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Biomedical subjects

G Heusch

Publications and source records attributed to G Heusch.

At least 19 recordsLinked to original sources
PubMed1996

Calcium responsiveness in regional myocardial short-term hibernation and stunning in the in situ porcine heart. Inotropic responses to postextrasystolic potentiation and intracoronary calcium.

BACKGROUND: We tested the hypothesis that decreased calcium responsiveness is responsible for the reduction in contractile function in regional hibernating and stunned myocardium in situ. METHODS AND RESULTS: In 19 anesthetized swine, the left anterior descending coronary artery flow was reduced to decrease anterior myocardial work index (sonomicrometry) by approximately 60%. During 90 minutes of hypoperfusion, creatine phosphate recovered (as determined by biopsy specimens and bioluminescence) and no necrosis developed (as determined by staining with triphenyl tetrazolium chloride). In 10 swine, changes in the intracellular calcium concentration were induced by systematic variation of the postextrasystolic time interval at a constant prematurity. In 9 additional swine, a graded IC calcium infusion was performed. Under control conditions, anterior myocardial work increased with a fully compensated postextrasystolic time interval from 380+/-93 (mean+/-SD) to 523+/-98 mm Hg . mm. IC calcium infusion increased anterior myocardial work under control conditions from 356+/-85 to a maximum of 428+/-93 mm Hg . mm. Although the maximal responses were decreased during postextrasystolic potentiation (222+/-68 versus 523+/-98 mm Hg . mm) and calcium infusion (176+/-32 versus 428+/-93 mm Hg . mm) after 90 minutes of ischemia, the relationships between increases in anterior myocardial work and, respectively, postextrasystolic time interval and IC calcium were not different. The same was true after 30 minutes of reperfusion. CONCLUSIONS: Both regional hibernating myocardium and stunned myocardium in situ are characterized by a decrease in overall myocardial calcium responsiveness; however, there appears to be no significant myocardial desensitization to calcium.

Animals↗
PubMed1996

No prevention of ischemic preconditioning by the protein kinase C inhibitor staurosporine in swine.

The delay of infarct size development by ischemic preconditioning involves the activation of protein kinase C in rats and rabbits. In dogs the role of protein kinase C in ischemic preconditioning is controversial. We investigated whether or not the activation of protein kinase C is a prerequisite for ischemic preconditioning in swine. Swine were used, since they are large mammals and since infarct development in this species, due to the lack of an innate collateral circulation, is similar to that in humans. In 20 enflurane-anesthetized swine, the proximal left anterior descending coronary artery was cannulated and perfused from an extracorporeal circuit. The impact of continuous intracoronary infusion of 10(-7) mol/L staurosporine, a potent protein kinase C inhibitor, on global and regional myocardial function (sonomicrometry), subendocardial blood flow (ENDO, microspheres), and infarct size (IS, triphenyltetrazolium chloride staining after 120 minutes of reperfusion) was analyzed. Staurosporine (10(-7) mol/L) abolished the 1.6-fold increase in coronary arterial resistance in response to 10(-6) mol/L IC 4 beta-phorbol 12-myristate 13-acetate, a potent protein kinase C activator. In the presence of staurosporine, 90 minutes of low-flow ischemia at an ENDO of 0.05 +/- 0.04 (mean +/- SD) mL.min-1.g-1 resulted in an IS of 12.5 +/- 8.6% (n = 10) of the area at risk. Also, in the presence of staurosporine, ischemic preconditioning by a cycle of 10 minutes of low-flow ischemia followed by 15 minutes reperfusion before the 90 minutes sustained ischemic period (ENDO, 0.05 +/- 0.03 mL.min-1.g-1) reduced IS to 3.3 +/- 3.4% (n = 10, P < .05). The protein kinase C inhibitor staurosporine does not prevent ischemic preconditioning in swine.

Alkaloids↗
PubMed1995

Stunned myocardium and the attenuation of stunning by calcium antagonists.

Myocardial "stunning" is characterized by a reversible postischemic contractile dysfunction despite full restoration of blood flow. The underlying mechanisms are not clearly understood. Inadequate energy supply and impaired sympathetic neurotransmission may have been excluded. Potential mechanisms, which are not mutually exclusive, may include damage to membranes and enzymes by free radicals, an increase in free cytosolic calcium during ischemia and reperfusion, and a lower calcium sensitivity of myofibrils. The equally pronounced increases in regional contractility in normal and stunned myocardium during postextrasystolic potentiation and the infusion of calcium or the calcium-sensitizing agent AR-L-57, however, suggest an unchanged calcium sensitivity in reperfused myocardium. Pretreatment with calcium antagonists before ischemia attenuates myocardial stunning. This effect is probably related to a lessened myocardial calcium overload during early ischemia. The potential benefit of treatment with calcium antagonists after reperfusion is established remains controversial.

Animals↗
PubMed1995

Involvement of endogenous adenosine in ischaemic preconditioning in swine.

Adenosine release and the subsequent activation of adenosine receptors are involved in ischaemic preconditioning in dogs and rabbits. In the present study, we investigated whether adenosine also mediates ischaemic preconditioning in swine. Swine were used since, due to the lack of an innate collateral circulation, infarct development in this species most closely resembles that observed in humans. In 36 enflurane-anaesthetized swine the impact of increased adenosine breakdown with exogenous porcine adenosine deaminase (5 IU/ml blood/min) on global and regional myocardial function (sonomicrometry), subendocardial blood flow (ENDO, microspheres) and infarct size (IS, triphenyl tetrazolium chloride staining following 90 min ischaemia and 120 min reperfusion) were analysed. Low-flow ischaemia for 90 min at an ENDO of 0.09 +/- 0.04 (mean +/- SD) ml/min/g caused an IS of 13.2 +/- 9.7% (n = 8) of the area at risk. Ischaemic preconditioning by a cycle of 10 min low-flow ischaemia followed by 15 min reperfusion prior to the 90-min ischaemic period (ENDO = 0.06 +/- 0.03 ml/min/g) reduced IS to 2.6 +/- 3.0% (n = 11, P < 0.05). The interstitial adenosine concentration (microdialysis) increased from 1.60 +/- 0.87 nmol/ml to above 10 microM during ischaemia; with intracoronary adenosine deaminase, the interstitial adenosine concentration fell from 1.65 +/- 0.23 to 0.12 +/- 0.07 nmol/ml and did not increase during ischaemia. Adenosine deaminase per se did not alter IS after 90 min ischaemia (n = 7, ENDO = 0.08 +/- 0.04 ml/min/g, IS = 12.1 +/- 6.9%) but abolished the beneficial effect of ischaemic preconditioning (n = 10, ENDO = 0.06 +/- 0.03 ml/min/g, IS = 8.8 +/- 5.8%). For any given ENDO, IS was significantly reduced in the ischaemic preconditioned group compared with the other three groups. Global and regional myocardial function were comparable among all groups of swine. We conclude that endogenous adenosine mediates ischaemic preconditioning also in swine.

Adenosine↗
PubMed1995

Characterization of hibernating and stunned myocardium.

Both the hibernating and the stunned myocardium are characterized by reversible contractile dysfunction. In hibernating myocardium, perfusion is still reduced, whereas in stunned myocardium blood flow is fully or almost fully restored. Both the hibernating and the stunned myocardium retain an inotropic reserve. In hibernating myocardium the increase in contractile function is at the expense of metabolic recovery, whereas in the stunned myocardium no metabolic deterioration occurs during inotropic stimulation. Therefore, inotropic stimulation in combination with metabolic imaging may help not only to identify viable, dysfunctional myocardium but also to distinguish hibernating and stunned myocardium. The therapy of hibernating myocardium is to restore blood flow to the hypoperfused tissue. Myocardial stunning per se requires no therapy at all, since, by definition, blood flow is normal and contractile function will recover spontaneously. If, however, myocardial stunning is severe, and it involves large parts of the LV and thus impairs global LV function, it can be reversed with inotropic agents and procedures. In the experimental setting, anti-oxidant agents, calcium antagonists and ACE inhibitors attenuate stunning, but most effectively when administered before ischaemia.

Animals↗
PubMed1995

Low-frequency spectral power of heart rate variability is not a specific marker of cardiac sympathetic modulation.

BACKGROUND: Heart rate variability in the frequency domain has been proposed to reflect cardiac autonomic control. Therefore, measurement of heart rate variability may be useful to assess the effect of epidural anesthesia on cardiac autonomic tone. Accordingly, the effects of preganglionic cardiac sympathetic blockade by segmental epidural anesthesia were evaluated in humans on spectral power of heart rate variability. Specifically, the hypothesis that cardiac sympathetic blockade attenuates low-frequency spectral power, assumed to reflect cardiac sympathetic modulation, was tested. METHODS: Ten subjects were studied while supine and during a 15-min 40 degrees head-up tilt both before and after cardiac sympathetic blockade by segmental thoracic epidural anesthesia (sensory block: C6-T6). ECG, arterial pressure, and respiratory excursion (Whitney gauge) were recorded, and a fast-Fourier-transformation was applied to 512-s data segments of heart rate derived from the digitized ECG at the end of each intervention. RESULTS: With cardiac sympathetic blockade alone and the subjects supine, both low-frequency (LF, 0.06-0.15 Hz) and high-frequency (HF, 0.15-0.80 Hz) spectral power remained unchanged. During tilt, epidural anesthesia attenuated the evoked increase in heart rate (+11.min-1 +/- 7 SD vs. +6 +/- 7, P = 0.024). However, while during tilt cardiac sympathetic blockade significantly decreased the LF/HF ratio (3.68 +/- 2.52 vs. 2.83 +/- 2.15, P = 0.041 vs. tilt before sympathetic blockade), a presumed marker of sympathovagal interaction, absolute and fractional LF and HF power did not change. CONCLUSIONS: Although preganglionic cardiac sympathetic blockade reduced the LF/HF ratio during tilt, it did not alter spectral power in the LF band during rest or tilt. Accordingly, low-frequency spectral power is unlikely to specifically reflect cardiac sympathetic modulation in humans.

Adult↗
PubMed1995

Bradycardic agent UL-FS 49 attenuates ischemic regional myocardial dysfunction and reduces infarct size in swine: comparison with the beta-blocker atenolol.

Heart rate (HR) is a major factor determining the severity of myocardial ischemia, and HR reduction is an effective therapy for myocardial ischemia. We tested the effects of HR reduction induced by either UL-FS 49 or atenolol on regional myocardial blood flow, function, and infarct size (IS) in a porcine model of 90-min low-flow ischemia and 2-h reperfusion. In 24 Göttinger miniswine, the left anterior descending coronary artery (LAD) was cannulated and hypoperfused at constant inflow to reduce anterior systolic wall thickening (AWT, sonomicrometry) by approximately 85%. Eight swine served as a placebo group, and 8 other swine received UL-FS 49 (0.60 mg/kg intravenously, i.v.) after 10-min ischemia. In the remaining 8 swine, atenolol was infused after 10-min ischemia at a dosage [mean 1.75 +/- 1.20 (SD) mg/kg i.v.] to mimic the HR reduction observed with UL-FS 49. Systemic hemodynamics, subendocardial blood flow (ENDO, microspheres) and AWT were measured under control conditions, at 10 and 90 min of ischemia. In the swine receiving UL-FS 49 or atenolol, additional measurements were made 5 min after administration of the respective drug. After 2-h reperfusion, IS (percentage of area at risk) was determined with TTC-staining. Five minutes after administration of UL-FS 49, HR was decreased from 113 +/- 9 to 83 +/- 13 beats/min (p < 0.05) and remained unchanged when ischemia was prolonged to 90 min. In the swine receiving atenolol, HR was reduced from 117 +/- 14 to 93 +/- 7 beats/min (p < 0.05) 5 min after drug administration and decreased further to 87 +/- 10 beats/min when ischemia was prolonged to 90 min. After 10 min of ischemia, AWT in the placebo, UL-FS 49, and atenolol group was decreased to 7.0 +/- 5.5, 6.4 +/- 3.5, and 6.2 +/- 3.3% (all p < 0.05 vs. control), respectively. The reduction in ENDO was also comparable among the three groups. In the placebo group, AWT remained unchanged when ischemia was prolonged to 90 min (4.4 +/- 2.6%). In swine receiving atenolol, AWT tended to increase (13.6 +/- 10.5%), whereas in swine receiving UL-FS 49, AWT was significantly increased to 21.4 +/- 7.1% (p < 0.05 vs. 10-min ischemia and vs. the placebo and atenolol groups). IS was significantly reduced in swine receiving atenolol (3.9 +/- 3.5%) or UL-FS 49 (5.8 +/- 4.6%) as compared with the placebo-group (10.4 +/- 8.9%).(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1995

Cholinergic and alpha-adrenergic coronary vasomotion [corrected] with increasing ischemia-reperfusion injury.

Ischemia-reperfusion-induced injury of the coronary vasculature could result in an attenuated vasodilator or increased vasoconstrictor tone that might impact on myocardial recovery and viability. In 30 open-chest dogs the left circumflex coronary artery was occluded for 15 or 60 min and then reperfused, and responses to intracoronary acetylcholine, the alpha 1-adrenergic agonist methoxamine, and the alpha 2-adrenergic agonist BHT-933 (n = 10 each) were measured. In the experiments with 60 min of occlusion, triphenyltetrazolium chloride (TTC) staining was used to distinguish reversibly (TTC+) and irreversibly (TTC-) injured myocardium. After 15 min of occlusion, the vasodilator response to acetylcholine was not altered but was significantly reduced in TTC+ subendocardium and midmyocardium after 60 min of occlusion and was further reduced in TTC- subendocardium, midmyocardium, and also in subepicardium. The vasoconstrictor responses to methoxamine and BHT-933 were not altered after 15 or 60 min of occlusion in both TTC+ and TTC- myocardium. Posterior wall thickening was not affected by acetylcholine, methoxamine, or BHT-933. Thus, in reversibly injured myocardium after 15 min of occlusion, cholinergic and alpha-adrenergic coronary vasomotor responses are unchanged. With increasing duration of ischemia, reversibly and even more so irreversibly injured reperfused myocardium are characterized by an impaired cholinergic coronary vasodilation but not an enhanced alpha-adrenergic coronary vaso-constriction.

Acetylcholine↗
PubMed1995

Regional short-term myocardial hibernation in swine does not involve endogenous adenosine or KATP channels.

Short-term hibernating myocardium is characterized by reduced contractile function during persistent ischemia, the recovery of metabolism over time, a recruitable inotropic reserve, and the lack of necrosis. The mechanisms underlying myocardial hibernation are unclear. The present study addressed the role of endogenous adenosine and that of activation of ATP-dependent potassium (KATP) channels. In 22 enflurane-anesthetized swine, coronary inflow was reduced to decrease regional myocardial work (W, measured by sonomicrometry) by 60-70% at 5 min of ischemia; this flow reduction has previously been shown to be compatible with the development of myocardial hibernation. Systemic hemodynamics, W, subendocardial blood flow (measured by microspheres), and the myocardial creatine phosphate content (measured by biopsies, mumol/g wet wt) were measured under control conditions and during 90 min of ischemia, with an intracoronary dobutamine infusion during the last 5 min of ischemia. The impact of endogenous adenosine was eliminated by infusion of intracoronary adenosine deaminase (ADA), and the impact of activation of KATP channels by glibenclamide. Creatine phosphate content recovered in the placebo-treated swine (n = 8, 3.8 +/- 1.9 to 5.8 +/- 2.0 mumol/g wet wt) as well as in swine receiving ADA (n = 7, 4.1 +/- 1.2 to 6.0 +/- 1.7 mumol/g wet wt) or glibenclamide (n = 7, 2.8 +/- 1.3 to 6.7 +/- 1.6 mumol/g wet wt) when ischemia was prolonged from 5 to 85 min. At the end of 90 min of ischemia, W increased during intracoronary dobutamine in all three groups to a comparable extent, and myocardial necrosis was absent in all three groups of swine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1995

Intraischemic preconditioning. Increased tolerance to sustained low-flow ischemia by a brief episode of no-flow ischemia without intermittent reperfusion.

Ischemic preconditioning (IP) and myocardial hibernation (MH) are both adaptive phenomena during acute myocardial ischemia, characterized by preserved myocardial viability and attenuated alterations of energy metabolism. Recent data from isolated buffer-perfused rabbit hearts pointed to a further link between IP and MH, in that an initial stimulus of no-flow ischemia was required to permit the development of MH during subsequent sustained low-flow ischemia. In the present study, we therefore investigated in the in situ pig heart whether a brief episode of no-flow ischemia enhances the myocardial tolerance to subsequent sustained low-flow ischemia. By blocking ATP-dependent potassium channels, we attempted to further determine whether such increased tolerance to ischemia is related to IP or MH, since blockade of ATP-dependent potassium channels abolishes the cardioprotection achieved by IP but not by MH. In 8 enflurane-anesthetized pigs serving as controls (group 1), the inflow into the cannulated left anterior descending coronary artery was reduced to achieve a 90% reduction in the anterior myocardial work index (sonomicrometry) for 90 minutes. In 15 pigs (group 2), a 10-minute no-flow ischemic episode preceded 80 minutes of sustained ischemia at a blood flow reduction identical to that in pigs of group 1. In 8 additional pigs (group 3), glibenclamide was administered before the 10-minute no-flow ischemic episode. In all pigs after 120 minutes of reperfusion, infarct size (IS, percentage of area at risk) was determined by triphenyltetrazolium chloride staining. In group 2, IS was reduced (6.8 +/- 6.0% [mean +/- SD], P < .05) when compared with groups 1 (13.2 +/- 9.8%) and 3 (16.7 +/- 8.3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1995

[Pathophysiology of the "hibernating" myocardium].

Myocardial ischemia has traditionally been viewed as an imbalance between energy supply and demand. Within the first few seconds following an acute reduction of myocardial blood flow, energy demand of the hypoperfused myocardium clearly exceeds the reduced energy supply. However, this imbalance between energy supply and demand is an inherently unstable condition since ischemia induces mechanisms which are not yet understood, but reduce contractile function and thus energy demand. In the subsequent steady-state condition, the amount of contractile dysfunction is in proportion to the reduction of myocardial blood flow. A situation of persistent ischemic contractile dysfunction in viable myocardium which normalizes upon reperfusion has been termed myocardial hibernation. The metabolic status of such hibernating myocardium improves over the first few hours as myocardial lactate production is attenuated and creatine phosphate, after an initial reduction, returns towards control values. The hibernating myocardium can respond to an inotropic stimulation by dobutamine with increased contractile function, however, at the expense of a renewed worsening of the metabolic status. This situation of an increased regional contractile function at the expense of metabolic recovery during inotropic stimulation can be used to identify hibernating myocardium. The development of such delicate balance between regional myocardial blood flow and function during early ischemia is disturbed by unfavorable alterations in supply and demand. When after 5 min of ischemia, at a blood flow reduction compatible with the development of myocardial hibernation over 90 min, energy supply is further reduced by a further reduction of myocardial blood flow, necroses develop. Likewise, increasing energy demand by continuous inotropic stimulation with dobutamine induces necroses. Thus, both the further reduction in energy supply by an increasing severity of ischemia and an enhanced energy expenditure by continuous inotropic stimulation impair the development of myocardial hibernation and precipitate myocardial infarction. Hibernation over the first few hours of ischemia (short-term hibernation) is well characterized in animal experiments. Increased release of endogenous adenosine and activation of ATP-dependent potassium channels as the underlying mechanisms have been ruled out. The existence of hibernation over weeks or months (long-term hibernation) can only be inferred from clinical studies. In long-term hibernating myocardium morphological alterations occur. In myocardial biopsies from patients with prolonged contractile dysfunction which was reversible after bypass surgery, myofibrils are reduced in number and disorganized. Myocardial glycogen content as well as the extracellular collagen network are increased. Thus, despite the fact that the myocardium remains viable during persistent ischemia and contractile dysfunction is reversible upon reperfusion, there are severe morphological alterations. Understandably, full functional recovery following reperfusion can therefore require weeks or even months.

Animals↗
PubMed1994

Involvement of activation of ATP-dependent potassium channels in ischemic preconditioning in swine.

This study evaluated the importance of ATP-dependent potassium channels (KATP) for ischemic preconditioning (IP) in swine. Swine were studied because due to the sparsity of their innate collateral circulation infarct size (IS) development closely resembles that observed in humans. Ninety minutes of ischemia at a blood flow reduction sufficient to reduce regional myocardial work by 90% caused 13.2 +/- 8.9% (SD) IS of the area at risk. A single cycle of 10-min preconditioning ischemia followed by 15-min reperfusion reduced IS after 90 min of ischemia to 2.8 +/- 2.7%. The epicardial monophasic action potential duration at 50% repolarization (MAP50) was decreased more markedly during the initial 10 min of the prolonged ischemia than during the first 10 min of the preconditioning ischemic period (84 +/- 4 vs. 89 +/- 2%). Transmural myocardial adenosine (ADO) uptake was reversed to net release during both ischemic periods and during the initial phase of reperfusion. Glibenclamide (0.5 mg/kg, followed by 50 micrograms/min i.v.) abolished the reduction in MAP50 without altering ADO release. Glibenclamide did not alter IS per se (13.0 +/- 7.6%) but abolished the beneficial effect of IP (IS: 13.6 +/- 6.2%). Thus blockade of KATP with glibenclamide abolishes the IS-reducing effect of IP in swine but does not reduce ADO release.

Action Potentials↗