Depressor effects of muscarinic and non-muscarinic mediation induced by lateral hypothalamic stimulation in the cat

Transient sympathetically-mediated depressor effects were induced by stimulation of a small locus in the lateral hypothalamic peri-fornical region, medial to the fields of Forel. The ganglionic blocking agent, atropine methyl nitrate (ATMN), was used to show that muscarinic as well as non-muscarinic sympathetic ganglion receptor neurotransmission was involved. Evidence is presented that stimulation of this LH site co-activates a number of mechanisms and that depending on which of these are activated, the ganglionic blocking agent ATMN may either block, reverse or potentiate the depressor effect.     

Sympatho-inhibitory mechanisms acting at sympathetic ganglia to attenuate hypothalamic-induced pressor effect in the cat

Summary Pressor and tachycardic effects induced in the cat by stimulation of a lateral hypothalamic (LH) site, are shown to be mediated by sympathetic ganglia nicotinic receptor, and potentiated under atropine methyl nitrate sympathetic ganglia blockage. It is postulated that a sympatho-inhibitory pathway muscarinic ganglionic mechanism, co-activated by the LH stimulation, attenuates the pressor and tachycardic effects, the potentiation presumably being a manifestation of blockage of that mechanism.     

Long-term depressor effects of noradrenaline and dopamine neurons transplanted into the third ventricle of the brain of salt-loaded hypertensive rats

Summary Neural tissues including A 6 group noradrenaline neurons in the locus ceruleus or A 10 group dopamine neurons in the substantia nigra were transplanted into the third ventricle at the preoptic-anterior hypothalamic level of rats made hypertensive by salt loading. Either transplant exerted a long-lasting depressor effect.     

Histamine receptors in the cat mesenteric circulation.

The distribution of histamine receptors was studied in the isolated perfused vascular bed of the cat terminal ileum. The results indicated that the depressor effect of histamine is mediated through the stimulation of metiamide-sensitive H2-receptors, while the pressor effect of the amine is mediated by the stimulation of mepyramine-sensitive H1-receptors.     

Über einige pharmakologische Untersuchungen synthetischer Alkoxy-tropinderivate

Summary Some pharmacological properties of new synthetic alkoxy-tropine derivatives are reported. The tertiary compounds were relatively potent local anaesthetics with a low anti-cholinergic action. Acetylcholine inhibition, as well as the spasmolytic activityin vivo of the benzilic acid esters were markedly increased by quaternisation while their toxicity decreased. 6-Methoxytropine benzilic acid ester brom-methylate was the most active compound of this series. A pronounced inhibitory activity on neurogenically induced intestinal constriction was found in low doses, whereas larger doses exerted a ganglionic blocking effect.     

Central IL-1 differentially regulates peripheral IL-6 and TNF synthesis

Centrally given interleukin (IL)-1 is known to induce a rapid rises in blood IL-6. To extend this and to examine the mechanism by which this occurs, the effects of intracerebroventricular (icv) injection of human recombinant IL-1β on mRNA expression of IL-6 and tumour necrosis factor (TNF) in the spleen and liver were examined in rats. Icv injection of IL-1 produced a rapid rise of the tissue mRNA levels of IL-6 and TNF in both organs, prior to and/or in parallel with an increase in their serum levels. Pretreatment with chlorisondamine, a ganglionic blocking agent, inhibited the IL-6 responses, while it had little influence on the TNF responses. The results suggest that brain IL-1 induces peripheral production of IL-6, but not of TNF, through autonomic nervous system activation. Received 27 October 1997; received after revision 15 December 1997; accepted 12 January 1998     

Sympatho-inhibitory mechanisms acting at sympathetic ganglia to attenuate hypothalamic-induced pressor effect in the cat

Pressor and tachycardic effects induced in the cat by stimulation of a lateral hypothalamic (LH) site, are shown to be mediated by sympathetic ganglia nicotinic receptor, and potentiated under atropine methyl nitrate sympathetic ganglia blockage. It is postulated that a sympatho-inhibitory pathway muscarinic ganglionic mechanism, co-activated by the LH stimulation, attenuates the pressor and tachycardic effects, the potentiation presumably being a manifestation of blockage of that mechanism.     

The effect of L-dopa on pupillary diameter in mice

Summary Injection of L-dopa in mice produces dose-dependent mydriasis. Pre-treatment with peripheral dopa-decarboxylase inhibitors (carbidopa and benserazide) or with an alpha-adrenergic blocking agent (phentolamine) abolishes the pupillary dilation caused by L-dopa. Pretreatment with fusaric acid, an inhibitor of dopamine-beta-hydroxylase, also antagonizes the mydriatic effect of L-dopa. Thus, our results suggest that the mydriasis produced in mice following the injection of L-dopa is caused by its peripheral conversion to noradrenaline, which stimulates alpha-adrenergic receptors in the dilator iridis. There was no evidence that stimulation of specific dopaminergic receptors was involved.We are grateful to N. Rothschild, Head of Laboratory Animal Department, Sackler School of Medicine, for his help.     

Pharmakologische Charakteriserung von synthetischem Hypertensin

Summary Synthetic hypertensin, RH II, a Val₅octapeptide shows the same pattern of activity as natural hypertensin (angiotonin). In the normal rat, and in the rat pretreated with ganglionic blocking substances, the hypertensive activity corresponds to that of nor-adrenaline while it is enhanced in the nephrectomised animal. In the intact animal, hydralazine diminishes the hypertensive effect, while Regitin, Chlorpromazine and Reserpine are without effect. On the perfused vessels of the rabbit's hind limb, RH II produces a vasoconstriction which is diminished by Chlorpromazine and hydralazine, but not by Regitin. RH II is not destroyed by heating, but by freshly prepared kidney extract.     

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.     

Histamine receptors in the cat mesenteric circulation

Summary The distribution of histamine receptors was studied in the isolated perfused vascular bed of the cat terminal ileum. The results indicated that the depressor effect of histamine is mediated through the stimulation of metiamidesensitive H₂-receptors, while the pressor effect of the amine is mediated by the stimulation of mepyramine-sensitive H₁-receptors.The authors are indebted to Dr.W. A. M. Duncan, Research Institute, Smith Kline and French Laboratories, Welwyn Garden City, Hertfordshire, England, for his generous gift of metiamide. This work is supported in part by Eczacibasi Research Found. Levent, Istanbul, Turkey.     

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.     

Frequency-dependent effect of verapamil on rat soleus muscle

Summary In the presence of verapamil (0.1 mM) rat soleus muscle fibers failed to generate action potentials with overshoots. In fibers with their V_m set to a local level of –90 mV, verapamil produces a gradual reduction in the amplitude of the repetitive action potentials; this effect is more pronounced at high rates of stimulation (100 Hz). Our results suggest a local anesthetic action of this drug that could contribute with its calcium channel blocking effect to the diminished mechanical tension observed in the presence of the drug.Acknowledgments. We thank A. Losavio and M. Stefanolo for technical assistance. This work was supported by grants from CONICET and SUBCYT, Buenos Aires, Argentina and Muscular Dystrophy Association, USA.     

The effects of dopaminergic blocking agents on the glucose tolerance test in 6 humans and 6 dogs.

Pre-treatment with low doses of sulpiride, an atypical dopaminergic blocking agent, but not haloperidol, a classical dopaminergic blocking agent, decreased tolerance to glucose and increased blood serotonin levels in 6 normal humans and 6 normal dogs investigated.     

The principal toxin of Delphinium brownii Rydb., and its mode of action.

Examination of D. brownii, a stock-poison of Western Canada, revealed that the principal toxin was methyllycaconitine: a potent neuromuscular blocking agent which appears to act competitively at nicotinic receptors.     

Enhanced depressor reflex by stimulation of superior cervical ganglion and by propranolol

Summary The systemic depressor reflex in cats evoked by inflation of an intrasinusal balloon is enhanced by stimulation of the superior cervical ganglion and by close infusion of 20g/ml/min of (d, 1) propranolol.This work was supported by grant No. 22600-1 NIH, Heart, Lung and Blood Institute, Bethesda, MD.     

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.     

Hymenin, a novel alpha-adrenoreceptor blocking agent from the Okinawan marine sponge Hymeniacidon sp

A novel bromine-containing alkaloid, hymenin, has been isolated from the Okinawan marine sponge Hymeniacidon sp. as a potent alpha-adrenoceptor blocking agent and its structure determined to be 1 on the basis of the spectral data.     

Struktur und Wirkung des Muscarins,des Muscarons und ihrer Stereoisomeren

Summary All synthetic isomers of (+)-muscarine, the racemic forms of epi-muscarine, allo-muscarine, and epiallo-muscarine are at least 100 times less potent on blood pressure of cats and isolated frog hearts than the natural alkaloid. Only muscarones are more potent and exhibit strong nicotinic action on the frog rectus and in blocking ganglionic and neuro-muscular transmission in the cat. They closely resemble acetylcholine in their structure and action.The activity of the isomers depends on the position of the constituents on the tetrahydrofurane ring. Steric hindrance of the hydroxy or carbonylgroup and of etheroxygen plays an important part in the contact with the cholinergic receptor. As nor-muscarine without the quarternary nitrogen is inactive, at least 3 different points of contact have to be considered. This is stressed by the fact that muscarine is highly stereospecific in its action, whereas muscarone is not.     

The principal toxin ofDelphinium brownii Rydb., and its mode of action

Summary Examination ofD. brownii, a stock-poison of Western Canada, revealed that the principal toxin was methyllycaconitine: a potent neuromuscular blocking agent which appears to act competitively at nicotinic receptors.We thank the University of Calgary, The National Research Council of Canada, and the Alberta Agriculture Department, for financial assistance.