bq-123 and Heart-Failure

It is now becoming clear that two major systems namely the sympathetic nervous system and the renin-angiotensin system are activated in response to ischemic injury; these result in the elevation of plasma catecholamines and angiotensin II during the development of myocardial infarction as well as congestive heart failure. Although plasma levels of several other hormones including aldosterone, endothelin, vasopressin, natriuretic peptides, growth factors and inflammatory cytokines are also increased in heart failure, their relationship with changes in catecholamine and/or angiotensin levels as well as their significance for the induction of congestive heart failure are poorly understood. In this article we have examined the evidence regarding the role of endothelin and vasopressin in the pathogenesis of cardiac hypertrophy and congestive heart failure in addition to evaluating the significance of their antagonism by using their receptor blockade for treatment of congestive heart failure. Endothelin appears to maintain blood pressure by its vasoconstricting action whereas vasopressin primarily produces similar effect by retention of body fluid. Myocardium is also known to express both ET-A and ET-B receptors in addition to V1 and V2 receptors for vasopressin, which have been shown to induce cardiac remodeling. Out of various ET-1 receptor antagonists, which are available, a non-selective endothelin receptor antagonist, bosentan, as well as an ET-A receptor antagonist, BQ-123, seem most promising for the treatment of congestive heart failure. Likewise, vasopressin antagonists such as a non-selective antagonist, conivaptan, as well as V2 selective antagonist, tolvaptan, may prove highly valuable for the therapy of this condition. Since most of the existing interventions are helpful in treating patients with congestive heart failure only partially, there appears to be a real challenge for developing some combination therapy for the treatment of congestive heart failure.

Topics: Angiotensin II; Animals; Antidiuretic Agents; Antihypertensive Agents; Benzazepines; Biomarkers; Bosentan; Catecholamines; Drug Therapy, Combination; Endothelin-1; Heart Failure; Humans; Peptides, Cyclic; Renin-Angiotensin System; Sulfonamides; Sympathetic Nervous System; Tolvaptan; Treatment Outcome; Vasopressins

Less than 20 years after its discovery, endothelin is recognized as playing a central role in the pathogenesis of chronic heart failure. Endothelin is not only one of the most potent known vasoconstrictors; it also has multiple other actions. It mediates pathologic hypertrophy and fibrosis of both ventricular and vascular tissues, it potentiates the effects of other neurohormones, and it acts as a proarrhythmic. Endothelin receptor antagonists have been developed to investigate the hypothesis that these adverse effects could be prevented, and experimental studies showed promise in this regard. Clinical studies have confirmed the ability of these new agents to improve hemodynamics, but beneficial effects on clinical outcomes have been more difficult to demonstrate. Further analysis of the data from these trials, as well as other ongoing studies, may provide insight into these disparate findings and guidance for future investigations.

Topics: Animals; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelins; Heart Failure; Humans; Peptides, Cyclic; Receptors, Endothelin; Sulfonamides; Treatment Outcome; Vasoconstriction

Topics: Acute Kidney Injury; Animals; Biomarkers; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Erythropoietin; Fibrosis; Glycopeptides; Heart Failure; Humans; Hypotension; Kidney Failure, Chronic; Peptides, Cyclic; Peritoneal Dialysis; Peritoneum; Prognosis; Recombinant Proteins; Renal Dialysis

Topics: Animals; Biomarkers; Clinical Trials as Topic; Drug Design; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression; Heart Failure; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neovascularization, Pathologic; Peptides, Cyclic; Phenylpropionates; Pyrimidines; Transcription Factors; Vasoconstriction; Ventricular Remodeling

Mixed ET(A/B) and selective ET(A) receptor antagonists showed promising hemodynamic and symptomatic improvements in patients with heart failure. Randomized, clinical trials to investigate the effects of ET receptor antagonists on survival in patients with heart failure still need to be conducted. Also, the effects of selective ET(A) and mixed ET(A/B) receptor antagonists on the clinical outcome of patients with CHF will have to be assessed.

Topics: Animals; Bosentan; Cardiovascular Agents; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelins; Heart Failure; Humans; Isoxazoles; Oligopeptides; Peptides, Cyclic; Phenylpropionates; Piperidines; Pyridines; Pyrimidines; Sulfonamides; Tetrazoles; Thiophenes; Treatment Outcome

Although an initial study of endothelin receptor blockade reported positive findings, subsequent experiments and clinical trials in humans found little or no benefit.. We applied meta-analytic methods to assess the methodologic rigor of preclinical studies of endothelin blockade and to quantitatively evaluate the totality of evidence regarding the effect of endothelin receptor blockers in experimental heart failure. A total of 396 animals were assigned to control and 594 were assigned to experimental therapy in the pooled analysis. Of the 9 studies identified, no study reported a priori sample size justification. Although there was a tendency to increased mortality with early administration (relative risk 1.39, P=.15) and decreased mortality with late administration (relative risk 0.85, P=.6), in the overall analysis, there was no significant evidence of benefit or harm (relative risk 1.03, P=.9). Studies with a small sample size had estimated effects that tended to deviate further from the pooled estimate of all studies.. Consideration of mortality effects in the totality of studies revealed no significant effect of endothelin antagonists in animal models of experimental heart failure. Given the potential for between-study variability, reliance on studies with small sample size may lead to unrealistic expectations when extrapolating preclinical experimental results to future research.

Topics: Animals; Atrasentan; Cardiotonic Agents; Endothelin Receptor Antagonists; Heart Failure; Peptides, Cyclic; Phenylpropionates; Pyrimidines; Pyrrolidines; Rats; Risk; Survival Rate

Congestive heart failure (CHF) is characterized by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. Thus, mediators involved in the control of myocardial function and vascular tone may be involved in its pathophysiology. The family of endothelins (ET) consists of four closely related peptides, ET-1, ET-2, ET-3 and ET-4, which cause vasoconstriction, cell proliferation and myocardial effects through activation of ETA receptors. In contrast, endothelial ETB receptors mediate vasodilation via release of nitric oxide and prostacyclin. In addition, ETB receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Thus, infusion of an ETA-receptor antagonist into the brachial artery in healthy humans leads to vasodilation, whereas infusion of an ETB-receptor antagonist causes vasoconstriction. Endothelin-1 plasma levels are elevated in CHF and correlate both with hemodynamic severity and symptoms. Plasma levels of ET-1 and its precursor, big ET-1, are strong independent predictors of death after myocardial infarction as well as in CHF. Endothelin-1 contributes to increased systemic and pulmonary vascular resistance, vascular dysfunction, myocardial ischemia and renal impairment in CHF. Selective ETA, as well as combined ETA/B-receptor antagonists, have been studied in patients with CHF, and their use has shown impressive hemodynamic improvement (i.e., reduced peripheral vascular and pulmonary resistance as well as increased cardiac output). These results indicate that ET-receptor antagonists, indeed, have a potential to improve hemodynamics, symptoms and, potentially, prognosis in patients with CHF, which still carries a high mortality.

Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Forecasting; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Myocardial Contraction; Peptides, Cyclic; Phenylpropionates; Predictive Value of Tests; Prognosis; Pyrimidines; Sulfonamides; Time Factors; Vascular Resistance; Vasoconstriction; Ventricular Function, Left

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

Despite conventional therapy, there is still much room for improvement in the prognosis of patients with chronic systolic heart failure. Evidence supports a role for endothelin-1 (ET-1), a potent vasoconstrictor, in the pathophysiology of heart failure. Given its potentially deleterious effects, the optimal treatment of heart failure may need to include efforts directed toward antagonizing this hormone. In support of this notion, the use of ET receptor antagonists produces a number of beneficial effects in heart failure, including both improvements in hemodynamics and reductions in the levels of other vasoconstricting neurohormones. There are at least 2 receptors for ET-1 (the ET-A and ET-B receptor), and the effects of ET-1 binding differ depending on the receptor involved. It is still unclear whether blockade of the ET-A receptor alone or the combined blockade of both the ET-A and ET-B receptors will be most efficacious as a therapeutic strategy. Long-term benefits have been achieved with the use of a mixed ET-A/B receptor antagonist, when added to standard triple-drug therapy, in patients with severe heart failure. We await the results of ongoing trials to determine if these agents will fulfill the promise of adding substantial incremental benefit to the treatment of the disease.

Topics: Bosentan; Carboxylic Acids; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Indans; Peptides, Cyclic; Prognosis; Pyridines; Pyrimidines; Receptors, Endothelin; Sulfonamides; Treatment Outcome

Topics: Animals; Atrial Natriuretic Factor; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Peptides, Cyclic; Renin-Angiotensin System

Topics: Animals; Bosentan; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; Humans; Mice; Myocardial Infarction; Myocardium; Peptides, Cyclic; Rats; Receptors, Endothelin; Stroke Volume; Sulfonamides; Time Factors

The vasoconstrictor action of endothelin-1 (ET-1) is mediated through ET(A) and ET(B) receptor subtypes on vascular smooth muscle. ET(B) receptors are also present on the vascular endothelium where they mediate vasodilation. Animal studies suggest that the ET(B) receptor also acts as a clearance receptor for endothelin.. To investigate the effects of a selective ET(A) and a selective ET(B) receptor antagonist alone and in combination on haemodynamics and circulating concentrations of ET-1 in patients with chronic heart failure.. Infusion of BQ-123 (n=10), a selective ET(A) receptor antagonist, led to systemic vasodilation and did not change plasma ET-1 concentrations (1.38+/-0.82 to 1.38+/-0.91 fmol/ml, ns). Infusion of BQ-788 (n=8) led to systemic vasoconstriction with a rise in plasma ET-1 (1.84+/-1.06 to 2.73+/-0.99 fmol/ml, p<0.01). The addition of BQ-123 to BQ-788 led to systemic and pulmonary vasodilation with no further increase in plasma ET-1 concentrations (2.80+/-1.14 to 2.90+/-1.20 fmol/ml, ns).. The rise in plasma ET-1 concentrations in response to selective blockade of ET(B) receptors and the associated adverse haemodynamic effects suggest that ET(B) receptors have a role in the clearance of ET-1 in man and that their blockade may not be advantageous for patients with heart failure.

Topics: Aged; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines

Topics: Endothelin Receptor Antagonists; Heart Failure; Hemodynamics; Humans; Peptides, Cyclic; Time Factors; Vascular Resistance; Ventricular Dysfunction, Left

The importance of endothelin-1 in chronic heart failure (CHF) is unclear. We therefore investigated the effects of endothelin-converting enzyme (ECE) inhibition and endothelin ETA receptor blockade in CHF patients treated with ACE inhibitors. We also compared the function of ETA and ETB receptors in healthy subjects and patients with CHF.. Locally active doses of study drugs were infused into the nondominant brachial artery while forearm blood flow (FBF was measured by venous occlusion plethysmography. In CHF patients (n = 10), phosphoramidon (a combined ECE and neutral endopeptidase inhibitor) and BQ-123 (an ETA receptor antagonist) increased FBF by 52 +/- 10% (P = .0006) and 31 +/- 6% (P = .002), respectively, and thiorphan (a selective neutral endopeptidase inhibitor) reduced FBF by 15 +/- 5% (P = .0007). Forearm vasoconstriction to endothelin-1 (an ETA and ETB receptor agonist) was significantly blunted in CHF patients compared with control subjects (both n = 10; CHF versus control subjects, P < .001), whereas vasoconstriction to sarafotoxin S6c (an ETB receptor agonist) was significantly enhanced in CHF patients compared with control subjects (both n = 10; CHF versus control subjects. P < .05).. ECE inhibitors and ETA receptor antagonists may be useful as vasodilator agents in CHF patients already receiving treatment with an ACE inhibitor. Both ETA and ETB receptors can mediate agonist-induced vasoconstriction in healthy subjects and patients with CHF, but further studies are required to clarify the contribution of each receptor subtype in mediating the effects of endogenous endothelin-1.

Topics: Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Aspartic Acid Endopeptidases; Brachial Artery; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Female; Glycopeptides; Heart Failure; Humans; Male; Metalloendopeptidases; Middle Aged; Neprilysin; Peptides, Cyclic; Protease Inhibitors; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Regional Blood Flow; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Viper Venoms

Increasing renal pelvic pressure results in PGE2-mediated release of substance P, leading to increases in afferent renal nerve activity (ARNA) and natriuresis, that is, a renorenal reflex response. The renorenal reflexes are impaired in congestive heart failure (CHF). Impairment of the renorenal reflexes may contribute to the increased renal sympathetic nerve activity and sodium retention in CHF. Endothelin (ET)-1 contributes to the pathological changes in cardiac and renal function in CHF. Therefore, we examined whether the ETA receptor antagonist BQ123 altered the responsiveness of renal mechanosensory nerves in CHF. The ARNA responses to increasing renal pelvic pressure were suppressed in CHF but not in sham-CHF rats. In CHF, increasing renal pelvic pressure by 7.5 mm Hg before and during renal pelvic perfusion with BQ123 increased ARNA 12% +/- 3% and 21% +/- 3% (p < 0.05 vs. vehicle). In isolated renal pelvises from CHF rats, PGE2 increased substance P release from 5 +/- 0 to 7 +/- 1 pg/min without BQ123 and from 4 +/- 1 to 9 +/- 1 pg/min with BQ123 in the bath (p < 0.01 vs. vehicle). BQ123 had no effect on the ARNA responses or substance P release in sham-CHF. In conclusion, activation of ETA receptors contributes to the impaired responsiveness of renal mechanosensory nerves in CHF rats by a mechanism(s) at the renal sensory nerve endings.

Topics: Afferent Pathways; Animals; Antihypertensive Agents; Dinoprostone; Disease Models, Animal; Endothelin A Receptor Antagonists; Heart Failure; Hydrostatic Pressure; Kidney; Kidney Pelvis; Male; Mechanoreceptors; Myocardium; Organ Size; Peptides, Cyclic; Perfusion; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Sodium; Substance P; Ventricular Dysfunction, Left

Endothelin 1 (ET-1) is increased in heart failure, both in plasma and within the central nervous system. Centrally, ET-1 induces sympathetic hyperactivity and arginine vasopressin (AVP) secretion. Both sympathetic activity and AVP secretion are regulated by the arterial baroreflex, which is typically impaired in heart failure. We hypothesized that central blockade of ETA receptors (ETAR) alters the baroreflex response of heart rate, renal sympathetic nerve activity (RSNA), and plasma AVP levels in a cardiomyopathic model of heart failure. Female Sprague-Dawley rats received weekly intraperitoneal injections of doxorubicin 2.5 mg x kg(-1) (doxorubicin heart failure, doxo-HF) or saline vehicle (control). After 8 weeks, they were instrumented, conditioned to the study environment, and then studied in the awake, non-restrained state. Baseline mean arterial pressure (MAP), RSNA, and plasma osmolality were similar in both groups, but heart rate (p<0.02), left ventricular pressure (p<0.001), and plasma AVP (p<0.01) were higher in the doxo-HF group. ET-1 dose dependently increased MAP, but the rise was significantly attenuated in doxo-HF rats at all doses. Baseline baroreflex control of heart rate and RSNA was similar in both groups. ETAR blockade with 4 nmol BQ123 i.c.v. significantly decreased both the upper plateau (p<0.05) and the range (p<0.05) of the baroreflex response of both heart rate and RSNA in doxo-HF but not in control rats. Despite higher basal plasma levels of AVP, ET-1 evoked a rise in plasma AVP of 13.6+/-3.2 pg x mL(-1) in doxo-HF compared with 0.4+/-0.4 pg x mL(-1) in control rats (p<0.001). To account for the blunted pressor response to ET-1 in the doxo-HF rats, gain of AVP release was calculated as DeltaAVP/DeltaMAP and was also found to be significantly greater in the doxo-HF rats (p<0.001). BQ123 prevented the rise in AVP and restored the gain in doxo-HF rats to that seen in controls. Thus, central ETAR contribute to the sympathoexcitation and AVP responses observed in heart failure due to doxorubicin cardiomyopathy.

Topics: Animals; Arginine Vasopressin; Baroreflex; Doxorubicin; Endothelin A Receptor Antagonists; Endothelin-1; Female; Heart Failure; Kidney; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System

Despite obvious participation of endothelins in pathogenesis of heart failure therapeutic approaches to the use of endothelin receptor antagonists remain to be elucidated. Experimental heart failure caused by prolonged infusion of norepinephrine is associated with diminished endothelin induced coronary constricting effect of stimulation of ET(A) receptors and inversion of coronary dilating effect of stimulation of these receptors. The latter effect is mediated by smooth muscle ET(B)-receptors and is indicative of functional derangement of vascular control by endothelial cells. The use of selective ET(A)-antagonist is effective on early stages of heart failure while on later stages administration of nonselective ET(AB)-antagonist produces more pronounced effect.

Topics: Animals; Antihypertensive Agents; Aorta, Thoracic; Coronary Vessels; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelium, Vascular; Heart Failure; In Vitro Techniques; Norepinephrine; Oligopeptides; Peptides, Cyclic; Rats; Vasoconstriction; Ventricular Function, Left

Cardiac endothelin-1 (ET-1) levels and ET receptor expression are increased in congestive heart failure (CHF). In order to determine whether this results in increased responsiveness of ET-A or ET-B receptors to ET-1, we evaluated the contractile effects of ET-1 in isolated papillary muscles isolated from hearts of control rats and from rats 4 weeks post myocardial infarction (MI) having received no therapy or chronic quinapril therapy. The ET-1 dose-response was biphasic in normal muscles. The use of the selective ET-A receptor antagonist BQ123 and the selective ET-B receptor antagonist BQ788 revealed that the initial decrease in tension was the result of ET-B receptor stimulation. Blockade of nitric oxide (NO) production with L-NAME abolished the initial decrease in tension. MI resulted in CHF that was partially reversed by quinapril. In MI, the positive inotropic effects of ET-1 were enhanced due to the loss of the initial ET-B receptor mediated decrease in tension, as well as an increase in the positive inotropic effects of ET-A receptors. This was associated with an increase in ET-A and ET-B receptor mRNA and a decrease in cardiac ecNOS protein. Four weeks of therapy with quinapril attenuated the positive inotropic effects of ET-1 and prevented the increase in ET-A receptor mRNA. Although quinapril did not restore the effects of ET-B receptor stimulation or prevent the increase in ET-B mRNA, it did restore cardiac ecNOS protein expression. Thus, the inotropic response to ET-1 is biphasic due to an overall positive inotropic effect of ET-A receptor stimulation and an ET-B receptor mediated decrease in contractility at low ET-1 concentrations which appears to be mediated by cardiac ecNOS (NO). In post-MI CHF, responsiveness to ET-A receptors increases and the ET-B mediated negative inotropic response is lost despite an increase in both receptor subtypes. Quinapril therapy attenuates these effects and normalises cardiac ecNOS protein.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Binding, Competitive; Body Weight; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; Isoquinolines; Kinetics; Male; Muscles; Myocardial Contraction; Myocardial Infarction; Myocardium; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oligopeptides; Organ Culture Techniques; Organ Size; Papillary Muscles; Peptides, Cyclic; Piperidines; Protein Binding; Quinapril; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrahydroisoquinolines; Time Factors; Vasoconstrictor Agents; Viper Venoms

A role of the potent and long-acting vasoconstrictor peptide endothelin (ET)- I in the pathophysiology of chronic human heart failure has been postulated, based upon indirect evidence such as elevated plasma ET-1 levels and their relationship to the degree of haemodynamic impairment. Acute heart failure shares many features of chronic heart failure, albeit in an exaggerated fashion. As both the mixed ETA/ETB-receptor antagonist bosentan and the selective ETA receptor antagonist BQ 123 acutely improved the haemodynamics of chronic heart failure patients, there seems to be good reason to believe that ET-1 receptor antagonism may also be of benefit in the setting of acute heart failure. However, appropriate trials will have to be performed to document the clinical benefit of such an approach. Finally, the question remains open as to whether mixed ET-1 receptor antagonists like bosentan will prove better, worse or equal to antagonists that block the ETA, receptor only.

Topics: Acute Disease; Animals; Antihypertensive Agents; Bosentan; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Peptides, Cyclic; Receptor, Endothelin A; Receptor, Endothelin B; Sulfonamides

The relative importance of ETA and ETB receptors in mediating the constrictor effects of endogenous endothelin-1 in patients with chronic heart failure is not known. The primary purpose of this study was to compare the acute effects of selective ETA and ETB receptor antagonists in vivo in healthy subjects and patients with chronic heart failure. Our secondary aim was to examine more closely the effect of chronic heart failure on endothelin biosynthesis.. We studied the effects of BQ-123 (a selective ETA antagonist) and BQ-788 (a selective ETB antagonist) in ten healthy subjects and ten patients with chronic heart failure. Locally active doses of each antagonist were infused into the non-dominant brachial artery for 90 min on separate days at least 1 week apart. Changes in forearm blood flow were measured by venous occlusion plethysmography. Venous blood samples were obtained prior to antagonist infusion for assay of total endothelin, big endothelin-1 and C-terminal fragment immunoreactivity.. BQ-123 (100 nmol/min) increased blood flow by 54+/-10% (P<0.001) and 30+/-5% (P<0.001) in controls and heart failure patients, respectively. BQ-788 (1 nmol/min) reduced blood flow by 15+/-5% (P=0. 036) and 9+/-4% (P=0.001) in controls and heart failure patients, respectively. Total endothelin immunoreactivity was non significantly greater in heart failure patients than controls (6. 8+/-1.4 vs. 4.6+/-0.5 pM; P=0.13). Big endothelin-1 (2.6+/-0.4 vs. 1. 7+/-0.1 pM; P=0.04) and C-terminal fragment immunoreactivity (2. 1+/-0.3 vs. 0.6+/-0.1 pM; P<0.0001) were each significantly greater in heart failure patients than controls.. Selective ETA receptor antagonism caused vasodilatation in the peripheral circulation of healthy subjects and patients with chronic heart failure while selective ETB receptor antagonism caused vasoconstriction in each group. ETB receptor antagonism may therefore cause potentially deleterious vasoconstriction in chronic heart failure. Chronic heart failure is associated with a significant increase in plasma big endothelin-1 and C-terminal fragment immunoreactivity.

Topics: Case-Control Studies; Endothelin Receptor Antagonists; Forearm; Heart Failure; Humans; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Plethysmography; Regional Blood Flow; Vasodilator Agents; Vasomotor System

The objective of this study was to define further the local activation of endothelin-1 (ET-1) and the ETA receptor as well as the functional consequences of activated ET-1 for renal hypoperfusion associated with experimental congestive heart failure (CHF). We studied eight rabbits permanently instrumented with Doppler flow probes around the renal arteries before and after the induction of epinephrine-induced CHF. CHF was characterized by left-ventricular dysfunction (fractional shortening 34+/-2% vs. 46+/-3%; p < or = 0.05) and dilatation (LVEDd 13.6+/-0.3 vs. 11.5+/-0.4 mm; p < or = 0.05), decreased mean arterial pressure (59.4+/-2.9 vs. 74.6+/-3.7 mm Hg; p < or = 0.05), increased heart rate (236+/-11 vs. 216+/-8 beats/min; p < or = 0.05) and renal vasoconstriction (vascular resistance 49.65 +/-8.55 vs. 24.61+/-5.85 U; p < 0.05; blood flow velocity, 1.58+/-0.21 vs. 3.63+/-0.31 kHz; p < 0.05). ET-1 concentrations were significantly increased not only in plasma (7.67+/-0.47 vs. 4.56 +/-0.69 pg/ml; p < 0.05) but also in renal tissue (4.8+/-0.5 vs. 3.5 +/-0.64 pg/mg; p < 0.05). Northern analysis revealed an unchanged expression of ETA receptor messenger RNA (0.79+/-0.05 vs. 0.77+/-0.04 arbitrary units; NS) in renal tissue, whereas expression of prepro-ET-1 was below the range of detection. In CHF, selective ETA-receptor antagonism with BQ-123 (1 mg/ kg bolus, i.v.) significantly increased renal blood flow velocity (3.07+/-0.38 vs. 1.33+/-0.19 kHz; p < 0.05) and reduced renal vascular resistance (29.63+/-6.22 vs. 58.17+/-8.75 U; p < 0.05) without significant effects on mean arterial pressure or heart rate. These studies demonstrate activation of the renal ET system, unaltered gene expression, and functional integrity of the renal ETA receptor in CHF. They indicate a principal functional role for the ETA receptor in renal vasoconstriction and suggest blockade of the renal ETA receptor as an important strategy to attenuate renal hypoperfusion in CHF.

Topics: Animals; Blotting, Northern; Echocardiography; Endothelin-1; Epinephrine; Heart Failure; Hemodynamics; Laser-Doppler Flowmetry; Male; Peptides, Cyclic; Rabbits; Radioimmunoassay; Receptors, Endothelin; Renal Artery; RNA; Sympathomimetics

We have reported that the production of endothelin (ET)-1 is markedly increased in the failing heart of rats with chronic heart failure (CHF) and that the long-term (3-month) treatment with the ETA receptor antagonist BQ-123 markedly ameliorated the long-term survival and hemodynamic parameters in rats with CHF. In this study we investigated whether this therapy affects the alteration of the mRNA expression of cardiac myosin heavy chain (MHC) isoforms in the hearts of rats with CHF. The change from alpha-MHC to beta-MHC is regarded as a molecular marker for heart failure. The expression of beta-MHC mRNA was dominant in the left ventricle (LV) of CHF rats treated with saline, whereas that of alpha-MHC was dominant in the LV of sham-operated rats treated with saline. Therefore, in the failing rat heart, a change from alpha-MHC to beta-MHC occurred. In the LV of CHF rats treated with BQ-123, this treatment effectively prevents the switching of MHC isoforms. These findings suggest that long-term BQ-123 treatment inhibits the change in MHC isoforms and suggest that this treatment ameliorates heart failure in CHF rats at the molecular level.

Topics: Animals; Chronic Disease; Endothelin Receptor Antagonists; Heart; Heart Failure; Male; Myocardium; Myosin Heavy Chains; Myosins; Peptides, Cyclic; Polymerase Chain Reaction; Rats; RNA, Messenger

Coronary dysfunctions identified in the presence of chronic heart failure are an important pathophysiologic abnormality that influences the prognosis of the disease. Because the endothelin pathway plays a significant role in the increased peripheral vascular tone associated with heart failure, we hypothesized that the endothelin pathway may be involved in the abnormal coronary vasomotion associated with this pathologic condition. Experiments were carried out in failing hearts (UM-X7.1 cardiomyopathic hamsters, aged 225-250 days) and normal hearts (Syrian LVG hamsters, also aged 225-250 days). Isolated hearts were perfused at constant flow and exposed to the blocker of the generation of endothelin-1 (ET-1), phosphoramidon (10 microM infusion), as well as to the selective ET(A)-receptor antagonist BQ 123 (10 microM infusion) and to a selective ET(B)-receptor antagonist BQ 788 (1 microM infusion). Coronary and cardiac effects of exogenous ET-1 (0.01-100 pmol) were also studied. Phosphoramidon, BQ 788, and BQ 123 did not altered coronary perfusion pressure either in normal or in failing hearts, whereas cardiac contractility was significantly impaired in the presence of phosphoramidon and BQ 123. Coronary sensitivity to exogenous ET-1 did not demonstrate a significant difference between normal and failing hearts [median effective concentration (EC50), 7 pmol in failing hearts vs. 12 pmol in normal hearts; p = NS]. In the presence of exogenous ET-1, cardiac contractility was significantly increased in both groups. In normal hearts, the exogenous ET-1-induced increase in coronary perfusion pressure was completely antagonized by BQ 123, whereas combined administration of BQ 788 and BQ 123 was necessary to induce complete inhibition in failing hearts. The positive inotropic effect elicited by exogenous ET-1 (EC50) was completely abolished in the presence of BQ 123, whereas BQ 788 had no significant effect. Results indicate that the endothelin pathway does not play a significant role in the altered coronary vasomotion observed in this model of chronic heart failure. On the contrary, the endothelin pathway appears to participate in the maintenance of myocardial contractility. According to these observations, administration of an inhibitor of ET-1 synthesis, as well as the use of an ET(A)-receptor antagonist, may be contraindicated in the presence of poor left ventricular function because the endothelin pathway contributes significantly to the maintenance of cardiac

Topics: Animals; Aspartic Acid Endopeptidases; Blood Pressure; Coronary Circulation; Coronary Vessels; Cricetinae; Electrocardiography; Endothelin Receptor Antagonists; Endothelin-Converting Enzymes; Glycopeptides; Heart; Heart Failure; Mesocricetus; Metalloendopeptidases; Oligopeptides; Peptides, Cyclic; Piperidines; Protease Inhibitors; Receptor, Endothelin A; Receptor, Endothelin B

The positive inotropic effect of endothelin-1 (ET-1) on normal myocardial contraction may be altered in pathological states. The purpose of this study was to assess the direct effect of ET-1 on cardiomyocyte performance and its cellular mechanism in congestive heart failure (CHF).. We measured the plasma levels of ET-1 and compared the effects of ET-1 (10(-10)-10(-8) M) on contractile performance and the [Ca2+]i transient in the myocytes of left ventricles (LV) from 15 age-matched normal adult rats and 15 rats with isoproterenol (ISO)-induced CHF.. With CHF, the plasma levels of ET-1 (19.7 +/- 6.3 vs. 4.1 +/- 0.5 fmol/ml, p < 0.05) were markedly elevated. In normal myocytes, superfusion of ET-1 caused significant increases in the systolic amplitude (SA, 8-16%) and the peak velocity of shortening (dL/dtmax, 20-35%; p < 0.01) without causing a change in the peak [Ca2+]i transient. In contrast, in myocytes from CHF rats, ET-1 produced significant reductions in SA (9-13%) and in the velocity of relengthening, dR/dtmax (10-14%; p < 0.05). The myocytes' dR/dtmax also decreased by 8-10% (p < 0.05). These changes were associated with a significant decrease in the peak [Ca2+]i transient (20-23%, p < 0.01). These responses to ET-1 were abolished by the incubation of myocytes with an ETA receptor antagonist (BQ123) or a protein kinase C (PKC) inhibitor (H-7 or staurosporine).. ISO-induced CHF is associated with elevated plasma ET-1 and an altered cardiomyocyte response to ET-1. After CHF, ET-1 produces a direct depression of cardiomyocyte contractile performance that is associated with a significant decrease in the peak [Ca2+]i transient. These effects are likely to be mediated through ETA receptors and involve the PKC pathway.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Amiloride; Animals; Anti-Arrhythmia Agents; Calcium; Cardiotonic Agents; Cell Size; Cells, Cultured; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Heart Failure; Hemodynamics; Isoproterenol; Male; Myocardial Contraction; Myocardium; Peptides, Cyclic; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin; Sodium-Hydrogen Exchangers; Staurosporine

The results of early acute haemodynamic studies with anti-endothelin agents are promising. Much still needs to be done, however, before endothelin antagonism is established as a therapeutic strategy in heart failure. We need to know, for example, whether the haemodynamic effects of anti-endothelin drugs are sustained. We need to ensure that there is no reflex activation of other neuroendocrine systems and, preferably, to demonstrate neuroendocrine suppression. Characterisation of the renal actions of endothelin receptor antagonists will also be important. Perhaps the most pressing issue in the development of these agents is elucidation of the role of the endothelial ETB receptor in heart failure. It is now clearly shown that vascular smooth muscle ETB receptors can mediate vasoconstriction in human blood vessels and that these receptors may be particularly important in heart failure. The effect of selective ETB receptor blockade in humans in vivo is not currently known, however, and whether endothelial ETB receptors might tonically offset ETA and ETB receptor mediated smooth muscle contraction remains conjectural. This question is directly relevant to whether selective ETA or non-selective ETA and ETB receptor antagonism might be the better therapeutic strategy in heart failure. ECE inhibition may become another therapeutic option in due course, but at present no specific and selective inhibitors of the enzyme have been developed. The recent demonstration that the selective ETA receptor antagonist BQ-123 improves long term survival in rats with heart failure induced by myocardial infarction suggests that anti-endothelin strategies may hold great therapeutic promise in heart failure.

Topics: Aspartic Acid Endopeptidases; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Glycopeptides; Heart Failure; Humans; Metalloendopeptidases; Peptides, Cyclic; Protease Inhibitors

Although it was demonstrated that circulating endothelin-1 (ET-1) levels are elevated in congestive heart failure (CHF), the production and roles of ET-1 in the failing heart are not known. We investigated the production of ET-1 in the heart and the density of myocardial ET receptors in rats with CHF. We also investigated the effects of intravenously infused BQ-123, an endothelin(A) (ETA) receptor antagonist, on both heart and myocardial contractility in rats with CHF.. We used the left coronary artery-ligated rat model of CHF (CHF rats). Three weeks after surgery, the rats developed CHF. Plasma ET-1 concentration was significantly higher in the CHF rats than in the sham-operated rats (P<.01). In the left ventricle, the expression prepro-ET-1 mRNA was markedly higher in the CHF rats than in the sham-operated rats. The peptide level of ET-1 in the left ventricle was also significantly higher in the CHF rats than in the sham-operated rats (500+/-41 versus 102+/-10 pg/g tissue, P<.01). Myocardial ET receptors were significantly higher in the CHF rats than in the sham-operated rats (243+/-20 versus 155+/-17 fmol/mg protein, P<.05). In the CHF rats, intravenous BQ-123 infusion (0.1 mg x kg(-1) x min(-1) for 120 minutes) significantly decreased both heart rate (P<.01) and LV+dP x dt(max) (P<.05) but not mean blood pressure. BQ-123 infusion did not affect these hemodynamic parameters in the sham-operated rats.. In the present study, we demonstrated that the production of ET-1 in the heart is markedly increased and that the density of myocardial ET receptors is significantly elevated in the CHF rats. Intravenous BQ-123 infusion significantly reduced both heart rate and LV+dP/dt(max) in the CHF rats but not in the sham-operated rats. Therefore, the ET receptor-mediated signal transduction system in the heart appears to be markedly stimulated in the CHF rats, and endogenous ET-1 may be involved in the maintenance of the cardiac function in these rats.

Topics: Animals; Endothelin-1; Endothelins; Heart; Heart Failure; Hemodynamics; Male; Peptides, Cyclic; Protein Precursors; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger

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

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