bq-123 and Myocardial-Ischemia

Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide derived from vascular endothelial cells. ET-1 can also be produced by other cell types such as smooth muscle cells and cardiomyocytes. Plasma levels of ET-1 are elevated during several different cardiovascular disorders like atherosclerosis, myocardial infarction and congestive heart failure. During and following myocardial ischaemia and reperfusion, the myocardial production and release of ET-1 is stimulated and the coronary constrictor response to ET-1 is enhanced. These findings all favour a pathophysiological role for ET-1 in the development of ischaemia/reperfusion injury. Accordingly, by using different pharmacological tools (monoclonal antibody, ET converting enzyme inhibitor or ET receptor antagonists) that block the biological actions of ET-1, myocardial ischaemia/reperfusion injury has been demonstrated to be reduced in experimental animal models, in terms of both reduction in final infarct size and improved recovery of myocardial performance and coronary flow. However, some studies have shown no cardioprotective effects of ET receptor antagonists. Possible explanations for these apparently conflicting results are differences in animal species used, route and timing of drug administration, experimental protocol and chemical nature of the antagonists. The potential mechanisms underlying the cardioprotective effects of ET antagonists are discussed and include prevention of no-reflow, inhibition of ET-induced neutrophil activation, abolishment of direct pro-ischaemic actions of ET on myocytes, and interruption of interference of ET with the renin-angiotensin system.

Topics: Endothelin-1; Humans; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Peptides, Cyclic

To explore the morphological and functional effect of selective and non-selective endothelin (ET)-receptor blockade in coronary artery disease (CAD).. Prospective randomised controlled trial.. University hospital.. 26 patients with stable CAD.. Intracoronary infusion (30 minutes) of the ET-A receptor blocker BQ-123 (40 nmol/min, group A, n = 13) alone or with the ET-B receptor blocker BQ-788 (10 nmol/min, group AB, n = 13) as well.. Fractional flow reserve (FFR), coronary flow reserve (CFR) and intramyocardial resistance (IMR) by PressureWire, mean arterial blood pressure (MAP), minimal lumen diameter (MLD) and average angiographic lumen diameter (mean LD) of the target vessel before and after intracoronary infusion of ET antagonists. Concentrations of C-terminal pro-endothelin-1 (CT-proET1) in arterial blood were determined before and after infusion.. Mean MLD, mean LD, FFR, CFR, IMR and MAP remained unaffected by ET-receptor blockade in both groups; their changes were comparable. Concentrations of CT-proET-1 increased by 6.2 (SD 5.9) pmol/l (95% CI 1.2 to 11.1 pmol/l; p = 0.022) in group A and by 4.1 (SD 4.3) pmol/l (95% CI 1.1 to 7.2 pmol/l; p = 0.014) in group AB.. We found a broad variety of individual haemodynamic responses to ET-receptor antagonists with an overall neutral effect after an infusion period of 30 minutes despite an overall effective blockade of ET-receptors. Prolonged infusion time may be needed to cause a more distinct vasomotor response.. NCT00427232.

Topics: Adult; Aged; Angina Pectoris; Antihypertensive Agents; Coronary Angiography; Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Female; Fractional Flow Reserve, Myocardial; Humans; Male; Middle Aged; Myocardial Ischemia; Oligopeptides; Peptides, Cyclic; Piperidines; Prospective Studies; Protein Precursors; Young Adult

Topics: Adult; Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Combined Modality Therapy; Coronary Angiography; Echocardiography; Endothelin Receptor Antagonists; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Peptides, Cyclic; Pilot Projects; Receptor, Endothelin A; Recurrence; Registries; Severity of Illness Index; Single-Blind Method; Stents; Treatment Outcome; Ultrasonography, Interventional

Myocardial ischemia and reperfusion are associated with increased production of endothelin (ET)-1.. We examined the effects of BQ-123, a selective ET(A) receptor antagonist, in 80 patients. All patients were randomly allocated to an intracoronary infusion of saline or BQ-123 (6 micromol/L over 20 minutes). The reference group consisted of 20 patients undergoing coronary angiography. BQ-123 produced a 10% (P:<0.005) increase in distal coronary artery diameter. The main study group consisted of 30 patients undergoing coronary angioplasty. All patients underwent a minimum of 3 balloon inflations (BIs). Surface and intracoronary electrocardiographic ST-segment shift as well as pain score were recorded at the end of each BI. BQ-123 or saline was given by intracoronary infusion between the second and the third BI in random allocation. In the saline group, intracoronary ST-elevation decreased from 1.26+/-0.55 mV during the first BI to 0.77+/-0.56 mV during the third BI (P:<0.05) and the surface ST elevation decreased from 0.20+/-0.15 to 0.10+/-0.07 mV (P:<0.05). In the BQ-123 group, the respective values were 1.22+/-0.48 mV and 1.13+/-0.62 mV (intracoronary) and 0.17+/-0.18 and 0.17+/-0.21 mV (surface) (both P:=NS). The decrease in pain score was significantly higher in the saline group (F:=5.97, P:=0.004). In 30 patients (collateral circulation group), the angioplasty protocol was repeated with the use of a pressure guide wire. BQ-123 produced a significant (F:=3.30, P:=0.04) decrease in coronary wedge pressure.. Acute ET(A) receptor antagonism prevents the normal reduction of myocardial ischemia on repeated BIs during angioplasty. This may be explained by a "steal" effect through coronary collaterals.

Topics: Angioplasty, Balloon, Coronary; Antihypertensive Agents; Blood Pressure; Collateral Circulation; Coronary Angiography; Coronary Vessels; Electrocardiography; Endothelin Receptor Antagonists; Female; Heart Rate; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Myocardial Ischemia; Pain Measurement; Peptides, Cyclic; Receptor, Endothelin A; Receptors, Endothelin; Treatment Outcome

NO plays an important role in the compensatory increase in coronary flow conductance against myocardial ischemia, and NO bioavailability is impaired in various diseases. We tested the hypothesis that, when NO production is inhibited, vasoconstrictor signals from the ischemic myocardium are unmasked. We investigated the involvement of endothelin type A (ETA) receptors in the transduction of the constrictor signal. To detect coronary vasoactive signals derived from ischemic myocardium, we used a bioassay system in which an isolated rabbit coronary microvessel (detector vessel, DV) was placed on beating myocardium perfused by the left anterior descending coronary artery (LAD) of an anesthetized open-chest dog (n = 38). The DV was pressurized to 60 cmH2O throughout the experiment and observed with an intravital microscope equipped with a floating objective. After the intrinsic tone of the DV was established, vehicle (n = 7), Nomega-nitro-L-arginine (L-NNA, 100 micromol/l; n = 13), L-NNA + BQ-123 (a selective ETA receptor blocker, 1 micromol/l; n = 7), or BQ-123 alone (1 micromol/l; n = 7) was superfused onto the DV. Thereafter, the LAD of the beating heart was occluded. Coronary occlusion produced significant dilation of the DV by 10 +/- 4%. When L-NNA was applied, the DV significantly constricted by 12 +/- 5% in response to LAD occlusion, and BQ-123 abolished the vasoconstriction. Pretreatment with BQ-123 alone produced an enhancement of the ischemia-induced dilation. We conclude that ischemic myocardium releases transferable vasomotor signals that produce coronary microvascular constriction during the blockade of NO production and the constrictor signal is mediated by ETA receptors.

Topics: Animals; Coronary Vessels; Dogs; Endothelin A Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; In Vitro Techniques; Male; Microcirculation; Myocardial Ischemia; Nitric Oxide; Nitroarginine; Peptides, Cyclic; Rabbits; Receptor, Endothelin A; Signal Transduction; Vasoconstriction

The aim of the present study was to investigate the putative role of endothelin (ET) in mediating ischemia/hypoxia-induced ANP release utilizing exogenous ET-1 or ET receptor antagonists (BQ-123 or Bosentan). Isolated rat hearts with non-distended atria were perfused using a Langendorff apparatus and heart rate maintained constant via atrial pacing. Global ischemia was induced either by direct reduction in perfusion or by infusion of exogenous ET-1 (5 x 10(-10) M) for 30 minutes. Perfusion with the ET receptor antagonists, BQ-123 (10(-6) M) or Bosentan (10(-5) M) was initiated 10 minutes before onset of ischemia. Moderate or severe ischemia was induced by reduction (52-61% and 70-82%, respectively) in perfusate flow. Thirty minutes of ischemia/hypoxia (5% O2) was followed by 30 minutes of reperfusion/re-oxygenation. Both moderate and severe ischemia increased ANP release. BQ-123 and Bosentan did not affect basal or ischemia-induced ANP release. Exogenous ET-1 perfusion induced a late increase in ANP release (P < 0.01) that did not exceed the increase in ANP release associated with equivalent direct flow reduction. Hypoxia induced an 8-fold increase in ANP release rate. The ANP release rate returned toward basal levels after re-oxygenation. Bosentan, but not BQ-123, significantly attenuated (P < 0.01) hypoxia-induced ANP release. In conclusion, in this system, ANP release is stimulated by moderate (or severe) ischemia and severe hypoxia independent of change in atrial distension; endogenous ET does not mediate basal and ischemia-induced ANP release; and hypoxia-induced ANP release is partially modulated via interaction with endogenous ET.

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Bosentan; Endothelin Receptor Antagonists; Endothelins; Heart; Hypoxia; Male; Myocardial Ischemia; Peptides, Cyclic; Radioimmunoassay; Rats; Sulfonamides

This study addressed the hypothesis that endothelin promotes neutrophil accumulation in ischemic/reperfused myocardium, not only via its direct effect on neutrophils, but also because it mediates post-ischemic endothelial injury. Langendorff-perfused guinea-pig hearts were subjected to 30 min ischemia/35 min reperfusion, and infusion of neutrophils between 15 and 25 min of reperfusion. The infusion of the endothelin ET(A)/ET(B) receptor antagonist, tezosentan, the endothelin ET(A) receptor antagonist, BQ 123 [cyclo(-D-Trp-D-Asp-Pro-D-Val-Leu-], and superoxide dismutase was terminated at reperfusion, 5 min before the start of the neutrophil infusion, to avoid the contact of the drugs with neutrophils. Coronary flow responses to acetylcholine and nitroprusside were used as measures of endothelium-dependent and -independent vascular function, respectively. Neutrophil adhesion and endothelium glycocalyx ultrastructure were assessed in histological preparations. Ischemia/reperfusion resulted in a 54%-impaired acetylcholine response, endothelium glycocalyx disruption, and enhanced neutrophil adhesion (21.6% of microvessels contained neutrophils vs. 2.6% in sham group), the latter prevented by a selectin blocker, sulfatide, 20 microg/ml. These alterations were completely prevented by 0.5 and 5 nM, but not 0.05 nM, tezosentan, and were greatly attenuated by BQ 123, 1 and 10 nM. The glycocalyx-protective effect of these interventions preceded their effect on neutrophil adhesion. Superoxide dismutase, 150 IU/ml, reported before by us to protect post-ischemic endothelium glycocalyx, here prevented the post-ischemic endothelial dysfunction and neutrophil adhesion. The data imply that neutrophil adhesion in ischemic/reperfused guinea-pig heart is a selectin-dependent process, secondary to mostly endothelin ET(A) receptor- and free radical-mediated functional and/or structural changes in the coronary endothelium. Thus, endothelin ET(A)/ET(B) as well as ET(A) receptor antagonists may be useful in attenuation of the inflammatory response in ischemic/reperfused heart. The antagonists may be effective because of their direct effect on neutrophils, as demonstrated by others, and because they provide endothelial protection, as demonstrated here.

Topics: Acetylcholine; Animals; Cell Adhesion; Endothelins; Endothelium, Vascular; Female; Guinea Pigs; Hemodynamics; Male; Myocardial Ischemia; Neutrophils; Peptides, Cyclic; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

The effects of the endothelin ET(A), (BQ-123) and endothelin ET(A/B) (PD161721) receptor antagonists were investigated on ischaemia-induced arrhythmias and on the maximum following frequency. The study was carried out in Langendorff perfused rat hearts subjected to coronary artery occlusion in which the severity of arrhythmias, coronary perfusion pressure and heart rate were measured. The % incidence of ischaemia-induced irreversible ventricular fibrillation (ventricular fibrillation) was reduced significantly from 58%, in control rat hearts, to 0% (at 10(-7) and 10(-6) M PD161721 and 10(-6) M BQ-123 P<0.05). Maximum following frequency was measured in guinea-pig isolated atria. In the presence of normal extracellular [K(+)], BQ-123 and PD161721, at 10(-6) M, significantly decreased the maximum following frequency from 9.0+/-0.7 to 7.2+/-0.4 and from 8.3+/-0.4 to 6.7+/-0.3 Hz, respectively (P<0.05). These effects were not potentiated by raising the extracellular [K(+)] with the exception of 10(-9) M PD161721. In contrast, lignocaine's ability to reduce the maximum following frequency was greater in elevated (e.g. at 1.7x10(-4) M from 8.4+/-0.3 to 2.5+/-0.6 Hz) than in normal [K(+)] (from 9.0+/-0.3 to 4.9+/-0.5 Hz). In conclusion, both BQ-123 and PD161721 had an anti-fibrillatory effect in isolated rat hearts that may be due, at least in part, to an ability to reduce the maximum following frequency. This latter effect is unlikely to be due to Na(+) channel blockade since it was not markedly potentiated by elevation of extracellular [K(+)].

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Function; Dioxins; Dose-Response Relationship, Drug; Electrophysiology; Endothelin Receptor Antagonists; Guinea Pigs; Heart; Heart Atria; Heart Rate; In Vitro Techniques; Lidocaine; Male; Muscle Contraction; Myocardial Ischemia; Peptides, Cyclic; Perfusion; Pressure; Rats; Rats, Sprague-Dawley

The aim of this study was to investigate the influence of endogenously released and exogenously applied endothelin-1 (ET-1) on ischaemia-induced arrhythmias.. Ischaemia was induced in pentobarbitone-anaesthetised rats by ligation of a coronary artery for 30 min. To determine the role of endogenous ET-1 in ischaemic arrhythmias, either the ETA receptor antagonist BQ123 (50 micrograms/kg/min, i.v.; n = 10) or the ETB receptor antagonist PD161721 (0.1 or 1 mg/kg i.v.; n = 10 per group) was administered before the onset of ischaemia. To assess the influence of exogenous ET-1 on arrhythmias, ET-1 (1.6 nmol/kg i.v.) was administered 5 min before ischaemia in the absence (n = 12) or presence of BQ123 (n = 10) or PD161721 (n = 10). The total number of ventricular ectopic beats (VEB's) were counted and expressed as median (Q1-Q3) and the incidence of ventricular fibrillation (VF) and ventricular tachycardia (VT) in each group was determined. Mean arterial blood pressure (MABP) and heart rate (HR) were measured.. In control animals (n = 20), the incidence of VF was 65% and the total VEB count was 2775 (1870-4041). Both BQ123 and the higher dose of PD161721 reduced the VEB count to 654 (348-1489; P < 0.05) and 782 (432-1153; P < 0.05) respectively. Only PD161721 reduced the incidence of VF (to 10%; P < 0.05). Administration of ET-1 reduced VEB's to 1530 (1204-2017); P < 0.05) and the incidence of VF to 17% (P < 0.05). Neither PD161721 nor BQ123 modified this antiarrhythmic effect of ET-1, but rather enhanced the reduction in arrhythmias. Before occlusion, ET-1 caused a transient fall in MABP (from 107 +/- 3 to 63 +/- 3 mmHg; P < 0.05). PD161721, but not BQ123, partially blocked this effect. Upon occlusion, MABP fell in control animals (from 106 +/- 4 to 67 +/- 4 mmHg at 1 min post-occlusion; P < 0.05). This was significantly attenuated by ET-1, although neither of the antagonists were able to block this effect of ET-1.. ET-1 released endogenously during ischaemia is arrhythmogenic whereas exogenous application of ET-1 may, under certain conditions, be antiarrhythmic.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Dioxins; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Male; Myocardial Ischemia; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Time Factors; Ventricular Premature Complexes

The vasoconstrictor effect of endothelins (ET) is mediated by endothelin A (ETA) and endothelin B (ETB) receptors. Furthermore, ETB receptor stimulation results in release of vasodilators. Hence, ETA receptor antagonists should attenuate ET-mediated vasoconstriction. The aim of the present study was to evaluate and compare the effects of BQ-123, an ETA receptor antagonist, and bosentan, an ETA and ETB receptor antagonist, on coronary vasomotor tone, left ventricular systolic function and ET-1 efflux in the presence or absence of myocardial ischaemia/reperfusion.. Isolated rat hearts were perfused using a Langendorff preparation. Global ischaemia was induced on average by 68 +/- 2% (+/- standard error of the mean) reduction of a baseline perfusion flow-rate 10 min after introduction of ET antagonists. Thirty minutes of ischaemia was followed by 30 min reperfusion. ET-1 efflux in coronary perfusate was measured by radioimmunoassay.. In non-ischaemic hearts (n = 7), BQ-123 (10(-6) M) perfusion induced a progressive decrease in coronary flow-rate compared with control group. This flow reduction persisted after wash-out of BQ-123. In contrast, bosentan (10(-5) M, n = 7) induced no change in perfusion rate. In the absence of ET antagonists (n = 16), there was a 22 +/- 6% post-ischaemic increase in perfusion flow-rate. BQ-123 (n = 5) but not bosentan (n = 12) abolished this post-ischaemic increase in flow-rate. Neither BQ-123 nor bosentan induced significant variation in force of contraction. In ischaemic hearts, ischaemia per se induced a transient decrease in force of contraction. Bosentan significantly (P < 0.05) accentuated and BQ-123 tended to accentuate (P = 0.06) this decrease in force of contraction during ischaemia. Bosentan but not BQ-123 significantly impaired the recovery of systolic function during reperfusion (P < 0.05). Both BQ-123 and bosentan perfusion increased ET-1 efflux rate to 730 +/- 188% and 315 +/- 81% respectively. This effect was abolished during ischaemia for BQ-123, but not for bosentan.. In isolated perfused rat hearts, both BQ-123 and bosentan increased ET-1 efflux, but only BQ-123 exerted vasoconstrictor effects. These results thus generated the hypothesis that: (1) ET-1 release within the coronary vascular bed may be physiologically subject to negative feedback regulation mediated via ETA receptors; (2) ETA receptor antagonists increase ET-1 efflux, which may lead to net vasoconstriction via unopposed ETB stimulation. Furthermore, the negative inotropic effects observed during ischaemia suggest that ET is critical to the maintenance of systolic function during ischaemia.

Topics: Animals; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Male; Myocardial Contraction; Myocardial Ischemia; Peptides, Cyclic; Perfusion; Rats; Rats, Inbred Strains; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Regional Blood Flow; Sulfonamides; Vasoconstriction; Ventricular Function, Left

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen involved in vascular development and angiogenesis. Recently we have observed increased VEGF expression in the normal myocardium after myocardial infarction in a rat heart. This study was designed to explore the mechanism responsible for this increase in VEGF expression. Induction of myocardial stretch in an isolated perfused Langendorff preparation by inflation of an intraventricular balloon to an end-diastolic load of 35 mmHg for 30 min resulted in a nearly sixfold increase in VEGF message level not only in the chamber subjected to stretch (left ventricle) but also in the unstretched right ventricle, thus raising the possibility of a soluble factor mediating stretch- induced induction of VEGF expression. This was further confirmed by demonstrating that coronary venous effluent collected from the stretched heart and used to perfuse isolated hearts in which no balloon was present was able to induce VEGF expression in these normal hearts. Inhibition of TGF-beta activity using a neutralizing antibody, but not antagonists/inhibitors of endothelin and angiotensin II, eliminated stretch-induced increase in VEGF expression. Staurosporine, a protein kinase C inhibitor, also blocked stretch-induced increase of VEGF expression. Measurement of TGF-beta concentration in the perfusate demonstrated increased amounts of the cytokine after myocardial stretch, and addition of TGF-beta protein to the perfusion buffer resulted in increased VEGF expression in control hearts. These results suggest that stretch-induced increase of VEGF expression in the heart is mediated at least in part by TGF-beta.

Topics: Angiotensin II; Animals; Antibodies; Catheterization; Diastole; Endothelial Growth Factors; Endothelin Receptor Antagonists; Endothelin-1; Heart; In Vitro Techniques; Lymphokines; Male; Myocardial Ischemia; Myocardium; Peptides, Cyclic; Protein Kinase C; Rats; Rats, Sprague-Dawley; RNA, Messenger; Saralasin; Staurosporine; Transcription, Genetic; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The intracellular mechanism for endothelial dysfunction after myocardial ischemia-reperfusion remains to be elucidated. It has been reported that activation of protein kinase C (PKC) occurs after myocardial ischemia-reperfusion and that the activation impairs endothelium-dependent relaxation. Thus we examined the role of PKC activation in the ischemia-reperfusion-induced endothelial dysfunction. Isolated rat hearts perfused with a constant flow were subjected to global ischemia for 15 min followed by reperfusion for 20 min. Coronary vascular responses to the endothelium-dependent vasodilators acetylcholine (ACh) and bradykinin (BK) and the endothelium-independent vasodilator sodium nitroprusside (SNP) were examined before and after the ischemia-reperfusion. Endothelium-dependent relaxations to ACh and BK were impaired after the ischemia-reperfusion, whereas endothelium-independent relaxations to SNP were unaffected. Pretreatment with a PKC inhibitor, staurosporine, H7, or calphostin C, prevented the impairments. Phorbol 12-myristate 13-acetate, a PKC-activating phorbol ester, attenuated the relaxations to ACh and BK but not those to SNP. These results suggest that PKC activation may be involved in part in the ischemia-reperfusion-induced endothelial dysfunction.

Topics: Animals; Endothelin Receptor Antagonists; Endothelium, Vascular; Enzyme Activation; Male; Myocardial Ischemia; Myocardial Reperfusion; Peptides, Cyclic; Protein Kinase C; Rats; Rats, Inbred WKY; Reperfusion Injury; Tetradecanoylphorbol Acetate; Vasodilation

The effects of intravenous (i.v.) infusions of exogenous endothelin-1 (ET-1, 0.05 and 0.1 nmol/kg/min) on incidence and severity of ventricular arrhythmias during 30-min period of acute myocardial ischemia were assessed in anesthetized rats. We examined the role of ETA-receptors in the proarrhythmic effects of both exogenous and endogenous ET using the ETA-receptor antagonist, BQ123. Exogenous ET-1 increased the severity and incidence of ischemic arrhythmias dose dependently. Both doses increased the total incidence of ventricular fibrillation (VF: from 30% in controls to 100 and 88% in rats given 0.05 and 0.1 nmol/kg/min ET-1, respectively); the higher dose also increased total arrhythmia count and duration of ventricular tachycardia (VT). BQ123 (10 micrograms/kg/min) completely abolished this proarrhythmic effect of exogenous ET-1. To assess the role of endogenous ET-1 in the genesis of ischemic arrhythmias, we studied the effects of a range of doses of BQ123 (5-100 micrograms/kg/min) on ischemic arrhythmias. Only one dose of BQ123 (10 micrograms/kg/min) attenuated arrhythmias by reducing total ventricular ectopic count (from 1,423 +/- 112 in controls to 677 +/- 159). The highest dose of BQ123 tested (100 micrograms/kg/min) increased arrhythmias by significantly increasing the incidence of irreversible VF (from 25 to 75%). These results suggest that exogenous ET-1 can aggravate ischemia-induced arrhythmias, an effect that is sensitive to ETA-receptor blockade. However, although endogenous ET-1 may make some contribution to the genesis of arrhythmias resulting from coronary occlusion through an action at ETA receptors, the observed proarrhythmic effect of BQ123 at high doses suggests that this may unmask an effect of ET-1 at other receptors.

Topics: Anesthesia; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Vessels; Electrocardiography; Endothelin Receptor Antagonists; Endothelins; Heart Rate; Infusions, Intravenous; Male; Myocardial Ischemia; Peptides, Cyclic; Rats; Rats, Sprague-Dawley

It has been proposed that myocardial ischaemic injury is modulated in part by the release of endothelin-1 from the coronary endothelium either during ischaemia or following reperfusion. Release of sufficient amounts of endothelin-1 would result in coronary vasoconstriction and could potentiate ischaemic damage. An endothelin-1 antagonist, BQ-123, was given intravenously to evaluate the role of endothelin-1 in postischaemic injury and determine whether blockade of the ETA receptor would afford protection from ischaemia/reperfusion injury.. Myocardial injury was induced in anaesthetised dogs using 90 min of left circumflex coronary artery occlusion followed by 4 h of reperfusion. Animals treated with a continuous intravenous infusion of BQ-123 (0.1 mg.kg-1.min-1), begun 10 min before ischaemia and continued throughout ischaemia and reperfusion, were compared to saline treated animals.. After 4 h of reperfusion the myocardial infarct size measured by triphenyltetrazolium chloride staining was not different between the two groups. Infarct size in the control group was 25.7 (SEM 5.4)% of the area at risk while BQ-123 treatment resulted in an infarct size of 29.2(7.1)% of the area at risk (p = 0.70). Plasma endothelin-1 concentration measured at the coronary sinus was only significantly increased following 5 min of reperfusion.. The intravenous administration of a specific ETA receptor antagonist does not protect against ischaemia/reperfusion injury. These results suggest that endothelin-1 receptor antagonists require access to the area at risk during occlusion to protect the myocardium from ischaemic injury.

Topics: Animals; Coronary Vessels; Dogs; Endothelin Receptor Antagonists; Endothelins; Infusions, Intravenous; Ligation; Myocardial Ischemia; Myocardial Reperfusion Injury; Peptides, Cyclic; Random Allocation

Endothelin (ET)-1 is produced in response to myocardial ischemia and reperfusion. It is a potent constrictor of coronary resistance vessels and may therefore contribute to myocardial injury and postischemic microvascular dysfunction. Isolated buffer-perfused rabbit hearts, under conditions of constant flow and isovolumic contraction, underwent 60 min of global ischemia and 60 min of reperfusion after pretreatment with selective ETA receptor antagonist BQ-123 (10(-7) M) in perfusate, exogenous ET-1 (10(-11) M), or control. Release of ET increased significantly at 20 and 60 min of reperfusion. BQ-123 did not enhance the recovery of left ventricular developed pressure or coronary perfusion pressure, whereas exogenous ET tended to worsen them. Cumulative creatine kinase release over 20 min of reperfusion did not differ significantly between groups. Maximum endothelium-dependent dilation to acetylcholine (ACh) was initially 62 +/- 6, 71 +/- 6, and 63 +/- 8% (SE) of U-46619-induced preconstriction in control, BQ-123-, and ET-treated hearts. At 20 min of reperfusion it was 37 +/- 5, 73 +/- 9, and 22 +/- 5%, and at 60 min of reperfusion it was 35 +/- 7, 79 +/- 6, and 22 +/- 3% (P < 0.001 for BQ-123 vs. control at 20 min and P < 0.0001 at 60 min). Endothelium-independent dilation to nitroglycerin was unaltered by ischemia and reperfusion. Neither BQ-123 alone nor a 1-h infusion of ET (10(-10) M) altered the response to ACh in nonischemic hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelins; Endothelium, Vascular; Male; Muscle, Smooth, Vascular; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Peptides, Cyclic; Rabbits; Time Factors

The current study was undertaken to define a biological role for the endothelin-A receptor in a clinically relevant model of altered systemic and renal function produced by suprarenal aortic cross-clamping. This model is associated with profound systemic and renal vasoconstriction, acute renal failure, and a significant increase in circulating endothelin. Studies were performed in three groups of anesthetized mongrel dogs. Group 1 (n = 5) underwent aortic cross-clamping for 1 hour; group 2 (n = 5) underwent aortic cross-clamping for 1 hour in the presence of BQ-123, a specific antagonist of the endothelin-A receptor; group 3 (n = 4) received BQ-123 alone. The marked systemic and renal vasoconstriction associated with aortic cross-clamping in group 1 was markedly attenuated in group 2 in the presence of BQ-123. Unlike the vasoconstrictor response, BQ-123 did not attenuate the decrease in glomerular filtration rate associated with this model. Under unstimulated conditions in group 3, BQ-123 had no actions on systemic or renal hemodynamics. In conclusion, the current study demonstrates that the systemic and renal vasoconstriction associated with aortic cross-clamping are in part mediated through the interaction of endothelin and the endothelin-A receptor. This study demonstrates the functional importance of increased endogenous endothelin in the regulation of vascular tone in this pathophysiological state.

Topics: Animals; Aorta; Blood Pressure; Cardiac Output; Disease Models, Animal; Dogs; Endothelins; Heart Rate; Hemodynamics; Ischemia; Kidney; Myocardial Ischemia; Peptides, Cyclic; Receptor, Endothelin A; Receptors, Endothelin; Vascular Resistance; Vasoconstriction

The effect of endothelin-1 (ET-1) and big ET-1 on coronary flow and contractile function was determined in isolated nonischemic and ischemic rat hearts. Both ET-1 (IC50 = 12 pMol) and big ET-1 (IC50 = 2 nMol) reduced coronary flow in a concentration-dependent manner, although ET-1 was > 100-fold more potent. Both compounds decreased contractility, an effect which was lost when coronary flow was held constant, indicating that ET-1 and big ET-1 decrease contractility secondary to reducing coronary flow. Mechanical reduction in coronary flow to levels equivalent to those seen for ET-1 or big ET-1 caused similar reductions in contractility. Both 30 pMol ET-1 and 10 nMol big ET-1 pretreatment significantly reduced the time to contracture in globally ischemic rat hearts, suggesting a proischemic effect. Phosphoramidon (100 microM, endothelin-converting enzyme inhibitor) and BQ-123 (0.3 microM, ETA receptor antagonist) abolished the preischemic increase in coronary perfusion pressure induced by big ET-1 as well as its proischemic effect, whereas only BQ-123 abolished the cardiac effect of ET-1. Neither phosphoramidon nor BQ-123 had an effect on severity of ischemia when given alone. Phosphoramidon was also given i.v. to rats subjected to coronary occlusion and reperfusion and was found to significantly reduce infarct size 24 hr postischemia. Thus, in isolated rat hearts, big ET-1 appears to be converted to ET-1 and is a potent coronary constrictor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Coronary Circulation; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin-1; Endothelins; Glycopeptides; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Peptides, Cyclic; Protein Precursors; Rats; Rats, Sprague-Dawley