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 effect of intracerebral injections of neuropeptide Y in rats at different environmental temperatures.

1. In order to characterize the thermoregulatory actions of brain neuropeptide Y (NPY), the effects of intra-third ventricular (I3V) injection of NPY on temperatures of colon (Tco), brown adipose tissue (TBAT) and tail skin (Ts) were observed at ambient temperatures (Ta) of 19 and 8 degrees C. 2. The injection of NPY in a dose of 8 mcg/100 g body wt evoked a fall of Tco by about 2 degrees C in both neutral and cold environments. NPY (4 and 8 mcg/100 g body wt) induced dose-dependent Tco falls in rats at thermoneutral environment. The thermolytic reactions induced by I3V administration of NPY were associated with a fall in TBAT but no changes in Is were observed. 3. The results suggest that NPY may mediate hypothermic response in neutral and cold environments mainly by its effects on the brown adipose tissues in the rat.

Comparison between thermoregulatory effects mediated by alpha 1- and alpha 2-adrenoceptors in normothermic and febrile rabbits.

1. In order to better delineate the profile of thermoregulatory action of alpha 1-adrenoceptor antagonists; corynanthine (CRN) and BMY 20064 (BMY), and alpha 2-adrenoceptor agonist; medetomidine (MDT) and B-HT 920 (BHT), the effect of intravenous administration of two doses of these drugs on rectal (Tre) and ear skin (Te) temperatures, metabolic rate (M), respiratory evaporative heat loss (Eres) and respiratory rate (Rr) were examined in febrile and non-febrile rabbits. 2. Results indicate that alpha 1-adrenoceptor antagonists as well as alpha 2-adrenoceptor agonists markedly lowered body temperature exhibiting antipyretic and hypothermic actions. The hypothermic and antipyretic effect after the CRN or BMY, and BHT or MDT, treatment was associated with inhibition of metabolic rate and/or with body heat redistributed to peripheral tissues and an increase of the potential for heat loss to the environment. 3. BMY also abolished the thermogenic response to cold. However, BMY did not affect metabolic heat production on exposure to a cold ambient temperature. This unexpected phenomenon is difficult to explain at the present moment. Possible mechanisms responsible for the thermoregulatory activity of BMY are discussed. 4. These results indicate that alpha 1- and alpha 2-adrenoceptor drugs' thermoregulatory actions are similar in event and suggest that both subtypes of alpha-adrenoceptor might be implicated functionally in a variety of thermoregulatory processes.

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.

Antipyresis as a result of alpha-1 adrenoceptor blockade.

1. Fever was produced by intravenous injection of lipopolysaccharide E. coli (LPS; 1 micrograms/kg). Immediately after pyrogen administration, body temperature started increasing until it reached a maximum level (1.7 degrees C) at the 3rd hour of the experiment. The febrile response was accompanied by stimulation of metabolic heat production (maximum by 0.31 W/kg), falls in Te (maximum 7.2 degrees C) and Eres (maximum 0.05 W/kg). 2. Thirty minutes after pyrogen administration, the rabbits were treated intravenously with alpha 1-adrenoceptor antagonist, in the form of a bolus injection (1 ml/kg). All the tested drugs reduced fever from 20% by CRN to 105% by PRA. The antipyretic effect of DOX, BMY, PRA, DHBP was associated with inhibition of metabolism and vasodilation of the ear skin. The rest of the compounds produced antipyresis mainly by depression of metabolism. Apart from PRA and CRN, which inhibited Eres three times, the other compounds did not affect heat exchange from the respiratory tract. 3. One may conclude that the antipyretic effect is a general feature of alpha 1-adrenergic blocking drugs, and is accompanied by inhibition of heat production and/or stimulation of heat loss processes. The antipyretic properties of these blockers might be significant from the clinical point of view.

The effect of BE 2254 on the metabolic response stimulated by pyrogen in rabbits.

1. Thermoregulatory effector processes were investigated in rabbits after treatment with 1 and 2 micrograms/kg of lipopolysaccharide Escherichia coli (LPS). Both doses produced a fever reaction resulting from stimulation of the metabolic rate and heat conservation responses. 2. BE 2254 administered in feverish rabbits reduced the metabolic as well as pyretic activity produced by both doses of pyrogen. 3. It is suggested that stimulation of the thermoregulatory heat production which contributes to a febrile rise in body temperature is dependent on alpha 1-adrenoceptor mechanisms.

Do central mechanisms participate in the thermoregulatory activity of prazosin?

1. Prazosin (PRA) was used in febrile (LPS; 1 mcg/kg; i.v.) and normothermic rabbits at ambient temperatures (Ta) of 5, 19 and 28 degrees C. This drug was given i.v. in the form of an infusion at a rate of 0.75 mg/kg/3 hr. 2. In normothermic animals, PRA produced significant hypothermia mainly at Ta of 5 and 19 degrees C. In a cold environment, the hypothermic effect of PRA was associated with inhibition of metabolic rate and evaporative heat loss. 3. Infusion of this drug significantly prevented the LPS-induced fever in all experimental conditions. In the cold environment, a drop in body temperature was correlated with an inhibition of metabolic rate; in the thermoneutral environment, antipyresis was associated with an increase in heat dissipation from the ear-skin area; in the hot environment, the correlation between antipyresis and mechanisms of heat dissipation was much less clear. 4. The possible action of PRA on the effector part of the central thermoregulatory system 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.

Inhibition of pyrogen Escherichia coli fever with intracerebral administration of prazosin, dihydrobenzperidol and nifedipin in the rabbits.

1. The thermoregulatory, effector processes were investigated after treatment with prazosin (PRA), dihydrobenzperidol (DHBP) and nifedipin (ADA) applied to the thermosensitive zone of the anterior hypothalamus (PO/AH) on normothermic and feverish rabbits (LPS, lipopolysaccharide E. coli; 1 meg/kg, i.v.). 2. The alpha 1-noradrenergic receptor antagonists, PRA and DHBP, applied to the PO/AH produced an abolishment of fever elicited by pyrogen i.v. injection mainly because of vasodilation of ear skin vessels and attenuation of metabolic rate. 3. Calcium channel blocker, ADA, also induced a decline in the rabbit's core temperature in the same manner. 4. All these drugs given to the PO/AH did not change the body temperature in normothermic rabbits. 5. These results, therefore, strongly suggest that alpha 1-noradrenergic receptors subserve the coordinated thermoregulatory mechanisms in PO/AH which are required for antipyresis. The inhibition of Ca2+ turnover is discussed as a possible mechanism of antipyretic action of these drugs given to the PO/AH.

The effect of prazosin pretreatment on hyperthermia produced by noradrenaline in rabbits.

1. Hyperthermia produced by noradrenaline (NA) was accompanied by increased metabolic rate and vasoconstriction of ear skin vessels and a fall in evaporation heat loss. 2. Prazosin (PRA), administered as a single injection, decreased of hyperthermia elicited by NA mainly of attenuation the processes concerned with the heat production and increased of heat loss from respiratory tract and ear skin surface. 3. PRA administered in a 3 hr infusion did not only produce an abolishment of NA-induced hyperthermia but also exerted a hypothermizing effect. 4. PRA introduced intracerebroventricularly also induced a decline in core temperature, inhibiting the metabolic rate stimulated by this amine. 5. These results seem to suggest that NA-caused hyperthermia may be controlled through central adrenergic structures, which are effectively blocked by PRA. Besides, we have presented one more proof concerning the antihyperthermizing activity of PRA and its central point of activity catch.

A comparative study on the thermoregulatory effects of prazosin, dihydrobenzperidol and nifedipin on 2,4-dinitrophenol induced hyperthermia in rabbits.

1. Thermal responses to prazosin (PRA) and dihydrobenzperidol (DHBP) (0.75 mg/kg) or nifedipin (ADA: 0.05 mg/kg) administered intravenously were investigated in hyperthermic rabbits. 2. Hyperthermia produced by dinitrophenol (DNP; 20 mg/kg; i.v.), resulted from stimulation of the metabolic rate. 3. All the investigated drugs; i.e. PRA, DHBP, ADA reduced the hyperthermic activity of DNP. Contrary to DHBP and ADA, PRA did not change DNP--stimulated metabolism. 4. Possible mechanisms responsible for prazosin antihyperthermizing action are discussed.

The effect of doxazosin, urapidil and indoramin pretreatment on fever produced by E. coli lipopolysaccharide in rabbits.

1. Thermal responses to i.v. administration of doxazosin (0.75 or 1.50 mg/kg), urapidil (5.0 or 10.0 mg/kg), or indoramin (0.75 or 1.50 mg/kg) were investigated in febrile rabbits (treated with Escherichia coli lipopolysaccharide) at an ambient temperature of 19 +/- 1 degree C. 2. All these alpha 1-adrenoceptor blockers produced statistically significant antipyresis which developed as a result of inhibition of metabolic heat production and/or stimulation of heat elimination from the ear skin area or respiratory tract. 3. It appears that the antipyretic effect is a general feature of alpha 1-adrenergic receptor blockers. The possible mechanisms by which antipyresis is produced are being considered.

Comparison of the effect of prazosin with that of dihydrobenzperidol and nifidepine on thermoregulatory responses produced by pyrogen in rabbits.

1. Thermal responses to prazosin (0.75 mg/kg; i.v.), dihydrobenzperidol (0.75 mg/kg or 2.25 mg/kg; i.v.), nifidepine (0.05 mg/kg or 0.16 mg/kg; i.v.) administered in the form of bolus injection or infusion were investigated in febrile rabbits. 2. Pyrogen (Escherichia coli lipopolysaccharide, LPS, 1 mcg/kg; i.v.) produced a fever reaction resulting from stimulation of the metabolic rate and heat conservation responses. 3. Prazosin (PRA) and dihydrobenzperidol (DHBP) reduced the pyretic as well as metabolic activity of pyrogen. The former drug enhanced heat elimination from the ear. 4. Nifidepine (ADA) did not significantly affect postpyrogen thermoregulatory parameters. 5. It is suggested that alpha-adrenergic receptor blockade might be responsible for the antipyretic activity of PRA and DHBP.

Antipyretic activity of prazosin.

Thermal responses to prazosin (0.75 mg/kg, i.v. as a bolus injection or 3 h infusion) were investigated in febrile rabbits (treated with E. coli lipopolysaccharide, PLPS) at 3 ambient temperatures (Ta) of 5, 19, 28 degrees C. The drug produced antipyresis which increased with the simultaneous drop of Ta. This antipyretic activity was accompanied by an inhibition of heat production or enhanced elimination of heat, depending on Ta. It is suggested that antipyresis produced by prazosin is mainly due to the effector part of the thermoregulatory system.

Effects of prazosin on metabolism and body temperature in normothermic rabbits.

An attempt was made to study the influence of prazosin on thermoregulatory parameters. Two sets of experiments were carried out in rabbits. In the first set of experiments prazosin was given as 3 h infusion intravenously, (iv) (0.1, 0.25 and 0.5 mg/kg/h) or intracerebroventricularly, (icv) (20, 50 and 100 micrograms/animal) at an ambient temperature of 22 degrees C. Iv infusion caused a fall while icv administration a rise in body temperature. In the second set of experiments at different ambient temperatures (Ta = 4, 22, 28 degrees C) the following thermoregulatory parameters were recorded: rectal (Tre) and ear skin (Te) temperatures, metabolic rate (M), respiratory heat loss (Eres). The most evident result of iv infusion of prazosin in a dose of 0.25 mg/kg/h was a fall in Tre accompanied by a decrease in metabolic rate at ambient temperature of 4 degrees C. At Ta of 22 degrees C and 28 degrees C prazosin iv (0.25 mg/kg/h) induced only minimal changes in measured parameters. The results of the experiments may suggest that prazosin given peripherally induced hypothermia at Ta of 4 degrees C by inhibition of non-shivering thermogenesis.

Differences between the effect of prazosin and lysine-acetylsalicylate on some thermoregulatory parameters in nonfeverish rabbits.

Thermoregulatory responses to prazosin and lysine-acetylsalicylate (LAS) were investigated in afebrile rabbits at different ambient temperatures, i.e. at 5, 21 and 28 degrees C. In cold as well as in heat prazosin significantly inhibited the metabolic rate. This effect was accompanied by falls in rectal temperatures, particularly at the ambient temperature of 5 degrees C. Increases in ear skin temperatures became visible only when this drug was used in rabbits maintained in the thermoneutral environment. On the other hand LAS in all tested conditions indicated a marked metabolic activity associated with an intensified respiratory heat loss. As a consequence, the rabbits responded with slight increases in body temperature. The possible mode of thermoregulatory activity of prazosin is being considered in confrontation with that of LAS.

The influence of prazosin on E. coli lipopolysaccharide-induced fever and noradrenaline hyperthermia.

We investigated the effect of prazosin on experimental fever induced by E. coli lipopolysaccharide (LPS) and on noradrenaline hyperthermia in the rabbit. LPS and prazosin were administered iv and ivc, noradrenaline was administered only iv. Prazosin inhibited both LPS fever and noradrenaline hyperthermia in a dose-dependent manner. The results indicate the participation of alpha-adrenoceptor in the pyrogen fever and noradrenaline hyperthermia.