Increased fibrin specificity and reduced paradoxical thrombin activation of the combined thrombolytic regimen with reteplase and abciximab versus standard reteplase thrombolysis.

In patients with acute myocardial infarction treated with thrombolytics, platelet activation as well as alterations of the hemostatic and fibrinolytic systems have been described favoring early infarct-related artery reocclusion. We investigated the effects of a newer thrombolytic regimen with half-dose double-bolus reteplase (2 x 5 IU, 20 patients) combined with abciximab versus full-dose reteplase (2 x 10 IU, 18 patients) on the fibrinolytic and the hemostatic system in patients with acute ST-segment elevation (in the electrocardiogram) myocardial infarction. The thrombolytic regimen with half-dose reteplase in combination with abciximab caused in vivo a lower systemic plasminemia and a lower paradoxical activation of the contact phase of the coagulation system (measured as activated factor XII); a lower paradoxical thrombin activation/generation; and a lesser extent of fibrinogen breakdown compared with the reteplase regimen. These results could be, at least in part, a possible explanation for the observed significantly lower rates of reinfarction until 7 days after enrollment and of recurrent ischemia in the combination group in the Global Use of Strategies to Open Occluded Coronary Arteries V (GUSTO V) trial.

Benefical effects of reteplase in combination with abciximab: platelet/leukocyte interactions and coagulation system.

Pathophysiological aspects of acute myocardial infarction include altered hemostatic and fibrinolytic systems as well as platelet activation. Treatment with thrombolytics and GP IIb/IIIa antagonists has been described as having an additional influence on these systems. We investigated the effects of a new thrombolytic regimen with half-dose double-bolus reteplase (2 x 5 IU, 20 patients) combined with abciximab versus full dose reteplase (2 x 10 IU, 18 patients) on platelet-granulocyte complexes and on thrombin-antithrombin III complexes in patients with acute ST-segment elevation myocardial infarction. In vivo, the thrombolytic regimen with half-dose reteplase in combination with abciximab caused fewer platelet-granulocyte aggregates (measured as percentage of CD41-positive granulocytes) and a lower paradoxical activation of the coagulation system (measured as thrombin-antithrombin III complex) compared with the reteplase regimen. The combination regimen could therefore have benefical effects on platelet-induced leukocyte activation and leukocyte-mediated proinflammatory/cytotoxic effects as well as on granulocyte-induced effects on endothelium, tissue damage and coagulation. This could be, at least in part, a possible explanation for the significantly lower rates of reinfarction, recurrent ischaemia and percutaneous coronary interventions observed during the early phase after an acute myocardial infarction in the combination group in the GUSTO-V trial.

Acute gender-specific hemodynamic and inotropic effects of 17beta-estradiol on rats.

Estrogen has cardioprotective effects. In addition to beneficial effects on lipid metabolism, estrogen affects the vascular tone and may reduce endothelial dysfunction. In the present study, we examined acute gender-specific hemodynamic and inotropic effects of 17beta-estradiol (17beta-E) versus the control situation in open-chest rats. In addition to measurements in the intact circulation, myocardial function was examined on the basis of isovolumic registration independent of peripheral vascular effects. Regarding the dose-dependent and gender-specific effects of 17beta-E, in female rats, 17beta-E (50, 100, or 200 ng/kg) increased cardiac output (CO) (26%, 43%, and 59% versus control animals) as a result of reduction in total peripheral resistance (TPR) (-13%, -18%, and -24%) without any effect on myocardial contractility (isovolumic left ventricular systolic pressure, -1%, 0%, and -6%). These vascular effects are less pronounced in male rats (for 200 ng/kg 17beta-E: CO, 34%; TPR, -14%). We investigated gender-specific effects of 200 ng/kg 17beta-E after pretreatment with the estrogen receptor (ER) antagonist ICI 182,780. ER blockade reduced the effects of estrogen in female rats (CO, 29%; TPR, -17%) and male rats (CO, 19%; TPR, -11%). Regarding the effects of 200 ng/kg 17beta-E after pretreatment with N(G)-nitro-L-arginine methyl ester, NO synthesis inhibition completely prevented the acute vascular effects of estrogen in female rats (CO, -4%; TPR, 1%). In addition, immunohistochemical staining revealed no gender-specific differences of the vascular ER distribution. 17beta-E caused an acute dose-dependent and gender-specific reduction in the afterload. ERs are involved in both genders in this vasodilative effect that is mediated by NO. This NO-mediated effect may explain in part the cardioprotective effect of estrogen.

Myocardial troponin T release is associated with enhanced fibrinolysis in patients with acute coronary syndromes.

Patients with acute coronary syndromes (ACS) frequently present with signs of disturbed fibrinolysis. The present study investigates the correlation of alterations in the fibrinolytic system and the amount of myocardial damage characterized by troponin release. In 85 patients with ACS markers of plasmin activation, plasminogen activator system and troponin T (TnT) were measured initially and after 48 h. Patients with TnT release (> or = 0.01 microg/l) at admission had higher TPA levels than those without release (10.2+/-0.7 ng/ml vs. 7.6+/-0.5 ng/ml; p <0.01). Additionally, patients with positive TnT had higher D-dimer levels initially (457+/-39 ng/ml vs. 316+/-22 ng/ml; p <0.01) and 48 h later (451+/-42 ng/ml vs. 275+/-37 ng/ml; p <0.01). The association of myocardial damage with a prothrombotic state and an enhanced fibrinolysis may explain the high prognostic value of troponin measurements in respect to future coronary events.

Fibrin specificity and procoagulant effect related to the kallikrein-contact phase system and to plasmin generation with double-bolus reteplase and front-loaded alteplase thrombolysis in acute myocardial infarction.

This study was undertaken to compare the effects of reteplase and alteplase regimens on hemostasis and fibrinolysis in acute myocardial infarction (AMI). Thrombolytic treatment in patients with AMI is hampered by paradoxical procoagulant effects that favor early reocclusion. In vivo data comparing this effect and the fibrin specificity of double-bolus reteplase and front-loaded alteplase regimens are not available. In a prospective, randomized study, 50 patients with AMI were either treated with double bolus (10 + 10 U) reteplase or with front-loaded alteplase (up to 100 mg) within 6 hours of symptom onset. Thirty apparently healthy persons served as controls. Molecular markers of coagulation and fibrinolysis were serially examined for up to 5 days. Paradoxical thrombin activation at 3 hours after initiation of therapy was comparable between reteplase and alteplase. Reteplase (65 +/- 5 U/L) and alteplase (72 +/- 8 U/L) caused significantly elevated kallikrein activity at 3 hours after adminstration (p <0.01 vs controls 30 +/- 1 U/L). Fibrin specificity was less for reteplase (p <0.05) with a decrease in fibrinogen at 3 hours to 122 +/- 27 mg/dl versus 224 +/- 28 mg/dl for alteplase (p <0.01 and p <0.05 vs controls). D-Dimer levels at 3 hours were higher (p <0.05) after reteplase (5,459 +/- 611 ng/ml) versus alteplase (3,445 +/- 679 ng/ml) (both p <0.01 vs controls 243 +/- 17 ng/ml). Plasmin generation (plasmin-antiplasmin complexes) was significantly (p <0.01) increased at 3 hours with both regimens to 27,079 +/- 3,964 microg/L (reteplase) and 19,522 +/- 2,381 microg/L (alteplase). The data from 3 hours after start of thrombolytic therapy proved less marked fibrin specificity of the reteplase regimen (in vivo) compared with front-loaded alteplase. Both regimens have a moderate procoagulant effect without differences in activation of the kallikrein system.

Inotropic effects of endothelin-1: interaction with molsidomine and with BQ 610.

-In vivo studies could not detect a positive inotropy of endothelin (ET)-1 as described in in vitro experiments. ET-induced direct positive inotropy, which seems to be mediated by ETB receptors, may be antagonized in vivo by an indirect cardiodepressive effect owing to an ET-induced coronary vasoconstriction via ETA receptors. This study compares the effects of a dose of 1 nmol/kg ET-1 alone on myocardial contractility and myocardial energy metabolism with the effects of 1 nmol/kg ET-1 after pretreatment with 5 mg/kg molsidomine or with 100 microg/kg of the ETA receptor antagonist BQ 610. We investigated the effects of ET-1 versus saline controls in open-chest rats. In addition to measurements in the intact circulation, myocardial function was examined by isovolumic registrations independent of peripheral vascular effects. We also studied the effect of ET-1 on myocardial high-energy phosphates. Pretreatment with molsidomine and BQ 610 attenuated the ET-induced reduction of cardiac output (ET-1: -62%; molsidomine+ET-1: -47%; BQ 610+ET-1: -27% different from controls). After a transient initial vasodilation, ET-1 raised total peripheral resistance (ET-1: +190%; molsidomine+ET-1: +171%; BQ 610+ET-1: +89%). BQ 610 was more effective in preventing ET-induced vasoconstriction. The increase of isovolumic peak first derivative of left ventricular pressure (ET-1: -2%; molsidomine+ET-1: +16%; BQ 610+ET-1: +19%) after pretreatment with molsidomine or BQ 610 indicates that these drugs unmask the positive inotropy of ET-1. ET-induced myocardial ischemia was abolished by molsidomine and BQ 610. Pretreatment with molsidomine or blockade of ETA receptors by BQ 610 can unmask the positive inotropy of ET-1 by preventing ET-induced myocardial ischemia. The positive inotropic effect of ET-1 seems to be mediated by ETB receptors.

Thrombolytic therapy in acute myocardial infarction: comparison of procoagulant effects of streptokinase and alteplase regimens with focus on the kallikrein system and plasmin.

BACKGROUND: Thrombolytic therapy in patients with acute myocardial infarction (AMI) is hampered by procoagulant effects. In vitro studies have indicated that plasmin stimulation activates the kallikrein-contact-phase system, resulting in thrombin activation. This prospective comparative study was designed to examine the procoagulant effects of streptokinase or alteplase in AMI. METHODS AND RESULTS: Sixty-one patients with AMI received 1.5 million U of streptokinase or front-loaded alteplase (up to 100 mg) and systemic heparin. Twenty-four patients with AMI and no thrombolytic therapy and 30 control subjects were examined for comparison. Molecular markers of thrombin, plasmin activation, and coagulation activities were determined before therapy and serially for up to 10 days. Moderate thrombin (initial thrombin-antithrombin [TAT] complex 18+/-5 versus 4+/-0.3 microg/L, P<0.05) and kallikrein (up to 45+/-4 versus 30+/-1 U/L at 3 hours, P<0.01) activation occurs in patients with AMI. D-Dimers are increased (P<0.01), and plasmin is stimulated (P<0.01). Streptokinase and alteplase increase TAT to 50+/-17 and 51+/-18 microg/L at 3 hours and to 50+/-17 and 33+/-14 microg/L at 6 hours, respectively (P<0.01). Kallikrein activity is elevated (P<0. 01) to 76+/-5 and 71+/-7 U/L at 3 hours and 64+/-6 and 47+/-5 U/L by streptokinase and alteplase, respectively, at 6 hours. Reductions in fibrinogen and increases in D-dimers and plasmin-antiplasmin complexes are more marked (P<0.05 and 0.01) after streptokinase versus alteplase. Correlations were found among TAT, kallikrein activity, and plasmin activation (P<0.01). CONCLUSIONS: The data indicate a more marked procoagulant action of the streptokinase regimen compared with front-loaded alteplase, thus supporting the hypothesis of a plasmin-mediated kallikrein activation with consecutive procoagulant action in vivo.

Energy generation in hypertrophied postischemic myocardium. Feasibility of prolonged inotropic stimulation with dopamine in hypertrophied reperfused left ventricles.

BACKGROUND: Non-hypertrophied reversibly injured postischemic myocardium can be stimulated for a prolonged period without detrimental effects. Since no data on hypertrophied myocardium are available, our aim was to examine the effects of a prolonged postischemic positive inotropic stimulation on moderately hypertrophied left ventricles. METHODS: Using a Langendorff-type isovolumically contracting isolated heart model, moderately hypertrophied (+50% of ventricular mass) hearts from spontaneously hypertensive rats (SHR) were investigated and compared to data from non-hypertrophied hearts of normotensive rats. A 30 minutes noflow ischemia was performed, and in the postischemic period dopamine was continuously administered for 20 minutes in order to stimulate the postischemic hearts to the control level of function. Data were compared to postischemic hearts without stimulation and to non-ischemic controls. After 50 minutes of reperfusion and cessation of the catecholamine steady state function, maximum contractile response, and high energy phosphates were determined. RESULTS: 30 minutes ischemia followed by 50 minutes reperfusion caused a significant reduction in developed LVP to 77.8 +/- 4.2% in SHR. Dp/dtmax was reduced to 67.0 +/- 2.3%. After cessation of dopamine stimulation developed LVP was 64.3 +/- 3.5% and dp/dtmax 69.3 +/- 3.7% in SHR. The double product was identically reduced in all postischemic groups. The contractile reserve was comparable in stimulated and non-stimulated postischemic SHR hearts. In hypertrophied myocardium, ATP was reduced to 1.1 +/- 0.1 mumol/gww (non-ischemic controls 2.5 +/- 0.3 mumol/gww) in unstimulated and to 1.0 +/- 0.1 mumol/gww in stimulated postischemic hearts. Comparably the ischemia-induced reduction in ATP in non-hypertrophied myocardium was 1.3 mumol/gww. Similar results were obtained for ADP and AMP. Creatine phosphate levels were normal in stimulated and non-stimulated postischemic myocardium of hypertrophied and non-hypertrophied hearts. CONCLUSION: These results indicate that prolonged stimulation of stunned hypertrophied myocardium is feasible without detrimental effects on post-stimulation contractile function. The energy generating apparatus is capable to deliver sufficient energy during stimulation of stunned hypertrophied hearts.

Inotropic response of stunned hypertrophied myocardium: responsiveness of hypertrophied and normal postischemic isolated rat hearts to calcium and dopamine stimulation.

OBJECTIVE: Severely hypertrophied myocardium was described to have a reduced tolerance towards ischemia. For non-hypertrophied hearts inconclusive findings on the Ca(2+)-responsiveness are reported. Information sensitivity to reversible ischemia and on postischemic Ca(2+)-responsiveness of hearts with clinically common moderate hypertrophy is lacking. Thus, the responsiveness of hypertrophied and normal postischemic myocardium to positive inotropic stimulation should be investigated in the present study. METHODS AND RESULTS: Hearts from spontaneously hypertensive rats (SHR, 4 months old) with significant LV-hypertrophy (+ 50%) and hearts from normotensive 4 months old Wistar rats were investigated using an isovolumic beating isolated heart model (8 hearts/each of the 8 groups). Functional recovery after 30 min of no-flow ischemia was 78 +/- 1% and 77 +/- 3% of preischemic control data in hypertrophied and non-hypertrophied hearts assessed as developed left ventricular pressure (non-ischemic controls: 95 +/- 2% in hypertrophied and 93 +/- 3% in non-hypertrophied controls). Maximum short-term stimulation with Ca2+ revealed a decreased peak left ventricular pressure of 124 +/- 4% in hypertrophied and 120 +/- 5% in non-hypertrophied postischemic hearts, as compared with non-ischemic controls 138 +/- 3% and 157 +/- 5%, respectively ( p < 0.01). A maximum dose of dopamine stimulated hypertrophied and non-hypertrophied postischemic hearts comparable to Ca2+. Analysing the dose-response curve for Ca(2+)-stimulation, the sensitivity expressed as fraction of the maximum was identical in non-ischemic and postischemic myocardium of hypertrophied and non-hypertrophied ventricles in spite of the reduced peak values. CONCLUSION: The findings demonstrate that after moderate reversible ischemia the steady-state function is similarly decreased in hypertrophied and non-hypertrophied postischemic myocardium. The maximum response to Ca2+ is significantly reduced in both types of myocardium, while the Ca2+ sensitivity is unchanged. Identical results after maximum dopamine stimulation as after Ca2+ indicate that the releasibility of Ca2+ and the beta-adrenoceptors are not the critical causes for the postischemic dysfunction in hypertrophied or non-hypertrophied myocardium.

Comparison of circulating endothelin-1 and big endothelin-1 levels in unstable versus stable angina pectoris.

The pathophysiologic meaning of elevated circulating endothelin-1 (ET-1) levels in various cardiovascular diseases is not understood. The aim of this study was to measure ET-1 and big ET-1 levels in patients with unstable angina pectoris (UAP) and within 5 days after stabilization. These values were compared to those of patients with stable angina pectoris (SAP) and to healthy controls (Co). In addition, a venous occlusion test was performed as an endothelial provocation test to characterize endothelial function. Big ET-1 levels were increased to 2.6 +/- 1.5 fmol/ml during unstable angina pectoris compared to normal values of 0.52 +/- 0.07 fmol/ml (p < 0.03; n = 14). After stabilization, big ET-1 decreased to 1.5 +/- 0.4 fmol/ml within 5 days (n.s.). ET-1 levels were not increased during UAP and after stabilization. ET-1 and big ET-1 levels from patients with SAP did not differ from those of healthy controls. The venous occlusion test resulted in an increase of ET-1 levels (0.3 +/- 0.02 to 0.46 +/- 0.02 fmol/mg, p = 0.008; SAP 0.3 +/- 0.04 to 0.39 +/- 0.05 fmol/ml, p = 0.009) in healthy controls and in patients with SAP. In contrast, patients with UAP showed no significant increase in ET-1 with this test. After stabilization for 5 days, the provocation test induced an increase in circulating ET-1 in patients with UAP comparable to that of controls (0.62 +/- 0.18 fmol/mg vs. 0.95 +/- 0.25 fmol/mg; p < 0.02). In summary, during UAP big ET-1 values are significantly increased and ET-1 values tend to be elevated. In an endothelial provocation test, ET-1 values did not increase. This might reflect a general activation of the endothelium in UAP during the acute stage, because the normal response is recovered 5 days later.

Hemodynamic and inotropic effects of the endothelin A antagonist BQ-610 in vivo.

The positive inotropy of endothelin-1 (ET-1) described by in vitro studies is not detectable in vivo because this effect is antagonized by cardiodepressive effects due to ET-induced vasoconstriction with subsequent myocardial ischemia. This vasoconstriction is mainly mediated by ETA receptors. In a previous in vivo study with a selective ETB receptor agonist, we showed that ETB receptors play an important role in the ET-induced positive inotropy. The present in vivo study examined whether selective ETA receptor blockade can unmask the ETB receptor-mediated positive inotropy of endogenous ET-1 by preventing its cardiodepressive effects via ETA receptors. In an open-chest rat model, we compared the acute hemodynamic and inotropic effects of the highly selective ETA receptor antagonist BQ-610 (100 micrograms/kg) with NaCl controls during and after a 7-min infusion. In addition to measurements in the intact circulation, the effects on myocardial contractility were studied by isovolumic registrations (peak LVSP, peak dP/dtmax), which are independent of peripheral vascular effects. Acute blockade of the ETA receptors by BQ-610 had no effect on blood pressure and heart rate. BQ-610 caused vasodilatation (total peripheral resistance -7.5% vs. control at the end of infusion; p < 0.01) with a consecutive increase in stroke volume (+15.3%; p < 0.01), cardiac output (+15.4%; p < 0.001), and ejection fraction (+10.4%; p < 0.01). The isovolumic measurements indicated a significant positive inotropic effect of BQ-610 (peak LVSP + 4.2%, p < 0.01; peak dP/dtmax + 5.5%, p < 0.01). Therefore, selective ETA receptor blockade by BQ-610 improves the hemodynamics in the intact circulation by causing a reduction in afterload and an increase in myocardial contractility. The positive inotropic effect of BQ-610 may be mediated by the positive inotropy of endogenous ET-1 via ETB receptors after selective ETA receptor blockade.

Preconditioning preserves energy metabolism in prolonged low-flow ischemia.

BACKGROUND: A reduction in coronary flow leads to a parallel decrease in contractile function. Thus, a flow/function balance is established in the myocardium under certain circumstances avoiding the development of a necrosis (referred to as "hibernating" myocardium). The impact of a preconditioning period on this critical balance was examined. METHODS: In 116 isovolumetrically beating rat hearts, 3 h of hypoperfusion with 15% of control coronary flow were performed followed by 1 h reperfusion; 40 hearts served as controls. As a preconditioning period, in half of the rat hearts a 5 min no-flow ischemia followed by 10 min reperfusion was performed, preceding the prolonged hypoperfusion. RESULTS: Systolic function was identically reduced in both groups after 3 h hypoperfusion (LVP: 39 +/- 2 mmHg, 40 +/- 2 mmHg vs. controls 90 +/- 3 mmHg; p < 0.01). Without preconditioning hypoperfusion resulted in a marked initial decrease in function. This period was followed by an adaptation to a higher steady state level of function compared with non-preconditioned hypoperfused hearts (p < 0.05). After preconditioning hypoperfusion directly resulted in this level of contraction. Contractile reserve was reduced (p < 0.01) identically in both hypoperfusion groups. Adenine nucleotides were decreased (p < 0.01) after 3 h hypoperfusion to 2.1 +/- 0.2 mumol/gww vs. controls (4.7 +/- 0.2 mumol/gww). After initial preconditioning adenine nucleotides were better preserved (3.2 +/- 0.2 mumol/gww) going ahead with a creatine phosphate overshoot of 126% (p < 0.01). After reperfusion, systolic function and contractile reserve were identical in both groups. CONCLUSION: A period of preceding no-flow ischemia followed by reperfusion modifies functional adaptation to hypoperfusion and preserves high energy phosphates. Therefore, the metabolic balance during hypoperfusion is improved by preconditioning, although no impact on contractile reserve or the functional status of reperfused myocardium after low-flow ischemia can be seen.

Hemodynamic effects of antiarrhythmic compounds: intrinsic effects and autonomic modulation.

Besides their proarrhythmic side-effects, most antiarrhythmic drugs exert varying degrees of depressant action on hemodynamics, which may limit their utility, especially in patients with compromised left ventricular function. Antiarrhythmic drugs have not only myocardial inotropic effects but also act on the coronary and peripheral circulation and the heart rate. Thus, sophisticated and appropriate experimental conditions are necessary to define the effect of their direct negative inotropic actions versus their circulatory effects and the impact of drug-induced autonomic modulation. This study describes an extended comparison of amiodarone, d-sotalol, d,l-sotalol, and dofetilide as class III antiarrhythmic drugs with the actions of several class I antiarrhythmic drugs in an open-chest model. The experimental model permits not only measurements in the intact circulation but also measurements of isovolumic indexes of contractility, which are independent of drug-induced changes in ventricular preload and afterload. Furthermore, after autonomic blockade, hemodynamic effects can be measured independently of modulatory adrenergic effects in such a model. d-Sotalol and amiodarone had cardiodepressant effects only at doses significantly higher than the highest doses used clinically. Dofetilide did not have a negative inotropic effect at doses up to 40 ng/kg. However, these results might be modified in experimental models with severely compromised left ventricular function, as was shown for class I antiarrhythmic drugs and for d,l- and d-sotalol. The sensitivity to a drug's negative inotropic action is markedly increased in functionally impaired myocardium. Furthermore, in a model of postischemic myocardial dysfunction, the depressant effect of d-sotalol could largely be avoided by previous autonomic blockade, indicating the importance of the residual beta-blocking potency of d-sotalol in the doses used in our experiments. Thus, in clinically relevant doses amiodarone, d-sotalol, and dofetilide were found to be devoid of negative inotropic actions in the setting of normal left ventricular myocardium. In failing hearts, such effects become more readily evident than they do in normal hearts after high doses of amiodarone and d-sotalol. From beta-blocking experiments in hearts with left ventricular dysfunction, it could be inferred that residual beta-blocking and other negative inotropic mechanisms may produce a net negative inotropic action, thus masking the minor positive class III effects postulated from in vitro experiments. These observations may have significant clinical implications, because they suggest that the intrinsic myocardial effects of antiarrhythmic drugs may be modified by autonomic effects, the status of ventricular function, and changes in preload and afterload.

Effects of positive inotropic stimulation on postischemic myocardium with graded dysfunction.

OBJECTIVE: To investigate the effects of moderate prolonged and of maximum short-term positive inotropic stimulation of postischemic myocardium as a function of the severity of stunning. METHODS: Stunned isolated rat hearts (n = 116) after 30 min and 45 min of ischemia were stimulated with dopamine to raise systolic function (double product) back to control levels. In the isovolumetrically beating hearts, left ventricular developed pressure, double product, dp/dtmax, coronary flow, and myocardial oxygen consumption were determined during steady-state conditions. After maximum stimulation the contractile reserve was examined. Measurements of adenine nucleotides (n = 47) and electron microscopy (n = 9) were made. RESULTS: 30 min ischemia resulted in moderate postischemic dysfunction (LVP 81 +/- 3%; P < 0.05). After 45 min ischemia, function was more severely reduced (LVP 66 +/- 5%; P < 0.01). Coronary flow tended to be lower after ischemia. Myocardial oxygen consumption was not reduced in parallel with the dysfunction. Adenine nucleotides were gradually reduced after ischemia (ATP: 2.5 +/- 0.2 and 1.2 +/- 0.1 vs. 4.2 +/- 0.2 mumol/gww; P < 0.01). Contractile reserve also decreased in relation to the previous ischemic injury (after 45 min ischemia max. LVP 105 +/- 10% vs. max. LVP 152 +/- 8% in controls, P < 0.01). Prolonged stimulation did not result in further reduction in adenine nucleotides and function. CONCLUSIONS: Contractile reserve is decreased in postischemic myocardium in parallel with the previous ischemic burden. Depending on the degree of contractile dysfunction a disturbed function-flow-oxygen consumption relation is present. Prolonged stimulation of stunned myocardium with dopamine back to the control level of function has no harmful short-term effects, indicating sufficient mitochondrial energy generation.

Circulatory and myocardial effects of endothelin.

The endothelin peptide family consists of the 21 amino acid isoforms endothelin-1, endothelin-2, endothelin-3, and sarafotoxin (a snake venom). Endothelin-1 has been isolated from the supernatant of endothelial cells and has subsequently been shown to be the most potent vasoconstrictor known to date and to be positively inotropic. This review summarizes some of the current literature pertaining to circulatory and myocardial effects of endothelins. Exogenously administered endothelin-1 has been demonstrated to increase peripheral resistance and blood pressure in a dose-dependent manner. However, during the first minutes of intravenous administration endothelins also decrease peripheral resistance and blood pressure, presumably due to the release of vasodilatory compounds such as nitric oxide, prostacyclin, and atrial natriuretic peptide. Endothelins appear to be involved in the pathogenesis of salt-dependent and renovascular animal models of experimental hypertension. Although endothelins appear to contribute to basal vascular tone, the role of endothelins in the pathophysiology of human hypertension remains unclear. In addition, a role has been suggested for endothelins in specific vascular lesions and inflammatory conditions (e.g., restenosis after coronary angioplasty, atherosclerotic coronary lesions, acute myocardial infarction, and vasculitis, glomerulonephritis). Endothelins are positively inotropic peptides in cardiac myocyte and papillary muscle preparations. They have also been demonstrated to induce hypertrophy of cardiac myocyte and may play an important role in ventricular processes that lead to chronic cardiac failure. The pathophysiological relevance of the endothelin system in human disease states is elucidated using selective (ET[A]) and nonselective (ET[A/B]) inhibitors of the endothelin receptors.

Significance of endothelinB receptors for myocardial contractility and myocardial energy metabolism.

Positive inotropy of endothelin-1 (ET-1), which has already been described in vitro, has not been detected in vivo. Combination with vasodilators has been shown to unmask a positive inotropic effect of ET-1. The ET-induced direct positive inotropy, which seems to be mediated by endothelinB (ETB) receptors, is antagonized in vivo by an indirect negative inotropy due to an ET-induced coronary vasoconstriction via ETA receptors. This study examines the significance of ETB receptors on myocardial contractility and myocardial energy metabolism. The dose-dependent hemodynamic and inotropic effects of the highly specific ETB agonist IRL 1620 (0.4, 1.0, 2.0, 4.0 nmol/kg vs. NaCl controls) were investigated in open-chest rats during and after a 7-min infusion. In addition to measurements in the intact circulation, we examined the myocardial function by isovolumic registrations independent of peripheral vascular effects. Furthermore, the effect of IRL 1620 on myocardial high-energy phosphates was studied. IRL 1620 causes a biphasic pressure response, with an initial decrease followed by a rise (differences of 0.4, 1.0, 2.0 and 4.0 nmol/kg IRL 1620 compared with the controls 5 min after infusion; mean aortic pressure: +37%, +33%, +29%, +20%). IRL 1620 has a positive chronotropic effect (HR: +2%, +14%, +16%, +6%). After an initial vasodilation, IRL 1620 augments the total peripheral resistance: +35%, +31%, +66%, +82%. Because the maximum of the isovolumic left ventricular systolic pressure (+7%, +7%, +12%, +12%) and the corresponding maximum first derivative of the left ventricular pressure (+13%, +14%, +23%, +18%) were increased under IRL 1620, these measurements indicate a positive inotropic effect of IRL 1620 in vivo. Myocardial high-energy phosphates were not changed by IRL 1620. In contrast to nonselective activation of ETA and ETB receptors by ET-1, the selective activation of ETB receptors by IRL 1620 causes a positive inotropy. This discrepancy can be explained by a less pronounced vasoconstriction with absence of myocardial ischemia after ETB receptor activation by IRL 1620.

Effect of endothelin-1 and its combination with adenosine on myocardial contractility and myocardial energy metabolism in vivo.

Contradictory results have been reported about the inotropic effects of the vasoconstrictive peptide endothelin-1 (ET-1). In contrast to in vitro experiments, in vivo studies could not demonstrate a positive inotropy of ET-1. It may be possible, that the direct positive inotropic effect of ET-1 observed in in vitro studies is counterbalanced in vivo by an indirect negative inotropy due to its coronar-constrictive effect. This study examined the hemodynamic and inotropic effects of 2500 ng ET-1/kg without and after pretreatment with the vasodilating nucleoside adenosine (0.5, 2.0, 5.0 mg ADO/kg/min). Data were compared with NaCl controls in open-chest rats during and after a 7-min infusion. Besides measurements in the intact circulation isovolumic measurements were carried out for quantification of myocardial contractility independently of peripheral vascular effects. We further examined the effect of ET-1 and its combination with 2.0 mg ADO/kg/min on myocardial high-energy phosphates (ATP, AMP, ADP, creatine phosphate). ET-1 causes a strong and longlasting vasoconstriction (+ 186% v preinfusion values), which is dose-dependently antagonized in part by ADO (+ 109%, + 136%, + 60%). While the maximum of the isovolumic LVSP (peak LVSP) and the corresponding dP/dtmax (peak dP/dtmax) were unchanged with sole ET-1 (peak LVSP: +5%, peak dP/dtmax: -2%), these indexes of myocardial contractility were increased after pretreatment with ADO (peak LVSP: +11%, +13%, +4%; peak dP/dtmax: +9%, +20%, +10%) indicating a positive inotropic effect of ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the Na+ antagonist cibenzoline on left ventricular function of postischemic hearts.

The negative inotropic effect of antiarrhythmic drugs is a major drawback in antiarrhythmic drug therapy, especially in patients with reduced contractile function of the left ventricle. The circulatory and myocardial effects of the new class I antiarrhythmic drug (a Na+ antagonist), cibenzoline (2 mg/kg i.v.), were investigated in 47 open-chest rats with normal and postischemic myocardium (3 x 4 minutes of global ischemia). Hemodynamic measurements in the intact circulation and isovolumic registrations (peak isovolumic left ventricular systolic pressure and peak isovolumic dP/dtmax) were compared to saline controls. In rats with postischemic myocardium, cibenzoline caused a significant (p < 0.001) decrease in the cardiac output for 38%, in the dP/dtmax for 30%, and in the peak isovolumic dP/dtmax for 19% at the end of infusion (compared to the control). The heart rate was reduced by 22% (p < 0.001), the mean aortic pressure by 22% (p < 0.001), and the calculated systemic resistance by 20% (p < 0.001). In contrast to the results with postischemic myocardium, no important changes in the hemodynamics were detectable after an identical dose in normal animals without left ventricular dysfunction. The results indicate that standard doses of the Na+ antagonist cibenzoline may induce significant cardiodeperessant effects on postischemic left ventricles with reduced function.

Effects of endothelin-1 and IRL 1620 on myocardial contractility and myocardial energy metabolism.

In contrast to in vitro studies, experiments in intact animals could not detect a positive inotropic effect of endothelin-1 (ET-1). We presumed that the ET-induced direct positive inotropy is antagonized in vivo by an indirect cardiodepressant effect due to a mainly ETA-mediated and ET-induced coronary constriction, with consequent myocardial ischemia. To confirm this hypothesis we examined in thoracotomized rats the effects of a nonselective activation of ETA and ETB receptors by 1 nmol/kg ET-1 with and without the vasodilator adenosine (2.0 mg/kg/min), and the effects of a selective activation of ETB receptors by the ETB agonist IRL 1620 (2 nmol/kg) on myocardial contractility and energy metabolism (ATP, ADP, AMP). In addition to recordings in the intact circulation, isovolumic measurements (peak LVSP, peak dP/dtmax) were performed for quantification of myocardial contractility. ET-1 had no positive inotropic effect (peak dP/dtmax -2% vs. control, n.s.) due to a marked vasoconstriction with a consequent fall in the myocardial ATP content (-17%; p < 0.01). Adenosine antagonized the ET-induced vasoconstriction in part, normalized myocardial energy metabolism (ATP -7%), and thus unmasked the positive inotropic effect of ET-1 (peak dP/dtmax +20%; p < 0.01). Selective activation of ETB receptors by IRL 1620 had only a small vasoconstrictor effect, which did not produce myocardial ischemia (ATP + 10%; n.s.) and thus caused a positive inotropic effect in vivo (peak dP/dtmax +22%; p < 0.01). The positive inotropic effect of ET-1 is not detectable in vivo as its marked, mainly ETA-mediated, vaso- and coronary constriction causes myocardial ischemia that thus produces an indirect negative inotropic effect.

In vivo hemodynamic and inotropic effects of the endothelinB agonist IRL 1620.

The endothelinB (ETB) receptor is involved in endothelin-induced vasoconstriction and appears to play a role in ET-induced positive inotropy. Our previous study could not detect a positive inotropic effect of ET-1 in vivo. To evaluate specifically the effects of the ETB receptor on hemodynamics and inotropy of ET-1 in the intact circulation, we examined in the open-chest rat model the dose-dependent hemodynamic and inotropic effects of the highly specific ETB agonist IRL 1620 (0.4, 1.0, 2.0, and 4.0 nmol/kg vs. NaCl controls) during and after a 7-min infusion. In addition to measurements in the intact circulation, isovolumic recordings (peak LVSP, peak dP/dtmax) were performed for quantification of myocardial contractility independently of peripheral vascular changes. IRL 1620 caused a significant biphasic blood pressure response with an initial fall and a sustained increase, reflecting the vasoactive effects of IRL 1620, with a transient vasorelaxation followed by dose-dependent and long-lasting vasoconstriction. Although IRL 1620 has a positive chronotropic effect the reduction in stroke volume (probably due to the elevated afterload) causes a decrease in cardiac output. Nevertheless, the isovolumic measurements indicate a significant positive inotropic effect of IRL 1620. Therefore, the selective activation of ETB receptors causes a positive inotropic effect, which is also detectable in vivo, as the vasoconstrictor and coronary constrictor effects are less pronounced compared to activation of both ETA and ETB receptors by ET-1.