The antipyretic activity of adenosine agonists.

1. Thermoregulatory reactions after IV administration of A1 [N6-cyclohexyladenosine (CHA); 0.15 mg/kg] and A2 [5'-N-ethylcarboxamidoadenosine (NECA); 0.15 mg/kg] receptor agonists were investigated in pyrogen-treated rabbits (lipopolysaccharide; 1 microgram/kg IV) at an ambient temperature of 20 +/- 1 degrees C. 2. Both compounds produced antipyresis, which was accompanied by inhibition of metabolic rate. NECA, additionally, reversed the inhibitory effect of pyrogen on respiratory rate. 3. Neither CHA nor NECA affected postpyrogen drops in ear skin temperature. 4. The mechanisms underlying the antipyretic action of the compounds in question are discussed.

The effect of N6-cyclohexyladenosine and 5'-N-ethylcarboxamidoadenosine on body temperature in normothermic rabbits.

1. Thermal responses to i.v. administration of N6-cyclohexyladenosine (CHA; 0.15 mg/kg), A1 adenosine receptor agonist, or 5'-N-ethylcarboxamidoadenosine (NECA; 0.15 mg/kg), A2 adenosine receptor agonist, were investigated in normothermic rabbits at an ambient temperature (Ta) of 20.0 +/- 1.0 degrees C. 2. Although both compounds inhibited metabolic heat production, only NECA produced hypothermia. 3. NECA showed strong hypotensive activity. 4. Both compounds produced vasoconstriction of the ear skin vessels and CHA, in addition, slowed down the respiratory rate. 5. The role of A1 or A2 adenosine receptors in the thermoregulatory activity of these compounds is discussed.

Do sodium nitroprusside and L-NAME affect pyrogen fever in rabbits?

Thermoregulatory responses after treatment with nitric oxide (NO) donor, sodium nitroprusside (SNP-3 mg/kg/h), or NO synthase inhibitor, NG-nitro-L-arginine methylester (L-NAME-100 mg/kg) were investigated in febrile rabbits (lipopolysaccharide E. coli-1 meg/kg). Pretreatment with SNP attenuated pyrogen fever as well as metabolic rate. L-NAME also inhibited postpyrogen increases in metabolism; however, this effect did not lead to antipyresis.

Thermoregulatory activity of sodium nitroprusside and arginine vasopressin.

1. Thermal responses to sodium nitroprusside (SNP, 3 mg/kg/hr) and arginine vasopressin (AVP, 3 micrograms/kg) were investigated in normothermic and febrile rabbits (LPS, 1 microgram/kg) at ambient temperature of 20.0 +/- 1.0 degrees C. Furthermore, blood pressure after these drugs was tested on a separate group of animals. 2. I.v. infusion of SNP produced hypothermia and attenuated pyrogen fever. On the other hand, AVP increased body temperature and intensified the febrile response. 3. Both drugs affected in an opposite way blood pressure, i.e. SNP produced falls and AVP increases in this parameter. 4. The relationship between the activity of the vascular and thermoregulatory systems in normothermic or febrile state is discussed.

Hypotensive drugs, sodium nitroprusside and prazosin inhibit the metabolic rate in rabbits.

1. Thermoregulatory responses (metabolic rate, rectal and ear skin temperatures, respiratory rate) were measured after treatment with two antihypertensive drugs, i.e. when sodium nitroprusside (6 mg/kg/2 hr) or prazosin (0.75 mg/kg/3 hr) were applied to normothermic or febrile rabbits under thermoneutral conditions (19 +/- 1 degree C). 2. Both drugs significantly decreased blood pressure and metabolic rate. 3. These changes were accompanied by antipyresis. 4. In the case of normothermic rabbits only sodium nitroprusside produced prominent falls in body temperature. 5. The relationship between changes in blood pressure and the intensity of metabolic rate is discussed.

Changes in pre- or postsynaptic adrenergic mechanisms modify the thermoregulatory responses produced by pyrogen in rabbits.

1. Thermoregulatory responses to BHT 920, prazosin (PRA) and 6-hydroxydopamine (6-OHDA) were investigated in pyrogen (lipopolysaccharide Escherichia coli, LPS) treated rabbits. 2. All the compounds in question, despite their different selectivity for pre- or postsynaptic adrenergic structures, significantly reduced pyrogen fever. Antipyresis was associated with inhibition of the metabolic rate. 3. The role of adrenergic mechanisms in fever, with particular respect to those of postsynaptic alpha-2, is discussed.

A comparative study on the effect of verapamil and prazosin on the thermoregulatory responses induced by cold or exogenous noradrenaline.

1. Thermoregulatory responses to verapamil (VER; 5 mg/kg/hr) and prazosin (PRA; 0.75 mg/kg/3 hr) were investigated in rabbits exposed to cold (4 degrees C) and compared with those observed after treatment with noradrenaline (NA; 1.2 mg/kg/2 hr) under thermoneutral conditions (21 degrees C). 2. Both drugs abolished the thermogenic response to cold. 3. In the case of NA hyperthermia, only PRA was effective, i.e. the drug inhibited the thermal, metabolic and vasoconstricting actions of this amine. 4. Possible mechanisms, responsible for the thermoregulatory activity of both drugs are being discussed.

The effect of verapamil on the thermoregulatory responses produced by endotoxin or noradrenaline in rabbits.

1. Thermal responses to verapamil (5 mg/kg per hr) were investigated in pyrogen (lipopolysaccharide Escherichia coli) or noradrenaline (NA) treated rabbits. 2. The compound reduced the pyretic, metabolic and vasoconstricting activity of pyrogen. 3. On the other hand, verapamil did not significantly affect NA-induced hyperthermia. 4. Possible mechanisms responsible for the thermoregulatory activity of verapamil are discussed.

The effect of 6-hydroxydopamine pretreatment on the metabolic response produced by endotoxin in rabbits.

The thermoregulatory, effector processes were investigated in rabbits after treatment with 6-hydroxydopamine (6-OHDA) and lipopolysaccharide Escherichia coli (LPS). Pyrogen (1 microgram/kg, i.v.) produced a fever reaction resulting from stimulation of the metabolic rate and heat conservation responses. Pretreatment with 6-OHDA (3 X 500 micrograms, i.c.v.) reduced the metabolic as well as pyretic activity of pyrogen. It is suggested that stimulation of the thermoregulatory heat production which contributes to the febrile rise in body temperature is dependent on the intact adrenergic structures in the central nervous system.

The acid-base balance during the time course of endotoxin fever and sodium salicylate antipyresis in the rabbit.

Blood acid-base balance in sodium salicylate antipyresis was investigated in adult rabbits at ambient temperature of 21.5 +/- 0.5 degrees C. The experimental fever elicited by iv injection of lipopolysaccharide Escherichia coli 1 microgram/kg/ was accompanied by a slight metabolic acidosis. A decrease in pH by 0.09 and HCO3- by 4.8 mEq/1 was noticed during the rising phase of pyrogen fever. There were no concomitant changes in blood PCO2 during that period of time. Although the concentrations of HCO3- were decreasing till the end of the experiment, the parallel falls in PCO2 led to a partial compensation of the noticed acidosis. Pretreatment with 200 mg/kg of sodium salicylate /an hour's iv infusion/reduced the febrile response by 42% and completely reversed the postpyrogen changes in pH and HCO3-. The falls in PCO2 during antipyresis, however, were similar to those observed in febrile rabbits. Possible mechanisms by which sodium salicylate could affect the pyrogen-induced disturbances of acid-base balance are being considered.

Copper salicylate complex: thermoregulatory and biochemical effects.

The antipyretic properties of copper (II) salicylate and its effect on plasma copper, iron, zinc and ceruloplasmin concentrations was investigated in adult rabbits at an ambient temperature of 21.5 +/- 0.5 degrees C. The experiments indicated that copper salicylate (200 mg/kg/h i.v.) was a more potent antipyretic than sodium salicylate given in the same manner and doses. This pharmacological activity was found on a model of experimental fever induced by i.v. injection of lipopolysaccharide Escherichia coli at a dose of 1 microgram/kg. Furthermore, unlike sodium salicylate, this copper complex caused a decrease in core temperature in normothermic rabbits. At the same time copper salicylate activated heat dissipation much more efficiently than the parent drug, as manifested by decreases in vasomotor tone and reversal of postpyrogen inhibition of RF. As was expected, treatment with copper salicylate increased plasma copper and ceruloplasmin levels in both normothermic and febrile rabbits. These increases did not lead to any disturbances in iron and zinc concentrations. Neither salicylate affected postpyrogen falls in plasma iron concentrations. They both, however, delayed the appearance of zinc decreases in febrile rabbits. The results of this study suggest that copper modifies the thermoregulatory effects of salicylate. Moreover, the increased amounts of this metal do not seem to disturb seriously the ionic status of the blood.

The metabolic rate during the time course of salicylate antipyresis in the rabbit.

The processes concerned with the production and loss of body heat in sodium salicylate or acetylsalicylic acid antipyresis were investigated in adult rabbits at an ambient temperature of 21.5 +/- 0.5 degrees C. The experimental fever elicited by i.v. injection of lipopolysaccharide Escherichia coli (1 microgram/kg) was accompanied by increases in O2 consumption and CO2 production as well as decreases in convective heat loss. Pretreatment with 200 mg/kg of sodium salicylate (an hour's i.v. infusion) or with the same dose of acetylsalicylic acid (per os) significantly reduced pyrogen fever but the magnitude of O2 consumption and CO2 production remained at least at the febrile level. In the case of sodium salicylate, the level was even exceeded. At the same time both salicylates activated heat dissipation as manifested by decreases in vasomotor tone and tachypnea. Thus, it is apparent that the antipyretic effect of salicylates may develop without the inhibition of heat production. Heat loss processes initiated by these drugs are responsible for the antipyresis.