Pharmacologic study of several alpha-adrenolytics

Six alpha-adrenoceptor blocking agents have been investigated in dogs and rats. 170 150 and 170 153 have been found the most potent of these agents. At low doses (0,1 microgram/kg) they reversed the pressor response to low doses of adrenaline (0,1 and 0,3 microgram/kg) and suppressed the response to high doses of adrenaline. They reduced the pressor response to noradrenaline. In addition, in dogs 170 150 increased the tachycardia caused by stimulation of the cardiac nerve. The compound prevented and reversed the inhibition caused by clonidine on the effects of cardiac nerve stimulation. 170 153 did not increase the tachycardia caused by cardiac nerve stimulation, but it prevented and reversed the inhibitory effects of clonidine on this stimulation. The results show that 170 150 and 170 153 are potent alpha-adrenoceptor blocking agents acting on both pre and post-synaptic alpha-adrenoceptors which could be interesting pharmacological tools.     

Action of N-butylnorsympathone on the effects of cardioaccelerator nerve stimulation in the dog]

In Dogs anaesthetized with pentobarbital (30 mg . kg-1), N-butylnorsympathone (20 mg . kg-1 i.v.) reduced the bradycardia induced by stimulating the cardiac nerve (1, 2, 5, 10 Hz). Phentolamine (1 mg . kg-1 i.v.) or yohimbine (0.3 mg . kg-1 i.v.), two potent alpha-adrenoceptor blocking agents known to block presynaptic alpha-adrenoceptor induced a recovery of the effect of cardiac nerve stimulation. Prazosine (0.050 mg . kg-1 i.v.) an alpha-adrenoceptor blocking agent known to be ineffective on presynaptic alpha-adrenoceptors did not induce a recovery. However neither phentolamine or yohimbine were able to prevent the effects of N-butylnorsympathone. Neither haloperidol (0.050 to 2 mg . kg-1 i.v.) or pimozide (0.20 to 1 mg . kg-1 i.v.) induced a recovery or prevented the effects of N-butylnorsympathone. These results suggest that N-butylnorsympathone may stimulate presynaptic receptors which do not resemble classical presynaptic alpha-adrenoceptors or dopamine receptors.     

Influence of clonidine on experimental hypertension induced by cholinergic stimulation

Summary Hypertension may be induced by pharmacologic activation of central cholinergic receptors either indirectly, through the injection i.v. of physostigmine, or directly, through the injection i.v. of arecholine in anesthetized rats. Activation of peripheral preganglionic cholinergic receptors with dimethylphenylpiperazinium iodide (DMPP) also produced a hypertensive response. Pretreatment with various doses of clonidine caused inhibition of the pressor response to central cholinergic stimulation but was without effect on the response to ganglionic cholinergic stimulation.     

Zur peripheren sympathikushemmenden Wirkung des Clonidins

Summary The influences of clonidine, tetracaine and procaine on the effects of electrical stimulation of the postganglionic sympathetic cardiac nerves have been compared in the isolated perfused rabbit heart. Much lower concentrations of clonidine than of tetracaine were necessary to antagonize the output of noradrenaline and the rise of frequency and contractility. Procaine even in the highest concentration tested did not inhibit the effects of nerve stimulation. In addition to its known central depression of sympathetic tone, clonidine exerts a specific inhibitory action on postganglionic sympathetic neurons.     

Oxytocin antagonism of hypothalamic-induced angina-like ECG changes and pressor effects in the cat

Electrical stimulation of a specific site in the lateral hypothalamus of the cat, in a region posterior to Hess' defense area, results in pressor effects and angina-like ECG changes which consist either of T-wave inversion and ST-segment prolongation or in the appearance of tall T-waves. Oxytocin (10 U, i.v.) administered 15 min prior to stimulation, prevents the former ECG changes and BP rise in 90%, and the latter ECG changes and BP rise in 50% of the animals.     

Influence of flupirtine, a novel nonopioid analgesic agent on somatosensory evoked potentials in rats.

The effect of flupirtine, a novel nonopioid analgesic, on somatosensory evoked potentials (SEP) was investigated in anesthetized rats. Primary somatosensory potentials were evoked in the cerebral cortex by stimulation of the skin of the whiskery part of the face. Flupirtine injected i.p. dose-dependently prolonged the latency and reduced the amplitude of SEP with ID50-values of 5.4 mg/kg (2.6-9.3 mg/kg) and 7.9 mg/kg (3.9-13.8 mg/kg), respectively. This effect of flupirtine (10 mg/kg, i.p.) on the latency and the amplitude of SEP, did not change when naloxone (1 mg/kg, i.p.) was given before flupirtine. The results indicate that the analgesic flupirtine decreases the primary somatosensory evoked potential by diminishing the excitability of cortical neurons. Opioid mechanisms are not involved.     

Stimulierung der Atmung durch Bradykinin und Kallidin

Summary In guinea pigs and rabbits small doses of bradykinin and kallidin (1–8 µg/kg i.v.), which have no bronchoconstrictor effect, stimulate respiration causing tachy- and hyperpnea. Bilateral vagotomy as well as salicylates (4–40 mg/kg i.v.) abolish these respiratory responses.     

Influence of flupirtine,a novel nonopioid analgesic agent on somatosensory evoked potentials in rats

The effect of flupirtine, a novel nonopioid analgesic, on somatosensory evoked potentials (SEP) was investigated in anesthetized rats. Primary somatosensory potentials were evoked in the cerebral cortex by stimulation of the skin of the whiskery part of the face. Flupirtine injected i.p. dose-dependently prolonged the latency and reduced the amplitude of SEP with ID₅₀-values of 5.4 mg/kg (2.6–9.3 mg/kg) and 7.9 mg/kg (3.9–13.8 mg/kg), respectively. This effect of flupirtine (10 mg/kg, i.p.) on the latency and the amplitude of SEP, did not change when naloxone (1 mg/kg, i.p.) was given before flupirtine. The results indicate that the analgesic flupirtine decreases the primary somatosensory evoked potential by diminishing the excitability of cortical neurons. Opioid mechanisms are not involved.     

Zur Blutdruckwirkung von Aludrin und Adrenalin

Summary The depressor action of small doses of adrenaline on the blood pressure (B.P.) of the decapitated cat may be abolished by pretreatment with pilocarpine; atropine restores the original depressor action. The fall in B.P. due to adrenaline after ergotamine once more becomes an increase when pilocarpine has been given earlier. After atropine a fall in B.P. again occurs. This effect of pilocarpine and atropine on a depressor response has already been described in the case of Aludrine (N-isopropyl-noradrenaline) byFromherz.     

Failure of (+)-naloxone to accelerate feline colonic transit

Summary To determine whether the colonic transit accelerating effect of (–)-naloxone (0.3 mg/kg, i.m.) is due to an action at opioid receptors or a direct pharmacologic effect, its enantiomer, (+)-naloxone (0.3 mg/kg, i.m.) was administered to cats and compared to saline control using colonic transit scintigraphy. Transit was not accelerated by (+)-naloxone. The effects of naloxone on colonic transit are thus stereospecific, and are probably mediated by opioid receptors.     

The COMT inhibitor tolcapone potentiates the anticataleptic effect of Madopar in MPP+-lesioned mice

Orally administered Madopar (levodopa/benserazide 41) dose-dependently antagonized haloperidol-induced (1 mg/kg s.c.) catalepsy in MPP⁺-lesioned mice. Pretreatment with a new selective catechol-O-methyltransferase (COMT) inhibitor, tolcapone (30 mg/kg p.o.), slightly potentiated the antagonistic effect of Madopar (15 mg/kg p.o.) on haloperidol-induced catalepsy. The ability of tolcapone to increase the Madopar effect was significantly attenuated by high doses of 3-O-methyldopa (3-OMD) (800 mg/kg i.p.). This might suggest a competitive blockade of the active transport of levodopa through the blood-brain barrier. In conclusion, the inhibitory effect of tolcapone on the O-methylation of levodopa to 3-OMD by COMT is largely due to improved levodopa and dopamine availability in the brain, and to the reduced formation of 3-OMD.     

Failure of (+)-naloxone to accelerate feline colonic transit

To determine whether the colonic transit accelerating effect of (-)-naloxone (0.3 mg/kg, i.m.) is due to an action at opioid receptors or a direct pharmacologic effect, its enantiomer, (+)-naloxone (0.3 mg/kg, i.m.), was administered to cats and compared to saline control using colonic transit scintigraphy. Transit was not accelerated by (+)-naloxone. The effects of naloxone on colonic transit are thus stereospecific, and are probably mediated by opioid receptors.     

Piroxicam-induced analgesia: Evidence for a central component which is not opioid mediated

Piroxicam is a nonsteroidal anti-inflammatory drug with a potent analgesic effect. In order to establish whether the analgesic action of Piroxicam has a central component, we studied the effect of the drug on the nociceptive orbicularis oculi reflexes evoked by electrical stimulation of the cornea and supraorbital nerve in healthy subjects. Piroxicam significantly suppressed the corneal reflex and R3 component of the blink reflex by 28% (p<0.05) and 50% (p<0.01), respectively. This effect was not reversed by the i.v. injection of naloxone. Beta-endorphin levels did not change. Piroxicam administration induces distinct inhibitory changes in nociceptive reflexes, which suggests that the analgesic action of the drug has a central component. The ineffectiveness of naloxone, and the lack of beta-endorphin changes, indicate that this central action is independent of the opioid system; other pain regulatory systems are probably involved.     

Chemical sympathectomy reveals pre-and postsynaptic effects of neuropeptide Y (NPY) in the cardiovascular system

Summary Intravenous injection of neuropeptide Y (NPY) caused short-lasting dose-dependent pressor responses in anesthetized rats. NPY was equipotent with noradrenaline in producing proportional pressor effects. Chemical sympathectomy, following the administration of 100 mg/kg 6-hydroxydopamine (6-OHDA), significantly potentiated the systemic pressor effects elicited by NPY or noradrenaline. Pretreatment with 2 nmol NPY enhanced the noradrenaline-induced pressor response in control rats. NPY did not change the basal tension of isolated rat aortic strips but significantly potentiated the contractile activity induced by 16 nM noradrenaline. This effect of NPY was not observed in aortic strips from rats pretreated with 6-OHDA. The presence of pre-and postsynaptic sites of action for NPY in the cardiovascular system of the rat is discussed.     

Piroxicam-induced analgesia: evidence for a central component which is not opioid mediated.

Piroxicam is a nonsteroidal anti-inflammatory drug with a potent analgesic effect. In order to establish whether the analgesic action of Piroxicam has a central component, we studied the effect of the drug on the nociceptive orbicularis oculi reflexes evoked by electrical stimulation of the cornea and supraorbital nerve in healthy subjects. Piroxicam significantly suppressed the corneal reflex and R3 component of the blink reflex by 28% (p < 0.05) and 50% (p < 0.01), respectively. This effect was not reversed by the i.v. injection of naloxone. Beta-endorphin levels did not change. Piroxicam administration induces distinct inhibitory changes in nociceptive reflexes, which suggests that the analgesic action of the drug has a central component. The ineffectiveness of naloxone, and the lack of beta-endorphin changes, indicate that this central action is independent of the opioid system; other pain regulatory systems are probably involved.     

Chemical sympathectomy reveals pre- and postsynaptic effects of neuropeptide Y (NPY) in the cardiovascular system

Intravenous injection of neuropeptide Y (NPY) caused short-lasting dose-dependent pressor responses in anesthetized rats. NPY was equipotent with noradrenaline in producing proportional pressor effects. Chemical sympathectomy, following the administration of 100 mg/kg 6-hydroxydopamine (6-OHDA), significantly potentiated the systemic pressor effects elicited by NPY or noradrenaline. Pretreatment with 2 nmol NPY enhanced the noradrenaline-induced pressor response in control rats. NPY did not change the basal tension of isolated rat aortic strips but significantly potentiated the contractile activity induced by 16 nM noradrenaline. This effect of NPY was not observed in aortic strips from rats pretreated with 6-OHDA. The presence of pre- and postsynaptic sites of action for NPY in the cardiovascular system of the rat is discussed.     

Synergism between long-acting bromocryptine microcapsules and cyclosporine A in the prevention of various autoimmune diseases in rats

Pre-treatment of male Sprague-Dawley rats with long-acting bromocryptine microcapsules (CBLA) significantly inhibited the arthritic response to Freund's complete adjuvant and reduced weight loss, thymolysis, splenomegaly and leukocytosis. In the prevention of adjuvant arthritis (AA), the combination of CBLA plus sub-optimal doses of cyclosporine A (CsA) was more efficient than either of the drugs alone. Sub-optimal doses of CsA were 0.1 and 1.0 mg/kg/day s.c. for 5 days. Furthermore, CBLA alone did not decrease the incidence of experimental allergic uveitis (EAU) in the male Lewis rats. Low-dose CsA reduced the incidence of uveitis by 50%, and with the addition of CBLA, 100% of rats were protected. Low-dose CsA was 2 mg/kg/day i.m. for 14 days. Long-term treatment of male Sprague-Dawley rats with CBLA alone reduced the incidence and severity of spontaneous autoimmune periateritis nodosa (PN) in a dose-dependent manner; CsA was less potent than CBLA, and only additive effects were obtained. Finally, for the prevention of spontaneous autoimmune insulin-dependent diabetes (DM), the administration of CBLA did not improve the effect of a low-dose CsA in male BB rats. Nevertheless, a delay in onset of DM could be achieved. A sequential therapy using CsA plus CBLA clearly showed beneficial effects. The dose of CsA was 10 mg/kg p.o. 6 days/week for 21 weeks. Compared with Sprague-Dawley or Lewis male rats, BB male rats showed only weak prolactin suppression after the same doses of CBLA. It is suggested that the use of CBLA may be particularly beneficial in autoimmune disorders. The effectiveness of the combination therapy CBLA plus CsA, however, was dependent on the model considered. Various factors could play a role: (1) the different ways of administering CsA (s.c. in AA, i.m. in EAU and PN, oral in DM); (2) strain-dependency in the capacity of CBLA to suppress Prl secretion; and(3) at least in the BB rats, the transient increase of CsA bioavailibility which was possibly induced by CBLA.     

Lack of pyrogenic tolerance transmission between brain and periphery in the rabbit

Summary Successive injections of lipopolysaccharide (LPS) either intravenously (i.v.) or intracerebroventricularly (i.c.v.) induced pyrogenic tolerance to LPS in rabbits. Tolerance was shown by a decrease of the magnitude of the fever response to repeated doses of LPS, irrespective of the route of pyrogen administration. A significantly greater and more dramatic decrease of the fever index, however, was observed in rabbits made tolerant to pyrogen given i.v. than when the pyrogen was given i.c.v. Transmission of the pyrogenic toleraance between brain and peripheral tissues, however, has not been ascertained.     

Lack of pyrogenic tolerance transmission between brain and periphery in the rabbit

Successive injections of lipopolysaccharide (LPS) either intravenously (i.v.) or intracerebroventricularly (i.c.v.) induced pyrogenic tolerance to LPS in rabbits. Tolerance was shown by a decrease of the magnitude of the fever response to repeated doses of LPS, irrespective of the route of pyrogen administration. A significantly greater and more dramatic decrease of the fever index, however, was observed in rabbits made tolerant to pyrogen given i.v. than when the pyrogen was given i.c.v. Transmission of the pyrogenic tolerance between brain and peripheral tissues, however, has not been ascertained.     

Areas in the amygdala necessary to the operation of the vagosympathetic pressor reflex.

Lesions of portions of the basal and cortical amygdaloid nuclei and the stria terminalis reversed or abolished arterial pressor responses to ipsilateral centripetal vagal stimulation (CVS). Destruction of these particular limbic structures in the rat did not affect cardiopulmonary responses to CVS.