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At least 19 recordsLinked to original sources

PubMed1979

The effect of harmaline on intestinal sodium transport and on sodium-dependent D-glucose transport in brush-border membrane vesicles from rabbit jejunum.

Harmaline inhibition of sodium uptake and of sodium-dependent D-glucose transport was investigated using brush-border membrane vesicles from frozen rabbit jejunum. Under sodium-gradient conditions, "initial" D-glucose uptake (20 s) was inhibited by harmaline at concentrations above 0.5 mM, but at lower harmaline concentrations D-glucose uptake was stimulated by 10--15%. When a similar potassium gradient was used, harmaline had no effect. At concentrations up to 2 mM, harmaline did not alter the equilibrium uptake of D-glucose or D-mannitol. After pre-equilibration with sodium (25 mM), G-glucose uptake was inhibited at harmaline concentrations ranging from 0.1 to 2 mM. Sodium (10 mM) uptake was also inhibited by harmaline. Increasing the sodium concentration reduced the inhibitory effect of harmaline on tracer sodium uptake as well as on sodium-dependent D-glucose uptake. Similar to phlorizin, harmaline (1 mM) was able to prevent glucose-induced sodium influx across the brush-border membrane. Sodium uptake into brush-border membrane vesicles seems to be inhibited at lower harmaline concentrations than sodium-dependent D-glucose uptake. At high (2 mM) inhibitor concentrations, however, sodium-dependent glucose uptake is more strongly inhibited than sodium uptake. These results suggest that harmaline inhibits both sodium and sodium-dependent transport across intestinal brush-border membranes by interacting with specific sodium-binding sites.

Alkaloids↗

PubMed1978

Kinetics of the co-transport of sodium and phenylalanine in the guinea-pig samll intestine. III - Influence of harmaline on sodium and phenylalanine fluxes.

The effect of harmaline on sodium and phenylalanine influxes in guinea-pig small intestine has been examined kinetically. Harmaline behaves as a fully competitive inhibitor of the saturable component of sodium influx; this property has been revealed from experiments in which the sodium concentration was varied and the harmaline concentration maintained constant, and from a second series in which sodium was constant and harmaline levels were altered. A Ki-value for harmaline of 1.61 mM was deduced from these experiments. The effect of harmaline on phenylalanine influx is more complex, since only that component of entry which occurs in the form of the ternary complex is sensitive to the drug. Within the framework of a non-compulsory model for co-transport which appears to describe phenylalanine influx in this tissue, equations were derived to calculate the different components of influx under given experimental conditions. tJøala, the influx to phenylalanine in the form of the ternary complex, was found to be a Michaelis-Menten function of the sodium concentration. Assuming that the component in the form of the binary complex is unchanged by harmaline, that occurring in the ternary form in the presence of the drug can be evaluated by subtraction. This fraction is also a Michaelis-Menten function of the sodium concentration; the inhibition by harmaline is released on raising the sodium concentration. From these expressions, a Ki for harmaline under these conditions of 1.66 mM was derived. These observations support the proposal that harmaline interferes with the interaction of sodium with its specific sites on the carrier in the intestinal brush-border membrane.

Alkaloids↗

PubMed1975

New characteristics of harmaline inhibition of intestinal transport systems.

Harmaline strongly inhibits the uptake of phenylalanine by slices of guinea-pig intestine in vitro. The lowest concentration having a significant effect is 0.1 mM. The drug also inhibits the unidirectional flux of phenylalanine from the mucosal to serosal face of the tissue provided it is added to the solution bathing the mucosal surface. The unidirectional flux of sodium from the mucosa to the serosa was similarly reduced. Ion and water absorption in the perfused dog intestine in vivo is also diminished in the presence of harmaline. These results support the hypothesis, previously proposed in view of the rapid onset of harmaline inhibition of sodium-dependent uptake mechanisms in a variety of tissues, that harmaline interacts with the sodium-site of non-electrolyte carrier complexes. The effect of harmaline on phenylalanine uptake by the intesting is duplicated by other psychotropic indole analogues. The actions of harmine and harnalol are similar to that of harmaline, despite great differences in the liposolubility of the different compounds. N:N-dimethyl-tryptamine is equally inhibitory, but serotonin is inactive. Mescaline and lysergic acid diethylamide also inhibit phenylalanine transport, but to a much lesser extent than harmaline.

Alkaloids↗

PubMed1977

The mechanism of action of harmaline on renal solute transport.

The effect of the hallucinogenic drug harmaline was tested on rat kidney proximal tubular solute and water transport, using in vivo micropuncture and electrophysiological techniques as well as in vitro biochemical techniques. During peritubular application harmaline (5 mmol/l) was found to block net tubular volume absorption reversibly (by 85%) through inhibition of active Na+ transport and possibly active HCO-3 transport. The inhibition was accompanied by a rapid strong depolarization of the tubular cell membranes. As a biochemical equivalent harmaline inhibited the Na+-K+-ATPase and the Mg2+-ATPase of peritubular cell membrane fractions as well as the HCO-3-stimulated ATPase of a brush border membrane fraction with similar kinetics. By studying glucose tracer efflux and by measuring cell membrane potential and conductance changes in response to glucose perfusions, no evidence for a direct effect of harmaline on Na+-glucose (or amino acid) cotransport mechanisms in the brush border could be obtained. The data suggest that harmaline does not specifically compete with Na+ for transport sites. Neither are the cotransport systems in the brush border membrane specifically inhibited, nor could the inhibition of the Na+ pump in the peritubular cell membrane simply result from a competition between harmaline and Na+.

Adenosine Triphosphatases↗

PubMed1978

Vasopressin-like effects of a hallucinogenic drug--harmaline--on sodium and water transport.

To determine if harmala alkaloids affect transport systems other than (Na +K)-ATPase, effects of harmaline on Na and water fluxes were studied in amphibian skins. Net Na flux was evaluated from short-circuit current, and water flux monitored with automatic, volumetric methods. At 2 to 5 mM, harmaline consistently inhibited SCC and prevented the natriferic effects of oxytocin and norepinephrine. However, at 0.1 to 0.5 mM, harmaline produced an increase in SCC inhibitable with amiloride. The stimulatory effects of harmaline and oxytocin were either nonadditive or additive depending on whether the hallucinogen was present in the inner solution or in the outer solution bathing the skin, respectively. Water flow was not modified by harmaline on the outer medium. In contrast, addition of the drug to the inner medium elicited a conspicuous, sustained, vasopressin-like, hydrosmotic effect, comparable to and competive with those of vasopressin and norepinephrine. The ensemble of these results suggests that harmaline may affect three distinct transport systems: (i) the Na pump; (ii) the cyclic nucleotide system; (iii) the Na entry pathway at the outer membrane of the skin that is also activated by agents such as diphenylhydantoin, lanthanides and propranolol.

Alkaloids↗

PubMed1977

The indolaminergic innervation of the inferior olive. 2. Relation to harmaline induced tremor.

The possible involvement of serotoninergic mechanisms in the induction of harmaline generated tremor in the inferior olive has been investigated electrophysiologically in the cat and rat. Mass recordings of Purkinje cell activity in the cat showed that harmaline induces strong, synchronous and rhythmic activity in those parts of the climbing fibre system originating in the caudal part of the medial accessory olive and the caudolateral parts of the dorsal accessory nucleus. These are the areas of the cat olive shown to receive a dense serotoninergic innervation. In the rat, the selective removal of the serotoninergic innervation--produced by an intraventricular injection of 5,6-dihydroxytryptamine, or 5,7-dihydroxytryptamine in combination with desipramine--caused a significant attenuation of both the tremor and the climbing fibre activity induced by an intravenous harmaline injection. In the 5,6-dihydroxytryptamine-treated animals the reappearance of the harmaline tremor seemed to parallel the regrowth of new serotoninergic axon sprouts in the inferior olive. On the basis of the present results it is proposed that the serotoninergic afferents to the accessory olivary nuclei are of critical importance for the tremor induction of harmaline in the inferior olive. It is suggested that harmaline, rather than acting directly on the olivary neurones, exerts its effect through an interference with a serotoninergic (possibly inhibitory) innervation of these cells.

5,6-Dihydroxytryptamine↗

PubMed1976

[Inhibition of harmaline induced tremor by L-threo-3, 4-dihydroxyphenylserine, an L-norepinephrine precursor].

Effect of 3, 4-dihydroxyphenylserine (DOPS), a norepinephrine precurosr, on harmaline tremor was investigated in mice to elucidate the role of norepinephrine in the genesis of tremor. 1) Spontaneous motor activity was inhibited by L-threo-DOPS (200 mg/kg i.p.). 2) Tremor induced by harmaline (5 and 7 mg/kg i.p.) was enhanced by alpha-methyl-p-tyrosone (200 mg/kg i.p.). 3) The development and duration of tremor induced by harmaline (10 mg/kg i.p.) were inhibited significantly in a dose dependent manner by L-threo-DOPS (50, 70, 100, 150 and 200 mg/kg i.p.), but neither by D-threo-DOPS (200 mg/kg i.p.) nor DL-erythro-DOPS (200 mg/kg i.p.). 4) L-threo-DOPS (200 mg/kg i.-.) had no effect on the development of tremor induced by tremorine (5 and 10 mg/kg i.p.), while lacrimation and diarrhea caused by tremorine was markedly inhibited. 5) Administration of harmaline (10 mg/kg i.p.) produced an increase in brain 5-hydroxytryptamine content but not in that of norepinephrine. Administration of L-threo-DOPS (100 mg/kg i.p.) increased the norepinephrine content but not the 5-hydroxytryptamine content in the brain. Inhibition of harmaline tremor induced by L-threo-DOPS is attributed to the L-norepinephrine converted from L-threo-DOPS and the involvement of a noradrenergic mechanism in harmaline tremor has to be considered.

Alkaloids↗

PubMed1976

Differential effects of harmaline and ouabain on intestinal sodium, phenylalanine and beta-methyl-glucoside transport.

Harmaline inhibits both the Na+ -K+ -ATPase activity and the uptake of L-phenylalanine in guinea-pig intestinal mucosa. The latter effect is not a direct consequence of the former, since higher concentrations are needed to inhibit the enzyme than the influx into the mucosa; Furthermore the uptake is still sensitive to harmaline when the Na+ -K+ -ATPase has been fully inhibited by ouabain. Harmaline can inhibit L-phenylalanine influx at a concentration at which it does not affect intracellular ion concentrations. Ouabain, however, inhibits the uptake of L-phenylalanine only after a 30 min preincubation period, when the intracellular sodium concentration reached the extracellular level. Harmaline also interferes with the influx of beta-methyl-D-glucoside in the mucosa of the dog colon. Addition of harmaline at the mucosal face of the tissue suppresses all net transport of sodium and chloride ions and L-phenylalanine across the mucosa. Thus the same mode of action appears to apply in both the guinea-pig ileum and the dog colon.

Adenosine Triphosphatases↗

PubMed1977

Harmaline interaction with sodium-binding sites in intestinal brush border sucrase.

The effect of harmaline on rabbit brush border sucrase has been studied at pH 6.8. An initial analysis in classical kinetic terms revealed harmaline to be a fully competitive inhibitor of the substrate, sucrose. In spite of this result however, the following hypothesis has been tested. Harmaline, which is positively charged in the physiological range of pH, might in fact compete, not directly with the substrate site, but rather with an allosterically-related sodium-binding site which has been postulated to be involved in the activation of sucrase by the alkali-metal ions (Mahmood and Alvarado, Arch. Biochem. Biophys. 168, 585, 1975). Because of its size, harmaline, when bound to the metal site, could at least partially overlap with the substrate site, thereby behaving as if it were an authentic fully competitive inhibitor of the substrate. This hypothesis appears to be confirmed by the fact that the alkali metals can completely reverse the inhibition caused by harmaline.

Alkaloids↗

PubMed1979

Significance of central noradrenergic system on harmaline induced tremor.

Since there is degeneration of substantia nigra concomitant with that of locus coeruleus (LC) in patients with Parkinson's disease, the study was performed to determine the role of central norepinephrine (NE) on harmaline induced tremor. The duration of harmaline (10 mg/kg IP) induced tremor was significantly reduced by intraventricular administration of L-thero-3,4-dihydroxyphenylserine (200 micrograms/rat) and 1-NE (50 micrograms/rat) was increased NE levels in the cerebral cortex, striatum, diencephalon, cerebellum and brain stem. Electrical stimulation of bilateral LC suppressed harmaline-induced 10-12/sec EMG activities in the neck muscle. Bilateral LC lesion upon electrocoagulation and 6-hydroxydopamine treatment resulted in a significant prolongation of the duration of harmaline induced tremor, reducing NE levels in the brain. These data suggest that central NE originating in the LC neurons has an inhibitory effect on the development of the tremor induced by harmaline.

Alkaloids↗

PubMed1977

Effect of harmaline on sodium transport in Rana esculenta skin.

1 Harmaline, together with certain hallucinogenic alkaloids of the same group (harmine, 2 methyl harmin) stimulates sodium transport across the in vitro skin of Rana esculenta when it is added to the external medium at a low concentration (0.1 mM). This effect is due to an increase of the sodium influx, and is reversed by washing. It is suggested that harmaline intervenes at the sodium penetration sites at the external face of the transport compartment. 2 At a higher concentration (5 mM) added to the internal medium harmaline inhibits sodium net absorption. The inhibition is due mainly to an increase of the efflux, while the influx may be either inhibited or increased. Under these conditions the influx becomes insensitive to amiloride. It is suggested that the inhibition of sodium transport is the result of harmaline interfering with a transport ATPase, and also that harmaline induces new sites for the passage of sodium.

Alkaloids↗

PubMed1975

The effect of harmaline on force of contraction of the rat isolated atrium.

In rat isolated right atria, beating spontaneously at 30 degrees C, harmaline 8.3 times 10-5 M slowed atrial rate and enhanced force of contraction. The velocity of development of tension (dT/dt) increased and time to peak tension was lengthened. Electrical drive of otherwise quiescent left atria showed that (1) within the range of change of rate induced by harmaline the reduction of frequency of stimulation increased dT/dt and peak tension developed, and (2) at a constant rate of stimulation harmaline produced a prolongation of time to peak tension and an enhancement of peak tension. We concluded that two mechanisms are responsible for the inotropic action of harmaline on rat atrium: (1) an increase in dT/dt due to the lengthening of the interval between beats; (2) a direct action of harmaline on the processes responsible for atrial contraction, which determines a lengthening of time to peak tension.

Alkaloids↗

PubMed1977

[Experimental cholestasis by dibucaine and harmaline: effects on bile flow and hepatic transport of bile acids, ethacrynic acid and ouabain (author's transl)].

For further confirmation of the hypothesis that bile-salts independent bile flow depends on transepithelial Na+ fluxes, the effect of dibucaine (0.5 to 1.6 mM) and of harmaline (1.7 to 4.0 mM) on bile formation was studied in the isolated rat liver. Both compounds, which are known to inhibit passive Na+ entry into tissues other than liver, inhibit bile secretion in a dose-dependent fashion. Measurements of oxygen consumption and examination of liver tissue by electronmicroscopy exclude unspecific damage to liver cells as the cause for secretory failure. Cholestasis induced by dibucaine and harmaline is reversible upon wash-out of the drugs from the perfusion system. Simultaneously added choleretics, such as taurocholate, cholate, ethacrynic acid or ouabain, fail to elicit a secretory response. Since harmaline is an inhibitor of Na+-dependent transport processes, its effect and that of dibucaine on Na+-linked uptake of these choleretics by the isolated liver was determined. Harmaline and dibucaine reduce taurocholate transfer to the extent of the Na+-independent fraction only, but completely inhibit active entry of cholate, ethacrynic acid and ouabain. It is concluded that drug-membrane interactions primarily on the sinusoidal surface but possibly also at the canalicular pole of the hepatocytes are responsible for the impairment of basal and stimulated bile secretion.

Alkaloids↗

PubMed1979

[Effects of juxtafastigial stimulation on the rhythmic activity of Purkinje cells in harmaline-treated rats].

In the anaesthetized rat, harmaline induces an olivary activation which results in rhythmic complex-spike (CS) discharges of Purkinje cells (4--8/sec) in the vermian cortex. The temporal organization of the rhythmic CS activity was studied. While some Purkinje cells present long periods of continuous rhythmic activity, the rhythmic CS discharge of other cells is modulated by periodical suppression of activity, with a total cycle length of about 10 sec. This organization can be modified by electrical stimulation of the juxtafastigial region (JF). During periods without spontaneous rhythmical CS firing, single JF shocks produce a late reflex response (200--300 msec) of the Purkinje cells, which appears as a repetitive sequence of CS (up to 30) at the harmaline-like induced frequency. The response obtained is the same whether the electrical stimulus is single or given in succession at regular intervals; however, in order to obtain such an effect, the frequency of the JF stimulation has to be inferior to the rhythmic CS frequency produced by the drug. At a higher stimulation rate (10 c/sec, 3 sec) the JF-induced response of Purkinje cells is abolished and we observe the suppression--4 to 8 sec following stimulation - of any rhythmic CS activity. This experimental modulation of rhythmic activity of the Purkinje cells (inducement or suppression of the CS firing), controlled indirectly by the olivary system, reproduces the spontaneous fluctuations of the thythmicity under harmaline. A neurophysiological model is presented and the functional significance of the results is discussed.

Alkaloids↗

PubMed1977

Pharmacologically induced changes in the 3':5'-cyclic guanosine monophosphate content of rat cerebellar cortex: difference between apomorphine, haloperidol and harmaline.

Harmaline increases cerebellar 3':5'-cyclic guanosine monophosphate (cGMP) content in a dose-related manner; this increase is prevented by a pretreatment with 3-acetylpyridine (3-AP) (0.66 mmol/kg) which destroys climbing fibers and inhibits harmaline-induced tremor. The cerebellar cGMP content increases after isoniazid; this response remains unchanged in rats pretreated with 3-AP. Since isoniazid decreases cerebellar gamma-aminobuturic acid (GABA) levels, the increase in cGMP content might reflect a reduction in the availability of GABA at the level of postsynaptic receptors. Apomorphine (a dopamine receptor agonist) and haloperidol (a dopamine receptor blocker) increase or decrease the cGMP content of cerebellar cortex, respectively. Neither drug changes the guanylate cyclase activity of cerebellar homogenates; moreover their action on cerebellar cGMP content persists after 3-AP. Chloropromazine, like haloperidol, decreases the cerebellar cGMP content. The increase in cerebellar cGMP content elicited by apomorphine can be differentiated from that elicited by harmaline or isoniazid; presumably apomorphine indirectly activates mossy fibers. The decrease in cerebellar cGMP content elicited by haloperidol can be differentiated from that elicited by diazepam; perhaps haloperidol reduces the mossy fiber input to the cerebellum. We suggest that the cGMP content of cerebellar cortex fluctuates in response to changes in the afferent stimulatory input to the cerebellum; it increases when the activity of either climbing or mossy fibers is increased; it decreases when either of these two stimulatory inputs is reduced.

Alkaloids↗

PubMed1977

Cardiovascular actions of three harmala alkaloids: harmine, harmaline, and harmalol.

Each of three harmala alkaloids, harmine, harmaline, and harmalol, decreased heart rate and increased pulse pressure, peak aortic flow, and myocardial contractile force in intact normotensive anesthetized dogs. Harmine reduced systemic arterial blood pressure and total peripheral vascular resistance; harmaline-evoked decreases were frequently followed by a secondary increase; and the effects of harmalol on these two parameters were inconsistent. A direct negative chronotropic effect of harmala alkaloids was suggested by observations of bradycardia in the isolated perfused rat heart and in the intact dog; neither vagotomy nor atropinization affected harmala alkaloid-induced bradycardia in the dog. Reduction in femoral vascular resistance by the alkaloids was not apparently due to activation of cholinergic, beta-adrenergic, or histamine (H1) receptors.

Alkaloids↗

PubMed1977

Effect of harmaline on the cerebello-rubral system.

Harmaline induces synchronous rhythms in both the cerebellum and the red nucleus of the rabbit. The level of synchronization is lower in the red nucleus than in the cerebellar cortex, probably because the cerebello-rubral pathway and the red nucleus neurons only participate poorly in the harmaline-induced olivo-cerebellar rhythm.

Alkaloids↗

PubMedDate not supplied

The effect of harmaline on membrane potentials of rat atrial contractile fibers.

Rat atria either beating spontaneously or electrically driven were were perfused in vitro at 30 degrees C. When the preparations were exposed to harmaline 8.3 x 10(-5) or 16.6 x 10(-5) M the atrial rate showed down and the following changes in membrane potentials were observed: (1) a transient increase in the amplitude of the action potential (AAP), in the absence of any change in the magnitude of the resting potential (RP), followed by a progressive decrease of AaP; (2) a progressive decline of the slope of the fast ascending phase of the action potential, which was initially independent of any change in the magnitude of the rp; (3) a progressive increase of the duration of the action potential; (4) a fall in the magnitude of the resting potential. The conclusions proposed are that harmaline: (1) stimulates the slow current responsible for the last part of the upstroke and the beginning of the repolarization; (2) inhibits the sodium current responsible for the fast component of the upstroke; (3) slows doen the processes responsible for the repolarization; (4) inhibits the (Na+-K+) activated membrane ATPase.

Action Potentials↗