endothelin-1 and Edema

Endothelin plays an important role in the pathogenesis of atherosclerosis. The aim of the study was to evaluate the safety and hemodynamic and metabolic responses to 6 months treatment with atrasentan, the selective endothelin-A receptor antagonist. Seventy-two patients with multiple cardiovascular risk factors and nonobstructive coronary artery disease on coronary angiogram were randomly assigned in a double-blind manner to atrasentan or placebo. Mean aortic blood pressure decreased from 92+/-10 to 80+/-10 mm Hg (P<0.001) in the atrasentan group and did not change in the placebo group (93+/-10 and 92+/-11 mm Hg; P=0.84). The difference between the groups was significant (P<0.001). No effect on heart rate was observed. In a subgroup of patients not treated with angiotensin-converting enzyme inhibitor, creatinine level decreased in the atrasentan versus the placebo group (P=0.011). Fasting glucose (P=0.026), glycosylated hemoglobin level (P=0.041), triglyceride l (P=0.013), lipoprotein-A (P=0.046), and uric acid levels (P=0.048) decreased significantly in the atrasentan group compared with the placebo group. No progression of angiographic coronary disease was observed. The most common adverse effects with atrasentan were nasal stuffiness, headache, and edema. In conclusion, 6 months of treatment with atrasentan results in a reduction of blood pressure and improvement in glucose and lipid metabolism. These findings suggest the beneficial role of atrasentan in the treatment of hypertension and metabolic syndrome.

Topics: Adult; Antihypertensive Agents; Atrasentan; Blood Glucose; Blood Pressure; Coronary Artery Disease; Edema; Endothelin A Receptor Antagonists; Endothelin-1; Female; Follow-Up Studies; Humans; Hypertension; Kidney; Lipid Metabolism; Male; Metabolic Syndrome; Middle Aged; Pyrrolidines; Receptor, Endothelin A; Risk Factors; Treatment Outcome

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists can cause peripheral edema in susceptible individuals. To investigate the mechanistic basis underlying this adverse event, we performed a candidate gene analysis of patients enrolled in clinical trials of muraglitazar, an investigational PPARalpha/gamma dual agonist, and developed a cell culture-based gene expression assay and nonhuman primate model of edema to study the edemagenic properties of PPARgamma agonists.. A total of 213 single nucleotide polymorphisms (SNPs) in 63 genes were genotyped in 730 participants. Chi-square and logistic regression analyses were used to test for association with edema. Transcriptional responses to PPARgamma agonists were evaluated in Calu-6 cells using quantitative real-time PCR. Male Cynomolgus monkeys were treated with PPAR agonists and were evaluated for edema using MRI.. SNPs in renin (rs2368564) and endothelin-1 (rs5370) were associated with reduced risk of edema (P=0.003 and P=0.028, respectively) and an SNP in beta1 adrenergic receptor (rs1801253) was associated with increased susceptibility to edema (P=0.034). Gene expression studies revealed that renin and endothelin-1 were regulated by PPARgamma in Calu-6 cells. A survey of 10 PPARgamma agonists further revealed that a compound's in vitro potency was correlated with its edemagenic potential leading to the prediction that one of three previously uncharacterized PPARgamma agonists would cause less edema. This prediction was validated in a nonhuman primate model of PPARgamma agonist-induced edema.. Our results implicate a key role for renin and endothelin-1 in the edema caused by PPARgamma agonists and demonstrate how knowledge gained from pharmacogenetic studies can be applied in drug discovery.

Topics: Animals; Diabetes Mellitus, Type 2; Edema; Endothelin-1; Female; Gene Expression Regulation; Glycine; Humans; Macaca fascicularis; Male; Oxazoles; Pharmacogenetics; Polymorphism, Single Nucleotide; PPAR gamma; Regression Analysis; Renin

The aim of this study was to assess whether apocynin, an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase blocker, influences lipid peroxidation TBARS, hydrogen peroxide (H2O2) content, protein level, heart edema, tumor necrosis factor α (TNF-α) concentration or the glutathione redox system in heart homogenates obtained from endothelin 1 (ET-1)-induced oxidative stress rats.. Experiments were carried out on adult male Wistar-Kyoto rats. The animals were divided into 4 groups: Group I: saline-treated control; Group II: saline followed by ET-1 (3 μg/kg b.w., iv); Group III: apocynin (5 mg/kg b.w., iv) administered half an hour before saline; Group IV: apocynin (5 mg/kg b.w., iv) administered half an hour before ET-1 (3 μg/kg b.w., iv).. Injection of ET-1 alone showed a significant (p < 0.001) increase in thiobarbituric acid reactive substances (TBARS) and the hydrogen peroxide level (p < 0.01) vs. control, as well as a decrease (p < 0.001) in the GSH level. Apocynin significantly decreased TBARS (p < 0.001) and H2O2 (p < 0.05) level (vs. control) as well as improved protein level (p < 0.001) in the heart. Apocynin also prevented ET-1-induced heart edema (p < 0.05). The presence of ET-1 increased the concentration of TNF-α (p < 0.05) while apocynin decreased it (p < 0.05). Our results indicate that ET-1 may induce oxidative stress in heart tissue by reducing the GSH/GSSG ratio, stimulating lipid peroxidation and increasing TNF-α concentration. Apocynin diminished these measures of oxidative stress and TNF-α.. ET-1-induced formation of ROS in the heart is at least partially regulated via NADPH oxidase.

Topics: Acetophenones; Animals; Antioxidants; Edema; Endothelin-1; Glutathione; Lipid Peroxidation; Male; Myocardium; NADPH Oxidases; Oxidative Stress; Rats; Tumor Necrosis Factor-alpha

Independent studies in experimental models of Trypanosoma cruzi appointed different roles for endothelin-1 (ET-1) and bradykinin (BK) in the immunopathogenesis of Chagas disease. Here, we addressed the hypothesis that pathogenic outcome is influenced by functional interplay between endothelin receptors (ET(A)R and ET(B)R) and bradykinin B(2) receptors (B(2)R).. Intravital microscopy was used to determine whether ETR/B(2)R drives the accumulation of rhodamine-labelled leucocytes in the hamster cheek pouch (HCP). Inflammatory oedema was measured in the infected BALB/c paw of mice. Parasite invasion was assessed in CHO over-expressing ETRs, mouse cardiomyocytes, endothelium (human umbilical vein endothelial cells) or smooth muscle cells (HSMCs), in the presence/absence of antagonists of B(2)R (HOE-140), ET(A)R (BQ-123) and ET(B)R (BQ-788), specific IgG antibodies to each GPCRs; cholesterol or calcium-depleting drugs. RNA interference (ET(A)R or ET(B)R genes) in parasite infectivity was investigated in HSMCs.. BQ-123, BQ-788 and HOE-140 reduced leucocyte accumulation in HCP topically exposed to trypomastigotes and blocked inflammatory oedema in infected mice. Acting synergistically, ET(A)R and ET(B)R antagonists reduced parasite invasion of HSMCs to the same extent as HOE-140. Exogenous ET-1 potentiated T. cruzi uptake by HSMCs via ETRs/B(2)R, whereas RNA interference of ET(A)R and ET(B)R genes conversely reduced parasite internalization. ETRs/B(2)R-driven infection in HSMCs was reduced in HSMC pretreated with methyl-β-cyclodextrin, a cholesterol-depleting drug, or in thapsigargin- or verapamil-treated target cells.. Our findings suggest that plasma leakage, a neutrophil-driven inflammatory response evoked by trypomastigotes via the kinin/endothelin pathways, may offer a window of opportunity for enhanced parasite invasion of cardiovascular cells.

Topics: Animals; Bradykinin B2 Receptor Antagonists; Calcium; Cells, Cultured; Chagas Disease; CHO Cells; Cricetinae; Edema; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Kinins; Mice; Mice, Inbred BALB C; Myocytes, Cardiac; Myocytes, Smooth Muscle; Receptor, Bradykinin B2; Receptor, Endothelin A; Receptor, Endothelin B; Trypanosoma cruzi

Splice products of the Kiss1 protein (kisspeptins) have been shown to be involved in a diverse range of functions, including puberty, metastasis and vasoconstriction in large human arteries. Circulating Kisspeptin-10 (Kp-10) plasma levels are low in normal individuals but are elevated during various disease states as well as pregnancy. Here, we investigated the potential of Kp-10, the shortest biologically active kisspeptin, to influence microvascular effects, concentrating on the cutaneous vasculature. Kp-10 caused a dose-dependent increase in oedema formation (0.3-10 nmol/injection site), assessed by Evans Blue albumin dye extravasation, in the dorsal skin of CD1 mice. Oedema formation was shown to be inhibited by the histamine H(1) receptor antagonist mepyramine. The response was characterised by a ring of pallor at the injection site in keeping with vasoconstrictor activity. Therefore, changes in dorsal skin blood flow were assessed by clearance of intradermally injected (99m)technetium. Kp-10 was found to significantly reduce clearance, in keeping with decreased blood flow and providing further evidence for vasoconstrictor activity. The decreased clearance was partially inhibited by co-treatment with the cyclo-oxygenase inhibitor indomethacin. Finally evidence for the kisspeptin receptor gene (Kiss1R), but not the kisspeptin peptide gene (Kiss1), mRNA expression was observed in heart, aorta and kidney samples from normal and angiotensin II induced hypertensive mice, with similar mRNA levels observed in each. We have evidence for two peripheral vasoactive roles for kisspeptin-10. Firstly, plasma extravasation indicative of ability to induce oedema formation and secondly decreased peripheral blood flow, indicating microvascular constriction. Thus Kp-10 has vasoactive properties in the peripheral microvasculature.

Topics: Animals; Blood Circulation; Dose-Response Relationship, Drug; Edema; Endothelin-1; Female; Gene Expression Regulation; Histamine Antagonists; Humans; Indomethacin; Kisspeptins; Male; Mice; Microvessels; Organ Specificity; Pallor; Receptors, Calcitonin Gene-Related Peptide; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; RNA, Messenger; Substance P; Vasoconstriction; Vasoconstrictor Agents

Severe acute pancreatitis (SAP) is a commonly seen acute abdominal syndrome characterized by sudden onset, rapid progression and high mortality rate. The damage in peripheral organs may be more severe than that in the pancreas, and can even lead to multiple organ dysfunction. It is critical to recognize early pathological changes in multiple organs. This study aimed to assess the early pathological features of damaged organs in a rat model of SAP.. Thirty clean grade healthy male Sprague-Dawley rats weighing 250-300 g were randomly divided into a model control group (n=15) and a sham-operated group (n=15). The SAP rat model was induced by sodium taurocholate. Samples of blood and from multiple organs were collected 3 hours after operation. We assessed the levels of IL-6, TNF-alpha, PLA2, NO, ET-1, MDA, amylases and endotoxin in blood and observed the early pathological changes in multiple damaged organs.. Levels of IL-6, TNF-alpha, PLA2, NO, ET-1 and MDA in serum and of amylase and endotoxin in plasma of the model control group rats were significantly higher than those of the sham-operated group (P<0.01). Different degrees of pathological change were observed in multiple damaged organs.. Multiple organ injury may occur at the early stage of SAP in rats.

Topics: Acute Disease; Animals; Cytokines; Disease Models, Animal; Edema; Endothelin-1; Hemorrhage; Kidney; Liver; Lung; Male; Malondialdehyde; Necrosis; Nitric Oxide; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley

Lipoxin A(4) (LXA(4)) is a lipid mediator involved in the resolution of inflammation. Increased levels of LXA(4) in synovial fluid and enhanced expression of the formyl peptide receptor 2/lipoxin A(4) receptor (FPR2/ALX) in the synovial tissues of rheumatoid arthritis patients have been reported. Endothelins (ETs) play a pivotal pro-inflammatory role in acute articular inflammatory responses. Here, we evaluated the anti-inflammatory role of LXA(4), during the acute phase of zymosan-induced arthritis, focusing on the modulation of ET-1 expression and its effects.. The anti-inflammatory effects of LXA(4), BML-111 (agonist of FPR2/ALX receptors) and acetylsalicylic acid (ASA) pre- and post-treatments were investigated in a murine model of zymosan-induced arthritis. Articular inflammation was assessed by examining knee joint oedema; neutrophil accumulation in synovial cavities; and levels of prepro-ET-1 mRNA, leukotriene (LT)B(4), tumour necrosis factor (TNF)-α and the chemokine KC/CXCL1, after stimulation. The direct effect of LXA(4) on ET-1-induced neutrophil activation and chemotaxis was evaluated by shape change and Boyden chamber assays respectively.. LXA(4), BML-111 and ASA administered as pre- or post-treatment inhibited oedema and neutrophil influx induced by zymosan stimulation. Zymosan-induced preproET-1 mRNA, KC/CXCL1, LTB(4) and TNF-α levels were also decreased after LXA(4) pretreatment. In vitro, ET-1-induced neutrophil chemotaxis was inhibited by LXA(4) pretreatment. LXA(4) treatment also inhibited ET-1-induced oedema formation and neutrophil influx into mouse knee joints.. LXA(4) exerted anti-inflammatory effects on articular inflammation through a mechanism that involved the inhibition of ET-1 expression and its effects.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Aspirin; Edema; Endothelin-1; Gene Expression Regulation; Heptanoic Acids; Knee Joint; Lipoxins; Male; Mice; Mice, Inbred C57BL; Neutrophils; RNA, Messenger; Zymosan

The complex regional pain syndrome (CRPS) is characterized by enhanced neurogenic inflammation, mediated by neuropeptides. Neutral endopeptidase (NEP) is a key enzyme in neuropeptide catabolism. We used NEP knock out (ko) mice to investigate whether NEP deficiency leads to increased pain behavior and signs of neurogenic inflammation after soft tissue trauma with and without nerve injury. After chronic constriction injury (CCI) of the right sciatic nerve, NEP ko mice were more sensitive to heat, to mechanical stimuli, and to cold than wild type mice. Tissue injury without nerve injury produced no differences between genotypes. After CCI, NEP ko mice showed increased hind paw edema but lower skin temperatures than wild type mice. Substance P (SP) and endothelin 1 (ET 1) determined by enzyme immuno assay (EIA) were increased in sciatic nerves from NEP ko mice after CCI. Tissue CGRP content did not differ between the genotypes. The results provide evidence that pain behavior and neurogenic inflammation are enhanced in NEP ko mice after nerve injury. These findings resemble human 'cold' CRPS and suggest that ET 1 plays an important role in the pathogenesis of CRPS with nerve injury.

Topics: Animals; Cold Temperature; Edema; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Hindlimb; Hot Temperature; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Neprilysin; Neurogenic Inflammation; Pain; Pain Measurement; Physical Stimulation; Sciatic Nerve; Skin; Skin Temperature; Substance P

Acute renal failure (ARF) occurs in some adult patients with minimal change nephropathy (MCN). To investigate clinical and pathological factors associated with developing ARF, we compared clinical features and kidney pathological characteristics of endothelin 1 (ET-1) expression in patients with adult-onset MCN with and without ARF.. The patient population consisted of 53 patients consecutively diagnosed with adult-onset MCN during a 10-year period. Based on creatinine clearance, 25 patients were assigned to the ARF group and 28 patients were assigned to the non-ARF group.. Clinical data show that the ARF group had a higher blood pressure, higher serum cholesterol level, and lower serum albumin level than the non-ARF group. Pathological data showed more severe foot-process effacement, interstitial edema, and flattened tubular epithelium in the same group. Greater ET-1 expression was detected in vessels, tubules, and glomeruli of the ARF compared with non-ARF group. The ARF group experienced a lower steroid response rate. However, there was no significant difference in stability of remission to steroid treatment in patients who achieved a remission.. ARF associated with enhanced kidney ET-1 expression is a reversible complication of MCN that occurs frequently in patients with apparently expanded extracellular fluid. Presumptively, ARF may develop as an amplification of the underlying pathogenesis of MCN involved in enhanced ET-1 expression, which may be superimposed by a transient episode of circulatory insufficiency during diuretic treatment.

Topics: Acute Kidney Injury; Adult; Age of Onset; Aged; Blood Pressure; Cholesterol; Cyclophosphamide; Diuretics; Edema; Endothelin-1; Epithelial Cells; Extracellular Fluid; Female; Humans; Kidney Glomerulus; Kidney Tubules; Male; Middle Aged; Nephrosis, Lipoid; Nephrotic Syndrome; Prednisolone; Remission Induction; Renal Circulation; Serum Albumin; Vasoconstriction

Topics: Adenosine; Allopurinol; Amylases; Animals; Disaccharides; Edema; Electrolytes; Endothelin-1; Female; Glutamates; Glutathione; Histidine; Insulin; Lipase; Mannitol; Organ Preservation; Organ Preservation Solutions; Oxygen Consumption; Pancreas; Pancreas Transplantation; Raffinose; Swine; Swine, Miniature

Endothelin-1 has been shown to reduce pancreatic blood flow and cause focal acinar cell necrosis similar to those seen in acute pancreatitis (AP), whereas therapy with endothelin receptor antagonists enhanced pancreatic capillary blood flow (PCBF) and decreased mortality rates. The current study evaluated the role of endothelin in the development of severe AP. Trypsinogen activation peptides, acinar cell necrosis, and PCBF were used as local indicators of disease severity, fluid sequestration, cardiorespiratory and renal parameters, and colonic capillary blood flow as systemic disease indicators. The following groups of animals were examined: 1) rats with mild edematous AP and 2) severe necrotizing AP treated with and without endothelin, 3) transgenic rats overexpressing endothelin with severe AP, and 4) rats with severe AP prophylactically treated with endothelin receptor antagonists. The following observations were made: endothelin superimposed on mild AP caused hemoconcentration, a decrease in PCBF, and necrosis and ascites not seen in this model without endothelin exposure. Endothelin superimposed on severe AP had no significant effects. After induction of severe AP, less PCBF and more acinar cell necrosis were observed in transgenic rats than in their normal littermates. Prophylactic endothelin receptor antagonists improved local (acinar necrosis, PCBF) and systemic parameters (ascites, urine production, colonic capillary blood flow) of disease severity in animals with severe AP. These observations underscore the role of endothelin as a mediator of disease severity in AP and suggest that endothelin receptor blockade may become a promising therapeutic tool in this disease.

Topics: Acute Disease; Animals; Animals, Genetically Modified; Blood Pressure; Capillaries; Ceruletide; Edema; Endothelin-1; Gene Expression; Hematocrit; Male; Pancreas; Pancreatitis; Pancreatitis, Acute Necrotizing; Rats; Rats, Sprague-Dawley

Endothelin-1 causes ET(A) receptor-mediated enhancement of capsaicin-induced nociception in mice. We have assessed if this hyperalgesic effect of endothelin-1 is also accompanied by other pro-inflammatory effects, namely nociception and oedema, and characterized the endothelin ET receptors involved. Intraplantar (i. pl.) hind-paw injection of endothelin-1 (0.3 - 30 pmol) induced graded nociceptive responses (accumulated licking time: vehicle, 20. 5+/-3.3 s; endothelin-1 at 30 pmol, 78.1+/-9.8 s), largely confined to the first 15 min. Endothelin-1 (1 - 10 pmol) potentiated ipsilateral capsaicin-induced (0.1 microgram, i.pl.; at 30 min) nociception (vehicle, 40.2+/-2.6 s; endothelin-1 at 10 pmol, 98.4+/-5.8 s, but 30 pmol was inactive), and caused oedema (increase in paw weight 5 min after capsaicin: vehicle, 46.3+/-2.3 mg; endothelin-1 at 30 pmol, 100.3+/-6.1 mg). Selective ET(B) receptor agonists sarafotoxin S6c (up to 30 pmol) and IRL 1620 (up to 100 pmol) were inactive, whereas endothelin-3 (up to 30 pmol) induced only modest oedema. ET(A) receptor antagonists BQ-123 (1 nmol, i.pl. ) or A-127722-5 (6 micromol kg(-1), i.v.) prevented all effects of endothelin-1 (10 pmol), but the ET(B) receptor antagonist BQ-788 (1 or 10 nmol, i.pl.) was ineffective. BQ-788 (10 nmol, i.pl.) unveiled hyperalgesic effects of 30 pmol endothelin-1 and endothelin-3. Sarafotoxin S6c (30 pmol, i.pl.) did not modify endothelin-1-induced (10 pmol) nociception or oedema, but abolished hyperalgesia. Thus, endothelin-1 triggers ET(A) receptor-mediated nociception, hyperalgesia and oedema in the mouse hind-paw. Simultaneous activation of ET(B) receptors by endothelin-1 or selective agonists can limit the hyperalgesic, but not the nociceptive or oedematogenic, effects of the peptide.

Topics: Animals; Atrasentan; Capsaicin; Edema; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Hyperalgesia; Male; Mice; Nociceptors; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Piperidines; Pyrrolidines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Viper Venoms

The present study investigates the influence of endothelin (ET) related peptides (0.3-30 pmol/paw) on both phases of nociception and on edema induced by intraplantar injection of formalin (0.5% in 20 microL) in the mouse hind paw. The first phase of nociception (0-5 min after injection) was significantly potentiated by simultaneous injection of either ET-1 (10 or 30 pmol/paw) or ET-3 (10 pmol/paw), but not of the selective ET3 receptor agonist sarafotoxin S6c (SRTX-c; up to 30 pmol/paw). All three peptides potentiated the second phase (10-30 min after injection) of formalin-induced nociception (at 3-30, 1-30, and 10-30 pmol/paw for ET-1, ET-3, and SRTX-c, respectively), whereas only ET-1 (10 or 30 pmol/paw) effectively enhanced edema caused by formalin (30 min after injection). Histamine also potentiated all three responses triggered by formalin, but was 30- to 100-fold less potent than ET-1. Treatment with the mixed ETA/ETB receptor antagonist bosentan (10 mg/kg i.p., 1 h beforehand) did not influence nociceptive and edematogenic responses to formalin or their potentiation by histamine (3 nmol/paw), but did inhibit the potentiations induced by ET-1 (10 pmol/paw). Thus, ET-1 potentiates formalin-induced nociception and edema in the mouse. These actions are possibly mediated via ETB and ETA receptors, respectively, but their true identity and the mechanisms involved still remain to be fully elucidated.

Topics: Animals; Bosentan; Dose-Response Relationship, Drug; Drug Synergism; Edema; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-2; Formaldehyde; Male; Mice; Nociceptors; Pain Measurement; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides; Viper Venoms

1. The effects of the calcium channel blockers, verapamil and nifedipine on myocardial ischaemia and oedema evoked by endothelin-1 (ET-1) or IRL 1620, an ETB receptor-selective agonist were studied in anaesthetized and conscious rats. 2. Bolus injection of ET-1 (1 nmol kg-1, i.v.) or IRL 1620 (1 nmol kg-1, i.v.) to conscious chronically catheterized rats evoked a transient depressor response followed by a prolonged pressor effect. Corresponding to changes in blood pressure, a transient tachycardia and a sustained bradycardia were observed. Pretreatment of the animals with verapamil (1 mg kg-1, i.v.) or nifedipine (200 micrograms kg-1, i.v.) produced on average 5 mmHg decrease in mean arterial blood pressure. Both verapamil and nifedipine inhibited by 63 and 44% the pressor actions of ET-1 or IRL 1620 (1 nmol kg-1), respectively, and the accompanying bradycardia. Both verapamil and nifedipine potentiated the magnitude of the depressor action of ET-1 and IRL 1620 without affecting the accompanying tachycardia. Decreasing mean arterial blood pressure with hydralazine (0.2 - 0.3 micromol kg-1, i.v.) to levels comparable to those observed after verapamil or nifedipine had no significant effects on the haemodynamic responses to ET-1 or IRL-1620. 3. Intravenous bolus injection of ET-1 or IRL 1620 (0.1-2 nmol kg-1) into anaesthetized rats produced dose-dependent ST segment elevation of the electrocardiogram without causing arrhythmias. ST segment elevation developed within 30-50s and persisted for at least 10-20 min following injection of the peptides. 4. Pretreatment of the animals with verapamil (1 mg kg-1, i.v.) or nifedipine (200 micrograms kg-1, i.v.) inhibited on average by 79 and 76% the ST segment elevation elicited by ET-1 (1 nmol kg-1), respectively. Verapamil and nifedipine also attenuated IRL 1620 (1 nmol kg-1)-induced ST segment elevation on average by 71 and 74%, respectively. In contrast, no significant inhibition was observed with hydralazine (0.2-0.3 mumol kg-1). 5. Both ET-1 and, to a lesser extent, IRL 1620 (0.1-2 nmol kg-1) evoked albumin accumulation in cardiac tissues in a dose-dependent fashion as measured by the local extravascular accumulation of Evans blue dye in conscious rats. ET-1 and IRL 1620 (1 nmol kg-1) enhanced albumin extravasation by 109 and 82%, and 34 and 44% in the left ventricle and right atrium, respectively. ET-1 or IRL 1620-induced albumin extravasation was completely prevented by verapamil (1 mg kg-1) or nifedipine (200

Topics: Albumins; Animals; Blood Pressure; Calcium Channel Blockers; Dose-Response Relationship, Drug; Edema; Electrocardiography; Endothelin-1; Endothelins; Heart Rate; Hydralazine; Male; Myocardial Ischemia; Nifedipine; Peptide Fragments; Rats; Rats, Wistar; Receptors, Endothelin; Vasodilator Agents; Verapamil