Cardioprotective effects of bosentan in 5-fluorouracil-induced cardiotoxicity.

5-fluorouracil (5-FU) is a widely used chemotherapeutic agent but cardiotoxicity challenges its clinical usefulness. Thus, searching for more cardioprotective drugs is highly required to prevent the accompanied cardiac hazards. Up to date, the different mechanisms involved in 5-FU cardiotoxicity are still unclear and there is no evaluation of bosentan's role in controlling these cardiac complications. This forced us to deeply study and evaluate the possible cardiopreserving properties of bosentan and different mechanisms involved in mediating it. 32 Wistar albino rats were included in our experiment and induction of cardiotoxicity was performed via administration of 5-FU (150 mg/kg) on 5th day of the experiment by intraperitoneal (i.p.) injection with or without co-administration of bosentan (50 mg/kg/day) orally for 7days. Our data revealed that 5-FU could induce cardiotoxicity which was detected as significant increases of troponin I, lactate dehydrogenase (LDH), creatine kinase- MB (CK-MB), endothelin receptors, malondialdehyde (MDA), toll like receptor4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor kappa B (NFκB), and caspase 3 levels. However, there is marked decrease in endothelial nitric oxide synthase (eNOS), reduced glutathione (GSH) and total antioxidant capacity (TAC). In addition, the histopathological examination showed severe toxic features of cardiac injury. Interestingly, co-administration of bosentan could ameliorate 5-FU-induced cardiotoxicity via improving the detected biochemical and histopathological changes besides modulation of TLR4/MyD88/NFκB signaling pathway, eNOS, and endothelin receptors. Bosentan had a significant cardioprotective effect against 5-FU induced cardiac damage. This effect may be attributed to its ability to inhibit endothelin receptors, stimulates eNOS, anti-oxidant, anti-inflammatory, anti-apoptotic properties with modulation of TLR4/MyD88/NFκB signaling pathway.

Endothelin: 30 Years From Discovery to Therapy.

Discovered in 1987 as a potent endothelial cell-derived vasoconstrictor peptide, endothelin-1 (ET-1), the predominant member of the endothelin peptide family, is now recognized as a multifunctional peptide with cytokine-like activity contributing to almost all aspects of physiology and cell function. More than 30 000 scientific articles on endothelin were published over the past 3 decades, leading to the development and subsequent regulatory approval of a new class of therapeutics-the endothelin receptor antagonists (ERAs). This article reviews the history of the discovery of endothelin and its role in genetics, physiology, and disease. Here, we summarize the main clinical trials using ERAs and discuss the role of endothelin in cardiovascular diseases such as arterial hypertension, preecclampsia, coronary atherosclerosis, myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) caused by spontaneous coronary artery dissection (SCAD), Takotsubo syndrome, and heart failure. We also discuss how endothelins contributes to diabetic kidney disease and focal segmental glomerulosclerosis, pulmonary arterial hypertension, as well as cancer, immune disorders, and allograft rejection (which all involve ETA autoantibodies), and neurological diseases. The application of ERAs, dual endothelin receptor/angiotensin receptor antagonists (DARAs), selective ETB agonists, novel biologics such as receptor-targeting antibodies, or immunization against ETA receptors holds the potential to slow the progression or even reverse chronic noncommunicable diseases. Future clinical studies will show whether targeting endothelin receptors can prevent or reduce disability from disease and improve clinical outcome, quality of life, and survival in patients.

Endothelin-receptor antagonists in the management of pulmonary arterial hypertension: where do we stand?

Pulmonary arterial hypertension, a disease largely neglected until a few decades ago, is presently the object of intense studies by several research teams. Despite considerable progress, pulmonary arterial hypertension remains a major clinical problem, because it is not always easy to diagnose, treat, and prevent. The disease was considered incurable until the late 1990s, when Epoprostenol was introduced as the first tool against this illness. More recently, therapy for pulmonary arterial hypertension gained momentum after publication of the SERAPHIN and AMBITION trials, which also highlighted the importance of upfront therapy. This review also focuses on recent substudies from these trials and progress in drugs targeting the endothelin pathway. Future perspectives with regard to endothelin-receptor antagonists are also discussed.

Tanshinone IIA ameliorated endothelial dysfunction in rats with chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) during repetitive airflow cessations may cause endothelial dysfunction. Tanshinone IIA (Tan IIA) has been used to treat various circulatory disturbance-related diseases because of its pharmacological actions, including vasodilation. However, the mechanism of the effect of its vasodilation is not well established. The objective of this study was to explore the effect of Tan IIA in endothelium-dependent contracting factors and endothelin receptors in aortic endothelial dysfunction in CIH rats. Aortas of rats were retrieved for use in in vitro experiments (isometric force measurement), histological analysis, immunohistochemistry, and Western blotting. Tan IIA treatment increased the expression of endothelial nitric oxide synthase (eNOS) and formation of nitric oxide (NO), inhibited the production of endothelin-1 (ET-1), down-regulated ETA receptor expression, and up-regulated ETB receptor expression. In conclusion, Tan IIA protects endothelial function by inhibiting strain-induced ET-1 expression, decreasing ETA receptors, increasing ETB receptors, increasing the formation of NO, and up-regulating eNOS in CIH.

Measurement of troponin and natriuretic peptides shortly after admission in patients with heart failure-does it add useful prognostic information? An analysis of the Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Studies (VERITAS).

OBJECTIVE: Plasma concentrations of B-type natriuretic peptide (BNP) and troponin are often measured for diagnostic purposes when patients are admitted with heart failure, but their prognostic value when measured soon after admission is uncertain. We aimed to investigate the added prognostic value of admission measurements of BNP and troponins in patients with acute heart failure. METHODS AND RESULTS: Multivariable prognostic models for death or any worsening heart failure (WHF) or rehospitalization for WHF by 30 days, 30-day death or rehospitalization for WHF, and 90-day mortality were constructed using baseline data from the Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Studies (VERITAS) including BNP and troponin I. Of 1347 patients, the median (interquartile range) value of BNP was 422 (156-945) pg/mL and 855 (63%) had measurable troponin I. By 30 days, 432 patients had died or experienced WHF. Clinical variables had only moderate predictive performance that was not substantially improved by BNP or troponin I (c-indices 0.6528 and 0.6595, respectively). By 30 days, 150 patients died or were rehospitalized for WHF. The c-index using clinical variables (0.6855) was not improved by adding biomarkers. By 90 days, 135 patients had died. The c-index for mortality was somewhat better than for composite outcomes (0.7394) but improved little with biomarkers (0.7461). CONCLUSION: Routine clinical data recorded at the time of admission in patients with acute heart failure are poor at predicting recurrent admissions but somewhat better at predicting mortality. Neither BNP nor troponin measured at admission improved predictions; measurement closer to discharge, or of other novel biomarkers, might perform differently.

[Pulmonary hypertension : What is new in therapy?]. / Pulmonale Hypertonie : Was ist neu in der Therapie?

Pulmonary hypertension (PH) comprises a group of pulmonary vascular diseases that are characterized by progressive exertional dyspnea and right heart insufficiency ultimately resulting in right heart decompensation. The classification is into five clinical subgroups that form the absolutely essential basis for decisions on the indications for different pharmacological and non-pharmacological forms of treatment. The guidelines were updated in 2015 and in addition to the hitherto existing pharmacological treatment options of phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostacyclins, the soluble guanylate cyclase stimulator riociguat has now been incorporated for treatment of certain forms of PH. This article provides an overview of the new treatment recommendations in the current guidelines, e. g. for PH patients who are in intensive care units due to surgical interventions or progressive right heart insufficiency.

Endothelin, sex, and pregnancy: unique considerations for blood pressure control in females.

Endothelin-1 (ET-1) is a potent vasoconstrictor, and dysregulation of the endothelin (ET) system has been implicated in the development of hypertension. Sex differences in the ET system have been identified in ET receptor expression and activation, levels of ET-1, and downstream mediators of the ET system. More specifically, males have greater ET-1/ETA receptor activation, whereas females exhibit greater ETB receptor activation. These differences have been suggested to contribute to the sex differences observed in blood pressure control, with greater ETB receptor activation in females potentially acting as an important pathway contributing to the lower prevalence of hypertension in young females compared with age-matched males. This hypothesis is further supported by studies in pregnancy; the role of the ET system is enhanced during pregnancy, with dysregulation of the ET system resulting in preeclampsia. Further research is necessary to elucidate the relative roles of the ET system in blood pressure control in both sexes and to further explore the potential benefits of pharmacological ET blockade in women.

Air Pollution-Induced Vascular Dysfunction: Potential Role of Endothelin-1 (ET-1) System.

Exposure to air pollution negatively impacts cardiovascular health. Studies show that increased exposure to a number of airborne pollutants increases the risk for cardiovascular disease progression, myocardial events, and cardiovascular mortality. A hypothesized mechanism linking air pollution and cardiovascular disease is the development of systemic inflammation and endothelium dysfunction, the latter of which can result from an imbalance of vasoactive factors within the vasculature. Endothelin-1 (ET-1) is a potent peptide vasoconstrictor that plays a significant role in regulating vascular homeostasis. It has been reported that the production and function of ET-1 and its receptors are upregulated in a number of disease states associated with endothelium dysfunction including hypertension and atherosclerosis. This mini-review surveys epidemiological and experimental air pollution studies focused on ET-1 dysregulation as a plausible mechanism underlying the development of cardiovascular disease. Although alterations in ET-1 system components are observed in some studies, there remains a need for future research to clarify whether these specific changes are compensatory or causally related to vascular injury and dysfunction. Moreover, further research may test the efficacy of selective ET-1 pharmacological interventions (e.g., ETA receptor inhibitors) to determine whether these treatments could impede the deleterious impact of air pollution exposure on cardiovascular health.

Therapeutic potential of endothelin receptor antagonism in kidney disease.

Our growing understanding of the role of the endothelin (ET) system in renal physiology and pathophysiology is from emerging studies of renal disease in animal models and humans. ET receptor antagonists reduce blood pressure and proteinuria in chronic kidney disease and cause regression of renal injury in animals. However, the therapeutic potential of ET receptor antagonism has not been fully explored and clinical studies have been largely limited to patients with diabetic nephropathy. There remains a need for more work in nondiabetic chronic kidney disease, end-stage renal disease (patients requiring maintenance dialysis and those with a functioning kidney transplant), ischemia reperfusion injury, and sickle cell disease. The current review summarizes the most recent advances in both preclinical and clinical studies of ET receptor antagonists in the field of kidney disease.

Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension.

The Pregnancy Prevention Program (PPP) is in place to prevent drug-induced developmental malformations. Remarkably, among the ten PPP-enlisted drugs are three endothelin-1 (ET-1) receptor antagonists (ERA's: ambrisentan, bosentan and macitentan), which are approved for the treatment of Pulmonary Arterial Hypertension (PAH). This review describes the effects of ERA's in PAH pathobiology and cardiopulmonary fetal development. While ERA's hamper pathological remodeling of the pulmonary vasculature and as such exert beneficial effects in PAH, they disturb fetal development of cardiopulmonary tissues. By blocking ET-1-mediated positive inotropic effects and myocardial fetal gene induction, ERA's may affect right ventricular adaptation to the increased pulmonary vascular resistance in both the fetus and the adult PAH patient.

Modulation of Calcium Signaling of Angiotensin AT1, Endothelin ETA, and ETB Receptors by Silibinin, Quercetin, Crocin, Diallyl Sulfides, and Ginsenoside Rb1.

Angiotensin II and endothelin-1 are potent vasoconstrictive peptides that play a central role in blood pressure regulation. Both peptides exert their pleiotropic effects via binding to their respective G-protein-coupled receptors, i.e., angiotensin AT1 and endothelin type A and type B receptors. In the present study, we have selected six structurally different plant-derived compounds with known cardioprotective properties to evaluate their ability to modulate calcium signaling of the above-mentioned receptors. For this purpose, we used and validated a cellular luminescence-based read-out system in which we measured intracellular calcium signaling in Chinese hamster ovary cells that express the calcium sensitive apo-aequorin protein. Firstly, silibinin, a flavanolignan that occurs in milk thistle (Silybum marianum), was investigated and found to be an antagonist for the human angiotensin AT1 receptor with an affinity constant of about 9 µM, while it had no effect on endothelin type A or type B receptor activation. Quercetin and crocin partially impeded intracellular calcium signaling resulting in a non-receptor-related reduction of the responses recorded for the three investigated G-protein-coupled receptors. Two organosulfur compounds, diallyl disulfide and diallyl trisulfide, as well as the triterpene saponin ginsenoside Rb1 did not affect the activation of the angiotensin AT1 and endothelin type A and type B receptors. In conclusion, we were able, by using a nonradioactive cellular read-out system, to identify a novel pharmacological property of the flavanolignan silibinin.

Regulatory mechanism of endothelin receptor B in the cerebral arteries after focal cerebral ischemia.

BACKGROUND AND PURPOSE: Increased expression of endothelin receptor type B (ETBR), a vasoactive receptor, has recently been implied in the reduced cerebral blood flow and exacerbated neuronal damage after ischemia-reperfusion (I/R). The study explores the regulatory mechanisms of ETBR to identify drug targets to restore normal cerebral artery contractile function as part of successful neuroprotective therapy. METHODS: We have employed in vitro methods on human and rat cerebral arteries to study the regulatory mechanisms and the efficacy of target selective inhibitor, Mithramycin A (MitA), to block the ETBR mediated contractile properties. Later, middle cerebral artery occluded (MCAO) rats were used to substantiate the observations. Quantative PCR, immunohistochemistry, western blot and wire myograph methods were employed to study the expression and contractile properties of cerebral arteries. RESULTS: Increased expression of specificity protein (Sp1) was observed in human and rat cerebral arteries after organ culture, strongly correlating with the ETBR upregulation. Similar observations were made in MCAO rats. Treatment with MitA, a Sp1 specific inhibitor, significantly downregulated the ETBR mRNA and protein levels. It also significantly reduced the ETBR mediated cerebrovascular contractility. Detailed analysis indicated that ERK1/2 mediated phosphorylation of Sp1 might be essential for ETBR transcription. CONCLUSION: Transcription factor Sp1 regulates the ETBR mediated vasoconstriction in focal cerebral ischemia via MEK-ERK signaling, which is also conserved in humans. The results show that MitA can effectively be used to block ETBR mediated vasoconstriction as a supplement to an existing ischemic stroke therapy.

Reversal of severe angioproliferative pulmonary arterial hypertension and right ventricular hypertrophy by combined phosphodiesterase-5 and endothelin receptor inhibition.

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) are treated with vasodilators, including endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) inhibitors, soluble guanylyl cyclase activators, and prostacyclin. Despite recent advances in pharmacotherapy for individuals with PAH, morbidity and mortality rates in this patient population remain unacceptably high. Here, we tested the hypothesis that combination therapy with two PAH drugs that target distinct biochemical pathways will provide superior efficacy relative to monotherapy in the rat SU5416 plus hypoxia (SU-Hx) model of severe angioproliferative PAH, which closely mimics the human condition. METHODS: Male Sprague Dawley rats were injected with a single dose of SU5416, which is a VEGF receptor antagonist, and exposed to hypobaric hypoxia for three weeks. Rats were subsequently housed at Denver altitude and treated daily with the PDE-5 inhibitor, tadalafil (TAD), the type A endothelin receptor (ETA) antagonist, ambrisentan (AMB), or a combination of TAD and AMB for four additional weeks. RESULTS: Monotherapy with TAD or AMB led to modest reductions in pulmonary arterial pressure (PAP) and right ventricular (RV) hypertrophy. In contrast, echocardiography and invasive hemodynamic measurements revealed that combined TAD/AMB nearly completely reversed pulmonary hemodynamic impairment, RV hypertrophy, and RV functional deficit in SU-Hx rats. Efficacy of TAD/AMB was associated with dramatic reductions in pulmonary vascular remodeling, including suppression of endothelial cell plexiform lesions, which are common in human PAH. CONCLUSIONS: Combined therapy with two vasodilators that are approved for the treatment of human PAH provides unprecedented efficacy in the rat SU-Hx preclinical model of severe, angioproliferative PAH.

Current state of endothelin receptor antagonism in hypertension and pulmonary hypertension.

Endothelin 1 (ET-1), a potent vasoconstrictive substance, was discovered in 1988 by Yanagisawa and colleagues, and since then, a quarter of a century has passed. Understanding the biology of ET-1 has rapidly developed by characterizing the components of its receptors and processing enzymes. Numerous studies have revealed not only physiological but also various pathophysiological roles of the ET system. At first, ET-1 was the attractive and promising target for the treatment of hypertension owing to its potent vasoconstrictive nature and a variety of ET receptor antagonists (ERAs) were studied. However, the clinical application to treat hypertension was disappointing because of the side effects, including liver toxicity and fluid retention. On the other hand, ERAs have been established as orphan drugs for the treatment of pulmonary arterial hypertension and improved the prognosis of patients. Furthermore, multipotency of the ET system in the pathogenesis of multiple diseases has led to the development of translational research not only in the field of hypertension but in a variety of fields. Furthermore, a range of studies are ongoing to apply ERAs to clinical situations. In this article, we review the pathophysiological roles of the ET system in hypertension and pulmonary hypertension and the potential of ET receptor antagonism for the treatment of these diseases.

Endothelin and endothelin antagonists in chronic kidney disease.

The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020. Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident. Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD. Endothelin receptor antagonists (ERAs) have been demonstrated to ameliorate or even reverse renal injury and/or fibrosis in experimental models of CKD, whereas clinical trials indicate a substantial antiproteinuric effect of ERAs in diabetic and nondiabetic CKD patients even on top of maximal renin-angiotensin system blockade. This review summarizes the role of ET in CKD pathogenesis and discusses the potential therapeutic benefit of targeting the ET system in CKD, with attention to the risks and benefits of such an approach.

Endothelin-1 induces interleukin-18 expression in human osteoblasts.

OBJECTIVE: Both endothelin-1 (ET-1) and interleukin (IL)-18 induce osteoblast proliferation under normal and pathophysiological conditions. In the present study, we explored the interaction between the two proteins by examining the effect of ET-1 on IL-18 expression in cultured human osteoblasts. METHODS: Human osteoblasts were treated with ET-1 in different concentrations (1, 10, 20, 40, or 50 nM) for different length of time (1, 6, 12, 18, or 24 h) in the presence or absence of ET A receptor (ETAR) blocker BQ123, ET B receptor (ETBR) blocker BQ788, p38 mitogen-activated protein kinase (MAPK) siRNA, or different kinase inhibitors. RESULTS: ET-1 increased the IL-18 mRNA level in a statistically significant dose- and time-dependent manner within 18 h, which was reflected in dose-dependent induction of the human IL-18 gene promoter activity and IL-18 protein/secreted protein expression. BQ123 (1µ M) and p38 MAPK siRNA and inhibitor PD169316 (25 µM) completely abolished the promoting effect of ET-1 on IL-18 expression. [(3)H]thymidine incorporation assays showed that ET-1 lost a major part (57%) of its promoting effect on osteoblast proliferation when the endogenous IL-18 expression in osteoblasts was knocked down by 75%. CONCLUSIONS: ET-1 induces IL-18 expression in human osteoblasts at the gene promoter/transcription level via ETAR by a p38 MAPK-dependent mechanism, and that IL-18 mediates a major part of ET-1 induced osteoblast proliferation. This study provides the first evidence of interaction between ET-1 and IL-18 in osteoblast and adds new insights into bone physiology and pathophysiology.

Metastatic hormone refractory prostate cancer: recent advances in standard treatment paradigm, and future directions.

Until recently, docetaxel-based chemotherapy was the only established treatment for patients with metastatic hormone refractory prostate cancer (mHRPC). In 2010 to 2011, 3 more agents were shown to be associated with a survival benefit in mHRPC, including the dendritic cell vaccine sipuleucel-T, the 17,20 lyase inhibitor abiraterone, and the taxane cabazitaxel. The improved understanding of prostate cancer biology in recent years led to the development of drugs directed against precise tumorigenesis-associated molecular pathways. Molecular pathways involved in the progression of mHRPC include the androgen receptor, angiogenesis, endothelin receptor, tyrosine kinases (SRC, MET, vascular endothelial growth factor receptor, RET), and the receptor activator of nuclear factor-kB-ligand. This review will focus on recent advances in the standard treatments paradigm, and promising new targeted agents that are being investigated, in mHRPC.

Gene expression profiling and endothelin in acute experimental pancreatitis.

AIM: To analyze gene expression profiles in an experimental pancreatitis and provide functional reversal of hypersensitivity with candidate gene endothelin-1 antagonists. METHODS: Dibutyltin dichloride (DBTC) is a chemical used as a polyvinyl carbonate stabilizer/catalyzer, biocide in agriculture, antifouling agent in paint and fabric. DBTC induces an acute pancreatitis flare through generation of reactive oxygen species. Lewis-inbred rats received a single i.v. injection with either DBTC or vehicle. Spinal cord and dorsal root ganglia (DRG) were taken at the peak of inflammation and processed for transcriptional profiling with a cDNA microarray biased for rat brain-specific genes. In a second study, groups of animals with DBTC-induced pancreatitis were treated with endothelin (ET) receptor antagonists [ET-A (BQ123) and ET-B BQ788)]. Spontaneous pain related mechanical and thermal hypersensitivity were measured. Immunohistochemical analysis was performed using anti-ET-A and ET-B antibodies on sections from pancreatic tissues and DRG of the T10-12 spinal segments. RESULTS: Animals developed acute pancreatic inflammation persisting 7-10 d as confirmed by pathological studies (edema in parenchyma, loss of pancreatic architecture and islets, infiltration of inflammatory cells, neutrophil and mononuclear cells, degeneration, vacuolization and necrosis of acinar cells) and the pain-related behaviors (cutaneous secondary mechanical and thermal hypersensitivity). Gene expression profile was different in the spinal cord from animals with pancreatitis compared to the vehicle control group. Over 260 up-regulated and 60 down-regulated unique genes could be classified into 8 functional gene families: circulatory/acute phase/immunomodulatory; extracellular matrix; structural; channel/receptor/transporter; signaling transduction; transcription/translation-related; antioxidants/chaperones/heat shock; pancreatic and other enzymes. ET-1 was among the 52 candidate genes up-regulated greater than 2-fold in animals with pancreatic inflammation and visceral pain-related behavior. Treatments with the ET-A (BQ123) and ET-B (BQ-788) antagonists revealed significant protection against inflammatory pain related mechanical and thermal hypersensitivity behaviors in animals with pancreatitis (P < 0.05). Open field spontaneous behavioral activity (at baseline, day 6 and 30 min after drug treatments (BQ123, BQ788) showed overall stable activity levels indicating that the drugs produced no undesirable effects on normal exploratory behaviors, except for a trend toward reduction of the active time and increase in resting time at the highest dose (300 µmol/L). Immunocytochemical localization revealed that expression of ET-A and ET-B receptors increased in DRG from animals with pancreatitis. Endothelin receptor localization was combined in dual staining with neuronal marker NeuN, and glia marker, glial fibrillary acidic protein. ET-A was expressed in the cell bodies and occasional nuclei of DRG neurons in naïve animals. However, phenotypic expression of ET-A receptor was greatly increased in neurons of all sizes in animals with pancreatitis. Similarly, ET-B receptor was localized in neurons and in the satellite glia, as well as in the Schwann cell glial myelin sheaths surrounding the axons passing through the DRG. CONCLUSION: Endothelin-receptor antagonists protect against inflammatory pain responses without interfering with normal exploratory behaviors. Candidate genes can serve as future biomarkers for diagnosis and/or targeted gene therapy.

sGC stimulation totally reverses hypoxia-induced pulmonary vasoconstriction alone and combined with dual endothelin-receptor blockade in a porcine model.

AIM: Stimulation of soluble guanylate cyclase (sGC) with BAY 41-8543 was hypothesized to attenuate acute hypoxic pulmonary vasoconstriction alone and combined with dual endothelin (ET)-receptor antagonist tezosentan. METHODS: Measurements were taken in 18 anaesthetized pigs with a mean ± SEM weight of 31.1 ± 0.4 kg, in normoxia (FiO(2)~0.21) and hypoxia (FiO(2)~0.10) without (control protocol, n = 6), and with right atrial infusion of BAY 41-8543 at 1, 3, 6, 9 and 12 µg min(-1) per kg (protocol 2, n = 6) or tezosentan at 5 mg kg(-1) followed by BAY 41-8543 at 1, 3 and 6 µg min(-1) per kg (protocol 3, n = 6). RESULTS: Hypoxia (n = 18) increased (P < 0.001) mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR) by 14.2 ± 0.6 mmHg and 2.8 ± 0.3 WU respectively. During sustained hypoxia without treatment, MPAP and PVR remained stable. BAY 41-8543 (n = 6) dose-dependently decreased (P < 0.001) MPAP and PVR by 15.0 ± 1.2 mmHg and 4.7 ± 0.7 WU respectively. Tezosentan (n = 6) decreased (P < 0.001) MPAP and PVR by 11.8 ± 1.2 mmHg and 2.0 ± 0.2 WU, respectively, whereafter BAY 41-8543 (n = 6) further decreased (P < 0.001) MPAP and PVR by 6.6 ± 0.9 mmHg and 1.9 ± 0.4 WU respectively. Both BAY 41-8543 and tezosentan decreased (P < 0.001) systemic arterial pressure and systemic vascular resistance. Blood-O(2) consumption remained unaltered (P = ns) during all interventions. CONCLUSION: BAY 41-8543 totally reverses the effects of acute hypoxia-induced pulmonary vasoconstriction, and enhances the attenuating effects of tezosentan, without affecting oxygenation. Thus, sGC stimulation, alone or combined with dual ET-receptor blockade, could offer a means to treat pulmonary hypertension related to hypoxia and potentially other causes.