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1. The aim of the present study was to investigate the role of p38 mitogen-activated protein kinases (MAPK) in mediating the effect of noradrenaline (NA) on cardiomyocyte cell viability. 2. Cardiomyocytes from embryonic chick heart were treated with various concentrations of NA, phenylephrine or isoproterenol and p38 MAPK activation was determined by western blotting. Total cell death was assessed by the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Apoptosis was determined by specific DNA fragmentation. 3. At 100 micromol/L, NA produced a significant increase in cell death that was associated with microscopic changes and DNA fragmentation indicative of apoptosis. The p38 MAPK inhibitor SB202190 (at 1 micromol/L beginning 1 h before NA), reduced NA-induced p38 MAPK activation and significantly accentuated NA-induced cell death. In contrast, the mitogen-activated protein kinase kinase ERK1/2 inhibitor PD98059 (at 1 micromol/L beginning 1 h before NA) did not significantly alter NA-induced cell death. These effects of NA were mediated, in part, through alpha-adrenoceptor because phenylephrine (100 micromol/L), like NA, also induced p38 MAPK activation. However, 100 micromol/L isoproterenol produced a sustained dephosphorylation of p38 MAPK. 4. These data show that NA-induced p38 MAPK activation, through alpha-adrenoceptor, has a protective role in cardiomyocytes to antagonize NA-induced cell death. In contrast, beta-adrenoceptor stimulation produces dephosphorylation of p38 MAPK.

1. To determine whether morphine modulates the development of cardiac arrhythmias through mu opioid receptors by an action within the central nervous system (CNS). Catecholamine-induced ventricular arrhythmias were produced, in the rat, by continuous infusion of epinephrine at incremental doses until the development of fatal arrhythmias, usually ventricular fibrillation. 2. Morphine, 0.1 mg/kg i.v., significantly suppressed (P < 0.05) the development of epinephrine-induced arrhythmias compared with the control group. This was opposed by the mu opioid antagonist naloxone (1 or 2 mg/kg) in a dose-dependent manner. 3. To determine whether these effects were operative in the brain, rats received an injection of either morphine 50 micrograms/kg or its diluent (control) into the lateral cerebral ventricle intracerebroventricularly (i.c.v.). Morphine significantly increased (P < 0.05) the threshold for the development of arrhythmias. 4. To further explore whether this effect was operative at the mu opioid receptor, a more specific mu opioid receptor agonist morphiceptin (50 micrograms/kg) was administered i.c.v. and produced a significant increase (P < 0.05) in the threshold for cardiac arrhythmias compared with controls. 5. The action of morphine was further established to be operating through mu opioid receptors from experiments with the i.c.v. administration of naloxone (+) and naloxone (-) followed by morphine showing that the action of morphine in the brain was prevented by the opioid antagonist naloxone but not by its stereo-isomer that is not a mu opioid receptor antagonist. 6. These data suggest a role for morphine to modulate cardiac arrhythmias, specifically to increase arrhythmia threshold, through an action within the CNS at mu opioid receptors.

1. To evaluate and compare the effects of the calcium channel blockers, diltiazem and verapamil, on CNS modulation of blood pressure, unanaesthetized and unrestrained rats with catheters previously inserted into the lateral cerebral ventricle and femoral artery received intracerebroventricular (i.c.v.) administration of diltiazem or verapamil, 10 or 50 micrograms/kg, or their diluent. 2. Diltiazem, at both 10 and 50 micrograms/kg i.c.v., produced significant (P less than 0.05) decreases in systolic and diastolic blood pressure and heart rate. Verapamil, at 50 micrograms/kg but not at 10 micrograms/kg i.c.v., produced a significant (P less than 0.05) decrease in blood pressure, while both doses significantly (P less than 0.05) decreased heart rate. 3. To examine the endogenous opioid systems as potential modulators of the effects of these calcium antagonists, the mu opioid antagonist naloxone, 20 micrograms/kg, was administered i.c.v. either before or after each calcium antagonist. Naloxone reversed and prevented the reduction in blood pressure produced by both agents. The decrease in heart rate produced by verapamil but not diltiazem was reversed by naloxone. 4. The results suggest that: (1) calcium channels in neuron membranes in the CNS play a role in blood pressure regulation; (2) at least part of the blood pressure reduction produced by calcium blockers may be effected in the CNS; and (3) central opioid mechanisms modulate part of the action of the calcium antagonists verapamil and diltiazem on blood pressure.

1. The haemodynamic responses to progressive increments in positive end-expiratory pressure ventilation (PEEP) were assessed in dogs in the presence and absence of pericardial effusion (2.2 ml saline/kg). 2. Increasing levels of PEEP (3, 4, 8, 16 cm H2O) were associated with increases in right atrial, left atrial, pericardial and pulmonary artery diastolic pressure; increases in pulmonary vascular resistance; decreases in aortic blood pressure; and decreases in cardiac index or stroke index. 3. Pericardial effusion that was associated with an increase in pericardial pressure of 3 mmHg was not associated with significant changes in aortic blood pressure or stroke index. In contrast 8 cm PEEP was associated with significant decreases in both these haemodynamic variables yet pericardial pressure increased only 2.2 mmHg. 4. For these levels of PEEP and pericardial effusion, the same haemodynamic response to PEEP was observed regardless of the presence or the absence of pericardial effusion. 5. Similar changes in aortic blood pressure and stroke index despite different pericardial pressures is reflected by significantly different intercepts in the linear model relating these haemodynamic variables to pericardial pressure in the presence and absence of pericardial effusion. 6. The results suggest that these haemodynamic consequences of PEEP are primarily a function of pulmonary hyperinflation and are less dependent on increases in extracardiac pressure per se.

1. The role of the parasympathetic nervous system and the effect of morphine on cardiac arrhythmias induced by digitalis was assessed in guinea-pigs that had digitalis arrhythmias produced by digoxin 50 micrograms/kg intravenously plus 500 micrograms/kg per h. 2. Morphine produced a dose-dependent rightward shift in the relationship between digoxin dose and arrhythmias. Morphine 5 mg/kg subcutaneously (s.q.) was associated with significantly (P less than 0.05) higher digoxin doses both at the onset of ventricular arrhythmias and at development of fatal arrhythmias compared with the control group that received saline s.q. 3. Vagotomy and atropine prevented the effect of morphine so that the dose-response relationships and the mean digoxin dose at onset of ventricular arrhythmias and the development of fatal arrhythmias were not significantly different from the control group receiving saline. 4. These data indicate that morphine limits the development of digitalis arrhythmias and this effect is, at least in part, mediated through the parasympathetic nervous system.