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Biomedical subjects

M Tanguay

Publications and source records attributed to M Tanguay.

9 recordsLinked to original sources
PubMed1997

Reactivity to endothelium-dependent and -independent vasoactive substances is maintained in coronary resistance vessels of the failing hamster heart.

OBJECTIVES: Several studies suggest that regulation of coronary vasomotion is abnormal in heart failure, but controversies exist as to whether an altered endothelium-dependent dilation of the coronary vasculature contributes to these abnormalities. In the present study we evaluated the coronary reactivity to endothelium-dependent and -independent vasoactive substances in a model of chronic heart failure. METHODS: Isolated hearts from > 200-day-old cardiomyopathic hamsters (UM-X7.1) and age-matched normal Syrian hamsters were mounted on a Langendorff apparatus and retrogradely perfused at constant pressure (100 mmHg). Heart rate, left ventricular developed pressure (LVP) and coronary flow (CF) were measured. A first group of normal and failing hearts were challenged with increasing doses of acetylcholine (Ach), 1-1000 nM, and sodium nitroprusside (SNP), 0.01-10 microM. A second group was challenged with Ach (100 nM) and SNP (1 microM) before and during infusion of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Finally, normal and failing hearts were challenged with Ach (100 nM) before and during infusion of indomethacin (10 microM) or tetraethylammonium (1 mM). RESULTS: Myocardial contractility and coronary flow were significantly impaired in failing hearts (LVP = 32 +/- 5 vs. 50 +/- 4 mmHg in normal hearts; CF = 4.7 +/- 0.6 vs. 6.7 +/- 0.6 ml/min in normal hearts). Coronary flow increases with increasing doses of Ach (EC50 = 84 +/- 15 nM for failing hearts and 100 +/- 3 nM for normal hearts, P = ns). At concentrations exceeding the EC50, failing hearts were more sensitive to the coronary dilator effects of Ach. The reduction in coronary flow elicited by L-NAME was similar in normal (-41 +/- 2%) and failing hearts (-40 +/- 3%); in both normal and failing hearts, the acetylcholine vasodilator response was not significantly affected by L-NAME. Indomethacin infusion resulted in a slight increase in coronary flow and significantly reduced the coronary dilator effects of acetylcholine. Tetraethylammonium had no significant effects on basal coronary perfusion of normal and failing hearts. However, in the latter group, acetylcholine vasodilator response was significantly attenuated. CONCLUSION: Results obtained in isolated failing hamster hearts allow us to conclude that (1) significant coronary dysfunctions are present in this model of chronic heart failure, (2) neither the NO-synthase nor the cyclo-oxygenase pathway contributes to these coronary dysfunctions, and (3) an adequate coronary vasodilator response appears to be present in this model of chronic heart failure.

Acetylcholine↗
PubMed1997

Coronary and cardiac sensitivity to the vasoselective benzothiazepine-like calcium antagonist, clentiazem, in experimental heart failure.

Recent evidence suggests that newer vasoselective dihydropyridine calcium antagonists are not cardiodepressant and may be useful in the treatment of heart failure. No data are available on the efficacy of clentiazem, a vasoselective benzothiazepine-like calcium antagonist, in this pathological condition. Therefore, our objective was to assess coronary and cardiac sensitivity to clentiazem in an experimental model of chronic heart failure (cardiomyopathic hamster, UM-X7.1, > 200 day old). Left ventricular developed pressure (LVP) and coronary flow changes were assessed in isolated, perfused failing hearts and in normal Syrian hamster hearts. Clentiazem dose-response curves for both coronary dilation and negative inotropic effects were determined under control conditions and in the presence of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (L-NAME, 30 microM), and the cyclooxygenase inhibitor, indomethacin (10 microM). Baseline hemodynamics indicate a significant reduction in both LVP and coronary perfusion in failing hearts. Cardiac sensitivity to the negative inotropic effects of clentiazem were similar in normal and failing hearts (IC50 = 677 nM and 734 nM, respectively). However, the clentiazem-induced increase in coronary flow was significantly attenuated in failing hearts (EC50 = 56 +/- 9 nM vs. 15 +/- 3 nM in normal hearts, p < 0.01). To better characterize the reduced coronary sensitivity to clentiazem in the presence of heart failure, the contributions of the NO synthase and the cyclooxygenase pathways were evaluated. Although coronary sensitivity to clentiazem was significantly reduced in the presence of L-NAME, this attenuation was of the same magnitude in normal and failing hearts, suggesting that coronary "desensitization" to clentiazem in failing hearts does not involve the NO synthase pathway. Experiments carried in the presence of indomethacin indicate that the reduced coronary sensitivity to clentiazem observed in failing hearts does not involve the cyclooxygenase pathway. In conclusion, reduced coronary sensitivity to the vasoselective calcium antagonist clentiazem was observed in the failing hamster heart, while no exacerbation of clentiazem's cardiodepressant actions was present. Although the mechanisms involved in the vascular desensitization to clentiazem are still unknown, our findings may provide an additional explanation for the variable efficacy of calcium antagonists in the treatment of heart failure.

Animals↗
PubMed1996

Impaired coronary sensitivity to diltiazem in experimental heart failure: involvement of the cyclooxygenase but not the nitric oxide-synthase pathway.

Because controversies surround the increased negative inotropic effects of calcium antagonists in heart failure, other mechanisms may explain their lack of efficacy in this condition. We hypothesized that altered coronary sensitivity through endothelial dysfunctions may be involved. Our goal was to evaluate the effects of heart failure on coronary and cardiac sensitivity to the calcium antagonist diltiazem. Left ventricular developed pressure (LVP) and coronary flow (CF) were assessed in isovolumetrically beating, perfused, failing hearts from cardiomyopathic hamsters (UM-X7.1) and hearts from normal hamsters. Diltiazem concentration-response curves for both coronary dilation and its negative inotropic effects were charted under control conditions and in the presence of the specific nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 30 microM), and the cyclooxygenase inhibitor, indomethacin (10 microM). Diltiazem concentration-response curves for its negative inotropic action were similar in normal and failing hearts (IC50 1.2 and 2.3 microM, respectively). In contrast, the coronary dilator effects of diltiazem were impaired in failing hearts (EC50 for diltiazem-induced coronary dilation increased from 90 nM in normal hearts to 1.1 microM in failing hearts, p < 0.01). The involvement of endothelial dysfunctions in the observed coronary "desensitization" to diltiazem in heart failure was evaluated through the NO-synthase and cyclooxygenase pathways. Diltiazem concentration-response curves from failing hearts were not modified in the presence of L-NAME, whereas indomethacin normalized the coronary response to diltiazem in heart failure. These findings suggest that coronary "desensitization" to diltiazem occurs through parallel production and/or release of a vasoconstricting factor or factors originating from the cyclooxygenase pathway. Heart failure was not associated with increased cardiac sensitivity to diltiazem but rather with altered coronary sensitivity. These findings suggest that coronary desensitization may play a role in the lack of efficacy of diltiazem in heart failure and provide a better understanding of factors modulating the effects of calcium antagonists in heart failure.

Animals↗
PubMed1995

Resistance of the failing dystrophic hamster heart to the cardioprotective effects of diltiazem and clentiazem: evidence of coronary vascular dysfunctions.

Although hypothermia and cardioplegic cardiac arrest provide effective protection during cardiac surgery, ischemia of long duration, poor preoperative myocardial function, and ventricular hypertrophy may lead to heterogeneous delivery of cardioplegic solutions, incomplete protection, and impaired postischemic recovery. Calcium antagonists are potent cardioprotective agents, but their efficacy in the presence of cold cardioplegia is still controversial, especially in heart failure, since it is often believed that failing hearts are more sensitive to their negative inotropic and chronotropic actions. However, recent data have demonstrated that the benzothiazepine-like calcium antagonists diltiazem and clentiazem, in selected dose ranges, elicit significant cardioprotection independently of intrinsic cardiodepression, thus lending support to their use in cardioprotective maneuvers involving the failing heart. We therefore evaluated the cardioprotective interaction of diltiazem, clentiazem, and cold cardioplegia in both normal and failing ischemic hearts. Hearts were excised from 200- to 225-day-old cardiomyopathic hamsters (CMHs) of the UM-X7.1 line and age-matched normal healthy controls. Ex vivo perfusion was performed at a constant pressure (140 cmH2O; 1 cmH2O = 98.1 Pa) according to the method of Langendorff. Heart rate, left ventricular developed pressure (LVDP), and coronary flow were monitored throughout the study. Global ischemia was produced for 90 min by shutting down the perfusate flow, followed by reperfusion for 30 min. Normal and failing CMH hearts were either untreated (control) or perfused at the onset of global ischemia with one of the following combinations: cold cardioplegia alone (St. Thomas' Hospital cardioplegic solution, 4 degrees C, infused for 2 min), cold cardioplegia + 10 nM diltiazem, or cold cardioplegia + 10 nM clentiazem. The cardiac and coronary dilator properties of 10 nM diltiazem and 10 nM clentiazem alone were investigated in separate groups of isolated preparations. Failing CMH hearts had lower basal LVDP (42 +/- 2 vs. 77 +/- 2 mmHg (1 mmHg = 133.3 Pa) for normal hearts, p < 0.05), while coronary flow was only slightly reduced (5.6 +/- 0.2 vs. 6.2 +/- 0.2 mL/min for normal hearts). Following 90 min global ischemia, coronary flow was increased in both groups, but the peak hyperemic response declined only in failing CMH hearts (+50 +/- 17 vs. +82 +/- 17% in normal hearts). In normal hearts, LVDP virtually recovered within 5 min of reperfusion but steadily decreased thereafter (-37 +/- 4% at 30 min). In contrast, in failing CMH hearts, LVDP significantly decreased early during reperfusion but improved over time (-19 +/- 7% at 30 min). In normal hearts, the addition of diltiazem or clentiazem to cold cardioplegic solutions resulted in improved postischemic contractile function for the duration of reperfusion (85 +/- 4% vs. only 71 +/- 6% for cardioplegia, p < 0.05). The post-ischemic increase in coronary flow was similar in all groups. In failing CMH hearts, the addition of diltiazem or clentiazem afforded no significant contractile benefit at reperfusion. In nonischemic normal hearts, infusion of diltiazem or clentiazem (10 nM) alone increased coronary flow (+6 +/- 1% for diltiazem and +24 +/- 3% for clentiazem) without significant negative inotropic or chronotropic effects. In nonischemic failing CMH hearts, infusion of diltiazem or clentiazem did not elicit cardiodepression. In contrast their coronary dilator actions reverted to vasoconstriction (diltiazem) or were significantly attenuated (clentiazem). From these experiments we can conclude that, compared with the normal heart, the failing CMH heart adapted differently to global ischemia.

Animals↗
PubMed1994

Clentiazem, diltiazem, and cold cardioplegia in isolated ischemic rabbit hearts: relation between additive cardioprotection, physicochemical properties, and preservation of myocardial lipid components.

Diltiazem is known to exert significant cardioprotection, but its efficacy under hypothermic conditions has not been documented. Because of its lipophilicity and its better tissue penetration, clentiazem, a chlorobenzothiazepine derivative of diltiazem, may offer cytoprotection additive to cold cardioplegia. We investigated the cardioprotective actions of clentiazem and diltiazem (10(-8) and 10(-6) M) when added to cold cardioplegia (myocardial temperature of 10 degrees-12 degrees C), in isolated rabbit heart subjected to 90-min global ischemia. Functional recovery was assessed by measuring left ventricular developed pressure (LVDP), coronary flow (CF) and heart rate (HR). To explore the potential beneficial mechanisms of these agents, we measured myocardial lipids and total calcium at the end of a 30-min period of reperfusion as well as their myocardial accumulation. Addition of 10(-8) M clentiazem to cold cardioplegia resulted in significant improvement in mechanical recovery (postischemic LVDP of 88.5 mm Hg with cardioplegia alone vs. 105.5 mm Hg with added clentiazem at 25 mm Hg diastolic pressure, DP). The additive cardioprotection afforded by clentiazem appeared to be concentration dependent since significant cardiodepression (postischemic LVDP of 79.8 mm Hg and 18% reduction in HR) was observed at a higher concentration (10(-6) M) and these effects were correlated with myocardial accumulation of the drug. The additive cardioprotective effect of clentiazem appeared to be structure related because diltiazem at both 10(-8) and 10(-6) M concentrations offered no benefits in addition to cold cardioplegia. These results indicate that the additive cardioprotection observed with 10(-8) M clentiazem could be related to its coronary vasodilator action since it reversed the cold cardioplegia-induced attenuation of hyperemic CF at reperfusion. Other factors must be involved, however, because addition of 10(-6) M diltiazem resulted in increased postischemic CF but without improving myocardial recovery. The functional protection offered by 10(-8) M clentiazem was associated with preservation of myocardial lipid components. Myocardial cholesterol content, which is essential for maintenance of membrane integrity, was preserved in that group, whereas a loss was observed in groups treated with cardioplegia alone and in the other treated groups. Total myocardial phospholipids were preserved in groups receiving 10(-8) M clentiazem plus cold cardioplegia or cold cardioplegia alone. A reduction in plasmalogen content, the predominant myocardial phospholipid species, and an increase in total myocardial calcium were noted only in ischemic hearts that received neither cardioplegia nor benzothiazepines, suggesting that cold cardioplegia is sufficient to prevent irreversible damage. Clentiazem affords cardioprotective benefits additive to cold cardioplegia.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Beneficial effects of volatile anesthetics on decrease in coronary flow and myocardial contractility induced by oxygen-derived free radicals in isolated rabbit hearts.

Oxygen-derived free radicals have been implicated in reperfusion injury whereas volatile anesthetics have been shown to enhance myocardial recovery during reperfusion. To explore the mechanism by which these agents improve myocardial recovery, we measured the effect of volatile anesthetics on the free radical-induced reduction in left ventricular pressure (LVP), coronary flow, and endothelium-dependent dilation induced by acetylcholine (Ach). Isolated rabbit hearts were perfused in a Langendorff apparatus. Isovolumetric LVP and coronary flow were measured throughout the study. Oxygen-derived free radicals were produced by the electrolysis (direct current of 0.6 mA) of the perfusate. The following volatile anesthetics were used: halothane 0.5 or 1.0%, isoflurane 0.7 or 1.4%, and enflurane 1.0 or 2.0%. Oxygen free radicals induced a significant decrease in systolic LVP and coronary flow. Pretreatment of the heart with enflurane 1.0 or 2.0%, halothane 1.0%, or isoflurane 0.7% attenuated the effect of the free radicals on both systolic LVP and coronary flow. Free radicals reduced the dilating response induced by 0.1 microM Ach with or without addition of volatile anesthetics. These data suggest that the volatile agents have beneficial effects on the free radical cell damage pathway and that this protection is not related to the preservation of endothelium-dependent dilation.

Anesthetics↗
PubMed1991

Isoproterenol corrects the effects of bupivacaine on the electrophysiologic properties of the isolated rabbit heart.

The purpose of this study was to test the hypothesis that isoproterenol could reverse bupivacaine toxicity. In eight isolated rabbit hearts an electrophysiologic evaluation was performed then repeated during infusion of bupivacaine (1 microgram/mL) alone and bupivacaine plus isoproterenol (1-2 micrograms/mL). Bupivacaine alone increased electrocardiographic intervals (P wave, QRS complex, PR, AV, and QTc interval) and refractory periods of the myocardium and atrioventricular junction as well as the Wenckebach cycle and pacing thresholds. The addition of isoproterenol corrected partially or completely all bupivacaine-induced abnormalities, and decreased sinus cycle length, suggesting a potential therapeutic value in the treatment of bupivacaine intoxication.

Action Potentials↗
PubMed1990

Perception and representation of the Euclidean coordinates in mature and elderly men and women.

Research on gender differences in visuo-spatial tasks has been mostly limited to samples of preadolescents, adolescents, and young adults. In a life span perspective, the present study attempted to complete the available information by submitting mature and elderly men and women to three tasks involving the Euclidean spatial system. Aged 40 to 61, 62 to 72, and 73 to 84, and maximally equivalent across age and sex groups, the subjects performed the Rod-and-Frame Test, the water-level task, and a plumb-line task. Proficiency was expected to decrease with age and to be higher among men. It was found that, whatever their age, men surpassed women in the water-level and plumb-line tasks, whereas no gender difference was obtained on the Rod-and-Frame Test. Irrespective of sex, the oldest subjects were outperformed by the youngest on the Rod-and-Frame Test, while water-level and plumb-line achievement was independent of age. Depression and anxiety scores were not correlated with visuo-spatial performance. Discussion focused on the fact that the present highly homogeneous and selective sample allowed for the valid emergency of a distinctive pattern of gender and age contributions to the use of appropriate vertical and horizontal references once maturity is reached.

Adult↗