The cardiovascular effects of the administration of L-NAME during the early posthemorrhagic period.

1. The effects of the various doses of NG-nitro-L-arginine methyl ester (L-NAME, 10 and 30 mg/kg) on some cardiovascular and biochemical parameters during the early posthemorrhagic period were studied in anesthetized rabbits subjected to hemorrhagic hypovolemia. 2. Hemorrhagic shock was produced by intermittent bleeding of 40% of the estimated blood volume for 15 min. Blood samples were taken before and after bleeding (0, 15 and 60 min). Simultaneously, the mean arterial pressure (MAP) and the heart rate (HR) were measured. Hemorrhaged rabbits were treated by L-NAME10 or L-NAME30 (10 or 30 mg/kg, i.v. bolus injection, respectively) or the corresponding volumes of saline (0.6 ml, i.v. bolus) immediately after the end of bleeding. 3. The observed cardiovascular parameters (MAP, HR) were significantly reduced after the end of bleeding in all rabbits. 4. The rise of the MAP was significantly more pronounced 30 min after the injection of L-NAME30 in comparison with the corresponding values in the saline (S) group. In contrast, L-NAME10 produced only a small, insignificant increase in the MAP in hemorrhaged rabbits. 5. The L-NAME30-induced rise of the MAP was accompanied by a severe bradycardia, hyperkalemia and an aggravated metabolic acidosis, more severe than the corresponding disturbance of the acid-base status in the S group. The changes in the acid-base parameters were observed both in arterial (pH, excess base) and in venous blood (pH) of hemorrhaged rabbits. 6. In conclusion, the i.v. bolus injection of L-NAME30 (immediately after the end of bleeding) produced a significant increase in the MAP during the first hour after the injury, but the presumable inhibition of the endothelial constitutive nitric oxide synthase during the early posthemorrhagic period resulted in severe cardiovascular and metabolic disturbances.

The effect of physostigmine on acid-base status in arterial and venous blood of anaesthetized rabbits following hypovolemic shock.

1. The effects of physostigmine (70 micrograms kg-1, intravenously) on acid-base status in arterial and venous blood were studied in anaesthetized rabbits subjected to hemorrhagic hypovolemia. 2. Hemorrhagic shock was produced using intermittent bleeding of 50% of the estimated blood volume, during 30 min. Experimental group was treated with physostigmine (70 micrograms kg-1 body mass, intravenously) and the control group with the same volume (0.1 ml) of saline, immediately after bleeding. Blood samples were taken before and after bleeding (0, 15 and 60 min). 3. It was found that physostigmine increased the mean arterial blood pressure, did not change the heart rate, and improved survival of the animals. 4. These effects of physostigmine were associated with significant decrease in venous pH, produced mainly by increased PCO2. This can partly be explained in terms of additional vasoconstriction due to physostigmine action. 5. In arterial blood decreased pH, decreased standard bicarbonate, negative values of excess base and decreased PCO2 were observed both in physostigmine-treated and the control group of animals, indicating partly respiratory compensated metabolic acidosis. These findings indicate that the hypertensive effect of physostigmine in shock was not accompanied by more severe disturbance in arterial acid-base status than was observed in hypovolemic shock alone.

The effect of physostigmine on the haemorrhagic hypovolemia in anaesthetized rabbits.

1. The effects of physostigmine (70 micrograms kg-1, intravenously) on mean arterial blood pressure, blood volume and survival were studied in anaesthetized rabbits subjected to haemorrhagic hypovolemia. 2. It was found that physostigmine increased the mean arterial blood pressure, increased the residual blood volume, decreased the haematocrit values and increased the survival of the animals. 3. The increase of blood pressure might be due to a general adrenergic activation produced by physostigmine, whereas the increase in plasma volume might be due to changes in pre- to postcapillary resistance ratio. 4. The beneficial effect of physostigmine might also be due to antagonism of humoral factors known to aggravate the hypovolemia (e.g. endogenous opioids).

Beta-adrenergic receptors and catecholamines in the rat heart during tourniquet trauma.

Tourniquet trauma produced a decrease in the noradrenaline content in the heart of the rats through the period of tourniquet application (up to 4 hr). In the same period, the content of adrenaline was significantly increased. This relationship between noradrenaline and adrenaline remained the same in the posttraumatic period. Parallel to the observed changes in the catecholamine content of the heart, a significant decrease in the number of the beta-adrenergic receptors (Bmax) and an increase in their affinity (a decrease in KD) was also found in the hearts of rats exposed to tourniquet trauma. These changes remained throughout the posttraumatic period, with one exception: no change 30 min after trauma has been observed. Reapplication of tourniquet was associated with a restoration of the beta-adrenergic receptors and complete survival of the animals. The decrease in the beta-receptors density after trauma might be due to down-regulation produced by increased concentration of adrenaline, a beta-receptor agonist. Meanwhile, some other factors, particularly ischaemia, might also contribute to the observed changes in the beta-adrenergic binding sites.

[Pathophysiologic reactions in sheep to blast waves from detonation of aerosol explosives]. / Patofizioloske reakcije kod ovaca na udarni talas nastao detonacijom aerosolnog eksploziva.

In the controlled field experiments 18 sheep were exposed to the detonation of the aerosol explosive generating the blast wave necessary to produce death in 50% of cases. The time of death and characteristic damages on the predilection sites of some organs are interpreted as blast type injuries. General response of the body to blast wave was similar to the one produced by other etiological factors. A special characteristic of the experiment was the frequency and severity of pathologic changes on the internal organs of the chest and abdomen. According to the authors' opinion the severity and type of pathologic changes could be explained by effects of the complex blast wave generated by detonation of the aerosol explosives.

The life-saving effect of physostigmine in haemorrhagic shock.

The intravenous injection of physostigmine (70 micrograms kg-1) produces a life-saving effect in acute haemorrhagic shock in non-anaesthetized rabbits. This effect is most probably due to a transfer of tissue fluids into circulation. The crucial beneficial effect of physostigmine might be a decrease of the capillary hydrostatic pressure due to changes in pre- to postcapillary resistance ratio. Both lines of defence comprise a normalization of blood pressure and normalization of blood volume, thus saving the life of the animal.

Transmitter interactions in the central cholinergic control of blood pressure regulation.

There are at least five mechanisms by which the central nervous system regulates neural and humoral systems that control the blood pressure (BP). Particular attention has been paid to central cholinergic-adrenergic interactions in the regulation of BP. Physostigmine and other anticholinesterases which penetrate the blood-brain barrier, both carbamates and organophosphates, produce an increase of BP. This effect can be abolished by atropine, but not by methylatropine. The available evidence indicates that physostigmine and other AChE inhibitors initially produce an activation of central muscarinic receptors, which subsequently leads to an increase of the peripheral adrenergic activity. The hypertensive response to physostigmine is possible only if a functionally competent ChE is present in the brain. This effect of physostigmine is regularly associated with a dose-related increase in the neural activity in the preganglionic fibers of the cervical sympathetic nerve. BP rise after physostigmine is significantly less in immunosympathectomized animals and almost completely abolished after chemical sympathectomy. Physostigmine significantly increased the plasma concentration of catecholamines. After electrocoagulation of the locus coeruleus, not only did a significant decrease occur in the basic level of noradrenaline in plasma, but there was also a strong depression of the noradrenaline plasma response to physostigmine and immobilization. Physostigmine increased lipolysis and glycogenolysis, whereas neostigmine did not produce any change. Several directly acting cholinergic agonists alter the functions of the cardiovascular system when injected directly into the cerebral ventricular system, or directly into various brain regions. The most probable sites of action of AChE inhibitors and directly acting cholinergic agonists are the locus coeruleus, the nucleus tractus solitarii and the rostral ventrolateral medulla (RVLM). The primary activation of the cholinergic synapse is believed to take place in RVLM. Met-enkephalin, Leu-enkephalin and beta-endorphin, when applied exogenously, depress or even abolish the hypertensive effect of physostigmine. The same type of response was obtained after application of substances which inhibit the enkephalin-degrading enzymes (bestatin, phosphoramidon). Thus, the exogenous or endogenous enkephalins activate the opioid receptors in the brain and at the same time produce a depression of the cholinergic-adrenergic interaction in the central nervous system, which is a prerequisite for the hypertensive response to physostigmine. The functional role of the central cholinergic mechanisms in BP control under physiological conditions has not been established with certainty. These mechanisms might have a more significant role under pathological or homeostatic disturbances. For example, physostigmine showed a life-saving effect in acute hypovolemic shock in rabbits.

[Metabolic turnover of catecholamines in the heart of rats after nonfatal burns]. / Metabolicki obrt kateholamina u srcu pacova posle nesmrtne oparotine.

The content and metabolic turnover of noradrenaline (NA) and adrenaline (A) have been studied in the hearts of rats subjected to nonlethal scalding. The results of the study have shown that in an early phase of the general reaction of the organism to thermal trauma it has come to the decreased NA content while in the later phase the NA content was in the limits of control values. The increased contents of Na and A in the murine hearts after monoamineoxidase inhibition and injection of L-DOPA indicated the preservation of the synthesis and overtaking of catecholamines by the heart muscle. The increase of the metabolic turnover and shortening of the time of the metabolic turnover of NA and A have pointed that the increased NA content in the hearts of the traumatized animals is the consequence of the increased requirements of these catecholamines by the heart muscle in the early posttraumatic phase.

[Effects of non-lethal scalding on the density and affinity of beta adrenoreceptors in cardiac muscle in rats]. / Effets de l'échaudage non létal sur la densité et l'affinité des beta-adrénocepteurs dans le muscle cardiaque du rat.

Our results indicate changes in both Bmax and KD of the beta-adrenergic receptors in the ventricular heart muscle of the rat, submitted to non-lethal scalding, even in the early posttraumatic period. The changes of heart, plasma and urine noradrenaline and adrenaline contents indicate significant increase in sympatho-adrenal activity after non-lethal scalding. The parallel changes of the beta-adrenergic receptor characteristics, which depend on the changes of catecholamines in the heart muscle and plasma only at certain time intervals after trauma, tend to preserve normal-control values.