The relationship between the hepatic ischemia/reperfusion (I/R) injury and the balance of nitric oxide/endothelins (NO/ET) was studied. The changes of the ratio of NO/ET and the hepatic injury were observed in a rat hepatic I/R model pretreated with several tool drugs. In the acute phase of hepatic I/R injury, the ratio of plasma NO/ET was reduced from 1.58 +/- 0.20 to 0.29 +/- 0.05 (P < 0.01) and the hepatic damage deteriorated. NO donor L-Arg and ET receptor antagonist TAK-044 could alleviate the hepatic I/R injury to some degree, whereas NO synthase inhibitor L-NAME aggravated the damage. It was concluded that the hepatic I/R injury might be related with the disturbance of the NO/ET balance. Regulation of this balance might have an effect on the I/R injury.
Arginine ; Endothelins/*blood ; Liver/*blood supply ; NG-Nitroarginine Methyl Ester ; Nitric Oxide/*blood ; Receptors, Endothelin/antagonists & inhibitors ; Reperfusion Injury/*blood

Recently several kinds of new antihypertensive agents were introduced. Diuretics such as indapamide, metyrazone and eprelerone have less side effects compared to thiazide, and have an effect in renal insufficiency. Carvedilol, combined alpha- and beta- adrenergic blocker, has a vasodilating property and an effect on heart failure. The lipid soluble third generation calcium antagonists such as amlodipine, lacidipine and lercardipine are slow onset and long acting and have less side effects, which provide continued effect even if daily doses are missed. Multiple angiotensin converting inhibitors and angiotensin receptor blockers, and the specific aldosterone antagonist eprenolone to block renin-angiotensin-aldosterone system are now available. Additionally new class antihypertensive drugs such as the vasopeptidase inhibitor, the endothelin receptor blocker and the renin inhibitor have been under investigation and shown favorable clinical results, and will be available for clinical use soon.
Adrenergic Antagonists ; Aldosterone ; Amlodipine ; Angiotensin Receptor Antagonists ; Angiotensins ; Antihypertensive Agents ; Calcium ; Diuretics ; Heart Failure ; Hypertension* ; Indapamide ; Receptors, Endothelin ; Renal Insufficiency ; Renin ; Renin-Angiotensin System

BACKGROUND AND OBJECTIVES: Elevated endothelin (ET)-1 level is strongly correlated with the pathogenesis of pulmonary arterial hypertension (PAH). Expression level of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 4 is increased in the PAH patients. Ambrisentan, a selective endothelin receptor A (ERA) antagonist, is widely used in PAH therapy. The current study was undertaken to evaluate the effects of ambrisentan treatment in the monocrotaline (MCT)-induced PAH rat model. METHODS: Rats were categorized into control group (C), monocrotaline group (M) and ambrisentan group (Am). The M and Am were subcutaneously injected 60 mg/kg MCT at day 0, and in Am, ambrisentan was orally administered the day after MCT injection for 4 weeks. The right ventricle (RV) pressure was measured and pathological changes of the lung tissues were observed by Victoria blue staining. Protein expressions of ET-1, ERA, endothelial nitric oxide synthase (eNOS) and NOX4 were confirmed by western blot analysis. RESULTS: Ambrisentan treatment resulted in a recovery of the body weight and RV/left ventricle+septum at week 4. The RV pressure was lowered at weeks 2 and 4 after ambrisentan administration. Medial wall thickening of pulmonary arterioles and the number of intra-acinar arteries were also attenuated by ambrisentan at week 4. Protein expression levels of ET-1 and eNOS were recovered at weeks 2 and 4, and ERA levels recovered at week 4. CONCLUSIONS: Ambrisentan administration resulted in the recovery of ET-1, ERA and eNOS protein expression levels in the PAH model. However, the expression level of NOX4 remained unaffected after ambrisentan treatment.
Animals ; Arteries ; Arterioles ; Blotting, Western ; Body Weight ; Endothelin Receptor Antagonists ; Endothelins ; Gene Expression ; Heart Ventricles ; Humans ; Hypertension ; Hypertension, Pulmonary ; Lung ; Models, Animal ; Monocrotaline ; NADP ; NADPH Oxidase ; Nitric Oxide Synthase Type III ; Oxidoreductases ; Rats ; Receptors, Endothelin ; Victoria

OBJECTIVETo investigate the role of advanced glycation end products (AGEs) and their receptors (RAGE) in the pathogenesis of diabetic mellitus erectile dysfunction (DMED) and the effects of AGEs and RAGE on the activity of endothelin-1 (ET-1) in rat cavernosum.

METHODSForty male Sprague-Dawley rats were taken at random to construct 2 groups of diabetes mellitus (DM) models of equal number, one given free access to water and the other administered aminoguanidine hydrochloride (DM + AG) in water at the dose of 1 g/L. Another 20 male SD rats were equally divided into a normal control and an AG control group. After 8 weeks, the cavernosum tissues were harvested from all groups of rats, part of the isolated penile tissues homogenated to detect the content of AGE-peptide (AGE-P) and the activity of ET-1, and the AGEs and RAGE in the rest of the penile tissues analyzed by immunohisto- chemical assay.

RESULTSCompared with the normal controls, the expressions of AGEs and RAGE, the content of AGE-P and the activity of ET-1 in the cavernosum tissues were significantly high in the DM group (P < 0.05), while the administration of AG to the DM rats reversed the above results. No significant difference was observed between the normal control and AG control groups in any of the data (P > 0.05).

CONCLUSIONIn DM conditions, the joint effect of AGEs and RAGE may elevate the activity of ET-1 in rat cavernosum and thus promote the development of DMED.

Animals ; Diabetes Mellitus, Experimental ; metabolism ; physiopathology ; prevention & control ; Endothelin-1 ; metabolism ; Enzyme Inhibitors ; administration & dosage ; Glycation End Products, Advanced ; antagonists & inhibitors ; metabolism ; Guanidines ; administration & dosage ; Male ; Penis ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Cell Surface ; metabolism

Endothelin (ET) receptor antagonists have been developed to produce a reduction of ET related effects in various diseases, as well as in animal models of airway inflammation. We aimed to investigate the anti-inflammatory potential of bosentan on a rat model of emphysema. Thirty Wistar male rats were classified as control group (group 1), intratracheally (i.t.) instilled with saline, treated with vehicle solution; elastase group (group 2), i.t. instilled with porcine pancreatic elastase (PPE), treated with vehicle solution; and PPE+bosentan group (group 3), i.t. instilled with PPE, treated with bosentan. The levels of TNF-alpha, IL-1beta, IL-6, and IL-8 in bronchoalveolar lavage fluid (BALF) and lung tissue, cell counts in BALF, and histologic analysis of all groups were evaluated. Neutrophile granulocytes (NG) and alveolar macrophages (AM) were increased more in group 2 than in group 1 (P<0.001, P=0.04, respectively). Compared with group 2, neutrophil granulocyte (NG) and alveolar macrophages (AM) counts were decreased in group 3 (P< 0.001). Histological examination confirmed a diffuse neutrophilic inflammation and irregular alveolar air space enlargement in group 2. Treatment with bosentan partially reduced the enlarged lung volumes. Compared with group 1, the BALF levels of TNF-alpha and IL-6, and the lung tissue levels of IL-1beta, IL-6, and IL-8 were increased in group 2 (P=0.028, P=0.005, P=0.001, P=0.019, P<0.001, respectively). The TNF-alpha and IL-8 levels of BALF (P=0.007, P=0.001, respectively), and the TNF-alpha, IL-1beta, IL-6, and the IL-8 levels of lung tissue (P=0.031, P=0.017, P=0.007, P<0.001) were decreased in group 3 compared to group 2. In conclusion, bosentan decreased the inflammatory response by reducing numbers of inflammatory cells and proinflammatory cytokines.
Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Bronchoalveolar Lavage Fluid/cytology/immunology ; Cytokines/*biosynthesis ; Disease Models, Animal ; Emphysema/*drug therapy/etiology/immunology/pathology ; Inflammation Mediators/metabolism ; Lung/drug effects/immunology/pathology ; Male ; Pancreatic Elastase/administration & dosage/toxicity ; Rats ; Rats, Wistar ; Receptors, Endothelin/*antagonists & inhibitors ; Sulfonamides/*pharmacology

The myocardial protective effects of endothelin antagonist in ischemic cardiomyopathy (ICMP), doxorubicin-induced cardiomyopathy (DOX) and pressure-overload hypertrophy by transverse aortic constriction (TAC) models have been predicted to be different. The objective of this experiment, therefore, is to evaluate the myocardial protective effect of tezosentan, an endothelin receptor antagonist, in various experimental heart failure models. Sprague-Dawley rats (6-8 weeks old, 200-300 g) were randomized to three experimental groups (n=30 each): ICMP; DOX; and TAC group. Each of these groups was randomly assigned further to the following subgroups (n=10 each): sham-operated ischemia-reperfusion subgroup (SHAM); tezosentan treated ischemia-reperfusion subgroup (Tezo); and tezosentan non-treated ischemia-reperfusion subgroup (N-Tezo). Total circulatory arrest was induced for 1 hr, followed by 2 hr of reperfusion. The left ventricular developed pressure, peak positive and negative first derivatives, and coronary blood flow were significantly different (P<0.05) among the SHAM, Tezo, and N-Tezo subgroups of the ICMP group at 30 min of reperfusion, but there were no statistically significant differences among the subgroups of the DOX and TAC groups. In conclusion, tezosentan, an endothelin receptor antagonist, showed myocardial protection effects only on the ischemic cardiomyopathy rat model, but not in the non-ischemic heart failure rat models.
Animals ; Cardiomyopathies/chemically induced/drug therapy/physiopathology ; Coronary Vessels/physiology ; Disease Models, Animal ; Doxorubicin/toxicity ; Heart Failure/*drug therapy/physiopathology ; Hypertrophy/drug therapy/physiopathology ; Male ; Pressure ; Pyridines/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Receptors, Endothelin/*antagonists & inhibitors/metabolism ; Reperfusion Injury/*drug therapy/physiopathology/surgery ; Tetrazoles/*therapeutic use ; Vasodilator Agents/*therapeutic use ; Ventricular Function, Left/physiology