The cardioprotectant 3',4'-dihydroxyflavonol inhibits opening of the mitochondrial permeability transition pore after myocardial ischemia and reperfusion in rats.

The study aimed to determine the effect of 3',4'-dihydroxyflavonol (DiOHF) on mitochondrial function, in particular opening of the mitochondrial permeability transition pore (mPTP), respiratory function and reactive oxygen species (ROS) production, in isolated cardiac mitochondria after coronary artery occlusion and reperfusion in vivo. Opening of the mPTP, oxygen consumption and ROS production (assessed by measurement of H2O2) was determined in mitochondria isolated from normal hearts or from the ischemic zone of rat hearts subjected to 30min coronary artery occlusion and 15min reperfusion. Treatment of sham rats with DiOHF (10mgkg(-1) iv) significantly increased the concentration of Ca(2+) required to stimulate mPTP opening. This was accompanied by increased state 3 oxygen consumption and decreased H2O2 release. Ischemia and reperfusion (IR) significantly decreased the concentration of Ca(2+) required to stimulate mPTP opening, decreased state 3 oxygen consumption and increased H2O2 release, when pyruvate plus malate was provided as a substrate. Treatment with DiOHF prevented IR-induced changes in mPTP opening, state 3 oxygen consumption and H2O2 release so that there was no difference compared to sham. In isolated cardiac mitochondria from normal rats DiOHF had no effect on mPTP opening or on state 3 respiration but caused a small increase in state 4 respiration and decreased the respiratory control ratio. DiOHF, administered during ischemia just before reperfusion, inhibits mPTP opening and preserves mitochondrial function through a mechanism likely to be independent of its antioxidant activity or any direct effect on the mPTP.

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.

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.

Inhibition of mitochondrial membrane permeability as a putative pharmacological target for cardioprotection.

Myocardial ischemia-reperfusion injury is a major cause of morbidity and mortality in developed countries. To date, the only treatment of complete ischemia is to restore blood flow; thus the search for new cardioprotective approaches is absolutely necessary to reduce the mortality associated with myocardial ischemia. Ischemia has long been considered to result in necrotic tissue damage but the reduction in oxygen supply can also lead to apoptosis. Therefore, in the last few years, mitochondria have become the subject of growing interest in myocardial ischemia-reperfusion since they are strongly involved in the regulation of the apoptotic process. Indeed, during ischemia-reperfusion, pathological signals converge in the mitochondria to induce permeabilization of the mitochondrial membrane. Two classes of mechanisms, which are not mutually exclusive, emerged to explain mitochondrial membrane permeabilization. The first occurs via a non-specific channel known as the mitochondrial permeability transition pore (mPTP) in the inner and the outer membranes causing disruption of the impermeability of the inner membrane, and ultimately complete inhibition of mitochondrial function. The second mechanism, involving only the outer membrane, induces the release of cell death effectors. Thus, drugs able to block or to limit mitochondrial membrane permeabilization may be cytoprotective during ischemia-reperfusion. The objective of this review is to examine the pharmacological strategies capable of inhibiting mitochondrial membrane permeabilization induced by myocardial ischemia-reperfusion.

[Pharmacological protection against myocardial infarction: realities and actualities]. / La cardioprotection pharmacologique contre l'infarctus du myocarde: réalités et actualités.

Coronary heart disease and myocardial infarction remain a major problem of public health with an annual incidence of 120,000 cases in France. Although several techniques of early repermeabilization of the obstructed coronary arteries have been available for almost twenty years with an associated high degree of reduction in morbidity and mortality of post-infarction patients, such success still remains dependent on the delay to the procedure to enable maximal protection of the myocardium against necrosis. Thus, pharmacological "cardioprotection" against ischemic injury must be considered as an additional and complementary opportunity to enhance myocardial survival following acute infarction. On the basis of current knowledge of the pathological, physiological and pharmacological processes involved in pre- and postconditioning, new strategies of cardioprotection associated with reperfusion of the myocardium have been proposed in recent years. The efficacy of these new approaches has been proven pre-clinically using experimental models but their real clinical relevance and their ability to reduce human myocardial infarction-associated morbidity and mortality remains to be determined.

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.

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.

The aryl hydrocarbon receptor and its xenobiotic ligands: a fundamental trigger for cardiovascular diseases.

This review reconsiders a major cause of cardiovascular diseases, tobacco smoking, as the activation of the Aryl hydrocarbon Receptor (AhR), also known as the dioxin receptor, by aryl hydrocarbons from the tar fraction of tobacco in various organs of the cardiovascular domain. This concept sheds new light on well-known albeit controversial epidemiological concepts such as the Mediterranean diet and the French paradox. We also review the discovery that resveratrol, a natural AhR antagonist, may be of interest in the prevention and treatment of cardiovascular diseases.

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.

Effects of heart rate reduction with ivabradine on exercise-induced myocardial ischemia and stunning.

We investigated the effects of the selective bradycardic agent ivabradine, an I(f) channel inhibitor, on exercise-induced ischemia and resulting myocardial stunning. Seven dogs were chronically instrumented to measure left ventricular (LV) wall thickening (Wth), aortic pressure and coronary blood flow (CBFv) (Doppler). Circumflex coronary artery stenosis was set up to suppress the increase in CBFv during a 10 min treadmill exercise. During exercise under saline, LVWth in the ischemic zone was depressed (-70 +/- 4%) and a prolonged myocardial stunning was subsequently observed. Infusion of ivabradine started before exercise significantly reduced heart rate (HR) at rest (-22 +/- 7%), during exercise (-33 +/- 4%) and throughout the recovery period (-21 +/- 2%). By reducing HR during exercise, ivabradine simultaneously improved LVWth compared with saline (14 +/- 1% versus 7 +/- 1%, respectively) and subendocardial perfusion (microspheres). This anti-ischemic effect was subsequently responsible for a strong decrease in the intensity and severity of myocardial stunning. All these beneficial effects were abolished when HR reduction during exercise was suppressed by atrial pacing. Interestingly, when ivabradine infusion was started after exercise, LVWth was still significantly enhanced and myocardial stunning strongly attenuated. This direct effect of ivabradine on the stunned myocardium disappeared when HR reduction was suppressed by atrial pacing at rest. In conclusion, this study demonstrates that ivabradine exerts an anti-ischemic effect that is responsible for subsequent protection against myocardial stunning. Furthermore, administration of ivabradine after the ischemic insult still improves LVWth of the stunned myocardium.

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.

[Therapeutic perspectives in the treatment of stable angina]. / Perspectives thérapeutiques dans le traitement de l'angor stable.

Five groups of drugs are presently available to reduce the symptoms associated with angina pectoris: beta-blockers, calcium channel antagonists, nitrates, potassium channel agonists and trimetazidine. beta-blockers remain the drugs of first strategy since they are unique in reducing major cardiac events. Angiogenesis and gene therapy are still in the field of research. The second therapeutic goal is to reduce cardiovascular morbi-mortality. Inhibitors of platelet aggregation, hypolipemic agents and converting enzyme inhibitors have proved their efficacy in these fields. Conversely, vitamins C, E and B, antibiotics against intra-cellular germs and substitutive hormonotherapy of post-menopausal women must yet prove their efficacy.

Myocardial stunning in exercise-induced ischemia in dogs: lack of late preconditioning.

Late preconditioning (PC) against myocardial stunning develops after coronary artery occlusion (CAO) at rest and subsequent reperfusion. We investigated whether late PC occurs after exercise-induced ischemia (high-flow ischemia) in dogs. A circumflex coronary artery stenosis (by using occluders) was set up before the onset of treadmill exercise in nine chronically instrumented dogs to suppress exercise-induced increase in mean coronary blood flow velocity (CBFV, Doppler) without simultaneously affecting left ventricular (LV) wall thickening (Wth) at rest. Two similar exercises were performed 24 h apart. On day 1, LV Wth was reduced by 84 +/- 5% (P < 0.01), and exercise-induced increases in transmural myocardial blood flow (MBF, fluorescent microspheres) in the ischemic zone were blunted. LV Wth was depressed throughout the first 10 h and returned to its baseline value after 24 h. On day 2, changes in LV Wth and MBF were similar as was the time course for LV Wth recovery, indicating lack of late PC. Also, CBFV responses to acetylcholine, nitroglycerin, and reactive hyperemia (20-s CAO) were not significantly different on days 1 and 2. Similar results were obtained in a subgroup of four additional dogs with more severe stenosis during exercise. Late PC against myocardial stunning was confirmed to occur in a model of 10-min CAO followed by coronary artery reperfusion (CAR) in another four dogs. Thus in contrast with CAO at rest followed by CAR, severe myocardial ischemia in coronary flow-limited exercising dogs does not induce late PC against myocardial stunning.

Induction of apoptosis using sphingolipids activates a chloride current in Xenopus laevis oocytes.

The purpose of this study was to investigate whether the cell shrinkage that occurs during apoptosis could be explained by a change of the activity in ion transport pathways. We tested whether sphingolipids, which are potent pro-apoptotic compounds, can activate ionic currents in Xenopus laevis oocytes. Apoptosis was characterized in our model by a decrease in cell volume, a loss of cell viability, and DNA cleavage. Oocytes were studied using voltage-clamp after injection with N,N-dimethyl-D-erythrosphingosine (DMS) or D-sphingosine (DS). DMS and DS activated a fast-activating, slowly inactivating, outwardly rectifying current, similar to I(Cl-swell), a swelling-induced chloride current. Lowering the extracellular chloride dramatically reduced the current, and the channel was more selective for thiocyanate and iodide (thiocyanate > iodide) than for chloride. The current was blocked by 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and lanthanum but not by niflumic acid. Oocytes injected with a pseudosubstrate inhibitor of protein kinase C (PKC), PKC-(19-31), exhibited the same current. DMS-activated current was abolished by preexposure with phorbol myristate acetate. Our results suggest that induction of apoptosis in X. laevis oocytes, using sphingolipids or PKC inhibitors, activates a current similar to swelling-induced chloride current previously described in oocytes.

Stimulation of bradykinin B(1) receptors induces vasodilation in conductance and resistance coronary vessels in conscious dogs: comparison with B(2) receptor stimulation.

BACKGROUND: Constitutive bradykinin B(1) receptors have been identified in dogs; however, their physiological implications involving the coronary circulation remain to be determined. This study examined, in conscious dogs, the coronary response to des-Arg(9)-bradykinin (a B(1) receptor agonist) and the mechanisms involved. METHODS AND RESULTS: Eleven dogs were instrumented with a left ventricular micromanometer, a circumflex coronary catheter, a cuff occluder, a Doppler flow probe, and ultrasonic crystals to measure coronary blood flow velocity (CBFv) and coronary diameter (CD). Intracoronary des-Arg(9)-bradykinin (3 to 100 ng/kg) and bradykinin (0.1 to 10 ng/kg) did not modify systemic hemodynamics but dose-dependently increased CBFv and CD. Des-Arg(9)-bradykinin was less potent than bradykinin. Hoe 140 (a B(2) antagonist, 10 microg/kg) abolished the effects of bradykinin but did not influence the effects of des-Arg(9)-bradykinin. When CBFv increase was prevented by the cuff occluder, CD responses to bradykinin and des-Arg(9)-bradykinin were maintained. Intracoronary lisinopril (0. 75 mg) increased the CD response to bradykinin, with only minimal effect on CBFv, and extended the duration of the effect. Lisinopril did not alter des-Arg(9)-bradykinin responses. Intracoronary N(omega)-nitro-L-arginine (2 mg/kg) decreased the CD effect of bradykinin and prevented the CBFv and CD effects of des-Arg(9)-bradykinin. The relaxing effect of des-Arg(9)-bradykinin on isolated coronary rings was prevented by des-Arg(9), [Leu(8)]-bradykinin. CONCLUSIONS: In the conscious dog, B(1) receptors are present in coronary vessels, and their stimulation produces vasodilation in conductance and resistance vessels, which is mediated essentially by NO but not modulated by angiotensin-converting enzyme. However, the coronary vasodilation induced by B(1) receptor stimulation is not as great as that produced by B(2) receptor stimulation.

Pretreatment of brain dead rabbits with pinacidil before prolonged cold-storage with an extracellular solution alters aortic endothelial function.

OBJECTIVE: Endothelial injury occurs during heart transplantation and contributes to the development of cardiac allograft vasculopathy. We have evaluated in a brain death model in the rabbit whether pre-treatment with the potassium channel opener (PCO) pinacidil before prolonged hypothermic storage with an extracellular solution would improve vascular endothelial recovery. METHODS: Rabbits were randomized into 4 experimental groups (n = 8 per group). In the control group (CTRL), abdominal aortic rings were assessed immediately after 90 minutes of anesthesia. In the brain death group (BD), aortic rings were assessed immediately after 90 minutes of brain death. In the STH group, aortic rings taken from brain dead rabbits were stored for 24 hours at 4 degrees C with the extracellular preservation solution of St. Thomas Hospital (STH) before assessment. In the STH + PCO group, the potassium channel opener pinacidil, 1 mg/kg, was administered intravenously to brain dead rabbits 10 minutes before explantation. Aortic rings were then stored for 24 hours at 4 degrees C with the STH solution before evaluation. Brain death was induced by rapid inflation of a sub-durally placed balloon and validated by clinical and electroencephalographic data. Concentration-response curves to acetylcholine (ACH, 10(-9) to 10(-4) mol/liter) and nitroglycerin (NGL, 10(-9) to 10(-5) mol/liter) were constructed in phenylephrinepre-contracted rings. RESULTS: ACH evoked a similar concentration-dependent relaxation in the CTRL (E(max): 95.8 +/- 2.9%; EC(50): -6.86 +/- 0.13 log M) and BD groups (E(max): 90.8 +/- 3.8%; EC(50): -6.75 +/- 0.15 log M). The concentration-relaxation curve was shifted rightward in the STH group (E(max): 76.7 +/- 7.1%; EC(50): -6.75 +/- 0.16 log M) in comparison with the CTRL and BD groups, but there were no significant differences in either E(max) or EC(50) values. After pinacidil pre-treatment, there was a further significant shift to the right of the concentration-relaxation curve to ACH (E(max): 77.4 +/- 5.0%; EC(50): -6.14 +/- 0.19 log M, p < 0.05 vs CTRL, BD and STH). There were no significant differences between groups in the concentration-relaxation curves to NGL in endothelium-intact and endothelium-denuded vascular rings (either E(max) or EC(50)). CONCLUSION: Pre-treatment of brain dead rabbits with pinacidil before prolonged cold-storage with STH solution significantly impaired endothelium-dependent vasorelaxation in comparison to storage with STH solution. The role of PCO pre-treatment in the context of cardiac transplantation needs to be reconsidered.

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.

[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.

Beta 3-adrenoceptor stimulation induces vasorelaxation mediated essentially by endothelium-derived nitric oxide in rat thoracic aorta.

1. The relaxant effects of isoprenaline may result from activation of another beta-adrenoceptor subtype in addition to beta1 and beta2. This study evaluated the role of a third beta-adrenoceptor subtype, beta3, in beta-adrenoceptor-induced relaxation of rat thoracic aorta by isoprenaline. 2. Isoprenaline produced a concentration-dependent relaxation of phenylephrine pre-contracted rings of the thoracic aorta (pD2=7.46+/-0.15; Emax=85.9+/-3.4%), which was partially attenuated by endothelium removal (Emax=66.5+/-6.3%) and administration of the nitric oxide (NO) synthase inhibitor, L-NG-monomethyl arginine (L-NMMA) (Emax=61.3+/-7.9%). 3. In the presence of nadolol, a beta1- and beta2-adrenoceptor antagonist, isoprenaline-induced relaxation persisted (Emax=55.6+/-5.3%), but occurred at higher concentrations (pD2=6.71+/-0.10) than in the absence of nadolol and lasted longer. 4. Similar relaxant effects were obtained with two beta3-adrenoceptor agonists: SR 58611 (a preferential beta3-adrenoceptor agonist), and CGP 12177 (a partial beta3-adrenoceptor with beta1- and beta2-adrenoceptor antagonistic properties). SR 58611 caused concentration-dependent relaxation (pD2=5.24+/-0.07; Emax=59.5+/-3.7%), which was not modified by pre-treatment with nadolol but antagonized by SR 59230A, a beta3-adrenoceptor antagonist. The relaxation induced by SR 58611 was associated with a 1.7 fold increase in tissue cyclic GMP content. 5 Both relaxation and the cyclic GMP increase induced by SR 58611 were greatly reduced by endothelium removal and in the presence of L-NMMA. 6 We conclude that in the rat thoracic aorta, beta3-adrenoceptors are mainly located on endothelial cells, and act in conjuction with beta1- and beta2-adrenoceptors to mediate relaxation through activation of an NO synthase pathway and subsequent increase in cyclic GMP levels.