy in the groups administered BQ123. The preventive effect of BQ123 suggests that ET-1 is associated with the development of broilers' pulmonary hypertension, which leads to the development of ascites, and BQ123 can prevent the occurrence of pulmonary hypertension.

Topics: Age Factors; Animals; Antihypertensive Agents; Blood Pressure Determination; Chickens; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Endothelin A Receptor Antagonists; Environmental Exposure; Hematocrit; Hypertension, Pulmonary; Male; Peptides, Cyclic; Pulmonary Artery; Temperature; Time Factors; Ventricular Function, Right

Acute neonatal pulmonary hypertension is associated with increased activation of the endogenous endothelin pathway. We investigated the role of selective endothelin-A receptor blockade using i.v. BQ-123 in a piglet model of meconium aspiration syndrome. Meconium aspiration was induced in 18 anesthetized piglets. Six controls received no further intervention. Six piglets received 1 mg/kg BQ-123 at 120 min, with the addition of 20 ppm inhaled nitric oxide at 240 min. Six commenced nitric oxide therapy at 120 min, and were given i.v. BQ-123 at 240 min. The total study duration was 360 min. Meconium aspiration resulted in acute pulmonary hypertension and elevated endothelin-1 levels in all animals. There were no changes in pulmonary hemodynamics or endothelin-1 levels beyond 120 min in controls. In the group receiving BQ-123 first, this agent alone reduced the pulmonary artery pressure and pulmonary vascular resistance, and the subsequent addition of inhaled nitric oxide further reduced pulmonary artery pressure. In the group first receiving nitric oxide alone, this reduced the pulmonary artery pressure, and the addition of BQ-123 resulted in a fall in pulmonary vascular resistance. Endothelin-1 levels increased with both agents. BQ-123 was found to be a highly effective pulmonary vasodilator and augmented the effects of nitric oxide in this model of acute pulmonary hypertension.

Topics: Administration, Inhalation; Animals; Antihypertensive Agents; Endothelin A Receptor Antagonists; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Meconium Aspiration Syndrome; Nitric Oxide; Peptides, Cyclic; Receptor, Endothelin A; Swine; Syndrome

To evaluate the acute haemodynamic effect of BQ-123, a selective endothelin A receptor antagonist, in severe chronic pulmonary arterial hypertension (PAH) of primary or autoimmune origin or related to congenital heart disease.. Prospective open clinical study.. Cardiology tertiary referral centre.. 26 patients with chronic PAH were studied, with mean (SEM) age 29 (3) years (range 4-71 years), mean pulmonary artery pressure 68 (4) mm Hg, and pulmonary vascular resistance index 1694 (170) dyne x s x cm(-5). Patients were divided in three groups according to PAH aetiology: primary or autoimmune PAH (n = 12), and PAH associated with congenital heart defects with (n = 6) or without (n = 8) complete mixing.. BQ-123 200 nmol/min was infused for 60 minutes in the right atrium with sequential haemodynamic measurements at 30 minute intervals.. BQ-123 improved mean pulmonary artery pressure from 68 (4) to 64 (4) mm Hg (p < 0.05), pulmonary vascular resistance index from 1694 (170) to 1378 (145) dyne x s x cm(-5) (p < 0.001), pulmonary cardiac index from 3.0 (0.2) to 3.4 (0.3) l/min/m2 (p < 0.001), and effective cardiac index from 2.5 (0.2) to 2.7 (0.2) l/min/m2 (p < 0.01). Haemodynamic response was similar in all groups except for systemic cardiac index where a different (p = 0.0001, F = 5.53) response was observed; systemic cardiac index increased from 2.7 (0.2) to 2.9 (0.2) l/min/m2 (p < 0.001) when patients with complete mixing were excluded, in whom systemic cardiac index tended to decrease from 3.4 (1.0) to 3.0 (0.6) l/min/m2 (p = 0.06).. Acute endothelin A receptor antagonism induces substantial haemodynamic improvement in severe chronic PAH of primary or autoimmune origin or related to congenital heart disease.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Autoimmune Diseases; Blood Pressure; Child; Child, Preschool; Chronic Disease; Endothelin Receptor Antagonists; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Middle Aged; Peptides, Cyclic; Prospective Studies; Receptor, Endothelin A; Vascular Resistance

Pulmonary hypertension (PH) is a rare disease of the pulmonary vasculature with diverse pathogenetic mechanisms. Vasoactive substances such as endothelin A receptor (ET(A)) antagonists and prostanoids have been used to improve haemodynamics and clinical outcome. We compared the hemodynamic response to BQ-123 (an ET(A) receptor antagonist) and prostacyclin or its analogue iloprost in ten patients (four men) with a mean age of 35.9+/-15.6 years. Seven patients had primary PH and three had PH owing to connective tissue disease. Patients underwent haemodynamic evaluation before and after administration of intra-atrial BQ-123 (200 mmol/min for 60 min), intravenous prostacyclin (3 ng x kg(-1) x min(-1) for 4 h) or iloprost as an aerosol (100 microg over 24 h). Response to vasodilator administration was defined as >15% decrease in pulmonary vascular resistance index (PVRI). Of the ten patients, five showed a response to BQ-123 and eight responded to prostanoids. Four patients were responders and one patient was a non-responder to both agents. PVRI decreased by 16.6+/-13.4% with BQ-123, and 24.4+/-15.7% with prostanoids (not statistically significant). The aetiology of PH did not affect the response to either drug. In conclusion, response to ET(A) antagonist or prostanoid administration can be achieved in a large group of patients with severe PH, however few patients respond identically to both agents. These findings are consistent with a multifactorial mechanism involved in this disease.

Topics: Adolescent; Adult; Aged; Endothelin Receptor Antagonists; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Peptides, Cyclic; Receptor, Endothelin A; Vascular Resistance; Vasodilator Agents

In order to test the hypothesis that endothelin-1 (ET-1) directly contributes to the pathophysiology of pulmonary hypertension induced by meconium aspiration, we randomized 12 anesthetized and paralyzed piglets to receive BQ-123, a selective endothelin-A receptor antagonist (BQ group), or normal saline (NS group) after meconium aspiration. The animals were instilled with meconium mixture (3 mL/kg) via an endotracheal tube, and then given intravenous BQ-123 (2 mg/hr) or normal saline. Plasma ET-1 concentrations, arterial blood gases, and hemodynamics were measured at baseline and at 60, 120, 180, and 240 minutes after instillation. The results showed that plasma ET-1 concentrations were similar in both groups. However, in the BQ group, pulmonary artery pressure was significantly lower after 120 minutes (p < 0.05 at 120 min, p < 0.01 at 180 and 240 min) and pulmonary vascular resistance was significantly lower after 180 minutes (p < 0.01) than in the NS group. No significant difference was found in systemic hemodynamics. These data suggest that ET-1 directly contributes to the pathophysiology of pulmonary hypertension induced by meconium aspiration.

Topics: Animals; Animals, Newborn; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Humans; Hypertension, Pulmonary; Infant, Newborn; Meconium Aspiration Syndrome; Peptides, Cyclic; Swine

This investigation was made to elucidate the role of endothelin (ET) in hypoxic pulmonary hypertension and the preventing effects of BQ-123, an ETA receptor antagonist. Thirty male Wistar rats were divided into three groups and exposed to air, isobaric hypoxia or isobaric hypoxia plus BQ-123 for 3 weeks. The pulmonary artery pressure was measured by right cardiac catheterization. The plasma level of ET-1 was measured by RIA method. Histologic sections of the lungs were examined by a computerized image analyser. In hypoxic rats, the pulmonary artery pressure and the thickness of wall of arteriole were significantly increased, and right ventricular hypertrophy was developed. The plasma level of VEGF in rats treated with hypoxia (192.3 +/- 43.1 pg/ml) was significantly increased as compared with that of normal rats (128.2 +/- 28.1 pg/ml), P < 0.01. Chronic BQ-123 treatment prevented the developments of pulmonary hypertension, thickening of pulmonary arteriole and right ventricular hypertrophy induced by hypoxia. These result indicate that chronic hypoxia can result in hypoxic pulmonary hypertension and increased plasma level of ET-1, and the ETA receptor antagonist can prevent hypoxic pulmonary hypertension.

Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Hypertension, Pulmonary; Hypoxia; Male; Peptides, Cyclic; Pulmonary Artery; Rats; Rats, Wistar

The aim of this study was to assess the role of nitric oxide (NO) and endothelin (ET)-1 in the pathophysiology of persistent pulmonary hypertension of the newborn in fetal lambs with a surgically created congenital diaphragmatic hernia (CDH). The pulmonary vascular response to various agonists and antagonists was assessed in vivo between 128 and 132 days gestation. Age-matched fetal lambs served as control animals. Control and CDH lambs had similar pulmonary vasodilator responses to acetylcholine, sodium nitroprusside, zaprinast, and dipyridamole. The ET(A)-receptor antagonist BQ-123 caused a significantly greater pulmonary vasodilatation in CDH than in control animals. The ET(B)-receptor agonist sarafotoxin 6c induced a biphasic response, with a sustained pulmonary vasoconstriction after a transient pulmonary vasodilatation that was not seen in CDH animals. We conclude that the NO signaling pathway in vivo is intact in experimental CDH. In contrast, ET(A)-receptor blockade and ET(B)-receptor stimulation significantly differed in CDH animals compared with control animals. Imbalance of ET-1-receptor activation favoring pulmonary vasoconstriction rather than altered NO-mediated pulmonary vasodilatation is likely to account for persistent pulmonary hypertension of the newborn in fetal lambs with a surgically created CDH.

Topics: Acetylcholine; Animals; Antihypertensive Agents; Cyclic GMP; Dipyridamole; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Female; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Nitric Oxide; Nitroprusside; Peptides, Cyclic; Phosphodiesterase Inhibitors; Pregnancy; Pulmonary Circulation; Purinones; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sheep; Vasoconstrictor Agents; Vasodilator Agents; Viper Venoms

The study was designed to investigate the effects of acetylcholine (ACh) on pulmonary circulation with special regard to mediators that could be involved in the mediation of ACh-induced effects. ACh has been reported to induce either vasodilation or vasoconstriction in the pulmonary circulation of different species.. Prospective experimental study in rabbits.. Experimental laboratory in a university teaching hospital.. Sixty-six adult rabbits of either sex.. The experiments were performed on 66 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. ACh was injected in various concentrations after pulmonary artery preconstriction and in untreated lungs.. Pulmonary arterial pressure (PAP) and lung weight gain were monitored continuously. Perfusate samples were taken intermittently to determine endothelin-1 (ET-1), thromboxane A2 (TXA2), and prostacyclin (PGI2) concentrations. ACh in final dosages from 10(-5) to 10(-2) M (n = 6 each) was injected into the pulmonary artery of lungs treated with U46619 to induce pulmonary arterial hypertension or was injected into untreated lungs. To analyze the potential mechanisms of action, ACh (10(-5) M) was administered in additional experiments after pretreatment with either ETA receptor antagonist BQ123 (10(-6) M; n = 6) or the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). In preconstricted pulmonary vessels, ACh (10(-3) and 10(-2) M) initially induced a PAP rise for 10 mins followed by a sustained decrease. In untreated lungs, ACh induced an immediate dose-dependent increase in PAP, requiring as long as 30 mins to return to predrug levels. Simultaneously, significantly elevated TXA2 and PGI2 levels were observed. Furthermore, ET-1 was detected in the perfusate, which was free from ET-1 before ACh administration. Pretreatment with BQ123 reduced substantially the ACh (10(-5) M)-induced PAP increase and the release of TXA2 and PGI2. At 5 mins, the PAP maximum was reduced from 18.5 +/- 3.2 mm Hg to 9.9 +/- 0.65 mm Hg by BQ123 pretreatment (p < .01). An inhibition of PAP increase was also observed after diclofenac pretreatment (11.6 +/- 0.4 mm Hg at 5 mins; p < .05). Inhibitory effects at 5 mins were significantly more pronounced in the BQ123 group compared with the diclofenac group.. The effects of ACh on the pulmonary circulation of isolated rabbit lungs depend on ACh concentration and the basal tone of the arterial vasculature. In lungs with a normal pulmonary vascular resistance, ACh administration causes vasoconstriction via the release of ET-1 and TXA2, whereas vasodilation is induced in preconstricted pulmonary vessels.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Cyclooxygenase Inhibitors; Diclofenac; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Interactions; Endothelin Receptor Antagonists; Endothelin-1; Female; Hypertension, Pulmonary; In Vitro Techniques; Male; Peptides, Cyclic; Pulmonary Circulation; Pulmonary Wedge Pressure; Rabbits; Thromboxane A2; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

These studies document striking pulmonary vasoconstrictor response to nitric oxide synthase (NOS) inhibition in monocrotaline (MCT) pulmonary hypertension in rats. This constriction is caused by elevated endothelin (ET)-1 production acting on ETA receptors. Isolated, red blood cell plus buffer-perfused lungs from rats were studied 3 wk after MCT (60 mg/kg) or saline injection. MCT-injected rats developed pulmonary hypertension, right ventricular hypertrophy, and heightened pulmonary vasoconstriction to ANG II and the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA). In MCT-injected lungs, the magnitude of the pulmonary pressor response to NOS inhibition correlated strongly with the extent of pulmonary hypertension. Pretreatment of isolated MCT-injected lungs with combined ETA (BQ-123) plus ETB (BQ-788) antagonists or ETA antagonist alone prevented the L-NMMA-induced constriction. Addition of ETA antagonist reversed established L-NMMA-induced constriction; ETB antagonist did not. ET-1 concentrations were elevated in MCT-injected lung perfusate compared with sham-injected lung perfusate, but ET-1 levels did not differ before and after NOS inhibition. NOS inhibition enhanced hypoxic pulmonary vasoconstriction in both sham- and MCT-injected lungs, but the enhancement was greater in MCT-injected lungs. Results suggest that in MCT pulmonary hypertension, elevated endogenous ET-1 production acting through ETA receptors causes pulmonary vasoconstriction that is normally masked by endogenous NO production.

Topics: Angiotensin II; Animals; Drug Combinations; Endothelin-1; Endothelins; Enzyme Inhibitors; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Lung; Male; Monocrotaline; Oligopeptides; omega-N-Methylarginine; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Vasoconstriction

To assess the effect of endothelin type A (ET(A)) receptor antagonism in infants with pulmonary hypertension following corrective surgery for congenital heart disease.. Open label, preliminary study.. Tertiary paediatric cardiothoracic surgical centre.. Three infants (aged 3 weeks, 7 weeks, and 8 months) with postoperative pulmonary hypertension unresponsive to conventional treatment, including inhaled nitric oxide.. Patients received incremental intravenous infusions (0.1 to 0.3 mg/kg/h) of the ET(A) receptor antagonist BQ-123.. The response to BQ-123 administration was determined using continuous invasive monitoring of cardiorespiratory variables.. BQ-123 infusion caused a reduction in the ratio of pulmonary to systemic pressures (0.62 (0.01) to 0.52 (0.03), mean (SEM)) with an accompanying decrease in right ventricular stroke work index (4.6 (0.4) to 2.5 (0.3) g/m) and a tendency for the cardiac index to rise (2.1 (0.2) to 2.7 (0.6) l/min/kg/m(2)). This was associated with a well tolerated fall in the arterial partial pressure of oxygen (16.5 (4.1) to 12.4 (3.3) kPa) and mean systemic arterial pressure (57 (3) to 39 (3) mm Hg).. ET(A) receptor antagonism in infants with postoperative pulmonary hypertension after corrective surgery for congenital heart disease led to significant improvement in pulmonary haemodynamic indices. However, these benefits were associated with reductions in systemic blood pressure and arterial oxygen saturation, the latter consistent with a ventilation-perfusion mismatch. On the basis of these results, studies in pulmonary hypertension will need to proceed with caution.

Topics: Endothelin Receptor Antagonists; Female; Heart Defects, Congenital; Heart Rate; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Oxygen; Peptides, Cyclic; Postoperative Complications; Statistics, Nonparametric; Stroke Volume

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.

Topics: Administration, Inhalation; Animals; Animals, Newborn; Cardiomegaly; Chronic Disease; Constriction; Ductus Arteriosus; Endothelin Receptor Antagonists; Fetus; Hemodynamics; Hypertension, Pulmonary; Lung; Nitric Oxide; Peptides, Cyclic; Receptor, Endothelin A; Vasodilator Agents

The purpose of this study was to investigate whether 1) endothelin-1, a potent vasoconstrictor peptide, is involved in progression of pulmonary hypertension caused by congestive heart failure (CHF); and 2) whether long-term treatment with BQ-123, an endothelin receptor antagonist, ameliorates pulmonary hypertension caused by CHF.. Congestive heart failure accompanies pulmonary hypertension, and the severity of pulmonary hypertension is an important determinant of prognosis. Although we reported that production of endothelin-1 is increased in the failing heart in rats with CHF, it is not known whether production of endothelin-1 in the lung is altered by CHF.. Congestive heart failure was induced by coronary artery ligation in rats. Expression of preproendothelin-1 messenger ribonucleic acid (mRNA) in the lung and kidney was determined. Endothelin-1 staining (immunoreactivity) in the lung was studied by immunohistochemical analysis. Effects of long-term BQ-123 treatment on the rats were studied.. Two weeks postoperatively, CHF accompanied by pulmonary hypertension developed in the rats (CHF rats). Expression of preproendothelin-1 mRNA in the lung was markedly higher in the CHF rats than in the sham-operated rats, whereas that in the kidney did not differ between the two groups. Endothelin-1 staining on the pulmonary vascular endothelial cells was more intense in the CHF rats. BQ-123 treatment over a 2-week period in the CHF rats greatly reduced right ventricular systolic pressure and central venous pressure, but it did not affect blood pressure or left ventricular contractility (peak positive first derivative of left ventricular pressure) in these rats.. Long-term BQ-123 treatment greatly ameliorated pulmonary hypertension in the CHF rats. The present study suggests that endothelin-1 plays an important role in the progression of pulmonary hypertension caused by CHF and that an endothelin receptor antagonist may be a new therapeutic agent for CHF-induced pulmonary hypertension.

Topics: Animals; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Failure; Hemodynamics; Hypertension, Pulmonary; Immunohistochemistry; Kidney; Lung; Peptides, Cyclic; Protein Precursors; Rats; RNA, Messenger

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 mu g/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 < 0.05 versus 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 mu g/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 c

Topics: Animals; Chronic Disease; Ductus Arteriosus; Endothelin-3; Female; Hemodynamics; Hypertension, Pulmonary; Ligation; Lung; Peptides, Cyclic; Pregnancy; Receptors, Endothelin; Sheep; Time Factors

The selective endothelin-A (ETA)-receptor antagonist BQ-123 has been shown to prevent chronic hypoxia-induced pulmonary hypertension in the rat. Therefore in the current study we utilized BQ-123 to test the hypothesis that blockade of the ETA receptor can reverse as well as prevent the increase in mean pulmonary artery pressure, right ventricle-to-left ventricle plus septum ratio, and percent wall thickness in small (50-100 microns) pulmonary arteries observed in male Sprague-Dawley rats exposed to normobaric hypoxia (10% O2, 2 wk). Infusion of BQ-123 (0.4 mg.0.5 microliter-1.h-1 for 2 wk in 10% O2) begun after 2 wk of hypoxia significantly reversed the established pulmonary hypertension and prevented further progression of right ventricular hypertrophy during the third and fourth week of hypoxia. BQ-123 infusion instituted before exposure to hypoxia completely prevented the hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling. These findings suggest that, in the lung, hypoxia induced an increase synthesis of endothelin-1, which acts locally on ETA receptors to cause pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, while ETA-receptor blockade can both prevent and reverse these processes.

Topics: Animals; Cardiomegaly; Chronic Disease; Endothelin Receptor Antagonists; Hypertension, Pulmonary; Hypoxia; Infusions, Intravenous; Male; Peptides, Cyclic; Rats; Rats, Sprague-Dawley

Exposure to hypoxia is associated with increased pulmonary artery pressure and plasma endothelin-1 (ET-1) levels and with selective enhancement in ET-1 peptide and mRNA and endothelin-A (ETA) receptor mRNA levels in rat lung. The current study tested the hypothesis that endogenous ET-1 can account for hypoxia-induced pulmonary hypertension via a paracrine effect on ETA receptors in lung. Intravenous infusion of the ETA receptor antagonist BQ-123 (D-Trp-D-Asp-Pro-D-Val-Leu) (0.4 mg/microliters at 1 microliter/h) into Sprague-Dawley rats beginning 4 h before and for 90 min during normobaric hypoxia (10% O2) markedly attenuated the hypoxic response: mean pulmonary artery pressure increased from 17.2 +/- 0.7 to 29.0 +/- 1.2 mmHg in saline control rats but did not increase from baseline in BQ-123-treated rats. BQ-123 did not alter systemic arterial pressure, heart rate, or plasma endothelin-1 levels. These findings suggest that ET-1 synthesized in lung in response to hypoxia acts locally on ETA receptors to cause pulmonary hypertension.

Topics: Acute Disease; Animals; Blood Pressure; Endothelin Receptor Antagonists; Heart Rate; Hypertension, Pulmonary; Hypoxia; Male; Peptides, Cyclic; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

Increased concentrations of endothelin-1 (ET-1) are found in children with congenital heart diseases that produce increased pulmonary blood flow and pulmonary hypertension, but the role of ET-1 in the pathophysiology of pulmonary hypertension is unclear. Therefore, we investigated ET-1-induced vasoactive responses and ET-1 concentrations in an animal model of pulmonary hypertension and increased pulmonary blood flow. Vascular shunts were placed between the ascending aorta and main pulmonary artery in seven late-gestation fetal sheep. Four weeks after spontaneous delivery, ET-1 increased pulmonary vascular resistance by 29.7 +/- 34.4% (P < 0.05), the ETb-receptor agonist [Ala1,3,11,15]ET-1 (4AlaET-1) had no effect, and the ETa-receptor antagonist cyclo(D-Asp-L-Pro-D-Val-L-Leu-D-Trp) (BQ-123) decreased pulmonary vascular resistance by -16.0 +/- 5.6% (P < 0.05). In contrast, in six control lambs with a similar degree of pulmonary hypertension induced by U-46619, ET-1 and 4AlaET-1 decreased pulmonary vascular resistance by 24.8 +/- 17.6, and 20.0 +/- 13.8%, respectively (P < 0.05). In addition, systemic arterial concentrations of immunoreactive ET-1 were elevated in lambs with pulmonary hypertension (29.2 +/- 9.6 vs. 15.2 +/- 10.7 pg/ml, P < 0.05). Pulmonary hypertension and increased pulmonary blood flow alters the response of ET-1 from pulmonary vasodilation to vasoconstriction. These altered responses suggest a role for ET-1 and its receptors in the pathogenesis of pulmonary hypertension secondary to increased pulmonary blood flow.

Topics: Animals; Animals, Newborn; Blood Vessels; Endothelin Receptor Antagonists; Endothelins; Hemodynamics; Hypertension, Pulmonary; Peptides, Cyclic; Pulmonary Circulation; Receptors, Endothelin; Reference Values; Sheep

The goal of our studies is to elucidate the role of atrial natrluretic peptide (ANP) and endothelin-1 (ET-1) and their receptor mechanisms in hypoxia-induced pulmonary hypertension and the control of pulmonary artery pressure in patients with pulmonary hypertension. Our experimental model is the male Sprague-Dawley rat subjected to normobaric hypoxia (10% O2, 1 atm) x 4 weeks or less. Our hypothesis is that ET-1 and ANP gene expression are enhanced by exposure to hypoxia and that the ET-1 and ANP so generated have causal and protective, respectively, effects on the development of hypoxia-induced pulmonary hypertension. Results from our studies demonstrated that ANP gene expression and ANP secretion in the heart, and the sensitivity to both endogenous and exogenous ANP in the pulmonary vasculature of hypoxia adapted rats are enhanced during hypoxic exposure. These data defined a role for ANP as a modulator hormone that protects against the development of acute hypoxic pulmonary vasoconstriction and chronic hypoxic pulmonary hypertension. Our studies also demonstrated that ET-1 and endothelin-A receptor (ET-AR) gene expression were selectively enhanced in the pulmonary vasculature by exposure to hypoxia, and that the ET-1 so generated is an important mediator in acute and chronic hypoxia-induced pulmonary hypertension. These results suggest that the intrapulmonary ET-1, acting on ET-AR receptors in the pulmonary vasculature mediates the hypoxia-induced pulmonary vasoconstriction and hypertension. In addition, our recent experiments have demonstrated that administration of BQ-123, a selective ET-AR antagonist, abolished the pulmonary vasoconstrictor response to acute (0-90 min) and chronic (2 weeks) hypoxia, further suggesting that ET-1 plays an important role in the pathogenesis of hypoxia-induced pulmonary hypertension in the rat. Results from our studies also indicate that selective ANP analogs and ET-AR antagonists may be clinically useful for the treatment of pulmonary hypertension.

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Endothelins; Hypertension, Pulmonary; Hypoxia; Kidney; Liver; Lung; Male; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Spleen

To determine the potential contribution of endothelin (ET) to modulation of high pulmonary vascular resistance in the normal fetus, we studied the effects of BQ 123, a selective ET-A receptor antagonist, and sarafoxotoxin S6c (SFX), a selective ET-B receptor agonist, in 31 chronically prepared late gestation fetal lambs. Brief intrapulmonary infusions of BQ 123 (0.1-1.0 mcg/min for 10 min) caused sustained increases in left pulmonary artery flow (Qp) without changing main pulmonary artery (MPA) and aortic (Ao) pressures. In contrast, BQ 123 did not change vascular resistance in a regional systemic circulation (the fetal hindlimb). To determine whether big-endothelin-1 (big-ET-1)-induced pulmonary vasoconstriction is mediated by ET-A receptor stimulation, we studied the effects of big-ET-1 with or without pretreatment with BQ 123. BQ 123 (0.5 mcg/min for 10 min) blocked the rise in total pulmonary resistance caused by big-ET-1. CGS 27830 (100 mcg/min for 10 min), an ET-A and -B receptor antagonist, did not change basal tone but blocked big-ET-1-induced pulmonary vasoconstriction. Brief and prolonged intrapulmonary infusion of SFX (0.1 mcg/min for 10 min) increased Qp twofold without changing MPA or Ao pressures. Nitro-L-arginine (L-NA), a selective endothelium-derived nitric oxide (EDNO) antagonist, blocked vasodilation caused by BQ 123 and SFX. We conclude that: (a) BQ 123 causes sustained fetal pulmonary vasodilation, but did not change vascular resistance in the fetal hindlimb; (b) Big-ET-1-induced pulmonary vasoconstriction may be mediated through ET-A receptor stimulation; and (c) ET-B receptor stimulation causes pulmonary vasodilation through EDNO release. These findings support the hypothesis that endothelin may play a role in modulation of high basal pulmonary vascular resistance in the normal fetus.

Topics: Animals; Arginine; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Fetus; Hypertension, Pulmonary; Muscle Tonus; Nitric Oxide; Nitroarginine; Peptides, Cyclic; Perfusion; Protein Precursors; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sheep; Vascular Resistance; Viper Venoms

To investigate the role of endothelin-1 (ET-1) in the pathogenesis of hypoxic pulmonary hypertension, we studied the effects of a recently described endothelin-receptor antagonist (ETA), BQ123, on the development of this process. Intraperitoneal osmotic pumps were placed into 8-wk-old Sprague-Dawley rats that received either saline or BQ123 (0.15 mg/h). The rats were maintained in room air normoxia or placed in a hypobaric chamber (380 Torr) for 2 wk to induce hypoxic pulmonary hypertension. There were no hemodynamic differences between normoxic rats treated with either saline or BQ123. However, treatment with BQ123 attenuated the hypoxia-induced increase in pulmonary arterial mean pressure and total pulmonary resistance index by 60 and 87% respectively. There was also a reduction in hypoxia-induced right ventricular hypertrophy in the BQ123 group. Histological studies performed using a barium-gelatin fixation technique in hypoxic BQ123-treated animals demonstrated a decrease in medial wall thickness in arteries corresponding to the respiratory and terminal bronchioles, respectively. Similarly, there was a significant reduction in the degree of muscularization of more distal vessels at the level of alveolar ducts in BQ123-treated hypoxic rats. We conclude that the ETA-receptor antagonist BQ123 attenuates the development of hypoxic pulmonary hypertension in rats in vivo, thereby suggesting a possible contributing role for ET-1 and the ETA receptor in the pathogenesis of this process.

Topics: Animals; Blood Vessels; Endothelin Receptor Antagonists; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Male; Peptides, Cyclic; Pulmonary Circulation; Rats; Rats, Sprague-Dawley

Endothelin-1 (ET-1) is known to have potent contractile and proliferative effects on vascular smooth muscle cells and is known to induce myocardial cell hypertrophy. We studied the pathophysiological role of endogenous ET-1 in rats with monocrotaline-induced pulmonary hypertension. Four-week-old rats were given a single subcutaneous injection of 60 mg/kg monocrotaline (MCT rats) or saline (control rats) and were killed after 6, 10, 14, 18, and 25 days. In the MCT rats, right ventricular systolic pressure progressively increased and right ventricular hypertrophy developed in a parallel fashion. The venous plasma ET-1 concentration also progressively increased, and this increase preceded the development of pulmonary hypertension. The isolated pulmonary artery exhibited a significantly weaker response to ET-1 in the MCT rats on day 25 but not on days 6 and 14. In the MCT rats, the expression of prepro ET-1 mRNA as measured by Northern blot analysis significantly increased in the heart on days 18 and 25, whereas it gradually decreased in the lungs. The peptide level of ET-1 in the lungs also significantly decreased in the pulmonary hypertensive stage. The expression of prepro ET-1 mRNA had increased by day 6 only in the kidneys. Continuous infusion of BQ-123, a selective ETA receptor antagonist, by an osmotic minipump (14.3 mg per day per rat for 18 days) significantly inhibited the progression of both pulmonary hypertension (right ventricular systolic pressure, 77.8 +/- 4.2 [mean +/- SEM] mm Hg [n = 10] versus 52.3 +/- 2.4 mm Hg [n = 7]; P < .01) and right ventricular hypertrophy (right ventricle/[left ventricle +/- septum], 0.56 +/- 0.03 [n = 10] versus 0.41 +/- 0.02 [n = 7]; P < .01). Histological examination revealed that BQ-123 also effectively prevented pulmonary arterial medial thickening. The inhibition of right ventricular hypertrophy by BQ-123 may be partly ascribed to the blockade of excessive stimulation of the heart by ET-1, in addition to the prevention of pulmonary hypertension. The present findings suggest that endogenous ET-1 contributes to the progression of cardiopulmonary alterations in rats with MCT-induced pulmonary hypertension.

Topics: Animals; Endothelin-1; Endothelins; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; In Vitro Techniques; Lung; Male; Monocrotaline; Peptides, Cyclic; Protein Precursors; Pulmonary Artery; Rats; Rats, Wistar; RNA, Messenger; Vasoconstriction