Effects of nifedipine and verapamil on body temperature in cats

Nifedipine and verapamil injected into the cerebral ventricles of unanaesthetized cats produced a longlasting rise in the body temperature. The hyperthermic effect of nifedipine and verapamil were not dose-dependent. The hyperthermic effect of verapamil was preceded by a shortlasting fall in the body temperature, which was not dose-dependent. Calcium antagonists, nifedipine and verapamil also produced mydriasis, tachypnoea, dyspnoea, ataxia, tremor and muscular weakness. These symptoms were inconsistent and of slight intensity. In agreement with the theory of ionic set point controlling the body temperature, the most probable explanation is that calcium antagonists, nifedipine and verapamil produced changes in the body temperature by acting on sodium and calcium fluxes in the posterior hypothalamus.     

Area postrema: cholinergic and noradrenergic regulation of emesis. A new concept

In unanaesthetized cats the biochemical mechanisms and the functional characteristics of the emetic action of injection of noradrenaline and McN-A-343, a ganglionic muscarinic stimulant into the cerebral ventricle (i.c.v.) through chronically implanted cannulae were investigated. Both produced dose-dependent and shortlasting emetic response. The emesis evoked by noradrenaline was abolished, whereas the emesis induced by McN-A-343 was not completely blocked after ablation of the area postrema. Further, the emetic response to noradrenaline as well as to McN-A-343 was attenuated or blocked in cats pretreated with 6-hydroxydopamine (i.c.v.) and hemicholinium (i.c.v.); it was abolished in cats pretreated with reserpine (i.c.v.). On the other hand, the emetic response to i.c.v. noradrenaline and to i.c.v. McN-A-343 was not virtually altered in cats pretreated with bretylium (i.c.v.), alpha-methyl-p-tyrosine (i.c.v.) and 5,6-dihydroxytryptamine (i.c.v.). It is postulated that noradrenergic neurones as well as cholinergic axon terminals within the area postrema are necessary for the emetic action of noradrenaline, whereas cholinergic axon terminals within the area postrema subserve the emetic response to McN-A-343. A functional link between cholinergic terminals and noradrenergic neurones as well as a modulatory role of noradrenergic afferents on cholinergic afferents mediating emesis within the area postrema is further proposed. Thus, noradrenergic neurones might represent a common site of confluence of different inputs subserving the emesis in the area postrema. Finally, cholinergic terminals sometimes bypass this area and synapse in the emetic regions of the brainstem regulating emesis.     

Maitotoxin-Induced Intracellular Calcium Rise in PC 12 Cells: Involvement of Dihydropyridine-Sensitive and ω-Conotoxin-Sensitive Calcium Channels and Phosphoinositide Breakdown

The biological activities of maitotoxin are strictly dependent on the extracellular calcium concentration and are always associated with an increase of the free cytosolic calcium level. We tested the effects of voltage-sensitive calcium channel blockers (nicardipine and omega-conotoxin) on maitotoxin-induced intracellular calcium increase, membrane depolarization, and inositol phosphate production in PC12 cells. Maitotoxin dose dependently increased the cytosolic calcium level, as measured by the fluorescent probe fura 2. This effect disappeared in a calcium-free medium; it was still observed in the absence of extracellular sodium and was enhanced by the dihydropyridine calcium agonist Bay K 8644. Nicardipine inhibited the effect of maitotoxin on intracellular calcium concentration in a dose-dependent manner. The maitotoxin-induced calcium rise was also reduced by pretreating cells with omega-conotoxin. Pretreatment of cells with maitotoxin did not modify 125I-omega-conotoxin and [3H]PN 200-110 binding to PC12 membranes. Nicardipine and omega-conotoxin inhibition of maitotoxin-evoked calcium increase was reduced by pertussis toxin pretreatment. Maitotoxin caused a substantial membrane depolarization of PC12 cells as assessed by the fluorescent dye bisoxonol. This effect was reduced by pretreating the cells with either nicardipine or omega-conotoxin and was almost completely abolished by the simultaneous pretreatment with both calcium antagonists. Maitotoxin stimulated inositol phosphate production in a dose-dependent manner. This effect was reduced by pretreating the cells with 1 microM nicardipine and was completely abolished in a calcium-free EGTA-containing medium. The findings on maitotoxin-induced cytosolic calcium rise and membrane depolarization suggest that maitotoxin exerts its action primarily through the activation of voltage-sensitive calcium channels, the increase of inositol phosphate production likely being an effect dependent on calcium influx. The ability of nicardipine and omega-conotoxin to inhibit the effect of maitotoxin on both calcium homeostasis and membrane potential suggests that L- and N-type calcium channel activation is responsible for the influx of calcium following exposure to maitotoxin, and not that a depolarization of unknown nature causes the opening of calcium channels.     

Cholera and pertussis toxins inhibit differently hypothermic and anti-opioid effects of neuropeptide FF

In mice pretreated intracerebroventricularly (i.c.v.) with pertussis or cholera toxins, effects of neuropeptide FF (NPFF), on hypothermia and morphine-induced analgesia, were assessed. NPFF and a potent NPFF agonist, 1DMe (0.005-22 nmol) injected into the lateral ventricle decreased morphine analgesia and produced naloxone (2.5 mg x kg(-1), s.c.)-resistant hypothermia after administration into the third ventricle. Cholera toxin (CTX 1 microg, i.c.v.) pretreatment (24 or 96 h before) inhibited the effect of 1DMe on body temperature, but failed to reverse its anti-opioid activity in the tail-flick test. CTX reduced hypothermia induced by a high dose of morphine (8 nmol, i.c.v.) but not the analgesic effect due to 3 nmol morphine. Pertussis toxin (PTX) pretreatment inhibited both morphine-hypothermia and -analgesia but did not modify hypothermia induced by 1DMe. The present results suggest that NPFF-induced hypothermia depends on the stimulation of Gs (but not Gi) proteins. In contrast, anti-opioid effects resulting from NPFF-receptor stimulation do not involve a cholera toxin-sensitive transducer protein.     

TRH dissociates the aggressivity of vegetative and motor phenomena induced by carbachol in the cat

In these experiments interaction of thyrotropin releasing hormone (TRH) and carbachol injected into the cerebral ventricles of unanaesthetized cats has been investigated. Intracerebroventricular (i.c.v.) carbachol as well as i.c.v. TRH produced emotional behaviour, autonomic and motor phenomena. The most impressive feature of i.c.v. carbachol was the aggressive behaviour, whereas that of i.c.v. TRH the autonomic changes. In cats treated with i.c.v. TRH, the aggressive behaviour, but the autonomic and motor changes of i.c.v. carbachol was potentiated. Since there is evidence that carbachol acts mainly on muscarinic M-2 receptors, the potentiation by TRH of aggressive behaviour, but not the autonomic and motor changes induced by carbachol could indicate heterogeneity of central muscarinic M-2 receptors.     

Nicardipine inhibits axon conduction but causes dual changes of acetylcholine release in the mouse motor nerve

The effects of nicardipine, a dihydropyridine Ca2(+)-channel antagonist, on neuromuscular transmission and impulse-evoked release of acetylcholine were compared with those of nifedipine. In the isolated mouse phrenic nerve diaphragm, nicardipine (50 microM), but not nifedipine (100 microM), induced neuromuscular block, fade of tetanic contraction, and dropout or all-or-none block of end-plate potentials. Nicardipine had no significant effect on the resting membrane potential and the amplitude of miniature end-plate potentials but increased the frequency and caused the appearance of large size miniature potentials. The quantal contents of evoked end-plate potentials were increased. In the presence of tubocurarine, however, nicardipine depressed the amplitude of end-plate potentials. The compound nerve action potential was also decreased. It is concluded that nicardipine blocks neuromuscular transmission by acting on Na+ channels and inhibits axonal conduction. Nicardipine appeared to affect the evoked release of acetylcholine by dual mechanisms, i.e., an enhancement presumably by an agonist action on Ca2+ channels, like Bay K 8644 and nifedipine, and inhibition by an effect on Na+ channels, like verapamil and diltiazem. In contrast with its inactivity on the amplitude of miniature end-plate potentials, depolarization of the end plate in response to succinylcholine was greatly depressed. The contractile response of baby chick biventer cervicis muscle to exogenous acetylcholine was noncompetitively antagonized by nicardipine (10 microM), but was unaffected by nifedipine (30 microM). These results may implicate that nicardipine blocks the postsynaptic acetylcholine receptor channel by enhancing receptor desensitization or by a use-dependent effect.     

Mechanism of neurotensin-induced pressor effect and tachycardia in guinea pigs

Neurotensin (NT) was found to produce a dose-dependent increase of the systolic and diastolic blood pressure, and of the heart rate in anesthetized guinea pigs when injected intravenously (i.v.) as a bolus, or when infused i.v. over a 15 min period. In a small percentage (20%) of animals, bolus injections of NT evoked triphasic variations (e.g. increase followed by a decrease and a further increase) of the blood pressure associated with unpredictable changes of heart rate. The pressor effect of NT was consistently reduced by prior treatment of the animals with pentolinium, a ganglion blocking agent, a mixture of alpha and beta adrenergic receptor blocking drugs, reserpine, a drug known to deplete adrenergic neurons of their neurotransmitters, or guanethidine, a drug known to paralyse adrenergic neurons. NT-induced tachycardia was either unchanged or slightly potentiated following the administration of the latter autonomic blockers. Neither the pressor effect nor the tachycardia evoked by NT was affected by antihistaminics, antiangiotensin or by indomethacin, an inhibitor of prostaglandin synthesis. These results suggest that the pressor effect of NT in anesthetized guinea pigs is likely the result of an interaction (most likely an activation) between the peptide and the sympathetic nervous system. The increase of heart rate induced by NT appears to be due to a direct effect on the heart.     

Thermoregulatory responses of the unrestrained cat to acute and chronic intravenous administration of low doses of morphine and to naloxone precipitated withdrawal

Morphine in doses of 1, 2, and 4 mg/kg i.v. produced dose related elevations in cat body temperature while doses of 0.25 and 0.50 mg/kg had no such effect. Tolerance was found to develop to the hyperthermic response after seven days of daily morphine injection. Pretreatment with naloxone at a dose one-fourth the dose of morphine prevented the morphine induced rise in body temperature in all cats tested. When the cats received naloxone after twelve days of daily morphine a withdrawal syndrome resulted and was accompanied by a hypothermia that was proportional to the morphine maintenance dose and severity of withdrawal.     

Central cardiovascular and thermal effects of prostaglandin F2 alpha in rats.

Administration of PGF2 ALPHA (0.2--6.4 micrograms) into the lateral cerebral ventricle (i.c.v.) induced dose-dependent increases in blood pressure, heart rate and body temperature in urethane-anaesthetised rats, but had no effect on these parameters when the same dose range was administered intravenously. Peripheral pretreatment with sodium meclofenamate (50 mg/kg s.c.) shifted all the dose-response curves for PGF2 alpha (i.c.v.) to the left, but indomethacin (50 mg/kg s.c.) did not significantly affect those changes. Central pretreatment with sodium meclofenamate or indomethacin (1.25 mg per rat i.c.v.) failed to modify significantly the effects of centrally administered PGF2 alpha. The results support previous suggestions that PGF2 alpha may participate in the central control of the cardiovascular and thermoregulatory systems, and also suggest that there may be differences in the sites and/or modes of action between sodium meclofenamate and indomethacin.     

Comparative study of the effects of carbachol, eserine and dibutyryl cyclic guanosine monophosphate on the behaviour of the cat

Carbachol and eserine injected into cerebral ventricles of conscious cats evoked aggressive behaviour accompanied with autonomic and motor phenomena. However, db-cGMP also injected into cerebral ventricles of conscious cats elicited autonomic effects with miaowing, restlessness, ear twitching and scratching. When butyrate sodium and butyryc acide were injected intraventricularly no visible gross behavioural phenomena in conscious cats were observed. The gross behavioural effects of db-cGMP were substantially the same when the cats were pretreated by intraventricular injections of aminophylline.     

Cyclosporine A and purinergic receptors in rat kidney

Previous reports have demonstrated that Cyclosporine A (CyA) chronically administered induces an increase in adenosine plasma concentration by inhibiting adenosine uptake by red blood cells (RBC). We hypothesized that this effect may modulate, by a down regulation, the mRNA expression of adenosine receptors in rat kidney. Since high blood pressure (HBP) is a classical side effect of CyA treatment, nicardipine, a dihydropyridine calcium channel blocker, is often associated with CyA in treatment. To distinguish between the effects of CyA-induced HBP and the effects of CyA by itself, we have evaluated the effects of CyA and/or nicardipine on the mRNA expression of A1 and A2a adenosine receptors. The study was performed on five groups of rats (n= 8) receiving during 21 days either serum saline (0.5 ml i.p), CyA (12 mg/kg/day, i.p), nicardipine (1.2 mg/kg i.p) or nicardipine + CyA. The last (or fifth) group was injected with vehicle (0.5 ml i.p). Blood samples for adenosine assay were collected in the renal artery at day 21, just before the rat kidneys were removed for quantitation of adenosine A1 and A2a mRNA concentration by RT-PCR. We make two conclusions :i) Nicardipine induces a decrease in mRNA expression of A1 but not of A2a adenosine receptors. However, because nicardipine lowered both blood pressure and A1 mRNA expression, it is not possible to conclude if A1 mRNA decrease is implicated in the nicardipine effects on blood pressure.ii) CyA induces an increase in renal artery adenosine concentration and a decrease in mRNA expression of A1 and A2a adenosine receptors.     

Adrenoceptor mechanisms in the cardiovascular effects of cocaine in conscious squirrel monkeys.

The purpose of the current experiment was to study the role of various adrenoceptor subtypes in the cardiovascular response to cocaine in conscious squirrel monkeys. A variety of adrenoceptor antagonists were administered i.v. prior to the administration of 0.3 mg/kg cocaine (i.v.). Cocaine alone produced an increase in both blood pressure and heart rate. The non-selective alpha adrenoceptor antagonist phentolamine produced a dose-dependent antagonism of the pressor effect of cocaine, as did the alpha-1 selective antagonist prazosin. The alpha-2 selective antagonist yohimbine had no effect on the pressor effect of cocaine. The non-selective beta antagonist propranolol enhanced the pressor effect of cocaine as did the beta-1 selective antagonist atenolol. However, the effect of atenolol was not dose-dependent. The beta-2 selective antagonist ICI 118,551 and labetalol, which blocks both alpha and beta adrenoceptors, did not alter the pressor effect of cocaine. Propranolol, atenolol, and labetalol all antagonized the tachycardiac effect of cocaine in a dose-dependent manner, while the beta-2 antagonist ICI 118,551 did not. Phentolamine, prazosin and yohimbine also reduced the tachycardiac effect of cocaine, although these effects were dose-dependent only for yohimbine, which also significantly elevated baseline heart rate. These results indicate that alpha-1 adrenoceptor mechanisms mediate the pressor effect of cocaine, while beta-1 adrenoceptor mechanisms are involved in the tachycardiac effect of cocaine in squirrel monkeys. Propranolol potentiated cocaine's pressor effect through beta-2 independent mechanisms. Thus, neither alpha-2 nor beta-2 adrenoceptor mechanisms appear to be involved in cocaine's cardiovascular effects.     

Effect of GABA-acting drugs diazepam and sodium valproate on thermoregulation in rats

Gamma-aminobutyric acid (GABA) is involved in the mechanism of action of many drugs affecting different functions in the central nervous system. The present study has investigated the effect of diazepam, a positive allosteric GABA_A receptor modulator, and sodium valproate, a GABA transaminase inhibitor, on thermoregulation in rats. The experiments were designed into two main parts: (1) in vivo experiments on body temperature of conscious rats; (2) in vitro experiments on temperature sensitivity (temperature coefficient, TC) of rat PO/AH neurons in slice preparations. Central (i.c.v.) or systemic (i.p.) administration of diazepam, as well as sodium valproate produced dose-dependent hypothermia in rats. Both GABAergic drugs diazepam and sodium valproate increased temperature sensitivity (TC) in warm-sensitive rat PO/AH neurons. These results are in agreement with the neuronal model of temperature regulation and confirm the involvement of GABAergic mechanisms in thermoregulation.     

Central action of low-molecular weight polyphloretin phosphate fraction in rats

The central effects of a low-molecular weight fraction of polyphloretin phosphate (PPP) with molecular weight about 4600 were studied using several behavioural tests in animals (Lat's test, open-field test, hold-board test, irritability, spontaneous motor activity), chlorpromazine-induced catalepsy test, body temperature measurements, hexobarbital-induced sleep duration, reaction to thermal painful stimulus, measurements of arterial blood pressure, heart rate and respiratory rate. The activity of prostaglandin synthetase was determined also in the microsomes of bovine hypothalamic cells in vitro. Using some of the above tests the effect of PPP was studied on the central action of prostaglandins F2 alpha and E2 (PGF2 alpha and PGE2). PPP was administered intraventricularly (i.c.v.) in various doses (doses producing the lowest pharmacological effect in a given test) 10 minutes before i.c.v. administration of these prostaglandins in doses of 1 or 10 microgram. It was shown that PPP (low-molecular weight fraction) injected into the lateral cerebral ventricle of the rat exerted a biological effect on the central nervous system manifesting itself as behaviour changes in the tests used, and as changes of the arterial blood pressure. PPP i.c.v. antagonized certain central effects of PGF2 alpha and PGE2. The degree of inhibition of various prostaglandins differed in relation to the test used and was somewhat stronger in the case of PGF2 alpha.     

Effects of nicardipine on the spontaneous beat of isolated atria of guinea pigs

Nicardipine was found to produce a concentration-dependent depression of the isometric contraction of the isolated, spontaneously beating atria of the guinea-pig. It also depressed the atrial rate of the isolated, spontaneously beating atria of the guinea-pig. The effect of the increasing concentrations of nicardipine on the heart rate was negligibly weaker than its effect on the isometric contraction. A time-dependent depression of the isometric contraction and the atrial rate after the addition of a single dose of nicardipine was also found up to the 10th min. Calcium almost completely, isoprenaline completely and aminophylline partially antagonized the depressive action of nicardipine on the isometric contractility of the atria. Only isoprenaline antagonized the negative chronotropic action of higher doses of nicardipine. It is possible that these substances restore the contractility by compensating the calcium balance, previously changed by nicardipine, or by producing an increase in the intracellular cAMP content (isoprenaline and aminophylline).     

Effects of dynorphin A(1-13) and of fragments of beta-endorphin on blood pressure and heart rate of anesthetized rats.

The effect on blood pressure and heart rate of central administration of dynorphin A(1-13) and of beta-, gamma-, and alpha-endorphin related peptides was studied in urethane-anesthetized rats. Intracerebroventricular (i.c.v., 0.1-10 micrograms) administration of beta-endorphin resulted in a dose-dependent, naltrexone-reversible hypotension and bradycardia. N-terminally modified fragments of beta-endorphin did not reduce blood pressure and heart rate. On the other hand, a dose of 10 micrograms of beta-endorphin(1-27), which lacks the four C-terminal amino acid residues of beta-endorphin, induced a fall in blood pressure and had a biphasic effect on heart rate. These responses, however, were resistant to pretreatment with naltrexone. None of the fragments of beta-endorphin smaller than beta-endorphin(1-27) affected blood pressure when administered i.c.v. in a dose of 10 micrograms. A small transient bradycardia was observed after i.c.v. administration of 10 micrograms of beta-endorphin(1-26), alpha, and gamma-endorphin. The naltrexone-reversible bradycardic response of alpha- and gamma-endorphin was not present in des-tyrosine- and des-enkephalin-alpha- and gamma-endorphin and also not in alpha-endorphin(10-16) and gamma-endorphin(10-17). Upon i.c.v. administration (0.1-50 micrograms) a dose-dependent, naltrexone-reversible decrease in blood pressure and heart rate was induced by dynorphin A(1-13). The present data indicate a hypotensive influence of beta-endorphin, beta-endorphin(1-27), and dynorphin A(1-13), whereas other fragments of beta-endorphin had little or no effect on the cardiovascular parameters investigated.     

Nature of alpha receptors implicated in the hypertensive effect of high doses of isoprenaline in dogs and rats

Isoproterenol injected intravenously in dogs (3 mg/kg-1) and rats (5 mg/kg-1) induced an increase in blood pressure. After alpha 1 blockade (by AR-C 239, 0.1 mg . kg-1 i.v.) or alpha 2 blockade (by yohimbine, 1 mg/kg-1 i.v.) isoproterenol, as adrenaline, again induced an increase in blood pressure. This hypertensive effect was suppressed by an alpha 2 adrenoceptor blocking agent after an alpha 1 adrenoceptor blocking agent, and vice versa. These results are compatible with stimulation by high doses of isoproterenol of both alpha 1 and alpha 2 adrenoceptors to produce increase in blood pressure.     

Attenuation of capsaicin-induced acute and visceral nociceptive pain by alpha- and beta-amyrin, a triterpene mixture isolated from Protium heptaphyllum resin in mice

The triterpene mixture, alpha- and beta-amyrin, isolated from Protium heptaphyllum resin was evaluated on capsaicin-evoked nociception in mice. Orally administered alpha- and beta-amyrin (3 to 100 mg/kg) significantly suppressed the nociceptive behaviors--evoked by either subplantar (1.6 microg) or intracolonic (149 microg) application of capsaicin. The antinociception produced by alpha- and beta-amyrin against subplantar capsaicin-induced paw-licking behavior was neither potentiated nor attenuated by ruthenium red (1.5 mg/kg, s.c.), a non-specific antagonist of vanilloid receptor (TRPV1), but was greatly abolished in animals pretreated with naloxone (2 mg/kg, s.c.), suggesting an opioid mechanism. However, participation of alpha2-adrenoceptor involvement was unlikely since yohimbine (2 mg/kg, i.p.) pretreatment failed to block the antinociceptive effect of alpha- and beta-amyrin in the experimental model of visceral nociception evoked by intracolonic capsaicin. The triterpene mixture (3 to 30 mg/kg, p.o.) neither altered significantly the pentobarbital sleeping time, nor impaired the ambulation or motor coordination in open-field and rota-rod tests, respectively, indicating the absence of sedative or motor abnormality that could account for its antinociception. Nevertheless, alpha- and beta-amyrin could significantly block the capsaicin (10 mg/kg, s.c.)-induced hyperthermic response but not the initial hypothermia. These results suggest that the triterpene mixture, alpha- and beta-amyrin has an analgesia inducing effect, possibly involving vanilloid receptor (TRPV1) and an opioid mechanism.     

The effects of ouabain in the medullary site of the hypotensive action of clonidine

Blood pressure was studied in pentobarbital anesthetized rats and cats after central administration of ouabain. Intracerebroventricular (i.c.v.) injections caused a classical biphasic effect, a short lasting hypotension followed by a hypertensive phase. When injected directly into the nucleus reticularis lateralis region (NRL), ouabain (0.01–2 μg/kg) caused a dose-dependent pressor effect. In the same region, kryptofix 221, a sodium complexing agent, produced a fall in blood pressure. Moreover, central administration of ouabain prevented the hypotensive effect of i.v. clonidence whereas the central hypotensive effect of muscimol was not affected. It is concluded that sodium movements play an important role in the blood pressure regulation within the NRL region. We also report here that ouabain antagonizes the hypotensive effect of clonidine suggesting that sodium movement might be the essential link of this action.     

The effects of artificial analogue peptide TSKY isolated from the brain of hibernating ground squirrels in rats and mice

Elevation of the i.c.v. injection dose of TSKY from 4 to 8 microg increased the movement activity of rats; in EEG theta- and beta-rhythms were enhanced and alpha-rhythm was suppressed. On the contrary, after treatment of 15 microg the rats fell into sleepy-like state; theta- and beta2-rhythms suppression, delta-, alpha- and beta1-rhythms were increased. Exposure under hypoxia-hypercapnia conditions reduced body temperature of mice to 18-19 degrees C, and maintain this state about 3-4 h after transferring into conventional gas medium. Preliminary cooling mice were administrated with TSKY that at dose 100 microg intraperitonally induced a prolonged hypothermia up to 12 h. Analogous injection without cooling raised mice temperature by 1.2 degrees C during about 2 h.