The effect of sodium salicylate on dibutyryl cyclic amp fever in the conscious rabbit

Bilateral injections of dibutyryl cyclic adenosine-3',5'-monophosphate (dibutyryl cyclic AMP), in a dose of 1 μg per injection, into the anterior hypothalamus of the conscious New Zealand White rabbit, produced a fever (0.8 ± 0.1 °C) with a short latency of onset (3.8 ± 1.5 min). Prior administration of a bolus of sodium salicylate followed by a constant infusion failed to reduce the dibutyryl cyclic AMP-induced hyperthermia. This is consistent with previously reported data supporting a role for cyclic AMP in the pathogenesis of PGE₁ fevers.     

Plasma cyclic AMP in the morphine-tolerant rat

Effects of morphine on plasma cyclic AMP leveis in the rat were investigated. Morphine (20 $\text{mg}\text{kg}$, s.c. + 4 $\text{mg}\text{kg/hr}$, i.v.) produced an increase in plasma cyclic AMP concentrations at 1hr and sustained elevated levels for several hours, but the levels returned to normal levels at 48 hr. the 48 hr increase in plasma cyclic AMP elicited by morphine (20 $\text{mg}\text{kg}$, s.c.) was far smaller than that of 1 hr; the plasma concentration of morphine was at the same level as the 1 hr. This indicated the development of tolerance to the morphine induced increase in plasma cyclic AMP. At 48 hr an epinephrine challenge increased plasma cyclic AMP to the same extent as in naive rats. Therefore, desensitization of peripheral tissues as being responsible for the increase in the plasma cyclic AMP could be ruled out. the development of tolerance by the sympatho-adrenal reflex elicited by morphine was suggested. In naioxone-precipitated abstinence, plasma cyclic AMP showed a 4-fold increase but. on spontaneous withdrawal, it showed on a slight but significant increase. It was concluded that plasma cyclic AMP is a sensitive index of tolerance to and dependence on morphine.     

Inhibitory role of cyclic adenosine 3' 5'-monophosphate in histamine release from rat peritoneal mast cells in vitro.

Cyclic adenosine 3′,5′-monophosphate (cyclic AMP) accumulated in rat peritoneal mast cells during incubation with epinephrine and theophylline, correlating well with the inhibition of histamine release from the cells by these agents, but occurring on different time courses. During stimulation with epinephrine, the initial, rapid accumulation of radioactive cyclic AMP in mast cells previously labeled with radioactive adenine preceded the elevation of total cyclic AMP content and the increase in the inhibition of histamine release. Theophylline, on the other hand, rapidly elevated the cellular levels of cyclic AMP before the accumulation of radioactive cyclic AMP and the inhibition of histamine release became detectable. Cyclic AMP, dibutyryl cyclic AMP, epinephrine and theophylline were all effective in suppressing histamine release from mast cells and from isolated granules in isotonic sucrose solution, but were less effective or not effective in NaCl-containing media. Cyclic AMP also suppressed the extrusion of granules from mast cells induced by compound $\text{48}\text{80}$ in isotonic sucrose solution. These results indicate that the formation of cyclic AMP from special pools of ATP is required for inhibiting histamine release from mast cells, and also that cyclic AMP regulates histamine release by interfering in an early stage of the release process prior to the interaction of the granular amine with the extracellular cations.     

Stimulatory effects of substance P and nerve growth factor (NGF) on neurite outgrowth in embryonic chick dorsal root ganglia.

Synthetic Substance P at 10⁴ M and Nerve Growth Factor (NGF) at 2 $\text{ng}\text{ml}$ produced a 3-fold increase in the concentration of cyclic AMP 10 min after addition to cultured chick dorsal root ganglia. Subsequently, increased fiber outgrowth was observed 24 hrs after these additions. Dibutyryl cyclic AMP at 10^?3 M also produced a similar induction of fiber outgrowth.These studies suggest that Substance P and NGF might act by increasing cyclic AMP levels, which may then act as an initial “second messenger”, inducing the morphological differentiation at a later time.     

The effect of alkylating agents on adenosine 3',5'-monophosphate metabolism in Walker carcinoma.

The effect of some alkylating agents on the activity of the enzymes adenylate cyclase and cyclic 3′,5′-nucleotide phosphodiesterase has been studied using Walker carcinoma cells in tissue culture. The monofunctional agent 5-aziridinyl-2,4-dinitrobenzamide (CB 1954), which has previously been shown to elevate the level of adenosine 3′,5′-monophosphate (cyclic AMP) in sensitive Walker cells, has been shown to have no effect on the activity of adenylate cyclase either in the presence or absence of the protecting agent 4-amino-2-phenylimidazole-5-carboxamide (2-phenyl-AlC). Chlorambucil (p-N,N(di-2-chloroethylamino)phenylbutyric acid) (5 μg/ml) while having no effect on either the basal or fluoride-stimulated adenylate cyclase activity caused an inhibition of the high affinity form of the cyclic AMP phosphodiesterase which reached a maximum after 1 hr. This was accompanied by an increase in the intracellular level of cAMP which was proportional to the dose of chlorambucil up to a maximal 2-fold increase at 6.4 μg/ml, a dose which caused complete inhibition of cell growth. Further increases in the concentration of chlorambucil up to 100 μg/ml caused no further increase in cAMP level. Merophan ($\text{dl}\text{-}\text{o}\text{-N,N(}\text{di}\text{-2-}\text{chloroethylamino}\text{)}\text{phenylalanine}$) (0.5 μg/ml) similarly caused an inhibition of the low K_m form of the phosphodiesterase, but the rate of inhibition was slower than that observed with chlorambucil. The molecular forms of the cAMP phosphodiesterase in Walker cells sensitive or resistant to chlorambucil have been resolved using Sepharose 6B gel chromatography. The resistant lines displayed a reduction in the specific activity of the high affinity form of the enzyme which was accompanied by a shift to lower molecular weight forms. This could explain the lack of effect of chlorambucil on cAMP levels in Walker cells with acquired resistance to this agent.     

Inhibition of cyclic 3',5'-nucleotide phosphodiesterase-a possible mechanism of action of bifunctional alkylating agents.

The effect of anti-tumour alkylating agents on the adenosine 3′,5′-monophosphate (cyclic AMP) levels of sensitive and resistant Walker carcinoma cells in tissue culture has been investigated. Chlorambucil caused a two-fold elevation of cyclic AMP, in the sensitive line only, 8 hr after treatment with a dose of 5 μg/ml. A comparable increase is produced by the cyclic nucleotide phosphodiesterase inhibitor aminophylline at a dose which produces the same degree of inhibition of cell growth. The therapeutically-inactive monofunctional N-ethyl analogue of chlorambucil had no effect on the cyclic AMP level of the sensitive cells at a dose of 250 μg/ml after 8 hr, while the highly selective monofunctional alkylating agent, CB 1954, at 1 μg/ml caused an elevation of cyclic AMP in the sensitive line 24 hr after treatment. This is not a non-specific effect caused by an inhibition of cell growth for the antimetabolite methotrexate had no effect on the intracellular cyclic AMP of sensitive Walker cells at doses which produced complete inhibition of cell growth. The effect of the alkylating agents on cyclic AMP levels is probably due to a specific inhibition of the cyclic nucleotide phosphodiesterase with a low K_m value, since only this form of the enzyme is inhibited, and only in the sensitive cells, when an effect on cell growth and cyclic AMP content is observed. In the case of CB 1954, however, there was no inhibition of either form of the phosphodiesterase at a time when cyclic AMP levels were elevated. A linear relationship exists between the reciprocals of the intracellular cyclic AMP and the percentage growth inhibition produced by a given dose of chlorambucil.     

Some bronchoconstricting and bronchodilating responses of human isolated bronchi: evidence for the existence of -adrenoceptors

Isolated strips of human bronchi obtained during thoracic surgery exhibited pharmacological responses very similar to those of other species (e.g. guinea-pig). Analysis of the action of some sympathomimetic amines indicated that the human bronchi also possess a sparse population of α-adrenoceptors. Propranolol (>1 μg/ml) had a direct bronchoconstricting action, whereas another β-adrenoceptor blocking agent, alprenolol, produced bronchodilatation. Phentolamine (>4 μg/ml) also produced a bronchodilatation of its own. Theophylline and dibutyryl cyclic AMP produced dose-dependent relaxations. The strips were effectively contracted by acetylcholine, histamine, prostaglandin F₂α (PGF₂α), slow reacting substance (SRS) and bradykinin. Bradykinin, regardless of the dose, produced bronchoconstriction in some preparations and dilatation in others. 5-Hydroxytryptamine produced bronchodilatation but at very high concentrations a constriction was obtained.     

坤泰胶囊对初老雌性小鼠的戊巴比妥钠睡眠增强作用及其机制研究

目的评价坤泰胶囊对初老雌性小鼠戊巴比妥钠催眠作用的影响及其促睡眠机制。方法采用翻正反射试验考察坤泰胶囊0.8 g/kg对阈剂量戊巴比妥钠诱导的小鼠入睡潜伏期和睡眠时间的影响;采用RT-PCR技术检测坤泰胶囊0.8 g/kg对盐诱导激酶3(Sik3)和G蛋白偶联雌激素受体(Gper1)基因m RNA在不同睡眠状态下表达情况的影响。结果坤泰胶囊0.8 g/kg可以显著延长阈剂量戊巴比妥钠诱导小鼠的睡眠时间(P<0.05),缩短睡眠潜伏期(P<0.05);坤泰胶囊0.8 g/kg可升高视前区内Sik3 mRNA在6 h急性睡眠剥夺后的表达(P<0.05)。坤泰胶囊0.8 g/kg可一致性地降低大脑视前区和腹侧纹状体以及卵巢内Gper1 mRNA的表达,坤泰胶囊夺眠组显著降低腹侧纹状体和卵巢的雌激素受体基因Gper1 mRNA的表达(P<0.05)。结论坤泰胶囊可增强初老雌性小鼠的戊巴比妥钠催眠作用,其睡眠改善功效可能是通过提高Sik3和降低Gper1的表达而发挥作用。     

Esters of apomorphine and N,N-dimethyldopamine as agonists of dopamine receptors in the rat brain in vivo.

Subcutaneous injections of O,O'-diacetylapomorphine, at doses of 0.1 to 10.0 $\text{mg}\text{kg}$, produced stereotyped gnawing behaviour in the rat, indistinguishable from that induced by apomorphine. The dose-response relationship and time course of this effect were similar for the two drugs, although the ester appeared to be somewhat more potent and longer-lasting at higher doses. While apomorphine had no behavioural effects when given orally at doses up to 100 $\text{mg}\text{kg}$, diacetylapomorphine produced discernible stereotypy at oral doses as low as 10 $\text{mg}\text{kg}$. The injection of diacetylapomorphine into animals previously lesioned electrothermally in the left nigro-striatal tract provoked turning behaviour toward the side contralateral to the lesions, with an effectiveness similar to that of apomorphine. Apomorphine, but not diacetylapomorphine, stimulated the production of cyclic AMP when incubated with homogenates of corpus striatum. In analogous experiments, N,N-dimethyldopamine, but not its ester, O,O'-diacetyl-N,N-dimethyldopamine (another apparent agonist of central dopamine receptors in vivo), also stimulated the production of cyclic AMP in homogenates, and a similar failure to stimulate the production of cyclic AMP was obtained with O,O'-dibenzylapomorphine, which had prolonged behavioural effects in vivo. These results are compatible with the conclusion that catechol esters of certain structural analogues of dopamine can be hydrolysed in vivo to yield free catechols capable of stimulating central dopamine receptors.     

Studies on carbon tetrachloride-ethanol interactions in mice

Male C57BL/6J (C57) and DBA/2J (DBA) inbred mice were dosed with either corn oil or carbon tetrachloride (CCLQ in corn oil 24 h before a $\text{3.25}\text{g}\text{kg}$ i.p. dose of ethanol. The CCL₄ doses were increased in approximate half-log intervals ($\text{5, 15, 50, 150}\text{or}\text{500}\text{μl}\text{kg}$, intragastrically (i.g.)). Blood acetaldehyde concentrations were significantly increased l, 2, 3 and 4 h after ethanol administration at Ccl₄ doses of $\text{15}\text{μl}\text{kg}$ and higher, with DBA and C57 mice exhibiting similar dose-response effects up to the $\text{150}\text{μl}\text{kg}$ dose. A CCl₄ dose of $\text{500}\text{μl}\text{kg}$ produced differences in blood acetaldehyde elevation between the two inbred strains (DBA—5-fold, C57—3-fold). Associated with the elevation of blood acetaldehyde content was a decrease in the rate of elimination of ethanol from blood. Using male genetically heterogeneous stock (HS) mice it was shown that phenobarbital pretreatment potentiated the CCl₄-induced decrease in in vivo acetaldehyde oxidation. An equimolar dose of CHCl₃ ($\text{0.5}\text{mmol}\text{kg}$) was without effect in either control or phenobarbital-pretreated mice. Mice pretreated with $\text{0.5}\text{mmol}\text{kg}$, i.g., 1,2-dichloroethane, 1,1,2-trichloroethylene or bromobenzene did not exhibit significant interaction with ethanol. These data show that in vivo acetaldehyde oxidation is inhibited by very low doses of CCl₄ ($\text{15}\text{μl}\text{kg}$, i.g.) and that this inhibition is enhanced by the cytochrome P-450-inducing agent phenobarbital.     

Effect of adenosine on cyclic AMP accumulation in ventricular myocardium.

Adenosine stimulated cyclic AMP accumulation in guinea pig ventricular slice preparations. The response to adenosine was dose-dependent over the range 0.1 to 100 μM; half-maximal stimulation occurred at 25 μM. The response to the nucleoside was rapid; maximum levels of cyclic AMP were obtained in 3 min. Examination of a variety of adenosine analogues revealed that the 2'-, 3'-, and 5'-hydroxyl groups of the ribose moiety were important for activity. Agonist activity also required an amino group in the 6-position. Substitution of one hydrogen atom on the primary amino nitrogen did not alter activity, but substitution of both hydrogens abolished activity. Replacement of the N in position 7 of the purine ring with a C atom, or substitution of the hydrogen atom on position 8 with either an amino group or bromine atom abolished activity. Examination of the effect of several agents, papaverine, 5'-deoxyadenosine, 6-chloropurine riboside and $\text{6-N[(p-}\text{nitrobenzyl}\text{)}\text{thio}\text{]-9-β-}\text{d}\text{-}\text{ribofuranosyl}$ purine, which inhibited adenosine uptake into cardiac cells, provided evidence which suggested that the action of the nucleoside was mediated via interaction with a receptor on the external cell surface. Several phosphodiesterase inhibitors (papaverine, SQ 20009, RO-20-1724 and 3-isobutyl-1-methylxanthine) potentiated the effect of adenosine; theophylline, on the other hand, antagonized adenosine stimulation of cyclic AMP levels. Hexobencline potentiated the stimulatory action of low (10 μM) concentrations of adenosine, and seemed to do so by preventing adenosine uptake. Lidoflazine potentiated the action of both low (10 μM) and high (100 μM) concentrations of adenosine and appeared to act primarily as a phosphodiesterase inhibitor. Dipyridamole potentiated the actions of both low and high concentrations of adenosine probably by blocking adenosine uptake and by inhibiting phosphodiesterase.     

THE INTERRELATIONSHIPS BETWEEN ANTIDIURETIC HORMONE, ADENYL CYCLASE, TISSUE CYCLIC AMP AND DIFFUSIONAL WATER PERMEABILITY

1. Physiological concentrations of antidiuretic hormone increase diffusional water permeability but not measurable cyclic AMP content in the isolated papilla of the rat's kidney. 2. Theophylline (6 MM) increases diffusional water permeability and cyclic AMP content in the isolated papilla of the rat's kidney. 3. The increase in water permeability is detected with 5 μunits. ml^-1 of ADH and is maximal with 50 μunits. ml^-1. The same maximum was achieved with 6 MM theophylline. 4. Cyclic AMP and dibutyryl cyclic AMP both increase water permeability, but to a lesser extent than theophylline or ADH. 5. In the presence of theophylline, ADH causes a dose related generation of tissue cyclic AMP up to a dose of 2,000,000 μunits. ml^-1. 6. Adenyl cyclase is increasingly activated by ADH up to doses of 2,000,000 μunits. ml^-1. 7. These results suggest that while ADH activates the adenyl cyclase system and changes water permeability there are sufficient disparities to cast doubt on an exclusive role for cyclic AMP as the second messenger.     

Behavioural effects of dibutyryl cyclic 3',5' AMP, noradrenaline and cyclic 3',5' AMP in rats

It was shown that dibutyryl cyclic AMP (DAMP) injected intraventricularly in doses of 100–200 μg in rats causes the increase of locomotor and exploratory activity and convulsions, depending on the dose. DAMP increased excitatory behavioural effects of noradrenaline (NA) injected intraventricularly in doses of 10 or 50 μg. NA in a dose of 200 μg abolished convulsions evoked by DAMP. Cyclic AMP (cAMP) injected intraventricularly in doses of 100–400 μg had no effect on the rat's behaviour. Pretreatment of rats with dimethylsulphoxide and with theophylline caused in some animals behavioural phenomena after injection of cAMP, similar to the behavioural symptoms evoked by DAMP.     

Comparison of the antinociceptive effects of intracerebroventricular injection of kyotorphin,cyclo (N-methyl-tyr-arg) and met-enkephalin in mice

Intracerebroventricular (i.c.v.) administration of kyotorphin (l-Tyrosine-l-Arginine) or Met-enkephalin (Met-ENK) to conscious mice resulted in a dose-dependent antinociceptive effect as measured by three pain tests. Cyclo(N-methyl-l-Tyrosine-l-Arginine) (cyclo NMTA), an analogue of kyotorphin, increased the reaction time in the tail-pressure and tail-flick tests. Both dipeptides also decreased writhing induced by acetic acid. However, the antinociceptive activity of cyclo NMTA was substantially greater than that of kyotorphin or Met-enkephalin. At the maximum effective dose of 62.7 $\text{nmol}\text{mouse}$, this cyclic dipeptide produced a more long-lasting antinociceptive effect than did kyotorphin or Met-enkephalin. Antinociception induced by cyclo NMTA or kyotorphin was significantly reversed by pretreatment with naloxone (2 or 8 $\text{mg}\text{kg}$, i.p.), though naloxone was not as effective an antagonist of the antinociceptive action of these peptides as it was against Met-enkephalin. The results indicate that the antinociceptive effect induced by cyclo NMTA may in part involve the endogenous opioid system in mice.     

Physalaemin,a new potent antidipsogen in the rat

In this paper the effect on water intake of intracerebroventricular administration of the naturally occurring endecapeptide physalaemin is reported. Drinking was induced by intracerebroventricular injection of angiotensin II (100 ng/rat) or carbachol (300 ng/rat), water deprivation or NaCl load. Physalaemin produced a dose-dependent inhibition of water intake induced by angiotensin II. The inhibition was virtually complete at the dose of 500 ng/rat. The minimum dose employed (50 ng/rat) produced a 6% drinking inhibition. Physalaemin inhibited drinking induced by carbachol. The threshold dose was 125 $\text{ng}\text{rat}$. A virtually complete inhibition was produced by physalaemin, 1μg. The effect was dose-dependent.In water deprived rats 10 μg, but not lower doses, of the peptide produced a significant inhibition of water intake. The effect was short-lasting and ceased 30 min after the injection. Physalaemin was completely ineffective in sodium chloride-loaded rats, in spite of the very large doses employed (up to 5 mg/rat).The results of these experiments demonstrate that physalaemin is a potent antidipsogenic agent, but do not allow any conclusion to be made about the mechanism of its inhibitory effect. However, it is reasonable to propose that the effect is specific to the CNS and not simply due to the very marked vascular activity of the peptide.     

Effects of thiamin antagonists on drug hydroxylation and properties of cytochrome P-450 in the rat

The administration of small amounts of thiamin (0.3 $\text{μg}\text{day}$ or more, i.p., for 21 days) depressed musomal cytochrome P-450 content and the V_max of aniline hydroxylase when compared to values obtained from rats fed a thiamin-deficient diet (approximately 0.1 μg of thiamine/day in basal diet). The concurrent administration of neopyrithiamin (50 $\text{μg}\text{day}$, i.p.) eliminated the depressant effect of 10.0 μig of thiamin/ day, but was without significant effect in rats receiving more than 100 μg of thiamin/ day. In contrast, 100 μg of oxythiamin/day had no thiamin-opposing effect on cytochrome P-450 content and only partially counteracted the effects of 1 μg of thiamin/day on aniline hydroxylase activity. These treatments were without significant effect on the K_m for this reaction. Using ethyl isocyanide as the ligand, there appears to be a qualitative change induced in the cytochrome P-450 from thiamin-deficient rats. The absorption peak height ratios indicate that cytochrome P₁-450 is increased in a manner analogous to that produced by the administration of 3-methylcholanthrene. This was supported by the fact that aniline binding, as evidenced by increased ΔA_max, is enchanced in musomes from thiamin-deficient animals, whereas the hexobarbital spectral shift was unaltered.     

Effects of excitatory amino acids on locomotor activity after bilateral microinjection into the rat nucleus accumbens: Possible dependence on dopaminergic mechanisms

In order to study the role of excitatory amino acids on motor function, the effects of kainic, quisqualic, and $\text{N-}\text{methyl}\text{-}\text{dl}\text{-}\text{aspartic}$ acids on locomotor activity were determined after their direct injection into the nucleus accumbens. These three amino acids have been used in previous studies to classify receptors for excitatory amino acids in the mammalian spinal cord. After injection into the nucleus accumbens all three amino acids stimulated locomotor activity, with kainic acid being the most potent and $\text{N-}\text{methyl}\text{-}\text{dl}\text{-}\text{aspartic}$ acid the least potent. The maximum intensity of the stimulation produced by kainic and quisqualic acids was greater than that produced by $\text{N-}\text{methyl}\text{-}\text{dl}\text{-}\text{aspartic}$ acid. These results suggest that receptors in the nucleus accumbens, sensitive to kainic and quisqualic acids, play a more important role in the stimulation of locomotor activity than those sensitive to $\text{N-}\text{methyl}\text{-}\text{dl}\text{-}\text{aspartic}$ acid. In addition to the above amino acids, the administration of large doses of l-aspartic and d-glutamic acids also produced hyperactivity, while l-glutamic acid had no effect. To determine whether endogenous dopamine mediates the hypermotility produced by the excitatory amino acids, the response to these amino acids was studied after treatment with reserpine or dopamine receptor blocking agents. Reserpine (5 mg/kg, i.p.), haloperidol (0.8 mg/kg, i.p.) or fluphenazine [5.0 μg (total dose) injected into the nucleus accumbens] markedly attenuated the hypermotility induced by excitatory amino acids. These results suggest that the hypermotility produced by excitatory amino acids is mediated through release of dopamine and the subsequent stimulation of dopamine receptors in the nucleus accumbens.     

民康胶囊对小鼠睡眠功能影响实验研究

目的研究民康胶囊对小鼠睡眠功能的影响。方法给予小鼠连续灌胃给药30天后,分别进行直接睡眠实验、延长戊巴比妥钠睡眠时间实验、戊巴比妥钠阀下剂量催眠实验、巴比妥钠睡眠潜伏期实验。结果民康胶囊对小鼠无直接睡眠作用（P〉0．05）;0．81g·kg^-1。剂量组能明显延长戊巴比妥钠对小鼠的睡眠时间（P〈0．05）、增加戊巴比妥钠阁下催眠剂量入睡动物数（P〈0．05）．结论民康胶囊具有改善睡眠功效。     

EEG-behavioral dissociation after morphine-and cyclazocine-like drugs in the dog: further evidence for two opiate receptors.

Previous studies have suggested the presence of multiple opioid receptors. In the chronic spinal dog, the μ receptor was postulated to mediate behavioral indifference, whereas the $\text{k}$ receptor was associated with sedation. The effects of morphine, a μ agonist, were compared with those of Win 35,197-2 (ethylketocyclazocine) and ketocyclazocine, $\text{k}$ agonists, in the unrestrained intact dog. Intravenous administration of morphine (0.5 1.0 and 2.0 mg/kg), Win 35,197-2 (0.05 0.1 and 0.2 mg/kg), and ketocyclazocine (1.6 mg/kg) caused similar dissociation of the EEG and behavior. The dissociation was characterized by high voltage delta EEG synchrony primarily in the parietal cortex which accompanied ataxia and catalepsy in nonsleeping postures. Morphine increased total sleep and slow wave sleep, and lowered temperature and heart and respiratory rates. The $\text{k}$ agonists did not increase total sleep but increased temperature and heart and respiratory rates. Vomiting occurred more often after morphine than after the $\text{k}$ agonists. In certain instances, the effects of morphine were completely antagonized by a low dose of naloxone (30μg/kg), whereas 33 times the dose (1 mg/kg) was required to antagonize the effects of Win 35,197-2. The disparate effects of the μ and $\text{k}$ opioid agonists on behavior, sleep and the EEG and their differences in sensitivity to naloxone antagonism extend and support the concept of multiple opiate receptors in the brain. It was concluded, however, that the sedative effects of the opioids are mediated at the μ receptor.     

Glucagon in procainamide-induced cardiac toxicity

The effects of glucagon on the procainamide-induced cardiac toxicity were investigated in anesthetized dogs. Procainamide (50–100 mg/kg) produced a dose-dependent decrease in the heart rate, cardiac output, cardiac index, the first derivative ($\text{dp}\text{dt}$) and $\text{(dp}\text{dt}$)/IIP of left ventricular pressure, and left ventricular work index. It also produced lengthening of the duration of the P-R and Q-T intervals and the QRS complex. Glucagon at a dose of 50 μg/kg antagonized the effects of procainamide on the heart rate, cardiac output, cardiac index, $\text{dp}\text{dt}$, and $\text{(}\text{dp}\text{dt}$)/IIP of the left ventricular pressure, the left ventricular work index, and the electrocardiographic pattern. The effects of glucagon were apparent within 3 min. These results suggest that glucagon might be a promising agent for the treatment of procainamide-induced cardiac toxicity.