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Recent studies have indicated that sphingosine 1-phosphate (Sph-1-P) is released into the blood flow from activated platelets upon stimulation to exhibit a wide spectrum of biological functions. The purpose of the present study was to assess the acute cardiovascular effects of circulating Sph-1-P in the in vivo rat model. Intravenous administration of Sph-1-P decreased the heart rate, ventricular contraction and blood pressure, while it hardly affected the atrioventricular and intraventricular conduction. Sph-1-P did not affect the adenylate cyclase activities of the membrane preparations made from the right atrium and left ventricle. These results suggest that functional receptors like lysophospholipid receptor Edg-1, which can inhibit adenylate cyclase via Gi protein, are lacking in the rat heart. Moreover, these observations will provide a clue to better understand the various types of Sph-1-P-related pathophysiological processes.

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The effects of a highly selective Na+/H+ exchange inhibitor cariporide on the reperfused in situ heart were assessed. Male Sprague-Dawley (SD) rats weighing 200-300 g were anesthetized with pentobarbital sodium (60 mg/kg, i.p.) and divided into four groups; sham-operated (n = 6), vehicle (n = 15), 0.1 mg/kg (n = 15), and 1.0 mg/kg (n = 15) groups. The left coronary artery was ligated for 5 min and then released with ECG and blood pressure monitoring. Cariporide was intravenously given as a bolus 2 min before the reperfusion. The heart was rapidly excised and frozen 3 min after the onset of ventricular fibrillation, otherwise 10 min after the reperfusion. The adenosine triphosphate (ATP), creatine phosphate (CP), and glycogen contents were measured in the reperfused ischemic myocardium by using an enzymatic fluorometric assay technique. The incidence of the lethal ventricular fibrillation was 53% in the vehicle, 27% in the low-dose and 7% in the high-dose group. The concentrations (mean+/-SEM) of ATP, CP (nmol/mg protein), and glycogen (nmol as glucose/mg protein) were 74+/-4, 255+/-19, and 164+/-21 in the sham, 23+/-4, 763+/-70, and 61+/-7 in the vehicle, 27+/-4, 180+/-16, and 104+/-14 in the low-dose, and 32+/-4, 178+/-24, and 108+/-8 in the high-dose groups, respectively, indicating that cariporide significantly blunted CP overshoot as well as glycogenolysis during reperfusion. Thus cariporide can be expected to depress arrhythmogenesis and protect the metabolic status of the heart.

Polymorphic ventricular arrhythmias induced by astemizole overdose have been reported to be successfully managed with intravenous magnesium sulfate. This study was designed to assess the effects of magnesium sulfate on the cardiovascular system, complicating astemizole overdose, the better to understand the therapeutic utility and undesirable effects of magnesium sulfate. Beagle dogs were anesthetized with halothane inhalation (n = 6). Monophasic action potential of the right ventricle, electrocardiogram, and systemic and left ventricular pressure were continuously monitored. Cardiac output was measured by a thermodilution method. Effective refractory period of the right ventricle was assessed by programmed electrical stimulation. An intentionally high dose of astemizole (3 mg/kg, i.v.) prolonged the repolarization and refractory period, while it decreased the sinus automaticity, ventricular contraction, and conduction. A canine antiarrhythmic dose of magnesium sulfate (100 mg/kg, i.v.) was additionally injected 1 h after i.v. astemizole. Magnesium sulfate increased the atrioventricular conduction time, electrical vulnerability, and preload of the left ventricle, while it decreased the blood pressure and cardiac output, besides the effects similar to those observed after i.v. astemizole. The plasma concentration of astemizole was at least 10 times higher than its therapeutic concentration during the experimental period. Magnesium sulfate could be expected to act as a calcium channel blocker during astemizole overdose; however, it may not antagonize the proarrhythmic effects of astemizole.

1 Although Na + -H + exchange (NHE) inhibitors are reported to protect the myocardium against ischaemic injury, NHE activation has also been proposed as a potential mechanism of ischaemic preconditioning-induced protection. This study was performed to test any modi®able eect of cariporide, an NHE inhibitor, on cardioprotective eects of preconditioning. 2 Anaesthetized rats were subjected to 30 min of coronary artery occlusion and 150 min of reperfusion. The preconditioning (PC) was induced by 3 min of ischaemia and 10 min of reperfusion (1PC) or three episodes of 3 min ischaemia and 5 min reperfusion (3PC). Cariporide (0.3 mg kg 71 ) an NHE inhibitor, was administered 30 min (cari(30)) or 45 min (cari(45)) before coronary ligation (n=8 ± 11 for each group). 3 Ventricular arrhythmias during 30 min ischaemia and infarct size (measured by triphenyltetrazolium (TTC) and expressed as a per cent area at risk (%AAR)) were determined. Cari(30) reduced ventricular ®brillation (VF) incidence and infarct size (from 45 to 0% and 34+4 to 9+2%; each P50.05), whereas cari(45) did not. Likewise, 3PC reduced these variables (to 0% and 10+2%; P50.05 in each case) whereas 1PC did not. Moreover, subthreshold preconditioning (1PC) and cariporide (cari (45)), when combined, reduced VF incidence and infarct size (to 0% and 15+3%; each P50.05 ). 4 In conclusion, changes in NHE activity do not seem to be responsible for the cardioprotective action of ischaemic preconditioning. Protective eects of NHE inhibition and subthreshold preconditioning appear to act additively.