piperidines and Hypertension--Pulmonary

Topics: Anesthesia, General; Anesthesia, Inhalation; Anesthetics; Cardiac Catheterization; Cardiac Surgical Procedures; Child; Child, Preschool; Fentanyl; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Methyl Ethers; Perioperative Care; Piperidines; Postoperative Complications; Remifentanil; Sevoflurane; Vascular Resistance

According to the advanced comprehension of pathophysiology of primary pulmonary hypertension (PPH), a therapeutical approach to PPH has changed recently. One of the breakthrough to the treatment of PPH is application of prostacyclin. It has been revealed that intravenous administration of prostacyclin has improved the prognosis and patient's quality of life. Another development of endothelin receptor antagonists and phosphodiesterase inhibitors have provided a novel pulmonary-specific effect. An endothelin receptor antagonist has a great inhibitory effect against pulmonary vasculature remodeling. In this regard, this regard, this receptor antagonist has superior effect to other medicines. Furthermore, a phosphodiesterase inhibitor shows a great decreasing effect on pulmonary hypertension with less effect on systemic blood pressure. These drugs will provide a great potential to the treatment of pulmonary hypertension.

Topics: Animals; Endothelin Receptor Antagonists; Enzyme Inhibitors; Humans; Hypertension, Pulmonary; Methacrylates; Phosphodiesterase Inhibitors; Piperidines; Purinones; Quinazolines

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

Primary pulmonary hypertension is an uncommon but serious disease that often results in debilitating symptoms and early death. One approach to treatment has been to attempt reduction of pulmonary arterial pressure and right ventricular afterload by using vasodilator agents to decrease pulmonary arteriolar resistance. Use of a variety of vasodilators has yielded only limited and infrequent success. Although an occasional patient may respond to vasodilator therapy with improved pulmonary hemodynamics and symptomatic status, most patients do not. Reasons for lack of success include the presence of predominantly fixed vascular obstructive disease rather than active vasoconstriction, inexorable progression of disease, and adverse nonpulmonary vascular effects of vasodilators, such as systemic hypotension. Because of occasional beneficial responses, a trial of vasodilators is warranted in patients with primary pulmonary hypertension. Initiation of drug therapy should be undertaken during hemodynamic monitoring in order to allow assessment of response, identification of adverse effects, and comparison of different agents. No vasodilator is clearly superior in primary pulmonary hypertension.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Agonists; Blood Pressure; Calcium Channel Blockers; Captopril; Epoprostenol; Hemodynamics; Humans; Hypertension, Pulmonary; Ketanserin; Piperidines; Serotonin Antagonists; Vascular Resistance; Vasodilator Agents

Topics: Animals; Arachidonic Acids; Chemotaxis, Leukocyte; Chromones; Dogs; Guinea Pigs; Humans; Hypertension, Pulmonary; Inflammation; Ketanserin; Leukocyte Count; Leukocytes; Lung; Piperidines; Platelet Activating Factor; Pulmonary Embolism; Respiratory Distress Syndrome; Serotonin; Serotonin Antagonists; SRS-A; Thromboxane A2

The authors compared the effects of remifentanil with fentanyl on the hemodynamic and respiratory variables in children with left-to-right shunting and pulmonary hypertension.. A prospective, randomized, and controlled design.. University hospital.. Children aged between 3 months and 6 years undergoing pediatric cardiac surgery for correction of left-to-right intracardiac shunting.. Children were assigned to 1 of the 2 opioids for intraoperative use. Fentanyl was given as a 20 microg/kg intravenous bolus followed by infusion at a rate of 20 microg/kg/h in group 1 (control, n=15), and remifentanil was given as a 2 microg/kg intravenous bolus followed by infusion at a rate of 2 microg/kg/min in group 2 (n=18).. Mean arterial pressures at 30 to 40 minutes postbypass and the first 2 hours postsurgery were higher in the remifentanil group (p<0.05). Heart rates, pulmonary artery pressures, and airway pressures did not differ at any time between groups. Peripheral oxygen saturation values were lower at 30 and 45 minutes in the prebypass period and higher at 1 to 4 hours in the intensive care unit in the remifentanil group (p<0.05). After protamine administration, transient peripheral oxygen desaturation was observed with 10 children in the remifentanil group and with 3 children in the fentanyl group without any hemodynamic deterioration (p=0.029).. There were no clinically important differences in hemodynamic and respiratory measurements intraoperatively and during the initial 24 hours postoperatively between fentanyl and remifentanil in pediatric patients undergoing surgical repair of defects with left-to-right shunts.

Topics: Cardiovascular Surgical Procedures; Child; Child, Preschool; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Intraoperative Care; Piperidines; Prospective Studies; Remifentanil

Halofuginone is a febrifugine derivative originally isolated from Chinese traditional herb Chang Shan that exhibits anti-hypertrophic, anti-fibrotic and anti-proliferative effects. We sought to investigate whether halofuginone induced pulmonary vasodilation and attenuates chronic hypoxia-induced pulmonary hypertension (HPH).. Patch-clamp experiments were conducted to examine the activity of voltage-dependent Ca. Halofuginone increased voltage-gated K

Topics: Animals; Calcium; Hypertension, Pulmonary; Hypoxia; Mice; Myocytes, Smooth Muscle; Pharmaceutical Preparations; Phosphatidylinositol 3-Kinases; Piperidines; Pulmonary Artery; Quinazolinones

Topics: Animals; Bone Morphogenetic Protein 2; Cell Line; Cell Proliferation; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Leukotriene B4; Piperidines; Pulmonary Artery; Rats; Signal Transduction; Stem Cells

Topics: Animals; bcl-2-Associated X Protein; Cardiomegaly; Cyclin-Dependent Kinase Inhibitor p27; Electrocardiography; Hemodynamics; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Piperidines; Proliferating Cell Nuclear Antigen; Protective Agents; Pulmonary Artery; Quinolizidines; Rats, Sprague-Dawley; rho-Associated Kinases; rhoA GTP-Binding Protein; RNA, Messenger; Vascular Remodeling

Pulmonary hypertension (PH) is serious, fatal disease which is promoted by oxidative stress. Aloperine have antioxidation effects, which effects on pulmonary arteries remain unclear. Therefore, this study is designed to investigate whether aloperine has protective effects on PH induced by monocrotaline and whether these effects are associated with oxidative stress. PH was induced by monocrotaline (60mg/kg), and subsequently oral administration of aloperine (25, 50, 100mg/kg/day). At the end of the experiment, hemodynamic, pathomorphologic, electrocardiographic and echocardiographic data from the rats were obtained. At same time, oxidative stress biomarkers (superoxide dismutase, malonyldialdehyde, catalase, glutathione peroxidase, total antioxidant capacity) and the protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-2, NOX-4 in the lung of rat has been detected. The result shows that aloperine treatment showed significantly improvement in hemodynamic, pathomorphologic, electrocardiographic and echocardiographic data. Moreover, aloperine treatment can alleviate the changes of oxidative stress biomarkers and suppress the expression levels of NOX-2, NOX-4. In summary, this study indicates that aloperine have protective effects on monocrotaline-induced PH. And these effects may be related to inhibit oxidative stress.

Topics: Animals; Antioxidants; Biomarkers; Dose-Response Relationship, Drug; Echocardiography; Electrocardiography; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Oxidative Stress; Piperidines; Protective Agents; Pulmonary Artery; Pulmonary Circulation; Quinolizidines; Rats; Rats, Sprague-Dawley

Recent studies have demonstrated that the expression of sphingosine kinase 1, the enzyme that catalyses formation of the bioactive lipid, sphingosine 1-phosphate, is increased in lungs from patients with pulmonary arterial hypertension. In addition, Sk1(-/-) mice are protected from hypoxic-induced pulmonary arterial hypertension. Therefore, we assessed the effect of the sphingosine kinase 1 selective inhibitor, PF-543 and a sphingosine kinase 1/ceramide synthase inhibitor, RB-005 on pulmonary and cardiac remodelling in a mouse hypoxic model of pulmonary arterial hypertension. Administration of the potent sphingosine kinase 1 inhibitor, PF-543 in a mouse hypoxic model of pulmonary hypertension had no effect on vascular remodelling but reduced right ventricular hypertrophy. The latter was associated with a significant reduction in cardiomyocyte death. The protection involves a reduction in the expression of p53 (that promotes cardiomyocyte death) and an increase in the expression of anti-oxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). In contrast, RB-005 lacked effects on right ventricular hypertrophy, suggesting that sphingosine kinase 1 inhibition might be nullified by concurrent inhibition of ceramide synthase. Therefore, our findings with PF-543 suggest an important role for sphingosine kinase 1 in the development of hypertrophy in pulmonary arterial hypertension.

Topics: Animals; Biomarkers; Body Weight; Cells, Cultured; Disease Models, Animal; Enzyme Inhibitors; Female; Heart Ventricles; HEK293 Cells; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Methanol; Mice, Inbred C57BL; Models, Biological; Myocytes, Smooth Muscle; Phosphotransferases (Alcohol Group Acceptor); Piperidines; Pressure; Pulmonary Artery; Pyrrolidines; Signal Transduction; Sulfones; Ventricular Remodeling

Ascorbic acid bound to KMUP-1 and sildenafil were examined for their antioxidant effects on vascular endothelium growth factor (VEGF) and endothelium nitric oxide synthase (eNOS) in hypoxic pulmonary artery (PA). Inhaled KMUP-1 and oral sildenafil released NO from eNOS. The effect of buffered l-ascorbic acid, alone and bound to KMUP-1 or sildenafil, for treating pulmonary arterial hypertension (PAH) is unclear. In this study, the antioxidant capacity of ascorbic acid increased the beneficial effects of KMUP-1 on PAH. KMUP-1A and sildenafil-A (5 mg/kg/d) were administered to hypoxic PAH rats. Pulmonary artery blood pressure, and VEGF, Rho kinase II (ROCK II), eNOS, soluble guanylate cyclase (sGC-α), and protein kinase G expression in lung tissues were measured to link PAH and right ventricular hypertrophy. Hypoxic rats had higher pulmonary artery blood pressure, greater PA medial wall thickness and cardiac weight, and a higher right ventricle/left ventricle + septum [RV/(LV+S)] ratio than normoxic rats. Oral KMUP-1A or sildenafil-A for 21 days in hypoxia prevented the rarefaction of eNOS in immunohistochemistry (IHC), reduced the IHC of VEGF in PAs, restored eNOS/protein kinase G/phosphodiesterase 5A; unaffected sGC-α and inactivated ROCK II expression were also found in lung tissues. In normoxic PA, KMUP-1A/Y27632 (10μM) increased eNOS and reduced ROCK II. ROCK II/reactive oxidative species was increased and eNOS was reduced after long-term hypoxia for 21 days. KMUP-1A or Y27632 blunted ROCK II in short-term hypoxic PA at 24 hours. l-Ascorbic acid + l-sodium ascorbate (40, 80μM) buffer alone directly inhibited the IHC of VEGF in hypoxic PA. Finally, KMUP-1A or sildenafil-A reduced PAH and associated right ventricular hypertrophy.

Topics: Amides; Animals; Ascorbic Acid; Endothelium, Vascular; Hypertension, Pulmonary; Hypoxia; Male; Nitric Oxide Synthase Type III; Piperidines; Pulmonary Artery; Pyridines; Rats; Sildenafil Citrate; Vascular Endothelial Growth Factors; Xanthines

This study investigates whether endothelin-1 (ET-1) mediates monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) and right ventricular hypertrophy (RVH), and if so, whether the G-protein coupled receptor antagonist KMUP-1 (7-{2-[4-(2-chlorobenzene)piperazinyl]ethyl}-1,3-dimethylxanthine) inhibits ET-1-mediated PA constriction and the aforementioned pathological changes. In a chronic rat model, intraperitoneal MCT (60 mg/kg) induced PAH and increased PA medial wall thickening and RV/left ventricle + septum weight ratio on Day 21 after MCT injection. Treatment with sublingual KMUP-1 (2.5 mg/kg/day) for 21 days prevented these changes and restored vascular endothelial nitric oxide synthase (eNOS) immunohistochemical staining of lung tissues. Western blotting analysis demonstrated that KMUP-1 enhanced eNOS, soluble guanylate cyclase, and protein kinase G levels, and reduced ET-1 expression and inactivated Rho kinase II (ROCKII) in MCT-treated lung tissue over long-term administration. In MCT-treated rats, KMUP-1 decreased plasma ET-1 on Day 21. KMUP-1 (3.6 mg/kg) maximally appeared at 0.25 hours in the plasma and declined to basal levels within 24 hours after sublingual administration. In isolated PA of MCT-treated rats, compared with control and pretreatment with l-NG-nitroarginine methyl ester (100 μM), KMUP-1 (0.1-100 μM) inhibited ET-1 (0.01 μM)-induced vasoconstriction. Endothelium-denuded PA sustained higher contractility in the presence of KMUP-1. In a 24-hour culture of smooth muscle cells (i.e., PA smooth muscle cells or PASMCs), KMUP-1 (0.1-10 μM) inhibited RhoA- and ET-1-induced RhoA activation. KMUP-1 prevented MCT-induced PAH, PA wall thickening, and RVH by enhancing eNOS and suppressing ET-1/ROCKII expression. In vitro, KMUP-1 inhibited ET-1-induced PA constriction and ET-1-dependent/independent RhoA activation of PASMCs. In summary, KMUP-1 attenuates ET-1-induced/ET-1-mediated PA constriction, and could thus aid in the treatment of PAH caused by MCT.

Topics: Animals; Blood Pressure; Body Weight; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Endothelin-1; Guanylate Cyclase; Heart Rate; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; In Vitro Techniques; Male; Monocrotaline; Nitric Oxide Synthase Type III; Piperazines; Piperidines; Pulmonary Artery; Purines; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Sildenafil Citrate; Soluble Guanylyl Cyclase; Sulfonamides; Vasoconstriction; Xanthines

This study investigates the actions of KMUP-1 on RhoA/Rho-kinase (ROCK)-dependent Ca(2+) sensitization and the K(+)-channel in chronic pulmonary arterial hypertension (PAH) rats.. Sprague-Dawley rats were divided into control, monocrotaline (MCT), and MCT+KMUP-1 groups. PAH was induced by a single intraperitoneal injection (i.p.) of MCT (60 mg/kg). KMUP-1 (5 mg/kg, i.p.) was administered once daily for 21 days to prevent MCT-induced PAH. All rats were sacrificed on day 22.. MCT-induced increased right ventricular systolic pressure (RVSP) and right ventricular hypertrophy were prevented by KMUP-1. In myograph experiments, KCl (80 mM), phenylephrine (10 microM) and K(+) channel inhibitors (TEA, 10 mM; paxilline, 10 microM; 4-AP, 5 mM) induced weak PA contractions in MCT-treated rats compared to controls, but the PA reactivity was restored in MCT+KMUP-1-treated rats. By contrast, in beta-escin- or alpha-toxin-permeabilized PAs, CaCl(2)-induced (1.25 mM, pCa 5.1) contractions were stronger in MCT-treated rats, and this action was suppressed in MCT+KMUP-1-treated rats. PA relaxation in response to the ROCK inhibitor Y27632 (0.1 microM) was much higher in MCT-treated rats than in control rats. In Western blot analysis, the expression of Ca(2+)-activated K(+) (BK(Ca)) and voltage-gated K(+) channels (Kv2.1 and Kv1.5), and ROCK II proteins was elevated in MCT-treated rats and suppressed in MCT+KMUP-1-treated rats. We suggest that MCT-treated rats upregulate K(+)-channel proteins to adapt to chronic PAH.. KMUP-1 protects against PAH and restores PA vessel tone in MCT-treated rats, attributed to alteration of Ca(2+) sensitivity and K(+)-channel function.

Topics: Animals; Blotting, Western; Calcium; Chronic Disease; Female; Hypertension, Pulmonary; Monocrotaline; Muscle Contraction; Muscle, Smooth, Vascular; Myography; Piperidines; Potassium Channels, Calcium-Activated; Potassium Channels, Voltage-Gated; Pulmonary Artery; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; rhoA GTP-Binding Protein; Up-Regulation; Xanthines

KMUP-1 is known to increase cGMP, enhance endothelial nitric oxide synthase (eNOS) and suppress Rho kinase (ROCK) expression in smooth muscle. Here, we investigated the mechanism of action of KMUP-1 on acute and chronic pulmonary artery hypertension (PAH) in rats.. We measured pulmonary vascular contractility, wall thickening, eNOS immunostaining, expressions of ROCK II, RhoA activation, myosin phosphatase target subunit 1 (MYPT1) phosphorylation, eNOS, soluble guanylyl cyclase (sGC), protein kinase G (PKG) and phosphodiesterase 5A (PDE-5A), blood oxygenation and cGMP/cAMP, and right ventricular hypertrophy (RVH) in rats.. In rings of intact pulmonary artery (PA), KMUP-1 relaxed the vasoconstriction induced by phenylephrine (10 microM) or the thromboxane A(2)-mimetic U46619 (0.5 microM). In endothelium-denuded PA rings, this relaxation was reduced. In acute PAH induced by U46619 (2.5 microg x kg(-1) x min(-1), 30 min), KMUP-1 relaxed vasoconstriction by enhancing levels of eNOS, sGC and PKG, suppressing those of PDE-5A, RhoA/ROCK II activation and MYPT1 phosphorylation, and restoring oxygenation in blood and cGMP/cAMP in plasma. Incubating smooth muscle cells from PA (PASMCs) with KMUP-1 inhibited thapsigargin-induced Ca(2+) efflux and angiotensin II-induced Ca(2+) influx. In chronic PAH model induced by monocrotaline, KMUP-1 increased eNOS and reduced RhoA/ROCK II activation/expression, PA wall thickening, eNOS immunostaining and RVH. KMUP-1 and sildenafil did not inhibit monocrotaline-induced PDE-5A expression.. KMUP-1 decreased PAH by enhancing NO synthesis by eNOS, with consequent cGMP-dependent inhibition of RhoA/ROCK II and Ca(2+) desensitization in PASMCs. KMUP-1 has the potential to reduce vascular resistance, remodelling and RVH in PAH.

Topics: Animals; Antihypertensive Agents; Calcium Signaling; Cells, Cultured; Cyclic GMP-Dependent Protein Kinases; Endothelium, Vascular; Enzyme Inhibitors; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; In Vitro Techniques; Lung; Male; Myocytes, Smooth Muscle; Nitric Oxide Synthase Type III; Nucleotides, Cyclic; Phosphorylation; Piperidines; Protein Phosphatase 1; Pulmonary Artery; Rats; Rats, Wistar; rho-Associated Kinases; rhoA GTP-Binding Protein; Vasodilation; Xanthines

Information about the muscarinic receptor subtype(s) mediating pulmonary circulatory vasodilator responses to acetylcholine (ACh) is limited. The aim of this study was to pharmacologically characterize the muscarinic receptors associated with ACh-induced pulmonary vasodilation in a pulmonary hypertension model. Vasodilation of rabbit isolated buffer-perfused lungs in which pulmonary hypertension was induced with the thromboxane A₂ analogue U-46619 was evoked by ACh at a just maximally effective concentration (2 x 10⁻⁷ M). The effects of cumulative concentrations of three specific muscarinic receptor subtype antagonists [pirenzepine (M₁), methoctramine (M₂), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, M₃] on ACh-induced pulmonary vasodilation were determined. Double vascular occlusion pressure was recorded to locate the muscarinic receptors within the pulmonary vasculature. Based on the 50% inhibitory concentrations (IC₅₀), the rank of order of antagonist potency was 4-DAMP >> pirenzepine > methoctramine. The vascular effects of all three inhibitors were localized to the precapillary segment. These findings suggest that the vasodilator action of ACh on rabbit isolated perfused U-46619 pretreated lungs is mediated by M₃ muscarinic receptors located in the pulmonary arterial bed.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Diamines; Hypertension, Pulmonary; Lung; Piperidines; Pirenzepine; Rabbits; Receptor, Muscarinic M3; Vasodilation

Topics: Adenoidectomy; Anesthetics, Intravenous; Anticoagulants; Antihypertensive Agents; Bosentan; Child; Down Syndrome; Elective Surgical Procedures; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Intubation, Intratracheal; Piperazines; Piperidines; Propofol; Purines; Remifentanil; Severity of Illness Index; Sildenafil Citrate; Sleep Apnea, Obstructive; Sulfonamides; Sulfones; Tonsillectomy; Treatment Outcome; Vasodilator Agents; Warfarin

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

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

Topics: Anesthesia, General; Bundle-Branch Block; Dermatomyositis; Dyslipidemias; Epoprostenol; Female; Fentanyl; Furosemide; Humans; Hypertension; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Mediastinal Diseases; Mediastinoscopy; Methyl Ethers; Middle Aged; Oxygen Inhalation Therapy; Piperidines; Preoperative Care; Raynaud Disease; Remifentanil; Sevoflurane; Spironolactone

Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow.. Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2+/-113.8 versus 209.8+/-61.8 pg/g, P<0.05). In shunt lambs (n=9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ETA receptor antagonist PD 156707 (n=3). This pulmonary vasoconstriction was mimicked by exogenous Ala1,3,11,15 ET-1 (4 Ala ET-1), the ETB receptor agonist, and was blocked by the ETB receptor antagonist BQ 788 (n=3). However, in control lambs (n=7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ETB receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs.. Over time, increased pulmonary blood flow and/or pressure results in the emergence of ETB-mediated vasoconstriction, which coincides with the emergence of ETB receptors on smooth muscle cells. These data suggest an important role for ETB receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.

Topics: Animals; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart Defects, Congenital; Hemodynamics; Hypertension, Pulmonary; Lung; Muscle, Smooth, Vascular; Oligopeptides; Piperidines; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Sheep; Vasoconstriction

A 36 year old parturient with known valvular heart disease was admitted with respiratory distress and fatigue after 35 weeks of pregnancy. Echocardiography revealed severe tricuspid regurgitation, mitral stenosis and aortic valve insufficiency. Following clinical examination and insertion of a radial and pulmonary artery catheter it was decided to perform a Caesarean Section. The pulmonary artery pressure upon arrival in the operating theatre was 105/50 mm Hg whereas cardiac output was 3.5 l/min. Induction of anesthesia was performed with a target controlled infusion of remifentanil and propofol combined with rocuronium bromide. Haemodynamic variables remained very stable during and after intubation. The lungs of the apnoeic baby were manually ventilated until spontaneous respiration began at 1 minute post delivery. Apgar scores were 3, 7 and 9 after 1, 5 and 10 minutes respectively. Umbilical artery pH was 7.29. The patient's haemodynamic status gradually improved over the following few days. Two months following delivery she underwent unevenful valvular surgery.

Topics: Adult; Anesthesia, Intravenous; Anesthesia, Obstetrical; Anesthetics, Combined; Anesthetics, Intravenous; Cesarean Section; Female; Heart Valve Diseases; Humans; Hypertension, Pulmonary; Infusion Pumps; Piperidines; Pregnancy; Pregnancy Complications, Cardiovascular; Propofol; Remifentanil

We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1- and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10(-5) M). The preferred substituents at the 1-position of the phthalazine were 4-hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthala zinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC(50) = 0.56 nM) with >1700-fold high selectivity over other PDE isozymes (PDE1-4). Compound 13 exhibited the most potent vasorelaxant action (EC(50) = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 +/- 3.1% when administered intravenously at 30 microg/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Antihypertensive Agents; Biological Availability; Blood Pressure; Coronary Vessels; Cyclic Nucleotide Phosphodiesterases, Type 5; Dinoprost; Hypertension, Pulmonary; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Phthalazines; Piperidines; Quinazolines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Swine; Vasodilator Agents

Endothelin (ET)-1 contributes to regulation of pulmonary vascular tone and structure in the normal ovine fetus and in models of perinatal pulmonary hypertension. The hemodynamic effects of ET-1 are due to activation of its receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, whereas the ET(B) receptor mediates vasodilation. In a lamb model of chronic intrauterine pulmonary hypertension, ET(B) receptor activity and gene expression are decreased. To determine whether prolonged ET(B) receptor blockade causes pulmonary hypertension, we studied the hemodynamic effects of selective ET(B) receptor blockade with BQ-788. Animals were treated with an infusion of either BQ-788 or vehicle for 7 days. Prolonged BQ-788 treatment increased pulmonary arterial pressure and pulmonary vascular resistance (P < 0.05). The pulmonary vasodilator response to sarafotoxin 6c, a selective ET(B) receptor agonist, was attenuated after 7 days of BQ-788 treatment, demonstrating pharmacological blockade of the ET(B) receptor. Animals treated with BQ-788 had greater right ventricular hypertrophy and muscularization of small pulmonary arteries (P < 0. 05). Lung ET-1 levels were threefold higher in the animals treated with BQ-788 (P < 0.05). We conclude that prolonged selective ET(B) receptor blockade causes severe pulmonary hypertension and pulmonary vascular remodeling in the late-gestation ovine fetus.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Carbon Dioxide; Endothelin Receptor Antagonists; Endothelin-1; Female; Gestational Age; Hemodynamics; Hypertension, Pulmonary; Oligopeptides; Oxygen; Piperidines; Pregnancy; Pulmonary Circulation; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reference Values; Sheep; Vascular Resistance

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 test whether E4021, a potent selective cyclic guanosine 3'-5'-monophosphate (cGMP) phosphodiesterase inhibitor, causes pulmonary vasodilation and whether it enhances the vasodilator action of inhaled nitric oxide (NO), we studied its effects on pulmonary vascular tone and inhaled NO-induced pulmonary vasodilation in isolated perfused rat lungs. Lungs were perfused at a constant flow rate with salt-Ficoll solution and ventilated with air plus 5% CO2. After equilibration, vasodilator responses to either E4021, inhaled NO, or both were evaluated under conditions of increased perfusion pressure induced by infusion of U46619. E4021 had no effect on the baseline perfusion pressure, whereas it caused dose-dependent pulmonary vasodilation when the vasomotor tone was increased by U46619. Inhaled 1, 5, and 20 ppm NO reduced the increased perfusion pressure by 60+/-5%, 83+/-3%, and 92+/-2%, respectively. Pretreatment with E4021 significantly potentiated the vasodilator effect of 1 ppm NO (from 53+/-6% to 71+/-2%; p < 0.05) but did not alter that of 5 ppm NO (from 77+/-3% to 78+/-4%; p > 0.05). In addition, pretreatment with E4021 significantly augmented the vasodilator response to sodium nitroprusside but not to isoproterenol. These results indicate that E4021 causes pulmonary vasodilation and potentiates the vasodilator effect of low concentrations of inhaled NO, probably through a cGMP-dependent mechanism in salt-solution perfused rat lungs. We conclude that E4021 may possibly be useful for the treatment of pulmonary hypertension, either alone or in combination with inhaled NO.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Inhalation; Animals; Bronchodilator Agents; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Synergism; Hypertension, Pulmonary; In Vitro Techniques; Isoproterenol; Lung; Male; Nitric Oxide; Nitroprusside; Perfusion; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperidines; Pulmonary Circulation; Quinazolines; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasodilation

We investigated the effects of long-term treatment with a selective phosphodiesterase 5 inhibitor E4010, 4-(3-chloro-4methoxybenzyl)amino-1-(4-hydroxypiperidino)-6-phth alazin ecarbonitrile monohydrochloride, on the survival rate of rats with pulmonary hypertension induced by monocrotaline (MCT). After an s.c. injection of 40 mg/kg MCT (day 0), male Wistar rats of 4 weeks of age were divided into four groups. Vehicle-treated rats (control, n = 8) and MCT-treated rats (n = 32) were fed a commercial diet. E4010-treated rats were given a commercial diet containing 0.01% (E4010 0.01%, n = 32) and 0.1% (E4010 0.1%, n = 32) of E4010, respectively. At day 23, all rats in the control group and 28.1% of those in the MCT group (P <.01 versus control) were alive. Although the survival rate of E4010 0.01%-treated rats was not improved (50%) compared with MCT, those at 0.1% showed a significant difference (84. 4%, P <.01 versus MCT). For MCT rats (n = 9), right ventricle weight and the levels of plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cGMP, and cyclic AMP were higher compared with control (n = 8). In E4010 0.1%-treated rats (n = 27), the right ventricular hypertrophy was suppressed, and the increase in plasma cGMP level was amplified compared with MCT without any effects on plasma ANP, BNP, and cyclic AMP levels. Accordingly, we consider that the mechanism of action of E4010 may be related to the decreased pulmonary arterial pressure caused by the augmentation of pulmonary arterial relaxation through an ANP and/or BNP-cGMP system. These results suggest that E4010 will be useful for the treatment of pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Atrial Natriuretic Factor; Body Weight; Calcium Signaling; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Hypertension, Pulmonary; Ligands; Male; Monocrotaline; Nitric Oxide; Nitriles; Organ Size; Phosphodiesterase Inhibitors; Piperidines; Rats; Rats, Wistar; Survival Rate

The purpose of this study was to determine whether E-4010, a newly synthesized potent and selective orally active phosphodiesterase (PDE) 5 inhibitor, would prevent the development of chronic hypoxia-induced pulmonary hypertension in rats. In conscious, pulmonary hypertensive rats, a single oral administration of E-4010 (1.0 mg/kg) caused an acute, long-lasting reduction in mean pulmonary arterial pressure (PAP), with no significant effects on systemic arterial pressure, cardiac output, and heart rate. In rats that received food containing 0.01 or 0.1% E-4010 during the 3-wk exposure to hypoxia, mean PAP was significantly decreased (mean PAP 24.0 +/- 0.9, 16.2 +/- 0.8, and 12.8 +/- 0.5 mmHg in rats treated with 0, 0.01, and 0.1% E-4010-containing food, respectively), whereas mean systemic arterial pressure was unchanged and cardiac output was slightly increased compared with chronically hypoxic control rats. Right ventricular hypertrophy, medial wall thickness in pulmonary arteries corresponding to the respiratory and terminal bronchioles, and the degree of muscularization of more distal arteries were less severe in E-4010-treated rats. Long-term treatment with E-4010 caused an increase in cGMP levels in lung tissue and plasma but not in aortic tissue and no significant change in cAMP levels in either lung, aorta, or plasma. These results suggest that long-term oral treatment with E-4010 reduced the increase in PAP, right ventricular hypertrophy, and pulmonary arterial remodeling induced by exposure to chronic hypoxia, probably through increasing cGMP levels in the pulmonary vascular smooth muscle.

Topics: Animals; Aorta; Cyclic GMP; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Nitriles; Phosphodiesterase Inhibitors; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors

To test whether a potent cGMP-specific phosphodiesterase inhibitor, E 4021, is a selective pulmonary vasodilator in pulmonary hypertension, we studied its acute hemodynamic effects in conscious, chronically hypoxic pulmonary hypertensive rats. Chronically hypoxic pulmonary hypertension was induced by keeping adult Sprague-Dawley rats in a hypobaric chamber for 3 weeks. Two days after catheterization. E 4021 was injected intravenously at doses of 3, 10, 30, 100, 300, and 1,000 micrograms/kg at 10-min intervals. E 4021 caused significant decreases in mean pulmonary arterial pressure of 11 +/- 5, 12 +/- 6, and 18 +/- 5% at doses of 100, 300, and 1,000 micrograms/kg, respectively. In contrast to its depressor effect on mean pulmonary arterial pressure, E 4021 decreased mean systemic arterial pressure significantly (by 9 +/- 2%) at a dose of 1,000 micrograms/kg only. Heart rate and cardiac output were unchanged after the administration of E 4021. Tissue cGMP-specific phosphodiesterase activity was markedly higher in lung than in aorta. These results indicate that E 4021 is a relatively selective pulmonary vasodilator in chronically hypoxic pulmonary hypertensive rats. We conclude E 4021 may be useful for the treatment of pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Blood Pressure; Chronic Disease; Hypertension, Pulmonary; Hypoxia; Lung; Male; Phosphodiesterase Inhibitors; Piperidines; Pulmonary Artery; Quinazolines; Rats; Rats, Sprague-Dawley; Vasodilator Agents

We evaluated the effects of oral administration of E4021 (100 mg/kg/day), a type V phosphodiesterase inhibitor, on immunoreactivities of endothelin-1, endothelin receptors, and nitric oxide synthases in pulmonary arteries in a rat model of pulmonary hypertension. Immunoreactivities of endothelin-1 and endothelial nitric oxide synthase were observed significantly less frequently, together with significant reduction of right ventricular overload and medial thickening in rats treated with E4021 than in the control with monocrotaline on day 28. The levels of plasma endothelin-1 and serum nitrite and nitrate were significantly lower in rats that received E4021 than in the control with monocrotaline. Oral administration of E4021 modulates endogenous immunoreactivities of endothelin-1 and endothelial nitric oxide synthase with the improvement or right ventricular overload and medial thickening.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Animals; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Endothelin-1; Hypertension, Pulmonary; Immunohistochemistry; Male; Monocrotaline; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperidines; Pulmonary Artery; Quinazolines; Rats; Rats, Wistar; Receptors, Endothelin

It is well known that lung embolism is associated with an increase in pulmonary vascular resistance. Since the mechanisms of pulmonary vascular reactions during embolism are still unclear, the aim of this study was to investigate the potential involvement of endothelin-1 (ET-1) and thromboxane A2 (TXA2) as mediators of the pulmonary artery pressure (PAP) increase after embolism using the selective ETA receptor antagonist LU135252 [1], the ETB receptor antagonist BQ788 [2], and the cyclooxygenase inhibitor diclofenac.. Prospective experimental study in rabbits.. Experimental laboratory in a university teaching hospital.. 36 adult rabbits of either sex.. The experiments were performed in 36 isolated and ventilated rabbit lungs which were perfused with a buffer solution containing 10% of autologous blood. Embolism was induced by the injection of 0.75 ml air into the pulmonary artery.. PAP and lung weight, reflecting edema formation, were continuously recorded. Perfusate samples were drawn intermittently to determine TXA2 and ET-1 concentrations. Air injection resulted in an immediate increase in PAP up to 22.8 +/- 1.4 mm Hg at 2.5 min (control, n = 6), which was parallelled by an enhanced generation of TXA2. No relevant edema formation occurred during the observation period. Pretreatment with the ETA receptor antagonist LU135252 significantly reduced the pressure reaction after air embolism (p < 0.001) whereas the ETB receptor antagonist BQ788 (n = 6) was without marked effects. The administration of diclofenac (n = 6) did not alter the PAP increase 2.5 min after embolism, but significantly reduced the pressure reaction during the further observation period (p < 0.001). The application of LU135252 and diclofenac together (n = 6) also significantly reduced the PAP increase from 2.5 min during the total observation period (p < 0.001).. The acute pressure reaction after air embolism is mainly mediated via ET-1 by an ETA receptor related mechanism. TXA2 seems to maintain this reaction for a longer time.

Topics: Analysis of Variance; Animals; Cyclooxygenase Inhibitors; Diclofenac; Disease Models, Animal; Embolism, Air; Endothelin Receptor Antagonists; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Hypertension, Pulmonary; In Vitro Techniques; Oligopeptides; Perfusion; Phenylpropionates; Piperidines; Pulmonary Artery; Pulmonary Embolism; Pyrimidines; Rabbits; Radioimmunoassay; Thromboxane A2; Time Factors; Vascular Resistance

While it is known that nitric oxide (NO) is an important modulator of tone in the hypertensive pulmonary circulation, the roles of cyclic 3'-5'-guanosine monophosphate (cGMP) and cGMP-phosphodiesterase (PDE) are uncertain. We found that isolated lung perfusate levels of cGMP were over ninefold elevated in hypertensive vs. normotensive control rats. 98-100% of lung cGMP hydrolytic activity was cGMP-specific PDE5, with no significant decrease in PDE activity in hypertensive lungs, suggesting that the elevation in cGMP was due to accelerated production rather than reduced degradation. In pulmonary hypertensive rat lungs, in vitro, cGMP-PDE inhibition by E4021[1-(6-chloro-4-(3,4-methylbenzyl) amino-quinazolin-2-yl)piperdine-4-carboxylate], increased perfusate cGMP threefold, reduced hypoxic vasoconstriction by 58 +/- 2%, and reduced baseline pulmonary artery pressure by 37 +/- 5%. In conscious, pulmonary hypertensive rats, intravenous administration of E4021 reduced hypoxic vasoconstriction by 68 +/- 8%, pulmonary artery pressure by 12.6 +/- 3.7% and total pulmonary resistance by 13.1 +/- 6.4%, with no significant effect on cardiac output, systemic pressure, and resistance. Comparison of E4021 to inhaled nitric oxide demonstrated that cGMP-PDE inhibition was as selective and as effective as inhaled NO.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Calcium Channel Blockers; Cyclic GMP; Diltiazem; Hemodynamics; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Lung; Male; Nitric Oxide; Perfusion; Phosphodiesterase Inhibitors; Piperidines; Pulmonary Circulation; Purinones; Quinazolines; Rats; Rats, Sprague-Dawley; Vasodilation

We evaluated the effects of oral administration of 10, 30, and 100 mg/kg/day of E4021, a type V phosphodiesterase inhibitor, on development of monocrotaline-induced right ventricular overload and medial thickening of pulmonary arteries. Right ventricular systolic pressure, mass ratio of right ventricle to left ventricle, right ventricular wall thickness, right ventricular myocardial fiber diameter, medial thickness, and smooth muscle area in pulmonary arteries were significantly less in rats that received E4021 30 and 100 mg/kg/day than in the control with monocrotaline on day 28. Myofiber diameter, medial thickness, and smooth muscle area were significantly lower in rats treated with E4021 100 mg/kg/day than in those of E4021 30 mg/kg/day. E4021 100 mg/kg/day protected development of right ventricular overload and medial thickening of pulmonary arteries.

Topics: Animals; Disease Models, Animal; Heart Ventricles; Hypertension, Pulmonary; Male; Monocrotaline; Organ Size; Phosphodiesterase Inhibitors; Piperidines; Pulmonary Artery; Quinazolines; Rats; Rats, Wistar

We investigated the endothelin (ET) receptor subtypes that mediate vasoconstriction in human and rat pulmonary resistance arteries and the effect of pulmonary hypertension on endothelin (ET)-induced contractile responses in rat vessels. In human vessels, sarafotoxin S6c (SXS6c) was more potent than ET-1, but its maximal contractile response was only 20-30% of that to ET-1. Responses to ET-1 were resistant to the ETA antagonist FR 139317, and another, BMS 182874, inhibited responses only to high concentrations of ET-1. In all rat vessels, ET-1, ET-3, and the ETB receptor agonist SXS6c showed the following order of potency: SXS6c = ET-3 > ET-1, and responses to SXS6c were inhibited by the ETB receptor antagonist BQ 788 (1 microM). Maximal responses to ET-1 were greatest in chronic hypoxic (CH) pulmonary-hypertensive rats. In control rats, responses to ET-1 were unaffected by FR 139317 (1 microM) and were potentiated by BMS 182874 (1 microM) and by the mixed ETA/ETB receptor antagonist bosentan (1 microM). A combination of BMS 182874 (10 microM) and the ETB receptor antagonist BQ 788 (1 microM) had no effect on responses to ET-1. In the CH rats, responses to ET-1 were unaffected by FR 139317, BMS 182874, or bosentan. The results suggest the presence of an inhibitory ETA receptor in these vessels that may inhibit ET-1 activation of ETB receptors, and also suggest that the influence of this inhibitory ETA receptor is reduced in CH rat vessels. The results indicate a role for ETB receptors in ET-1-mediated vasoconstriction in both human and rat pulmonary resistance arteries.

Topics: Animals; Endothelins; Humans; Hypertension, Pulmonary; In Vitro Techniques; Oligopeptides; Piperidines; Pulmonary Artery; Rats; Rats, Wistar; Receptor, Endothelin B; Receptors, Endothelin; Vascular Resistance; Vasoconstriction; Viper Venoms

From 0.5 to 3 days after subcutaneous injection of monocrotaline (MCT) 60 mg/kg, prominent accumulation of platelets in the pulmonary capillaries accompanied with significant elevation of the plasma serotonin level was observed. To clarify the role of serotonin, the in vivo and in vitro effects of the selective 5-HT2 receptor antagonist, DV-7028, on MCT-induced pulmonary hypertension were studied. Oral administration of DV-7028 (10 mg/kg, twice daily) significantly suppressed the MCT-induced elevation of pulmonary arterial pressure, right ventricular hypertrophy and medial thickening of the muscular-type pulmonary arteries which occurred 23 days after MCT administration. The plasma level achieved by oral administration of 10 mg/kg DV-7028 was more than 10(-7) M. The hyperreactivity to serotonin in isolated pulmonary artery segments from MCT-treated rats was significantly reduced by DV-7028 (10(-7) M). The present study suggests that serotonin, released from platelets and accumulated in pulmonary capillaries, contributes to the initiation and/or progression of pulmonary hypertension in MCT-treated rats.

Topics: Animals; Blood Platelets; Disease Models, Animal; Hypertension, Pulmonary; In Vitro Techniques; Lung; Male; Monocrotaline; Piperidines; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists; Triazines; Vasoconstriction

To determine if NIP-121, a new antihypertensive agent with K+ channel-opening activity, would be an effective vasodilator in pulmonary hypertension, we studied its acute hemodynamic effects under normoxic conditions in conscious chronically hypoxic pulmonary hypertensive rats and in control pulmonary normotensive rats. In contrast to no pulmonary vasodilation by NIP-121 in control rats, the K+ channel activator (10-100 mg/kg i.v.) decreased both mean pulmonary arterial pressure (from 42 +/- 2 to 33 +/- 2 mmHg; P < 0.05) and total pulmonary resistance (from 278 +/- 30 to 213 +/- 32 mmHg.l-1 x min; P < 0.05) in hypertensive rats. NIP-121 produced similar dose-related decreases in mean systemic arterial pressure and total systemic resistance in both groups of rats. Both the pulmonary and the systemic vasodilations to NIP-121 were inhibited by pretreatment with the blocker of ATP-sensitive K+ channels, glibenclamide (20 mg/kg), but not with the inhibitor of endothelium-derived relaxing factor synthesis, nitro-L-arginine (10 mg/kg). The L-type voltage-gated Ca2+ channel blocker, nifedipine (10-1,000 mg/kg i.v.), failed to cause pulmonary vasodilation in normoxic hypertensive rats, although there was dose-related systemic vasodilation. These results show that in contrast to the Ca2+ channel blocker, nifedipine, the K+ channel activator, NIP-121, is a potent vasodilator of chronic hypoxia-induced pulmonary hypertension in the rat. The mechanism of its hypotensive action in the hypertensive pulmonary vasculature might be more than simply membrane hyperpolarization and indirect inhibition of the L-type voltage-gated Ca2+ channel.

Topics: Altitude; Animals; Chronic Disease; Glyburide; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Male; Nifedipine; Oxadiazoles; Piperidines; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasodilation

The aim was to clarify the role of serotonin (5-hydroxytryptamine, 5-HT) in monocrotaline induced pulmonary hypertension.. Plasma 5-HT levels, pulmonary capillary platelet count, and vascular responsiveness to 5-HT were evaluated in the model. The effects of the selective 5-HT2 receptor antagonist, DV-7028, on the development of pulmonary hypertension were also investigated.. Plasma 5-HT was raised 12 h to 3 d after monocrotaline administration (60 mg.kg-1), coinciding with accumulation of platelets in the pulmonary circulation. Isolated pulmonary arteries showed hyperreactivity to 5-HT at 14 and 21 d after monocrotaline. Administration of DV-7028 (20 mg.kg-1 x d-1) attenuated the increase in pulmonary arterial pressure, right ventricular hypertrophy, and medial thickening of the pulmonary arteries.. The present study suggests that 5-HT released from platelets contributes to the initiation and progression of monocrotaline induced pulmonary hypertension.

Topics: Animals; Blood Platelets; Culture Techniques; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Piperidines; Platelet Count; Pulmonary Artery; Rats; Serotonin; Serotonin Antagonists; Triazines

We report a case of vagal hypertonia syndrome in a newborn infant, developed after surgical repair of an aortic coarctation combined with banding of the pulmonary artery trunk. The parasympathetic activity had adverse repercussions on haemodynamics. The diagnosis was confirmed by prolonged asystole on the oculocardiac reflex and by concomitant arrhythmia and disorders of conduction demonstrated by Holter recordings. To our knowledge, no other case of vagal hypertonia associated with a congenital cardiopathy has yet been reported. Infants with this syndrome are at a high risk of sudden death. Treatment with vagolytic drugs is of questionable value, and prolonged supervision of the patient is mandatory.

Topics: Bradycardia; Cranial Nerve Diseases; Follow-Up Studies; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Parasympatholytics; Piperidines; Sudden Infant Death; Syndrome; Vagus Nerve

Pulmonary embolism may cause pulmonary hypertension by mechanical obstruction, which might be amplified by vasoconstriction induced by serotonin released from the emboli. The purpose of the present study was to examine whether 5-HT2-receptors are involved in serotonin-induced pulmonary hypertension. Ketanserin was used as 5-HT2-serotonergic antagonist. In nine anesthetized mongrel dogs, the effect of serotonin infusions (10, 50, 100 micrograms/kg . min) on mean pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), cardiac output (CO), stroke volume (SV), cardiac contractility (dP/dtmax), heart rate (HR), and mean aortic pressure (PAO) was studied with and without treatment by ketanserin (20 and 100 micrograms/kg). Serotonin caused dose-dependent increase in PAP, PVR, CO, SV, and dP/dtmax. A dose of 20 micrograms/kg ketanserin did not affect hemodynamics significantly, whereas 100 micrograms/kg of the compound significantly reduced PAO, TPR, and left ventricular dP/dtmax. The serotonin-induced increases in PAP, PVR, dP/dtmax, CO, and SV were reduced significantly by 100 micrograms/kg ketanserin; the lower dose of ketanserin had only a slight blocking effect. Ketanserin blocks serotonin-induced pulmonary vasoconstriction partly, but it seems also to antagonize the positive inotropic effect of the monoamine.

Topics: Animals; Dogs; Hypertension, Pulmonary; Ketanserin; Piperidines; Pulmonary Artery; Pulmonary Embolism; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Vascular Resistance

A persistent pulmonary artery hypertension, increased airways resistance, increased vascular permeability to protein, and hypoxia are characteristic of sepsis-induced ARDS in humans and are present in the late phase injury response seen in sheep after endotoxin. Our purpose was to determine the role of serotonin, 5-HT, in the steady-state pulmonary hypertension and decreased arterial oxygen tension seen beginning approximately 3 h after Escherichia coli endotoxin injury (2 micrograms/kg) in the adult sheep. Plasma 5-HT levels remained constant, whereas lung lymph values increased from a baseline of 60 +/- 40 to 180 +/- 70 and 270 +/- 90 ng/ml at 1-h and at 3- to 5-h periods, respectively, after endotoxin. Platelet count decreased significantly only at the 3-h time period. Ketanserin, a 5-HT antagonist, was infused (0.15 mg/kg/h) in 7 sheep during endotoxin injury. The degree of early pulmonary hypertension and hypoxia was not affected by ketanserin. Mean values for pulmonary artery pressure and arterial oxygen tension were 40 +/- 8 mmHg and 70 +/- 8 torr for endotoxin alone and 38 +/- 7 mmHg and 72 +/- 7 torr for the ketanserin group. Steady-state, protein-rich pulmonary perfusion was also not altered, being increased 3-fold in both groups. Pulmonary hypertension and hypoxia were significantly attenuated, however, at the 3- to 5-h period with ketanserin, compared with endotoxin alone, the pulmonary artery pressure decreasing from 29 +/- 5 to 22 +/- 4 mmHg and the PaO2 increasing from 75 +/- 4 to 83 +/- 5 torr.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Endotoxins; Escherichia coli; Hypertension, Pulmonary; Hypoxia; Ketanserin; Lung; Lymph; Oxygen; Piperidines; Platelet Count; Pulmonary Artery; Serotonin; Serotonin Antagonists; Sheep

The authors measured changes in pulmonary and systemic haemodynamics in seven patients following oxygen inhalation, nifedipine and Ketanserin administration. A significant decrease in mean pulmonary artery pressure, cardiac index and heart rate could be observed following 30-min oxygen inhalation. No significant changes were found in pulmonary haemodynamics 1 hour after sublingual administration of 20 mg Corinfar (nifedipine). Long-term treatment (6 months) with Corinfar (30-60 mg per day) was not followed by a significant change in mean pulmonary artery pressure. However, in 3 patients a decrease in mean pulmonary artery pressure (6-11 mmHg) could be observed. Ketanserin (10 mg intravenously) did not significantly change the mean pulmonary artery pressure in patients with hypoxic pulmonary hypertension.

Topics: Adult; Carbon Dioxide; Cardiac Output; Female; Heart Rate; Humans; Hypertension, Pulmonary; Hypoxia; Ketanserin; Lung Diseases, Obstructive; Lung Volume Measurements; Male; Middle Aged; Nifedipine; Oxygen; Oxygen Inhalation Therapy; Piperidines; Pulmonary Wedge Pressure; Serotonin Antagonists

Pulmonary hypertension secondary to sepsis is due, in part, to release of serotonin from platelets. This study examines the effects of ketanserin, a new, highly specific serotonin antagonist, on platelet aggregation and the cardiovascular changes associated with bacterial endotoxemia in dogs. Ketanserin markedly inhibits in vitro platelet aggregation induced by mixing serotonin and epinephrine. When ketanserin is administered to animals before endotoxin infusion, cardiac output is greater and mean pulmonary artery pressure (MPAP), pulmonary and systemic vascular resistance (PVR and SVR) and arteriovenous oxygen content difference [C(a-v)O2] are less than in animals not receiving ketanserin. Similar results for PVR, SVR, and C(a-v)O2 are obtained when ketanserin is administered after endotoxin infusion. The data indicate that ketanserin inhibits serotonin-induced platelet aggregation and modifies many cardiovascular changes associated with bacterial endotoxemia.

Topics: Animals; Dogs; Epinephrine; Hemodynamics; Hypertension, Pulmonary; Ketanserin; Male; Oxygen; Piperidines; Platelet Aggregation; Serotonin; Serotonin Antagonists; Shock, Septic

Topics: Adult; Aged; Antitussive Agents; Bronchiectasis; Bronchitis; Bronchopneumonia; Cough; Female; Humans; Hypertension, Pulmonary; Lung Neoplasms; Male; Middle Aged; Piperidines; Tracheitis

Topics: Aminophylline; Analgesics; Animals; Atropine; Blood Pressure; Bronchial Spasm; Epinephrine; Fibrinolysin; Histamine H1 Antagonists; Humans; Hypertension, Pulmonary; Injections, Intravenous; Iproniazid; Methods; Morphine; Muscles; Nitroglycerin; Papaverine; Phenothiazines; Piperidines; Pulmonary Circulation; Rats; Reserpine; Serotonin Antagonists; Vascular Resistance; Vasodilator Agents

Topics: Adolescent; Adult; Blood Pressure; Child; Female; Heart Defects, Congenital; Heart Valve Diseases; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen Consumption; Piperidines; Pyrazoles; Vascular Resistance

Topics: Adult; Animals; Dogs; Electrocardiography; Humans; Hypertension, Pulmonary; Piperidines; Pulmonary Heart Disease; Pyrazoles; Tremor

Topics: Adult; Aged; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperidines; Pyrazoles

Topics: Chronic Disease; Digitalis; Digitalis Glycosides; Humans; Hypertension, Pulmonary; Piperidines; Plant Extracts; Promethazine; Pulmonary Heart Disease