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Pharmacological control of local oxygen regulation mechanisms in brain tissue.

The effect of several agents active on autonomic nervous system functions was tested on brain oxygen autoregulation parameters. It was found that atropine, propranolol and isoproterenol had no influence in abolishing the measured parameters. Phenoxybenzamine, tolazoline and dibenamine all suppress autoregulation. In an additional experimental series, a phenoxybenzamine infusion was given during O2 breathing. The infusion induced, in most cases, an additional rise in TpO2 (tissue pressure of oxygen, which refers to the partial pressure [in mm Hg] of this gas at the measuring tip of the electrode). It is concluded that an alpha-adrenergic mechanism is part of the autoregulation process. Also, the increase in brain TpO2 induced by 59% O2-5% Co2 breathing seems to be blocked or reversed by alpha-adrenolytic drugs, thus supporting the thinking that the effect of CO2 on cerebral blood flow is at least in part mediated through an alpha-adrenergic response.

Animals↗

Propantheline bromide in the management of hyperhidrosis associated with spinal cord injury.

OBJECTIVE: To report 2 cases in which oral propantheline reduced the discomfort associated with sweating related to spinal cord injury (SCI), and to review the literature on the management of SCI-related sweating. CASE SUMMARIES: Case 1: A 27-year-old quadriplegic man with an American Spinal Injury Association (ASIA) Frankel class C injury to C5/C6 experienced profuse sweating and requested propantheline. He stated that he had received the medication previously and reported that propantheline 15 mg tid had controlled his sweating. Propantheline bromide was reinstituted, and within 24 hours, the patient's episodes of profuse sweating had decreased markedly in number and frequency. Case 2: A 35-year-old quadriplegic woman had an ASIA class D lesion at C3. Since her injury, she had experienced profuse sweating that worsened when she became cold and at night. She stated that her sweating was under control as long as she took propantheline. Propantheline therapy was continued and no further sweating episodes have occurred. DATA SOURCE: A MEDLINE search was used to identify pertinent literature including reviews. Standard texts and texts referenced in the pertinent literature also were examined. STUDY SELECTION: All available sources of information were reviewed. DATA SYNTHESIS: The earliest case reports of systemic therapy for hyperhidrosis described the use of the anticholinergic methantheline bromide. Methantheline in combination with ergoloid mesylates also was suggested for the treatment of congenital hyperhidrosis. Local topical therapy for hyperhidrosis, such as aluminum chlorohydrate and aluminum chloride, the active ingredients in some antiperspirants, have been tried with some success. Talc, starch, and other powders have been suggested to absorb excessive sweat. Formalin and glutaraldehyde also have been used. Topical propantheline bromide has been used successfully in treating palmar and plantar hidrosis. Clonazepam has been used successfully in a case of unilateral localized hyperhidrosis. Systemic phenoxybenzamine has been used with some success and there have been attempt at other systemic therapy using mecamylamine, atropine, propoxyphenel, and methenamine. Scopolamine patches also have been used successfully in a small number of patients. Other agents that have been used include dibenamine, piperoxan, and phentolamine. Systemic propantheline also has been listed as an agent with potential efficacy in treating the profuse sweating associated with SCI, but was not recommended primarily because of adverse effects and difficulty in titrating to the lowest effective dosage. However, studies or case reports specific to the use of propantheline in patients with SCI appear to be lacking, as are reports of direct comparison between propantheline and other agents. DISCUSSION: Concerning the mechanism of action of propantheline bromide for hyperhidrosis, it seems reasonable to attribute its effects to the drug's well-documented anticholinergic/antimuscarinic actions. At dosages used to effectively treat neurogenic bladder, propantheline bromide also should block the muscarinic receptors responsible for sweat gland stimulation. Central nervous system adverse effects should be minimal at usual clinical dosages, as propantheline does not cross the blood-brain barrier. CONCLUSIONS: It would appear that in some patients with SCI who are subject to incidental episodes of profuse sweating, oral propantheline may offer some relief and may, in fact, be well tolerated, as in the cases described. Additionally, propantheline would seem a good therapeutic choice in SCI patients with excessive sweating and neurogenic bladder dysfunction who may derive dual benefit from the agent.

Adult↗

A difference in pharmacological properties of histamine receptors in rabbit aorta and basilar artery.

An interaction of Ca entry blockers, D600 and diltiazem, with histamine receptors was tested in rabbit aorta and basilar artery. D600 caused a parallel rightward shift of the concentration response curve for histamine. The slope values from Schild plot analysis in aorta were not different from unity. Dibenamine pretreatment caused reduction of maximum response to histamine in aorta. Such reduction was diminished markedly by the presence of D600 or chlorpheniramine in aorta but not in basilar artery. However, diltiazem did not influence the concentration response curve for histamine. These findings suggest that pharmacological property of histamine receptors in rabbit aorta is distinct from that in basilar artery. Furthermore diltiazem seems not to interact with histamine receptors in both vascular tissues.

Animals↗

Propranolol blocks cocaine-induced potentiation of the contraction in the smooth muscle of the rat vas deferens.

In the smooth muscle of the rat vas deferens, 10(-5) M cocaine shifted the dose-response curve to norepinephrine to the left and enhanced the maximal contractions to norepinephrine and methacholine. Propranolol at 10(-4) M almost completely blocked these potentiating effects of cocaine. Sotalol or lidocaine at 10(-4) M did not block the potentiating action of cocaine. The cocaine-induced enhancement of the methacholine contraction and its blockade by propranolol was observed in the dibenamine-treated vas deferens. Propranolol also blocked the depolarization-induced enhancement of the methacholine contraction. Together with the previous study demonstrating the calcium-antagonist action for propranolol, these results suggest that propranolol blocks the cocaine-induced enhancement by inhibiting the calcium influx through the potential-dependent calcium channel in the rat vas deferens.

Animals↗

Effects of mazindol on the contractions in the rat vas deferens.

Effects of mazindol on the contraction induced by nerve stimulation and agonist drugs were investigated to examine the inhibition of catecholamine uptake by mazindol in the vas deferens. Mazindol at 10(-9)-10(-7) M potentiated a single electrical pulse-elicited neurogenic contraction which consisted of a twitch and phasic contraction. This potentiation was almost completely antagonized by prazosin. Mazindol leftwardly shifted the dose-response curve to norepinephrine in a dose-dependent manner; the dose-ratio was 6.2-fold and 83.2-fold at 10(-9) M and 10(-7) M mazindol, respectively. The dose-response curves to dopamine and methacholine were also slightly shifted by mazindol. In the dibenamine-treated vas deferens, mazindol did not affect the dose-response curve to methacholine. These results suggest that mazindol potently inhibits the norepinephrine uptake without acting on the smooth muscle cells in the rat vas deferens.

Animals↗

Purification of histamine receptor. (IV) Specificity of binding of various drugs to the histamine receptor-rich fraction and to solubilized binding sites.

Studies were made on tritiated histamine binding to the receptor-rich membrane fraction and solubilized sites and its displacement by various drugs. H1-Agonists and antagonists displaced histamine most effectively. A H2-agonist and atropine were less effective and propranolol, phentolamine and imidazole acetic acid had little effect. The solubilized binding sites showed the same specificity of binding as the membrane fraction. Membrane fragments had two binding constants, whereas solubilized sites had only one. Solubilized sites bound similar amounts of histamine and dibenamine: the latter was applied to intact tissue under conditions which would presumably cause specific binding to histamine receptors. These binding characteristics show that the method used was adequate for purification of histamine receptors from smooth muscle of cat small intestine.

Animals↗

A bradykinin-like substance in rat stomach.

A bradykinin (BK)-like substance (P1) in the rat stomach was extracted with acetic acid, n-butanol, distilled water and methanol. The gradient and equilibrium chromatography were carried out on SP-Sephadex C-25 columns with the extract containing P1. P1 had a different retention time from BK, kallidin and methionyl-lysyl-bradykinin (MLBK), on the equilibrium chromatography. The apparent molecular weight of P1 estimated by gel chromatography was over 1,300. P1 was classified as a biologically BK-like peptide of mammalian origin which is distinct from BK, kallidin and MLBK. Another kind of biologically active substance (P2) which contracts the isolated rat uterus and duodenum was detected during the course of the extraction and purification of P1. The contractile activity of P2 was abolished by the presence of dibenamine or methysergide, but was not influenced by chymotrypsin, trypsin or papain digestion. The hypotensive effect of P2 on rabbit blood pressure was similar to that of serotonin (5-HT). The retention times of P2 on the equilibrium chromatography on the SP-Sephadex C-25 column, and on the gel chromatography were the same as those of 5-HT. P2 proved to be 5-HT.

Animals↗

Actions of desoxynupharidine hydrochloride in the central nervous system of experimental animals (I).

The effects of desoxynupharidine hydrochloride (DN) as the extractive component of the Nuphar japonicum DC on the central nervous system were studied. In the acute cats, DN (1-3 mg/kg, i.v.) produced 8-10 Hz waves in the hypothalamus lateralis and amygdala, and the hippocampal arousal wave gave way to the irregular high amplitude slow waves. In the midbrain reticular formation, nucl. reticularis and cortex, 12-13 Hz waves and high amplitude slow waves increased. A sleep-like pattern with spindle burst-like waves formed the general pattern of all EEGs. These spontaneous EEG activities were significantly inhibited by epinephrine hydrochloride and were potentiated by tolazoline hydrochloride and dibenamine hydrochloride etc. The above EEG changes were obtained even in the spinal cats. DN depressed the EEG arousal response produced by high frequency stimulation of the sciatic nerve and increased the threshold of stimulation. In the chronic cats, DN (1 mg/kg, i.v.) produced spindle burst-like waves of 12-14 Hz in the cortex and sedation concomitantly. These findings suggest that DN has an inhibitory effect on the central nervous system and that adrenergic neurons are probably involved.

Alkaloids↗

Studies on chemotherapy of parasitic helminths (VI) effects of various neuropharmacological agents on the motility of Dipylidium caninum.

Effects of various neuropharmacological agents on the motility of Dipylidium caninum was studied. 5-HT stimulated the motility of D. caninum, while other drugs such as GABA, adrenaline, phenylephrine, isoproterenol, dibenamine, and propranolol showed little effect. The stimulatory action of 5-HT was antagonized by tryptophol. Stibnal caused paralysis which was blocked by the pretreatment with 5-HT. Paralytic effects were caused by eserine, dichlorovos, ACh, carbachol and DMPP, but not by pilocarpine and McN-A-343. d-Tubocurarine, hexamethonium, and atropine all showed little effect on the motility and on the paralytic action of eserine. Though guanidine showed little effect, strychnine remarkably stimulated the motility. The action of strychnine was stimulated by 5-HT but partially inhibited by tryptophol. Morphine and picrate slightly stimulated the motility, but showed little influence on the paralytic action of eserine. These two agents stimulated the paralyzed preparation by tryptophol transiently and sustainedly, respectively. These results on the cholinergic and serotonergic drugs basically showed good agreement with those reported in trematodes such as Schistosoma mansoni and Fasciola hepatica.

Animals↗

Comparison of alpha 1-adrenoceptors between rat brain and spleen.

Scatchard analyses of 3H-prazosin binding in rat brain membranes showed biphasic curves, which identified the presence of alpha 1High- and alpha 1Low-affinity sites. The alpha 1High-affinity site was completely inhibited by 0.1 microM phenoxybenzamine. On the other hand, 3H-prazosin binding in rat spleen membranes resulted in linear curves that were identical to the binding curve for the alpha 1High-affinity site in the brain. The displacement potencies of alpha 1-adrenergic antagonists were characterized by 3H-prazosin binding to alpha 1High-affinity sites in the rat spleen and brain and alpha 1Low-affinity sites in the brain in the presence of 0.1 microM of phenoxybenzamine. The affinities of WB-4101, phenoxybenzamine, phentolamine, chlorpromazine, labetalol and nifedipine for brain alpha 1High-affinity sites were significantly higher than those in the spleen. The affinities of most ligands for alpha 1Low-affinity sites were significantly lower than those for both alpha 1High-affinity sites in the brain and spleen, but chlorethylclonidine was significantly selective for alpha 1Low-affinity sites, and bunazosin, dibenamine and 5HT had the same affinities for the alpha 1Low- and both alpha 1High-affinity sites. These results show that two alpha 1-adrenoceptor subtypes, alpha 1High- and alpha 1Low-affinity, are present in the rat brain and that a different alpha 1High-subtype, exists in the rat spleen.

Adrenergic alpha-Antagonists↗

[A radioreceptor assay for catecholamines. II. A study with 4-(2-iodoethyl) pyrocatechol (author's transl)].

We have already reported on a radioreceptor assay for catecholamines utilizing the microsome fraction of bovine myocardium as a catecholamine (CA) receptor and 3H-norepinephrine as a labelled CA. In order to increase the sensitivity of the radioreceptor assay, we used 4-(2-iodoethyl) pyrocatechol (125I-CA) as a ligand instead of 3H-norepinephrine and performed a radioreceptor assay for CA. The following results were obtained: 1) 125I-CA was able to bind alpha-receptors prepared from bovine myocardium. 2) The optimal amount of the microsomal fraction was 250 micrograms/tube, when 125I-CA of 50,000 c.p.m. was used. The appropriate conditions for incubation were 90 minutes at 20 degrees C in a pH 7.0 sucrose solution. 3) By this method utilizing 125I-CA, norepinephrine was detectable in a range from 500 pg to 10 ng/tube. 4) Various compounds with a catechol nucleus showed cross-reaction in this radioreceptor assay system. 5) Whereas beta-adrenergic blocking agents did not inhibit the binding of 125I-CA, phentolamine, a short acting type of alpha-adrenergic blocking agents, was effective in inhibiting the binding. However, dibenamine and phenoxybenzamine, long acting types of alpha-adrenergic blocking agents, increased the binding of 125I-CA to the microsomal fraction. 6) Utilizing this phenomenon, norepinephrine was detectable in the range from 100 pg to 5 ng/tube.

Adrenergic alpha-Antagonists↗

Effects of gastrointestinal hormones on the electrical and mechanical activity of the cat stomach.

Effects of gastrointestinal hormones on electrical and mechanical activity of smooth muscle of cat stomach were studied. Spontaneous electrical activity of the antrum preparation consisted of slow waves with superimposed spike-like potentials. Phasic contractions occurred synchronously with the electrical activity. Pentagastrin, tetragastrin, pancreozymin and secretin increased frequency of slow wave component and amplitude of phasic contraction. Atropine and tetrodotoxin did not block the spike-like potential and slow wave component. Noradrenaline and verapamil blocked the phasic contraction. The excitatory effects of these gastrointestinal hormones were observed in the presence of atropine, tetrodotoxin and dibenamine, but not in verapamil. When the mechanical activity of the antral strips was depressed by caffeine or theophylline, the excitatory effects of gastrointestinal hormones were also suppressed. The excitatory effects produced by these hormones were potentiated by imidazole. These results suggest that gastrointestinal hormones have a direct excitatory action on the longitudinal smooth muscle of the antrum region and that the excitatory action is associated with phosphodiesterase activity and intracellular cyclic AMP content.

Action Potentials↗

Quantitative in vivo studies on the active Na-K transports in "tonic" muscle of the hypokalemic rat.

Central nervous system (CNS)-induced suppression on the muscle Na-pump activity was studied in soleus (SOL) muscles of hypokalemic rats. Peripheral nerve section, cervical soleus and brainstem transection, decerebration, and cortical spreading depression with 20% KCl activated the Na-pump in SOL muscles during hypokalemia. Blockage of the nerve conduction by tetrodotoxin (TTX) also activated the Na-pump in SOL muscles. The activation of Na-pump after the denervation was completely abolished by the pre-treatment of ouabain. However, the muscle cation contents were not affected by the injection of curare and atropine. The activation of Na-pump in the muscles after denervation in the curarized hypokalemic rats was completely removed by electrical stimulus of the distal nerve stump of cut sciatic nerve. alpha-Adrenoreceptor antagonists (phenoxybenzamine, phentolamine and dibenamine, and prazosin) stimulated the Na+ and K+ transports in the SOL muscles during hypokalemia while beta-adrenoreceptor antagonist (propranolol) had no effect. The denervation effect on SOL muscle cation contents was not affected with or without the presence of propranolol. It is concluded that CNS acts to inhibit the Na-pump mechanism in SOL muscles of hypokalemic rats and the inhibition is achieved by the apparent release of catecholamines onto muscle following neural activity. Thus, the CNS-induced suppression on the muscle Na-pump is prevented by denervation and by treatment with drugs that block either nerve conduction or alpha-adrenoreceptor.

Acetylcholine↗

Response of the isolated rabbit ciliary epithelium to adrenergic drugs following superior cervical ganglionectomy.

The fluid permeability of the isolated ciliary epithelium of the rabbit eye to adrenergic agonist's has been measured in paired normal and ganglionectomized tissues. The agonists norepinephrine (NE), epinephrine (E), phenylephrine (P) and isoproterenol (ISO) were used at concentrations from 10(-12) to 10(6)M in the presence and absence of cocaine 2.6 or 26x10(-6)M (C, to prevent uptake of agonist in the synapse); iproniazid (I) 3.6 x 10(-5)M, or clorgyline (CL) 5x10(-5)M (to inhibit 10(-5)M, or clorgyline (CL) 5x10(-5)M (to inhibit monoamine oxidase); dibenamine, (D) 1x10(-5) (to block extraneuronal uptake) and/or 1x10(-8)M phenoxybenzamine (PH) (an alpha-adrenergic antagonist). No supersensitivity to adrenergic agonists was found in ganglionectomized tissues. Normal tissues showed an increased fluid permeability after agonist alone with the other of efficacy at 10(-8)M being ISO greater than NE greater than E greater than P, while in ganglionectomized tissues the order at 10(-8)M was E = NE greater than ISO = P. Normal tissues showed a sensitivity to agonists at 10(-8)M in order E greater than NE greater than P greater than ISO after treatment with C, I and D, while ganglionectomized tissues revealed a sensitivity to NE greater than P greater than ISO greater than E, even though the quantitative response after C, I and D was reduced. It appears, therefore, that both alpha- and beta-receptors exist in the ciliary epithelium, and although ganglionectomy alters the tissues responsiveness to different adrenergic agonists it is not the site of the supersensitivity seen in the whole eye.

Animals↗

Lethal synergy between sarcoma-180/TG cells and vesicular stomatitis virus in mice.

An interaction between sarcoma-180/TG cells and vesicular stomatitis virus in adult mice resulted in the rapid onset of extensive mortality. This interaction, termed lethal synergy, occurred only at early stages of ascites induction in animals with no prior virus contact. A significant sparing effect conferred by the serotonin antagonist dibenamine was reversed by the administration of serotonin. The cause of death was not determined, but a mechanism involving hypersensitivity is indicated.

Animals↗

Chronic Chagas' disease in the mouse: contractile response of the isolated myocardium.

The effects of different pharmacological agents on the isometric developed tension (IDT) of right ventricles isolated from chronic chagasic C3HS mice were studied. The IDT in ventricles of chagasic animals was lower than in ventricles of normal mice (P less than 0.01). Chagasic ventricles exhibited hyperreactivity to norepinephrine but not to epinephrine. This hyperreactivity was masked by propranolol and not by dibenamine. Acetylcholine produced a reduction of IDT to similar values in normal and chagasic myocardia. The possibility that the effect of the drugs tested might not result from specially beta adrenoceptor-mediated reactions, but from alterations at other cellular sites is discussed.

Acetylcholine↗

[The role of catecholamines in the centrifugal regulation of taste receptors].

An electrophysiological method was used to study the centrifugal inhibition of the impulse activity of taste receptors of the frog tongue. A deficiency of catecholamines in the organism (reserpinization) or perfusion of the adrenaline-blocking agents through the lingual vessel (propranololi hydrochloridum, dibenamine) were found to prevent the centrifugal inhibition, while perfusion with an adrenomimetic agent (epinephrine) enhanced this effect. Such effects of the adrenergic agents were also observed in the animals which were subjected to desympathization by bilateral extirpation of the first ganglion of the sympathetic chain. A conclusion was drawn that catecholamines in the papilli were necessary to obtain the central inhibition influences on the function of the taste receptor apparatus.

Animals↗

[Hypothalamic stimulation effects on duodenal motility of rat. IV) Vias hypothalamo-duodenal (author's transl)].

UNLABELLED: Changes in duodenal motility, induced by electrical stimulation of hypothalamus, have been studied in rats, and registered by the baloon method. Localization of stimulated points was made by stereotaxic method, or by hostological control. Four animals were previously adrenalectomized. In 13 rats, the experiment has been repeated after bilateral cervical vagotomy. In 5 animals after total spinal cord transection, in the first dorsal segment. In 7 rats the experiment was reproduced after venous injections of atropine solution. In 5 rats after venous injections of dibenamine solution, and in other 5, after venous injection of hexamethonium solution. CONCLUSIONS: 1) Impulses that produced excitatory duodenal effects were mediated by the vagi nerves. 2) Impulses that produied inhibitory duodenal effects were not transmitted by the vagi nerves, but by sympathetic pathways.

Adrenalectomy↗