Role of nitric oxide and cyclooxygenase pathways in the coronary vascular effects of halothane, isoflurane and desflurane in red blood cell-perfused isolated rabbit hearts.

BACKGROUND: The coronary vascular endothelium could mediate some of the coronary effects of halogenated anaesthetic agents. The role of the endothelial vasodilator substances nitric oxide (NO) and prostaglandins (PGs) in the coronary effects of halothane and isoflurane remains to be determined and has not been investigated for desflurane. In this study, the roles of NO and cyclooxygenase pathways in the coronary effects of halothane, isoflurane and desflurane were studied in isolated red blood cell-perfused rabbit hearts. METHODS: Rabbit hearts were perfused by a Langendorf technique with red blood cells mixed with modified Krebs-Henseleit buffer. Coronary blood flow (CBF), oxygen consumption and myocardial performance were evaluated during exposure to 0.5, 1 and 2 rabbit minimum alveolar concentrations of halothane, desflurane and isoflurane. Thereafter, the same protocol was applied with the addition of N(G)-nitro-L-arginine (L-NNA), indomethacin or a combination of both inhibitors. RESULTS: Similar and significant increases in CBF were observed with increasing concentrations of isoflurane and desflurane. In contrast, CBF did not change with halothane. The combination of the two antagonists abolished desflurane-induced vasodilation, whereas it did not change the isoflurane-mediated increase in CBF. Halothane-induced vasoconstriction was observed in the presence of a combination of indomethacin with L-NNA. CONCLUSIONS: Halothane and desflurane induce the release of vasodilating prostaglandins and NO in rabbit coronary arteries. In contrast, these mediators are not involved in the coronary vasodilating properties of isoflurane.

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.

Myocardial and coronary effects of propofol in rabbits with compensated cardiac hypertrophy.

BACKGROUND: Myocardial effects of propofol have been previously investigated but most studies have been performed in healthy hearts. This study compared the cardiac effects of propofol on isolated normal and hypertrophic rabbits hearts. METHODS: The effects of propofol (10-1,000 microM) on myocardial contractility, relaxation, coronary flow and oxygen consumption were investigated in hearts from rabbits with pressure overload-induced left ventricular hypertrophy (LVH group, n = 20) after aortic abdominal banding and from sham-operated control rabbits (SHAM group, n = 10), using an isolated and erythrocyte-perfused heart model. In addition, to assess the myocardial and coronary effects of propofol in more severe LVH, hearts with a degree of hypertrophy greater than 140% were selected (severe LVH group, n = 7). RESULTS: The cardiac hypertrophy model induced significant left ventricular hypertrophy (136+/-21%, P < 0.05). The pressure-volume relation showed normal systolic function but an altered diastolic compliance in hypertrophic hearts. Propofol only decreased myocardial contractility and relaxation at supratherapeutic concentrations (> or = 300 microM) in SHAM and LVH groups. The decrease in myocardial performances was not significantly different in SHAM and LVH groups. Propofol induced a significant increase in coronary blood flow which was not significantly different between groups. In severe LVH group, the degree of hypertrophy reached to 157+/-23%. Similarly, the effects of concentrations of propofol were not significantly different from the SHAM group. CONCLUSIONS: Propofol only decreased myocardial function at supratherapeutic concentrations. The myocardial and coronary effects of propofol were not significantly modified in cardiac hypertrophy.

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.

Mechanisms of coronary vasoconstriction induced by high arterial oxygen tension.

In isolated rabbit hearts perfused with suspension of red blood cells, we investigated the role of the endothelium and of several substances in the coronary vasoconstriction induced by a high arterial blood oxygen tension (PaO2). Red blood cells in Krebs-Henseleit buffer were oxygenated to obtain control and high-PaO2 perfusates. Arterial oxygen content was kept constant in both perfusates by reducing hemoglobin concentration in the high-PaO2 perfusate. Coronary blood flow was kept constant so that oxygen supply would not vary with the rise in PaO2. Increases in perfusion pressure therefore reflected increased coronary resistance. The high PaO2-induced coronary vasoconstriction was not affected by administration of indomethacin, nordihydroguaiaretic acid, NG-nitro-L-arginine, or superoxide dismutase and catalase but was abolished after endothelium damage or by cromakalim. These results demonstrate that 1) the endothelium contributes to the high PaO2-induced coronary vasoconstriction; 2) this effect is independent of cyclooxygenase or lipoxygenase products, nitric oxide, or free radicals; and 3) the closure of ATP-sensitive K+ channels mediates this vasoconstriction.

Effects of eltanolone on myocardial performance and coronary flow in intact and catecholamine-depleted isolated rabbit hearts.

BACKGROUND: Experimental studies suggest that the new short-acting intravenous anesthetic agent eltanolone does not markedly alter hemodynamics or cardiac function. However, because its intrinsic effects on myocardial performance and coronary blood flow are not yet known, they were examined in isolated blood-perfused rabbit hearts. METHODS: Coronary blood flow, myocardial contractility, relaxation, and oxygen consumption were measured during perfusion of hearts with 0.1 to 10 micrograms/ml eltanolone (n = 7) or its vehicle (n = 7). To determine whether the cardiac effects of eltanolone are mediated by indirect sympathetic activation, the same dose-response curve was studied in another group of five hearts depleted of catecholamine with reserpine treatment. RESULTS: Coronary blood flow significantly increased with 10 micrograms/ml eltanolone and significantly decreased with 10 micrograms/ ml eltanolone vehicle. At eltanolone concentrations less than 10 micrograms/ml, myocardial contractility and relaxation remained unchanged but decreased at 10 micrograms/ml. Myocardial contractility and relaxation were not affected by perfusion of eltanolone vehicle alone. In eltanolone-perfused hearts, unchanged myocardial oxygen consumption was associated with significant increases in coronary venous oxygen content and tension, but in vehicle-perfused hearts, it was associated with reduced coronary venous oxygen content and tension. In catecholamine-depleted hearts, the variations in myocardial performance and coronary blood flow induced by eltanolone were similar to those observed in intact hearts. CONCLUSIONS: Eltanolone (0.1 to 3 micrograms/ml) did not alter myocardial performance or coronary blood flow in isolated blood-perfused rabbit hearts. These effects were not due to an eltanolone-induced indirect sympathetic activation. Cardiac depression and coronary vasodilatation were only observed at concentrations of eltanolone far greater than those in clinical range.

Mechanisms of increased myocardial contractility with hypertonic saline solutions in isolated blood-perfused rabbit hearts.

Hypertonic saline improves organ perfusion and animal survival during hemorrhagic shock because it expands plasma volume and increases tissue oxygenation. Because both decreased and increased myocardial performance have been reported with hypertonic saline, the effects of hyperosmolarity and the mechanism accounting for it were investigated in isolated blood-perfused rabbit hearts. Coronary blood flow (CBF), myocardial contractility, relaxation, and oxygen consumption were measured during administration of blood perfusates containing 140-180 mmol sodium concentrations ([Na+]). In two other series of experiments, the role of Na(+)-Ca2+ exchange in the inotropic effect of hyperosmolarity (160 mmol sodium concentration) and hypertonicity (sucrose) were also investigated. Hypertonic [Na+] induced a significant increase in contractility and relaxation, combined with a coronary vasodilation. Myocardial oxygen consumption (MVO2) increased at all hypertonic [Na+] without significant change in coronary venous oxygen tension (PVO2) and content (CVO2). Amiloride (0.3 mmol) inhibited the improved contractility observed with 160 mmol sodium. Similar Na(+)-Ca2+ exchanger blockade did not inhibit the inotropic effect of sucrose. These results confirm the positive inotropic effect of hypertonic [Na+]. The inhibition of this improvement by amiloride suggests that calcium influx through the sarcolemna could be the major mechanism of this effect.