Antithrombotic activity of a 2-kDa heparin fragment in an experimental model of carotid artery thrombosis in rats.

The antithrombotic activity of a 2-kDa heparin fragment was studied in a rat model of common carotid artery thrombosis that causes a completely occlusive thrombus with cessation of the blood flow within 10-15 min. The compound reduced thrombus formation in a dose-dependent manner, starting from an intravenous dose of 5 mg kg-1. A dose of 20 mg kg-1 completely prevented thrombus formation and apparently induced the almost complete lysis of the already formed occlusive thrombus. At none of the doses used did the compound cause increased bleeding or the formation of haematomas. The present results indicate that low molecular weight heparins, which have an established, highly beneficial effect in venous thromboembolism, are also highly effective in an animal model of arterial thrombosis.

The reversal of experimental hemorrhagic shock induced by nicotine and dimethylphenylpiperazinium is adrenal-dependent.

In a rat model of volume-controlled hemorrhagic shock causing the death of all control animals within 30 min, the intravenous injection of either nicotine (50 micrograms/kg) or dimethylphenylpiperazinium (DMPP) (0.5 micrograms/kg) produced a rapid and sustained reversal of the shock condition, with 100% survival 2 h after treatment. Bilateral adrenalectomy completely prevented the anti-shock effect of the two drugs, even though administered at higher doses (150 micrograms/kg in the case of nicotine; 10 micrograms/kg in the case of DMPP). It is concluded that stimulation of adrenaline release plays a fundamental role in the mechanism of action of nicotine- and DMPP-induced shock reversal.

Adrenocorticotropin release is not involved in the nicotine-induced reversal of hemorrhagic shock in anesthetized rats.

In a model of volume-controlled hemorrhagic shock causing the death of all control animals within 30 min, the intravenous injection of nicotine produced a rapid, sustained and dose-dependent restoration of cardiovascular and respiratory functions, with 60 and 100% survival 2 h after the administration of 3 and 12 micrograms/kg, respectively. An effect similar to that of the highest dose of nicotine were obtained with the intravenous bolus injection of ACTH(1-24) at the dose of 160 micrograms/kg. However, the ACTH plasma levels of hemorrhage-shocked rats treated with nicotine was not different from that of hemorrhage-shocked rats treated with saline, thus excluding the possibility that nicotine-induced shock reversal may be due to the massive release of ACTH. Since in rats pretreated with cycloheximide at a dose (20 mg/kg intraperitoneally) causing an 82% inhibition of protein synthesis, and then bled to hemorrhagic shock, the effect of nicotine was greatly reduced (only the dose of 50 micrograms/kg producing 100% survival 2 h after treatment), protein synthesis, however, seems to be important for the effect of nicotine in hemorrhagic shock, at least at the lowest doses.

[Endogenous anti-analgesic systems]. / Sistemi anti-analgesici endogeni.

Nociception is of vital importance for the organism, while its inhibition by endogenous opioid systems is usually a sign of surrender. Therefore, it must be assumed that endogenous analgesic systems are balanced, and in fact, under normal conditions, overwhelmed, by teleologically far more important anti-analgesic systems. The two main anti-analgesic systems--i.e., the melanotropinergic and the cholecystokininergic--are here reviewed for their role, not only in nociception, but in a wide variety of vital functions (endocrine, gastrointestinal, ingestive, reproductive, cardiovascular, immune, etc.). Available data strongly suggest that these systems (particularly the melanotropinergic one) play a key role in the overall homeostasis of the body. Moreover, modulation of endogenous anti-analgesic systems may disclose a new, unforeseen approach to the treatment of pain.

ACTH-induced reversal of hemorrhagic shock: further studies on the mechanism of action.

In a rat model of extremely severe hemorrhagic shock, invariably leading to death within 30 min, the i.v. bolus injection of ACTH-(1-24) at the dose of 160 micrograms/kg produced a dramatic and sustained reversal of the shock condition, with normalization of mean arterial pressure, pulse pressure and respiratory rate, and with survival of all rats at the end of the observation period (2 h). Such effect was neither prevented nor reduced by the bilateral anesthetization of carotid bodies, suggesting that chemoreceptors of these structures are of no relevance in the complex mechanism of the ACTH-induced reversal of hemorrhagic shock.

Comparison of the effects of ACTH-(1-24), methylprednisolone, aprotinin, and norepinephrine in a model of hemorrhagic shock in rats.

Rats bled to a severe condition of volume-controlled hemorrhagic shock were randomly assigned to one of the following treatments: (1) saline, 1 ml/kg i.v.; (2) saline, 0.2 ml/kg per min i.v. for 10 min; (3) ACTH-(1-24), 160 micrograms/kg i.v.; 4) methylprednisolone, 40 mg/kg i.v.; (5) methylprednisolone, 80 mg/kg i.v.; (6) aprotinin, 10,000 KIU/kg i.v.; (7) norepinephrine, 5 micrograms/kg per min i.v. for 10 min; (8) norepinephrine, 10 micrograms/kg per min i.v. for 10 min. All rats treated with saline or with either of the two doses of methylprednisolone, and half of the rats treated with aprotinin, died within the subsequent 2 h. On the other hand, rats treated with norepinephrine, at either dose, or with ACTH-(1-24) were all still alive 2 h later, a similar improvement in cardiovascular and respiratory parameters being obtained with the two treatments. The effect of ACTH on mean arterial pressure was however more sustained throughout the observation period. These results further support the potential usefulness of ACTH-(1-24) as first-aid treatment in cases of severe blood losses.

Effect of sulpiride on ischemia- and reperfusion-induced heart damage, in rats.

In an experimental model of heart ischemia, obtained in anesthetized rats with the permanent ligature of the left anterior descending coronary artery, the intravenous (iv) injection of I-sulpiride (6-25 micrograms/kg) dose-dependently reduced the lethality rate, the incidence and severity of ventricular dysrhythmias and infarct size during the early phase of ischemia (first 30 min after coronary ligation). Lethality and there incidence and duration of ventricular dysrhythmias were also significantly reduced by the same IV doses of I-sulpiride in a model of coronary reperfusion. These results show that a specific dopamine antagonist is able to limit ischemia- and reperfusion-induced myocardial damage and suggest that endogenous dopamine may exert a deleterious effect in such conditions.