Role of pentobarbitone anaesthesia and sympathetic tone in the haemodynamic effects of isosorbide dinitrate in rats with cirrhosis

The haemodynamic effects of nitrovasodilators and their mechanisms of action on portal hypertension remain unclear. The splanchnic and systemic haemodynamic response to the infusion of isosorbide dinitrate (100 μg/kg per min), a nitrovasodilator, was investigated in cirrhotic rats. The role of the conscious state in the haemodynamic response to isosorbide dinitrate was examined using rats that were anaesthetized with pentobarbitone. The role of sympathetic tone in the haemodynamic response to isosorbide dinitrate was examined using rats pretreated with the ganglion blocker hexamethonium. Isosorbide dinitrate had no haemodynamic effects in conscious, unblocked normal and cirrhotic rats. Isosorbide dinitrate had no haemodynamic effects in normal and cirrhotic rats treated with hexamethonium. In normal anaesthetized rats, isosorbide dinitrate significantly decreased systemic vascular resistance (414±25 vs 290±26 dyn.s/cm⁵ per 100 g). In cirrhotic anaesthetized rats, isosorbide dinitrate significantly decreased mean arterial pressure (98±6 vs 79±7 mmHg), systemic vascular resistance (318±30 vs 207±10 dyn.s/cm⁵ per 100 g), portal pressure (14.0±1.0 vs 11.3±0.9 mmHg) and portal territory vascular resistance (1362±163 vs 1031±182 dyn.s/cm⁵ per 100 g). In conclusion, this study shows that the portal hypotensive effects of isosorbide dinitrate depend upon the alterations of vascular tone by pentobarbitone.     

DNA-Analysis of Human Testicular Samples by Cytofluorometry

Germ cells in human testicular samples have been estimated by histology and quantitated by flow cytometry. There is an excellent relationship between the two techniques. These samples were classified histologically as "normal", "reduced number of germ cells" or "no germ cells". A definition of "normalcy" as determined by flow cytometry as having at least 38% of the cells in the haploid state, is proposed. Testicular samples from prepubertal boys with infiltrating leukemic cells often show an increase in the percentage of S-phase cells indicating the presence of tumor. These results indicate the value of flow cytometry in the identification of reproductive and neoplastic disorders.     

MODULATION OF ALCOHOL PREFERENCE BY NMDA ANTAGONISTS IN MALE RATS

Chronic alcoholization by alcohol inhalation was used to studythe properties of magnesium, a non-competitive NMDA receptorantagonist, and CGP 39551, a competitive NMDA receptor antagonist,on behavioural dependence as estimated by the free-choice paradigm[alcohol 10% (v/v) vs. water], on the hypermotility after alcoholwithdrawal, and finally on the cortical vascularization. Thefirst experimental group received the drugs per os during thewhole alcoholization period. Magnesium (20 mg/kg/day) decreasedthe alcohol dependence while CGP 39551 (5 and 10 mg/kg/day)increased, in a dose-dependent manner, the dependence to alcohol.A second group of animals received the same drugs at the samedosages, not simultaneously during chronic alcoholization, butimmediately after alcoholization in one shot i.p. injection.In this case, rats receiving 5 mg/kg CGP 39551 never showedany dependence towards alcohol, while 10 mg/kg CGP 39551 or20 mg/kg magnesium prolonged the number of days of alcohol dependence.These results thus indicate the close interaction between NMDAreceptor function and dependence for alcohol. Magnesium hadno effects on hypermotility, while CGP 39551-treated animalspresented a decrease in the hypermotility observed after alcoholwithdrawal. Neither drug affected the hypervasculanzation accompanyingthe chronic alcoholization.     

The Myocardial Lesions Produced by the Potassium Channel Opener Aprikalim in Monkeys and Rats Are Prevented by Blockade of Cardiac {beta}-Adrenoceptors

Aprikalim is a potent, specific, and selective opener of ATP-sensitiveK⁺ (K_ATP) channels. By virtue of this pharmacological property,aprikalim affords cardioprotection in experimental models ofischemia/reperfusion injury, and, at higher doses, also causesperipheral or coronary vasodilatation. Direct-acting peripheralvasodilators can cause myocardial lesions, particularly in ratsand dogs. However, unexpectedly, aprikalim produced this effectalso in monkeys. Thus, the primary aim of this investigationwas to assess whether in monkeys these myocardial lesions werethe direct or indirect consequence of the vascular effects ofaprikalim. Cyno-mologus monkeys were given the ß-adrenoceptorantagonist nado-lol (2 mg/kg po, twice daily) for 4 consecutivedays. On the third and fourth day of the experiment, they receivedaprikalim (1 mg/kg po). In another series, two monkeys carryingtelemetry transmitters for blood pressure and heart rate measurementswere also given aprikalim or its vehicle. Finally, aprikalim(1 mg/kg po for 2 days) or its vehicle was administered to ratswhich were concurrently treated with the ß-adrenoceptorantagonist atenolol (5 mg/ kg sc) or its vehicle. In cynomologusmonkeys, aprikalim produced focal and multifocal myocardialnecrosis of minimal to moderate intensity in or near the papillarymuscles of the left ventricle. These effects were abrogatedby nadolol. Similarly, necrotic lesions were caused by aprikalimonly in those rats which had not been pretreated with atenolol.In monkeys, aprikalim produced a marked and long-lasting decreasein aortic blood pressure, accompanied by an even more prolongedtachycardia. These results demonstrate that aprikalim can producemyocardial necrosis not only in rats but also in monkeys. Toour knowledge, this is the first time that such adverse effectsare reported for a vasodilator in monkeys. More importantly,these effects were prevented by blocking cardiac ß-adrenoceptors.Thus, the myocardial lesions produced by aprikalim may be attributedto its profound and prolonged hemodynamic effects.