Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive.

Hypothermia induced at the onset of ischemia is a potent experimental cardioprotective strategy for myocardial infarction. The aim of our study was to determine whether the beneficial effects of hypothermia may be due to decreasing mitochondria-mediated mechanisms of damage that contribute to the pathophysiology of ischemia/reperfusion injury. New Zealand male rabbits were submitted to 30 min of myocardial ischemia with hypothermia (32 °C) induced by total liquid ventilation (TLV). Hypothermia was applied during ischemia alone (TLV group), during ischemia and reperfusion (TLV-IR group) and normothermia (Control group). In all the cases, ischemia was performed by surgical ligation of the left anterior descending coronary artery and was followed by 3 h of reperfusion before assessment of infarct size. In a parallel study, male C57BL6/J mice underwent 30 min myocardial ischemia followed by reperfusion under either normothermia (37 °C) or conventionally induced hypothermia (32 °C). In both the models, the levels of the citric acid cycle intermediate succinate, mitochondrial complex I activity were assessed at various times. The benefit of hypothermia during ischemia on infarct size was compared to inhibition of succinate accumulation and oxidation by the complex II inhibitor malonate, applied as the pro-drug dimethyl malonate under either normothermic or hypothermic conditions. Hypothermia during ischemia was cardioprotective, even when followed by normothermic reperfusion. Hypothermia during ischemia only, or during both, ischemia and reperfusion, significantly reduced infarct size (2.8 ± 0.6%, 24.2 ± 3.0% and 49.6 ± 2.6% of the area at risk, for TLV-IR, TLV and Control groups, respectively). The significant reduction of infarct size by hypothermia was neither associated with a decrease in ischemic myocardial succinate accumulation, nor with a change in its rate of oxidation at reperfusion. Similarly, dimethyl malonate infusion and hypothermia during ischemia additively reduced infarct size (4.8 ± 2.2% of risk zone) as compared to either strategy alone. Hypothermic cardioprotection is neither dependent on the inhibition of succinate accumulation during ischemia, nor of its rapid oxidation at reperfusion. The additive effect of hypothermia and dimethyl malonate on infarct size shows that they are protective by distinct mechanisms and also suggests that combining these different therapeutic approaches could further protect against ischemia/reperfusion injury during acute myocardial infarction.

Correction to: Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive.

The original version of this article unfortunately contained a mistake.

Ultrafast and whole-body cooling with total liquid ventilation induces favorable neurological and cardiac outcomes after cardiac arrest in rabbits.

BACKGROUND: In animal models of cardiac arrest, the benefit afforded by hypothermia is closely linked to the rapidity of the decrease in body temperature after resuscitation. Because total liquid ventilation (TLV) with temperature-controlled perfluorocarbons induces a very rapid and generalized cooling, we aimed to determine whether this could limit the post-cardiac arrest syndrome in a rabbit model. We especially focused on neurological, cardiac, pulmonary, liver and kidney dysfunctions. METHODS AND RESULTS: Anesthetized rabbits were submitted to either 5 or 10 minutes of untreated ventricular fibrillation. After cardiopulmonary resuscitation and resumption of a spontaneous circulation, the animals underwent either normothermic life support (control) or therapeutic hypothermia induced by TLV. The latter procedure decreased esophageal and tympanic temperatures to 32°C to 33°C within only 10 minutes. After rewarming, the animals submitted to TLV exhibited an attenuated neurological dysfunction and decreased mortality 7 days later compared with control. The neuroprotective effect of TLV was confirmed by a significant reduction in brain histological damages. We also observed limitation of myocardial necrosis, along with a decrease in troponin I release and a reduced myocardial caspase 3 activity, with TLV. The beneficial effects of TLV were directly related to the rapidity of hypothermia induction because neither conventional cooling (cold saline infusion plus external cooling) nor normothermic TLV elicited a similar protection. CONCLUSIONS: Ultrafast cooling instituted by TLV exerts potent neurological and cardiac protection in an experimental model of cardiac arrest in rabbits. This could be a relevant approach to provide a global and protective hypothermia against the post-cardiac arrest syndrome.

Quantitative imaging of coronary flows using 3D ultrafast Doppler coronary angiography.

Coronary flow rate remains complex to assess in clinical practice using non-invasive, non-ionizing imaging tools. In this study, we introduce 3D ultrafast Doppler coronary angiography (3D UDCA), an ultrasound-based method to assess coronary blood flows in three-dimensions at high volume-rate and in one single heartbeat. We demonstrate that 3D UDCA can visualize the coronary vasculature with high temporal and spatial resolution and quantify the absolute flow. The feasibility of the technique was demonstrated in an open-chest swine model. The flow rate of the left-anterior descending artery (LAD) assessed by 3D UDCA was reconstructed successfully at the early diastolic and late diastolic phases and was in good agreement with an invasive gold-standard flowmeter during baseline, reactive hyperemia and coronary stenosis (r2 = 0.84). Finally, we demonstrate that a coronary stenosis on the LAD can be visualized as well as its associated flow acceleration.

Heart rate reduction by inhibition of If or by beta-blockade has different effects on postsystolic wall thickening.

BACKGROUND AND PURPOSE: Postsystolic wall thickening (PSWT) is part of thickening that occurs after end-systole and represents wasted effort as it does not contribute to ejection. The effects of antianginal drugs on PSWT remain to be established. We compared the effects on PSWT of two agents that reduce heart rate, the beta-blocker atenolol and the selective inhibitor of If current, ivabradine. EXPERIMENTAL APPROACH: Six dogs were prepared to measure wall thickening by sonomicrometry in the conscious state, at rest and during exercise, after administration of saline, atenolol (1 mg.kg-1) or ivabradine (1 mg.kg-1). KEY RESULTS: Atenolol and ivabradine similarly reduced heart rate vs saline at rest (about 10-20%) and during exercise (about 30%). Atenolol but not ivabradine decreased dP/dtmax. Concomitantly, PSWT increased with atenolol vs saline at rest (0.35+/-0.07 vs 0.21+/-0.03 mm, respectively) and during exercise (0.30+/-0.04 vs 0.15+/-0.04 mm, respectively). In contrast, ivabradine did not alter PSWT. Importantly, atenolol but not ivabradine increased the ratio of postsystolic to systolic wall thickening by 80+/-23%. This enhanced thickening during diastole with atenolol was accompanied by impeded isovolumic relaxation of the left ventricle, as illustrated by the significant correlation between the isovolumic relaxation time constant tau and the postsystolic to systolic wall thickening ratio. None of these effects of atenolol were abolished when heart rate was controlled with atrial pacing. CONCLUSION AND IMPLICATIONS: For a similar heart rate reduction at rest and during exercise, ivabradine, but not atenolol, did not alter PSWT and preserved the part of thickening contributing to ejection.

Lack of importance of NO in beta-adrenoceptor-mediated relaxation of large epicardial canine coronary arteries.

This study was designed to test the role of endothelium and the L-arginine/NO pathway in the relaxation of canine large coronary arteries to the beta-adrenoceptor agonist, isoprenaline. Relaxation of left circumflex (LCX) and left anterior descending (LAD) coronary arteries were measured in organ baths after contraction with the thromboxane analogue, U46619, either in absence or in presence of endothelium and in LCX arteries after pretreatment with NG-nitro-L-arginine-methyl-ester (L-NAME). LAD arteries with and without endothelium relaxed identically to isoprenaline but their maximal relaxation was smaller than corresponding LCX arteries with endothelium. A slight but non significant difference was observed in LCX arteries with endothelium as compared to rings without endothelium or pretreated with L-NAME. No difference was observed in the relaxation of LCX arteries to forskolin in arteries with or without endothelium. These results suggest that endothelium is not essential and that NO is not directly involved in the relaxation of large coronary arteries induced by isoprenaline.

Comparison of the effects of EXP3174, an angiotensin II antagonist and enalaprilat on myocardial infarct size in anaesthetized dogs.

1. In order to determine whether the renin-angiotensin system is involved in myocardial ischaemia-reperfusion injury, we investigated and compared the effects on infarct size of two different drugs which interfere with this system, i.e., an angiotensin II (AT1) antagonist, EXP3174, and an angiotensin I-converting enzyme inhibitor (ACEI), enalaprilat in a canine model of ischaemia-reperfusion. 2. EXP3174 (0.1 mg kg-1, i.v. followed by 0.02 mg kg-1 h-1 for 5.5 h) and enalaprilate (0.3 mg kg-1, i.v. followed by 0.06 mg kg-1 h-1 for 5.5 h) were used in doses inducing a similar level of inhibition (87 +/- 4 and 91 +/- 3%, respectively) of the pressor responses to angiotensin I. Control animals received saline. 3. Infarct size and area at risk were quantified by ex vivo dual coronary perfusion with triphenyltetrazolium chloride and monastral blue dye. Regional myocardial blood flows (ischaemic and nonischaemic, endocardial, epicardial) were assessed by the radioactive microsphere technique. 4. Both EXP3174 and enalaprilat induced a decrease in mean arterial blood pressure. However, non significant changes in regional myocardial blood flows, whether ischaemic or nonischaemic, were observed after administration of either the ACEI or the AT1 antagonist. 5. The size of the area at risk was similar in the three groups. By direct comparison, there were no significant differences between infarct sizes in the three groups. Furthermore, there was a close inverse relationship between infarct size and transmural mean collateral blood flow in controls, and none of the treatments altered this correlation. Thus, neither EXP3174 nor enalaprilat limited infarct size. 6. These results indicate that activation of the renin-angiotensin system does not contribute to myocyte death in this canine ischaemia/reperfusion model.

Comparisons of the effects of nicorandil, pinacidil, nicardipine and nitroglycerin on coronary vessels in the conscious dog: role of the endothelium.

1. The vasodilator properties of nicorandil on large and small coronary arteries were compared to those of nicardipine, pinacidil, nitroglycerin and acetylcholine in six conscious dogs. 2. Intravenous bolus injections of acetylcholine (0.1 micrograms kg-1), nitroglycerin (0.3-3 micrograms kg-1), pinacidil (10-100 micrograms kg-1), nicardipine (3-30 micrograms kg-1) and nicorandil (10-100 micrograms kg-1) dose-dependently increased circumflex coronary artery diameter and decreased coronary vascular resistance, indicating vasodilator effects on both conduit and resistance coronary arteries. 3. Three days after removal of the endothelium of the circumflex coronary artery (balloon angioplasty), pinacidil- and nicardipine-induced dilation of large coronary arteries was greatly reduced (both -76%, P < 0.01) whereas that produced by nitroglycerin and nicorandil was decreased only slightly and to a similar extent for both drugs (-19%, P < 0.01 and -28%, P < 0.05, respectively). 4. Thus in conscious dogs, nicardipine- and pinacidil-induced dilatation of large coronary arteries is endothelium-dependent. In contrast, the vasodilator effects of nitroglycerin and nicorandil on conduit vessels are endothelium-independent. 5. Finally, our results demonstrate that nicorandil dilates the large coronary arteries through its nitrate-like action and that the ATP-potassium channel opening properties of the drug are not involved in this effect in the conscious dog.

Pharmacological delayed preconditioning against ischaemia-induced ventricular arrhythmias: effect of an adenosine A(1)-receptor agonist.

1. The goal of this study was to investigate the effects of the delayed pharmacological preconditioning produced by an adenosine A(1)-receptor agonist (A(1)-DPC) against ventricular arrhythmias induced by ischaemia and reperfusion, compared to those of ischaemia-induced delayed preconditioning (I-DPC). 2. Eighty-nine instrumented conscious rabbits underwent a 2 consecutive days protocol. On day 1, rabbits were randomly divided into four groups: 'Control' (saline, i.v.), 'I-DPC' (six 4-min coronary artery occlusion/4-min reperfusion cycles), 'A(1)-DPC(100)' (N(6)-cyclopentyladenosine, 100 microg kg(-1), i.v.), and 'A(1)-DPC(400)' (N(6)-cyclopentyladenosine, 400 microg kg(-1), i.v.). On day 2, i.e., 24 h later, the incidence and severity of ventricular arrhythmias during a 30-min coronary artery occlusion and subsequent reperfusion were analysed in all animals, using an arrhythmia score. 3. I-DPC, A(1)-DPC(100) and A(1)-DPC(400) significantly reduced the infarct size (34+/-5, 42+/-3 and 43+/-7% of the area at risk, respectively) as compared to Control (55+/-3% of the area at risk). 4. During both ischaemia and reperfusion, neither the incidence nor the severity of ventricular arrhythmias were altered by A(1)-DPC(100), A(1)-DPC(400) or I-DPC as compared to Control. 5. Thus, despite reduction of infarct size induced by delayed preconditioning, A(1)-DPC as well as I-DPC failed to exert any anti-arrhythmic effect in the conscious rabbit model of ischaemia-reperfusion.

Comparative effects of frovatriptan and sumatriptan on coronary and internal carotid vascular haemodynamics in conscious dogs.

The effects of frovatriptan and sumatriptan on internal carotid and coronary vascular haemodynamics were investigated and compared in conscious dogs. Frovatriptan and sumatriptan (0.1 - 100 microg kg(-1)) induced a transient increase in external coronary artery diameter (eCOD) of up to 2.9+/-1.2 and 1.8+/-0.6%, respectively (both P:<0.05). This was followed by a prolonged and dose-dependent decrease in eCOD of up to -5.2+/-1.2 and -5.3+/-0.9% (both P:<0.05), with ED(50) values of 86+/-21 and 489+/-113 micromol kg(-1), respectively. In contrast, only a decrease in the external diameter of the internal carotid artery was observed (-6.0+/-0.6 and -6.2+/-1.4%, both P:<0.05, and ED(50) values of 86+/-41 and 493+/-162 micromol kg(-1), respectively). Frovatriptan was thus 5.7 fold more potent than sumatriptan at the level of both large coronary and internal carotid arteries. After endothelium removal by balloon angioplasty in coronary arteries, the initial dilatation induced by the triptans was abolished and delayed constriction enhanced. The selective antagonist for the 5-HT(1B) receptors SB224289 dose-dependently blocked the effects of sumatriptan on large coronary and internal carotid arteries whereas the selective antagonist for the 5-HT(1D) receptors BRL15572 did not affect any of these effects. In conclusion, frovatriptan and sumatriptan initially dilate and subsequently constrict large coronary arteries in the conscious dog, whereas they directly constrict the internal carotid artery. The vascular endothelium modulates the effects of these triptans on large coronary arteries. Finally, 5-HT(1B) but not 5-HT(1D) receptors are primarily involved in canine coronary and internal carotid vasomotor responses to sumatriptan.

Alpha 1 and alpha 2-adrenergic control of large and small coronary arteries during exercise in conscious dogs under beta-blockade.

The aim of this study was to determine the relative roles of alpha 1-and alpha 2-adrenoceptors at the level of large epicardial and small resistance coronary arteries when sympathetic tone is increased by exercise in conscious dogs. The responses of left circumflex coronary artery diameter and blood flow were investigated at rest and during graded treadmill exercise (5, 10 and 12 km/h) in six chronically instrumented dogs during control conditions (saline) and after administration of propranolol (1 mg/kg) either alone or in combination with either prazosin (50 micrograms/kg), or idazoxan (300 micrograms/kg), or the association of prazosin+idazoxan (same doses). In control conditions, graded treadmill exercise resulted in a progressive increase in coronary artery diameter (+3.8 +/- 0.6% from 3479 +/- 80 microns) and in a decrease in coronary vascular resistance (-46.0 +/- 4.5% from 8.49 +/- 1.51 mmHg/cm/s). Propranolol significantly constricted large (-4.4 +/- 0.6% from 3486 +/- 87 microns) and limited dilation of small coronary arteries during exercise. These coronary effects of propranolol remained unchanged following additional alpha 2-adrenoceptor blockade by idazoxan but were abolished following alpha 1-adrenoceptor blockade by prazosin, given either alone or combined with idazoxan. Thus, alpha 1- but not alpha 2-adrenoceptors are responsible for propranolol-induced constriction of large coronary arteries and limitation of small coronary arteries dilation during exercise in conscious dogs.

[Hemodynamic effects of sub-chronic NO synthase inhibition in conscious dogs: role of EDRF/NO in muscular exertion]. / Effets hémodynamiques résultant du blocage sub-chronique de la NO-synthétase chez le chien éveillé: rôle de l'EDRF/NO dans l'exercice musculaire.

Acute and chronic administration of nitric oxide (NO) synthase (NOS) inhibitors increase mean arterial blood pressure (MAP) in rats but their hemodynamic effects in other species remain unknown. Moreover, the role of NO in the control of exercise-induced vasodilation is still debated. To answer these questions, six dogs were instrumented for the continuous measurement of cardiac output (CO, electromagnetic flow probe on the aorta), MAP (aortic catheter) and left ventricular pressure (Konigsberg gauge). Total peripheral resistance (TPR) was calculated as MAP/CO ratio and dP/dt was used as an index of cardiac inotropism. The dogs were treated from day 0 (D0) to 7 (D7) by the NOS inhibitor, N omega-nitro-L-arginine (L-NNA), 20 mg/kg/day (IV). Such a dose regimen resulted in NOS inhibition evidenced (a) in vivo by a reduction of the hypotensive responses to graded doses of acetylcholine and bradykinin, (b) ex vivo by a decrease in the relaxation of the femoral artery to acetylcholine (EC 50 = 2.2 +/- 0.6 10(-7) M after L-NNA vs 2.2 +/- 0.8 10(-8) M in controls). One month after instrumentation, the dogs being conscious, MAP measured at rest remained unchanged following one week L-NNA treatment (from 90 +/- 2 at D0 to 91 +/- 5 mmHg at D7). However, TPR increased (from 3,600 +/- 290 at D0 to 6,300 +/- 510 dyn.s.cm-5 at D7) and CO decreased (from 2.1 +/- 0.2 at D0 to 1.2 +/- 0.1 l/min at D7) (all p < 0.01), partly as the result of a marked bradycardia (from 100 +/- 7 at D0 to 60 +/- 7 beats/min at D7). L-NNA induced-increase in TPR was completely reversed by a bolus injection of nitroglycerin (10 micrograms/kg). During treadmill exercise (12 km/h), heart rate (251 +/- 9 at D0 vs 226 +/- 11 beats/min at D7), CO (6.3 +/- 0.9 at D0 vs 4.3 +/- 0.7 l/min at D7) and stroke volume remained significantly lower, and TPR significantly higher (1,662 +/- 278 at D0 vs 2,621 +/- 489 dyn.s.cm-5 at D7) after L-NNA than in the control state. Thus, NOS inhibition in resting conscious dogs by L-NNA markedly increases peripheral resistance but does not increase arterial pressure. In addition, L-NNA blunts both exercise-induced peripheral vasodilation and increase in cardiac output, despite metabolic vasodilation.

Direct myocardial implantation of human embryonic stem cells in a dog model of Duchenne cardiomyopathy reveals poor cell survival in dystrophic tissue.

Duchenne muscular dystrophy is characterized by progressive muscle weakness and early death resulting from dystrophin deficiency. Spontaneous canine muscular disorders are interesting settings to evaluate the relevance of innovative therapies in human using pre-clinical trials.

Pharmacological postconditioning with the phytoestrogen genistein.

Estrogens are known to activate the phosphatidyl-inosityl 3-kinase (PI3K)/Akt pathway, which is central in the cardioprotection afforded by ischemic postconditioning. Therefore, our goal was to investigate whether a phytoestrogen, genistein, could induce a pharmacological postconditioning and to investigate potential mechanisms. We used low doses of genistein in order to avoid tyrosine kinases inhibition. Thus, pentobarbital-anesthetized rabbits underwent a coronary artery occlusion followed by 4 h of reperfusion. Prior to reperfusion, they randomly received an i.v. injection of either saline (Control), 100 or 1000 microg/kg of genistein (Geni(100) and Geni(1000), respectively), and 10 or 100 microg/kg of 17beta-estradiol (17beta(10) and 17beta(100), respectively). Infarct size (IS, % area at risk) was significantly reduced in Gen(100), Gen(1000) and 17beta(100) but not in 17beta(10) (6+/-2, 16+/-5, 12+/-3 and 29+/-7%, respectively) vs. Control (35+/-4%). A significant decrease in the percentage of TUNEL-positive nuclei within infarcted area was observed in Gen(100) and 17beta(100) vs. Controls. The estrogen receptor antagonist fulvestrant (1 mg/kg i.v.) and the PI3K inhibitor wortmaninn (0.6 mg/kg) abolished the cardioprotective effect of genistein. Western blots also demonstrated an increase in Akt posphorylation in Gen(100). In the same group, in vitro mitochondrial swelling studies demonstrated a significant inhibition of calcium-induced opening of mitochondrial transition pore vs. Controls. In conclusion, genistein exerts pharmacological postconditioning with a similar potency as 17beta-estradiol through a pathway involving activation of the estrogen receptor, of PI3K/Akt and mitochondrial preservation. Therefore, genistein should not be only considered as an inhibitor of tyrosine kinase but also as a cardioprotective estrogen.

[Nitric oxide and myocardial ischemic preconditioning]. / Monoxyde d'azote et préconditionnement du myocarde ischémique.

Preconditioning is an endogenous mechanism of cardioprotection that develops secondary to a brief ischemia and a dramatic reduction in infarct size is observed when the myocardium undergoes a subsequent and long period of ischemia after the induction of preconditioning. Since its initial discovery, it appears that the kinetic of preconditioning is biphasic. Early preconditioning is effective within 1 to 3 hours after the initial brief ischemia. A second windows of preconditioning has been also described within the following 24-48 h. Although late preconditioning against myocardial stunning is well established, its protection against infarction still remains debated. Whereas nitric oxide is not involved in the early preconditioning, its role during the late phase of preconditioning has been recently well described. Indeed, nitric oxide triggers the delayed cardioprotection through the formation of oxiradicals. This leads to the translocation of protein kinase C. Secondary, the activation of the tyrosine kinases pathway and the transcriptional factor NF kappa B induces iNOS. Therefore, nitric oxide also plays a key role in the late preconditioning phenomenon as a mediator of this cardioprotection, although its final effector still remains unknown. The knowledge of the mechanisms responsible for preconditioning is necessary in order to develop new pharmacological concepts in order to protect the heart against ischemia. It is interesting to underline that nitric oxide donors are able to mimic late preconditioning.

Divergence of beta-myosin heavy chain (betaMHC) expression in fetal rat cardiomyocytes in vitro and adult rat heart in vivo.

The myosin heavy chain gene products are an important determinant of myocardial functional properties. Although a strong positive element (beta f1) within the betaMHC promoter region has previously been identified, to date no species comparisons in promoter strength have been made. To examine this question, we have used betaMHC deletion constructs, containing the rat or human beta f1 enhancer region, to determine expression both in vitro using rat fetal cardiomyocytes and in vivo by direct injection into adult rat heart. When reporter constructs were transfected into cultured fetal rat cardiomyocytes, the human beta reporter was expressed more than 3 fold above the equivalent rat construct. Exchange of the beta f1 enhancer indicated that the human sequence of the beta f1 enhancer was largely responsible. However, these findings were not replicated when the reporters were injected into the adult rat heart. In the adult myocardium the levels of reporter expression were similar for the betaMHC promoter reporters studied. These findings demonstrate a divergence between primary cardiomyocytes maintained in culture and the cardiomyocytes found within the intact adult heart.

Spatial heterogeneity of myocardial blood flow presages salvage versus necrosis with coronary artery reperfusion in conscious baboons.

BACKGROUND: Myocardial blood flow distribution is known to be heterogeneous. It is also known that not all of the area at risk (AAR) infarcts with coronary artery occlusion (CAO) and coronary artery reperfusion (CAR). The goal of the present study was to determine whether the proportion of AAR that is salvaged or infarcted can be predicted by the pre-CAO level of myocardial blood flow, which varies considerably in individual samples as a result of natural heterogeneity. METHODS AND RESULTS: The effects of 90-minute CAO followed by 5- to 7-day CAR were examined in six conscious baboons instrumented with aortic and left atrial catheters and coronary artery occluders. AAR was determined by dual perfusion. Myocardial blood flow was measured by radioactive microspheres before and after CAO and CAR. The AAR was cut into small pieces (0.21 +/- 0.01 g) and separated into two categories; salvaged (n = 252) or infarcted (n = 133). Analysis of myocardial blood flow distribution revealed two distinct populations (P < .01); infarcted tissues demonstrated higher pre-CAO myocardial blood flow than salvaged tissues. Importantly, 50% of the salvaged tissue samples were characterized by pre-CAO myocardial blood flows of < 0.90 mL.min-1.g-1 compared with 29% for infarcted samples, whereas 51% of infarcted samples were characterized by pre-CAO myocardial blood flows of > 1.12 mL.min-1.g-1 compared with 22% of salvaged samples. Endocardial analyses were qualitatively similar to transmural analyses. CONCLUSIONS: This study suggests that heterogeneity of pre-CAO myocardial blood flows can predict the proportion of myocardium salvaged by CAR and can further explain the spatial heterogeneity of infarction that occurs after CAR, potentially independent of CAR injury.

Beneficial effects of the T- and L-type calcium channel antagonist, mibefradil, against exercise-induced myocardial stunning in dogs.

Abnormalities in calcium homeostasis such as calcium overload have been shown to participate in the pathogenesis of myocardial stunning. The goal of this study was to investigate the effects of mibefradil, a mixed T- and L-type calcium channels antagonist on exercise-induced ischemia (i.e., high-flow ischemia). Nine dogs were permanently instrumented to measure left ventricular wall thickening (Wth) and coronary blood flow (Doppler). Infusion of saline or mibefradil (30 and 40 microg/kg/min, i.v., for 20 min) was started 10 min before exercise (10 min, 14 km/h; slope, 13%) and stopped at its end. Circumflex coronary artery stenosis (pneumatic occluders) was set up 5 min before exercise to suppress exercise-induced increase in mean coronary blood flow without simultaneously affecting Wth at rest. Mibefradil (30 microg/kg/min) was also administered at the beginning of the recovery period in a subset of four dogs. During exercise with saline, Wth was dramatically reduced (-77 +/- 7%; p < 0.05) and recovered only after 24 h. Mibefradil at both doses significantly limited tachycardia during exercise (211 +/- 7 and 210 +/- 5 beats/min vs. 240 +/- 8 beats/min for mibefradil, 30 microg/kg/min, mibefradil, 40 microg/kg/min, and saline, respectively) but exerted no negative inotropic effects. Mibefradil at both doses significantly reduced the intensity of myocardial stunning and the time to recovery in Wth (3 h). Administration of mibefradil at the beginning of the recovery period did not protect against myocardial stunning. Administration of a mixed T- and L-type calcium channel antagonists before ischemia confers cardioprotection against exercise-induced myocardial stunning. This may potentially be related to the limitation of exercise-induced tachycardia and/or the prevention of calcium overload.