Study on the antinociceptive action of Tyr-K-MIF-1, a peptide from the MIF family.

1. Tyr-K-MIF-1 is a melanocyte inhibiting factor (MIF) neuropeptide, isolated from the brain. Opposite to other MIFs (Tyr-MIF-1, Tyr-W-MIF-1), it has a very low affinity for opiate mu-receptors, but interacts with Tyr-MIF-1 specific binding sites. Tyr-MIF-1 and Tyr-W-MIF-1 evoke antinociception mainly by activating opioid receptors. We investigated the possible antinociceptive effect of Tyr-K-MIF-1 and the involvement of histaminergic system in its mechanism of action. 2. Tested on rats by paw-pressure test, Tyr-K-MIF-1 (0.5, 1 and 2 mg kg(-1)) was associated with short-lasting analgesia, which was abolished by naloxone (1 mg kg(-1)). 3. Injected intraperitoneally (i.p.) 15 min before Tyr-K-MIF-1, antagonists of H(1) (diphenhydramine, 100 mg kg(-1)) or H(2) (famotidine, 0.3 and 0.6 mg kg(-1)) histamine receptors diminished peptide antinociceptive effect. Simultaneous H(1)- and H(2) blockade, as well as pretreatment with 5 mg kg(-1) dimaprit (H(2) agonist) abolished Tyr-K-MIF-1-induced analgesia. Tyr-K-MIF-1-induced analgesia was also abolished by treatment with R-(alpha)-methylhistamine (10 mg kg(-1), i.p.), an H(3) histamine receptor agonist that acts to inhibit histamine release. 4. Our results together with data reported in the literature support the conclusion that activation of the histaminergic system is involved in the mechanism of Tyr-K-MIF-1-induced antinociception.

Prejunctional modulation of non-adrenergic non-cholinergic (NANC) inhibitory responses in the isolated guinea-pig gastric fundus.

The inhibitory neurotransmission of the stomach was investigated in isolated guinea-pig gastric fundus. In preparations treated with guanethidine (1 micro mol L-1) and p-fluoro-hexahydro-sila-difenidol (1 micro mol L-1), electrical stimulation evoked neurogenic inhibitory responses not modified by hexamethonium (100 micro mol L-1), suggesting that inhibitory postganglionic non-adrenergic non-cholinergic (NANC) nerve fibres are involved. The nitric oxide (NO)-synthase inhibitor Nomega-nitro-l-argininine-methyl-ester hydrochloride (1-100 micro mol L-1) and the soluble guanylyl cyclase inhibitor ODQ (0.1-3 micro mol L-1) also abolished such relaxant response, suggesting the involvement of NO/Cyclic Guanosine 3',5' monophosphate (cGMP) system as the final mechanism of muscle relaxation. The alpha2-adrenoceptor agonist, UK 14 304 (10 nmol L-1-10 micro mol L-1) did not influence the electrical field stimulation (EFS)-evoked NANC responses. These latter responses were also refractory to a variety of receptor agonists and antagonists, acting at Gamma Aminobutyric Acid (GABA), serotonin 5HT1a, opioid micro , delta and kappa, muscarinic M1 and M2, histamine H2 and H3 and cannabinoid receptors. The NANC response was insensitive to the P/Q-type Ca2+-channel blocker omega-agatoxin TK (1 nmol L-1-0.1 micro mol L-1), but partially inhibited by the N-type Ca2+-channel blocker omega-conotoxin GVIA (0.1 nmol L-1-0.1 micro mol L-1), and by the L-type Ca2+-channel blockers nifedipine and calcicludine (0.1 nmol L-1-0.1 micro mol L-1). These data suggest that the NANC relaxation of the isolated guinea-pig gastric fundus is mediated by NO as the final inhibitory (neuro)transmitter at the longitudinal smooth muscle cells. The mechanism(s) promoting NO production is/are Ca2+-dependent, but apparently insensitive to presynaptic modulation. Both N- and L-type channels seem to occur in nitrergic nerve endings, where they contribute to trigger NO diffusion at the synaptic cleft.

Involvement of H2-receptors in the mechanism of analgesic action of Tyr-MIF-1.

The antinociceptive effects of H2-agents cimetidine (CIM) and dimaprit (DMP) as well as their effects on the Tyr-MIF-1-evoked analgesia have been studied after intraperitoneal (i.p.) administration in rats. In the paw-pressure (PP) test Tyr-MIF-1 (1 mg/kg), CIM (50 and 100mg/kg) and DMP (5 and 10mg/kg) induced analgesia. Injected before DMP, naloxone (NAL) and CIM diminished or completely prevented the pain-relieving effect of H2-agonist DMP. The antinociceptive effect of Tyr-MIF-1 has been potentiated by DMP dose-dependently. CIM (50mg/kg) decreased the antinociceptive action of the combination Tyr-MIF-1 + DMP, while CIM (100mg/kg) expressed a weaker inhibitory effect on it. The data obtained clearly show that H2-receptor activation is involved in the mechanism of the Tyr-MIF-1 antinociceptive action.

Effect of diphenylhydramine on the Tyr-MIF-1 antinociception in rats.

Tyr-MIF-1 is a representative of the MIF's family of endogenous peptides. It has been isolated from bovine hypothalamus and human parietal cortex that suggests its involvement in nociception. Tyr-MIF-1 can bind to the mu-receptors as well as to its specific non-opiate receptors in the brain. Data in the literature rise the idea that histamine (HA), a well known nociceptive agent, and Tyr-MIF-1 might have a common pathway in their effects on nociception. We tested that possibility by investigation of the combined action of diphenhydramine (DPH, an H (1) -antagonist) and Tyr-MIF-1 on nociception. The changes in the nociceptive effects were examined in the male Wistar rats by the Randall-Sellito paw-pressure (PP) and the tail-flick (TF) tests. Tyr-MIF-1 in a dose of 1 mg/kg exerted strong naloxone-reversible analgesic effects. DPH (100 microg/kg, i.p.) had an antinociceptive action, too. The co-administration of Tyr-MIF-1 and DPH enhanced the antinociceptive effect, as compared to DPH (PP) and to TYR-MIF-1 alone (TF). These effects were reversed when methylene blue (MB, 500 microg/rat) was applied 1h before the combination. However, naloxone (1 mg/kg, i.p.) only slightly affected the antinociceptive effect of DPH and TYR-MIF-1, compared to that of MB. The results obtained confirmed the hypothesis that cyclic nucleotides are involved in the realization of nociceptive effects of both HA and Tyr-MIF-1.

Interactions between histaminergic and cholinergic pathways of gastric motility regulation.

Smooth muscle preparations, isolated in a circular direction from guinea pig gastric fundus, were used to study the effects of H1 and H2 antagonists on acetylcholine (ACH)- and histamine (HA)-induced contractions as well as the effects of HA antagonists on spontaneous contractile activity. HA (1 x 10(-9) M to 1 x 10(-5) M) concentration-dependently enhanced the tone of the strips with ED50 = 3.5 x 10(-7) M. Applied 5 min before HA, the H1 antagonists (mepyramine, diphenhydramine, dimethpyrindene) and the H2 blockers (ranitidine, cimetidine, roxatidine) reduced HA-induced contractions. HA in concentrations of 1 x 10(-8) M to 1 x 10(-7) potentiated, and in higher concentrations (1 x 10(-6) M to 1 x 10(-5) M) inhibited, smooth muscle contractions evoked by low frequency electrical field stimulation (EFS). The H1 blockers (1 x 10(-6) M to 1 x 10(-4) M) concentration-dependently enhanced smooth muscle tone, the maximum contractions being about 50% smaller than the contractile responses to 1 x 10(-5) M ACH and 5 x 10(-5) M HA. Tetrodotoxin, atropine and indomethacin shifted to the right the concentration-response curve for mepyramine, reducing its maximum by 25, 58 and 62%, respectively. The H2 blocker ranitidine also suppressed (by 42%) mepyramine-evoked increase in the fundic strips tone. The H1 antagonists reduced ACH-induced contractions of the smooth muscle strips and did not affect the contractions in response to EFS. The H2 blockers had no effect on tone and ACH-evoked contractions of the smooth muscle strips but concentration-dependently enhanced both the contractions and [3H]-ACH release in response to EFS. The results demonstrate the presence of both H1 and H2 postsynaptic receptors which are involved in the direct myogenic action of HA on guinea pig gastric fundus smooth muscles. It also appears that HA might concentration-dependently modulate the cholinergic neurotransmission in gastric fundus. It could be suggested that H1 blockers have a direct myogenic effect on guinea pig gastric fundus smooth muscle and might also interact postsynaptically with muscarinic receptors in this tissue.

Different effects of H1 and H2 blockers on the tone and the contractile activity of guinea pig stomach fundus.

The action of H1 and H2 blockers on the spontaneous and evoked contractile activity of gastric fundus smooth muscles as well as the effects of H2 antagonists on the release of acetylcholine (ACh) from gastric myenteric neurons were studied. The experiments were performed on smooth muscle strips (25 x 3 mm) cut out in circular direction from guinea pig fundus region. In concentrations of 1 x 10(-7) M to 1 x 10(-4) M, the H1 blockers diphenhydramine (DPH), mepyramine (MEP) and dimethpyrindene (DMPD), but not the H2 blockers ranitidine (RAN), cimetidine (CIM) and roxatidine (ROX), increased in a concentration-dependent manner the smooth muscle tone, the maximum contractions being about 50% of the contractile effects of 1 x 10(-5) M ACH and 5 x 10(-5) M histamine (HA). The concentration-dependent contractions of the stomach fundus strips in response to electrical field stimulation (EFS) were enhanced by RAN, CIM and ROX (but not by MEP and DPH), all in concentrations of 1 x 10(-7) M to 1 x 10(-4) M. EFS increased the resting [3H]-ACh release by 67.8%, the S2/S1 ratio being 0.85 +/- 0.04. ROX in a concentration of 1 x 10(-5) M significantly increased (by 16.1%) the EFS-induced release with a S2/S1 ratio of 1.22 +/- 0.04. The ROX effect on the [3H]-ACh release was reduced or even abolished by 1 x 10(-6) M tetrodotoxin (TTX) and 1 x 10(-6) M scopolamine or in Ca(2+)-free medium, while 1 x 10(-6) M hexamethonium did not change it. It might be concluded that H2 blockers have no direct myogenic effect and do not interfere with muscarinic receptors in guinea pig stomach fundus. The H2 antagonists enhance the EFS-evoked contractions of the gastric smooth muscle most probably by increasing the release of ACH.

Involvement of Ca2+ and alpha 1-adrenoceptors in endothelin-1 effects on the tone and electrically evoked contractions of rabbit ear central artery.

Endothelin-1 (ET-1) is a neuropeptide strongly involved in the functions of the cardiovascular system. The aim of the present study was to reveal the role of alpha1-adrenoceptors and of Ca2+ in the effects of ET-1 on blood vessels. Preparations isolated from the proximal part of ear central arteries (REA) of male Chinchilla rabbits were used. A 30-40 mm long segment, cannulated at both ends, was fixed in an organ bath with Krebs-Henseleit solutions aerated with 95% O2 and 5% CO2. The preparations were perfused at a rate of 3.0 ml/min maintaining the arterial pressure in the range of 40-60 HPa and were allowed a 120-min adaptation at 37.5 degree C. Contractions were induced by low-frequency electrical stimulation (ES) and the effects of ET-1 (applied intralumenally or extralumenally) on the arterial tone and on the Es-evoked contractions were studied. Extralumenal ET-1 (1 x 10(-12)M-1 x 10(-9)M) did not change the tone and ES evoked contractions of REA. In concentrations of 1 x 10(-8)M-1 x 10(-7)M ET-1 slightly increased arterial tone and moderately potentiated ES contractions. ET-1, in concentrations higher than 1 x 10(-7)M, sharply, strongly and long-lastingly increased the smooth muscle tone and slightly enhanced the ES contractions. A 100 microM bolus injection with ET-1 (1 x 10(-9)M-1 x 10(-8)M) resulted in potentiation of the ES contractions and the arterial tone was not markedly affected. 100 microM of 1 x 10(-7)M ET-1 increased more than 2-fold the tone of the segments and moderately reduced the ES-evoked contractions. A 30-min perfusion with ET-1 (1 x 10(-12)M-1 x 10(-9)M) strongly increased the arterial tone and completely abolished the ES contractions. Perfusion with 1 x 10(-8)M ET-1 resulted in a 3-fold increase of the tone of the isolated segments. A 30-min perfusion with 1 x 10(-6)M prazosin (PRZ) did not affect the arterial tone and prevented the ES-evoked contractions. PRZ markedly reduced the contractile effects of 1 x 10(-12)M-1 x 10(-9)M ET-1 and the effect of 1 x 10(-8)M ET-1 on REA tone was even enhanced by PRZ. Under the same conditions 1 x 10(-6)M flunarizine (FLU) inhibited the ES-induced contractions of the isolated preparations and decreased their tone. FLU reduced the contractile effects of ET-1 (1 x 10(-12)M-1 x 10(-8)M). Applied extralumentally 1 x 10(-6)M FLU also decreased EG-1 effects on REA. The results obtained strongly support the assumption that alpha1-receptors and Ca2+ are involved in ET-1 contractile effects on blood vessels smooth muscles.

Role of histamine and histaminergic agents on noradrenaline uptake in smooth muscle preparations.

It has been shown that adrenergic neurotransmission in different tissues can be modified by histamine (HIST) but the mechanisms of this action have still not been fully clarified. This study aimed to demonstrate the possible involvement of H-receptor subtypes in the realization of histamine inhibitory effects on smooth muscle tissues. HIST, 2-(2-aminoethyl)thiazole (AET) and dimaprit (DMP) exerted a similar inhibition of noradrenaline (NA)-uptake1 in rat vas deferens and rabbit ear artery. After H1-blockade with mepyramine (MEP), HIST and DMP did not change the uptake1 in rat vas deferens and decreased NA neuronal accumulation in rabbit ear artery. The H2-blockade with ranitidine (RAN) did not affect HIST- and AET-induced inhibition of NA-uptake1 in rat vas deferens and completely abolished it in rabbit ear artery. These data suggest that different H-receptor subtypes might be involved in HIST inhibitory action on NA neuronal uptake in both tissues. It appears, however, that the inhibition of NA uptake1 plays only a minor role in the effects of HIST on smooth muscle contractions.

Comparative study of the hypotensive effect of a group of structural derivatives of glaucine.

A comparative study was made on the hypotensive effect of a group of dehydrogenated structural derivatives of the alkaloid glaucine. The compounds studied induced a slowly occurring marked decrease in the blood pressure. Applied intravenously, they did not manifest the initial brief and very pronounced phase of the hypotensive effect, typical of glaucine, and failed to change substantially the respiration and the cardiac activity of the experimental animals. The most marked hypotensive effect was demonstrated by 7-benzoyl-dehydroglaucine (DG4), which reduced the blood pressure by about 50 and 60% respectively, when applied in doses of 1 mg/kg and 2.5 mg/kg. Applied duodenally, the dehydrogenated glaucine derivatives also manifested a gradually occurring hypotensive effect, whereby DG4 again caused the most pronounced blood pressure drop. Depending on the DG4 and glaucine doses used, the pressor effects of noradrenaline (NA) and nicotine (NIC) were moderately to strongly suppressed or completely inhibited. In experiments on cat membrana nictitans glaucine also suppressed moderately (2.5 mg/kg) or markedly (5 mg/kg) the contractile effects of NIC and NA, while DG4 did not influence (1 mg/kg) or potentiated (2.5 mg/kg) these effects.

Study of the effects of nootropic agents on the adrenergic neurotransmission in smooth muscles of young and old animals.

The effects of compounds from the group of nootropic agents on the peripheral adrenergic neurotransmission in animals of different ages were studied in in vitro experiments. The experiments were performed on smooth muscle preparations isolated from young sexually mature (4-5-month-old) and old (22 month-old) rats treated twice daily for 7 days with 50 mg/kg of the nootropic agents piracetam, its structural analogues p-H and p-Cl, aniracetam and Ginseng extract. The animals were decapitated on the 7th day, the changes in the contractile responses of the smooth muscles to noradrenaline (NA) or electrical stimulation (ES) were studied in isolated preparations from vas deferens, aorta and anococcygeal muscle. The results show that the compounds studied can modulate the contractile effects of NA and ES, their action being most often potentiating and more pronounced in the smooth muscles manifesting weaker responses. In some cases the reactivity of the smooth muscle preparations to the stimuli applied was reduced after the nootropic agents. These effects can be partly explained with changes in the sensitivity of the pre- and postsynaptic alpha-adrenergic receptors. The possible variabilities in the influence on the two receptor populations in the different smooth muscles could explain the differences in the observed modulatory effects of the nootropic agents. The data obtained show that in prolonged therapeutic application of nootropic agents it is necessary to bear also in mind their possible influence on the peripheral neurotransmitter systems.

Smooth-muscle effects of substance P.

The effects of substance P (SP) on smooth-muscle contractions induced by noradrenaline (NA) or by high- or low-frequency electrical stimulation (ES) were studied on isolated rat vas deferens and musculus anococcygeus. Neither the contractile effects of NA nor those of high-frequency ES were significantly changed by SP. The peptide in concentrations of 1 x 10(-7) M and 1 x 10(-6) M strongly potentiated (up to 70%) vas deferens contractions in response to low-frequency ES but slightly reduced those of musculus anococcygeus. Inhibition of the opiate receptors by 1 x 10(-6) M naloxone did not change the potentiating SP-effect on vas deferens contractions. Blockade of the prostaglandin (PG) receptors by polyphloretin phosphate (PPP), 5 micrograms/ml, or of the PGs synthesis by indomethacin, 5 x 10(-6) M, resulted in a slight increase of the SP-potentiating effect. The present results suggest that specific presynaptic SP-receptors (excitatory or inhibitory) play a major role in the mechanism of the potentiating action of substance P.

Smooth-muscle effects of C-terminal tripeptide of substance P.

The effects of the C-terminal tripeptide fragment of substance P(SP-C-TP) and its interactions with substance P(SP) were studied on isolated smooth-muscle preparations (rat musculus anococcygeus and vas deferens and rabbit ear central artery). Like SP, SP-C-TP (1 x 10(-8) M-1 x 10(-4)M) potentiated contractions of vas deferens and musculus anococcygeus elicited by low frequency electrical stimulation (LFES), the effect of the fragment being much weaker than that of the neuropeptide. The potentiating effect of SP was strongly reduced by SP-C-TP. The fragment slightly decreased the noradrenaline (NA)-induced contractions of vas deferens only. When the pharmacological agents were applied extralumenally only high SP concentrations (1 x 10(-7)M and 1 x 10(-6)M) significantly potentiated the LFES-evoked smooth-muscle contractions. SP-induced potentiation was abolished by SP-C-TP. Intralumenal administration of the neuropeptide and its fragment always led to a marked inhibition of the LFES contractile effects. The observed effects suggest that SP-C-TP acts as a competitive dualist of SP. The data is interpreted in terms of the hypothesis that the neuropeptide fragments might perform as a natural antagonist of the peptides and may control their effects.

The role of H1- and H2-receptors in the modulatory effects of histaminergic agents on adrenergic neurotransmission in rat vas deferens.

The role of the H1- and H2-receptors in the modulatory effects of histamine and other histaminergic drugs on smooth muscle adrenergic neurotransmission was studied on isolated preparations from rat vas deferens. The typical biphasic action (potentiation by low concentrations and inhibition by high concentrations) of histamine and some H1- or H2-agonists on vas deferens contractions induced by low frequency electrical stimulation (ES) was markedly changed by H1- or H2-antagonists. After blockade of H1-receptors, the potentiating effect of histamine and the histaminergic agonists was diminished or even reversed. The inhibition of the smooth muscle contractions by the drugs tested was stronger after H1-antagonists. Blockade of H2-receptors usually enhanced the potentiating effect of the histaminergic agonists on ES-evoked vas deferens contractions. The inhibitory action of histamine and the histaminergic agents tested was decreased or even reversed after H2-receptor blockade. These results confirm the presence of H1-excitatory and H2-inhibitory receptors whose activation or inhibition can modulate adrenergic neurotransmission in vas deferens.

Histaminergic agents can modulate adrenergic smooth muscle neurotransmission.

The effects of histamine and some agonists and antagonists of the two types of histaminergic receptors on adrenergic smooth muscle neurotransmission were studied. The experiments were carried out on electrical stimulated (0.1 Hz, 1 pulse, 1 msec pulse duration, supramaximal voltage) prostatic part of rat vasa deferentia. Histamine, 2-(aminoethyl) thiazole and 2-methylhistamine (H1-agonists) as well as dimaprit (H2-agonist) had a biphasic effect on smooth muscle contractions induced by electrical stimulation (ES): low drug concentrations potentiated and high concentrations markedly inhibited the ES-contractions. The agonist of H1-receptors pyridylethylamine in low concentrations did not affect the smooth muscle contractions and in high concentrations decreased their amplitude. Diphenhydramine and mepyramine (H1-antagonists) strongly potentiated (up to 250%) the ES-contractions, while the H2-antagonist cimetidine did not change them. These effects might be due to the interaction of the drugs tested with different populations of the histaminergic receptors.

Experimental pharmacological study of three species from genus Salvia.

Fifteen extracts isolated from three species of genus Salvia were studied: two from Salvia officinalis, seven from Salvia triloba and six from Salvia verbenaca. Their effects on the blood pressure of cats and spontaneously hypertensive rats were examined. The smooth-muscle effects of the extracts were studied on isolated segments of guinea-pig ileum. The effects of some of the extracts on hexobarbital anaesthesia were investigated. Applied intravenously and duodenally, aqueous-alcohol extract of Salvia officinalis causes moderate but prolonged lowering of the blood pressure in cats. Decoction of Salvia triloba also possesses a similar effect (in experiments on spontaneously hypertensive rats). Most of the extracts isolated from Salvia officinalis and Salvia triloba inhibit to various degrees smooth-muscle contractions induced by acetylcholine, histamine, serotonin and BaCl2, whereas extracts of Salvia verbenaca usually potentiate them. Substances isolated from Salvia triloba prolong hexobarbital sleep. Future studies of substances isolated from Salvia officinalis and Salvia triloba are promising with a view to their spasmolytic and hypotensive actions. There exist marked interspecies differences in the pharmacological effects of biologically active substances isolated from genus Salvia.

Protamine inhibits adenylate cyclase activity: a possible reason for the toxicity of protamine.

Protamine is an effective inhibitor of the various activated forms of adenylate cyclase of liver plasma membranes. Inhibition of adenylate cyclase may account for its toxic but not its antitumor effects.

Interaction of histamine with adrenergic smooth-muscle neurotransmission. II. Significance of calcium ions for the effects of histamine on contractions induced by endogenous noradrenaline.

The role of Ca2+ for the effects of histamine on contractions induced by electrostimulation has been studied on smooth-muscle organs with adrenergic neurotransmission (rat anococcygeal muscle and vas deferens). The low Ca2+-concentrations in the organ bath (below 1.8 mM) reduce the amplitude of the smooth-muscle contractions in response to electrostimulation (more markedly at the low frequency), at the same time potentiating the inhibitory action of histamine on the electrostimulation-induced contractions of the isolated preparations. Raising the Ca2+-concentration in the nutrient medium increases the magnitude of the contractions in response to electrostimulation. At the same time the high Ca2+-concentrations weaken the second (inhibitory) phase of the action of histamine on the electrostimulation-induced contractions of the smooth-muscle preparations. The potentiating action of histamine on contractions in response to electrostimulation is not essentially influenced by the changes in Ca2+-concentration. The data obtained show that Ca-ions may play a role in the mechanism of the inhibitory action of histamine on the smooth-muscle adrenergic neurotransmission, which is assumed to be mediated by presynaptic H2-histaminergic receptors.

Interaction of histamine with adrenergic smooth-muscle neurotransmission. III. Significance of magnesium ions for the effects of histamine on contractions induced by endogenous noradrenaline.

The significance of Mg2+ for the effects of histamine on smooth-muscle contractions in response to electrostimulation with different frequency has been studied in organs with adrenergic neurotransmission (prostatic part of vas deferens and anococcygeal muscle of rats). Reduction of the concentration of Mg-ions below 1.05 mM usually markedly potentiates the electrostimulation-induced contractions, whereas high Mg2+-concentrations (above 1.05 mM) sharply reduce their magnitude. The changes in the concentration of the Mg-ions in the nutrient medium do not influence essentially the inhibitory effects of histamine on smooth-muscle contractions in response to electrostimulation. In the presence of lower concentrations muscle contractions in response to electrostimulation. In the presence of lower concentrations of Mg-ions, the potentiating effect of histamine on electrostimulation does not change substantially. The rise in Mg2+-concentration above 1.05 mM considerably increases the potentiating action of the low histamine concentrations on the electrostimulation-induced contractions. This effect was more pronounced in smooth-muscle preparations stimulated with a lower frequency. The data obtained suggest that histamine counteracts the contractile response to electrostimulation induced by high concentrations of Mg-ions. It may be assumed that Ca-ions also participate in the realization of this histamine effect.

Interaction of histamine with adrenergic smooth muscle neurotransmission. I. Effects of histamine on smooth muscle contractions induced by exogenous or by endogenous noradrenaline.

The effects of histamine on contractions in response to exogenous noradrenaline or to electrical stimulation were studied on two smooth muscle preparations with adrenergic neurotransmission--rat anococcygeal muscle and vas deferens. Histamine (1 X 10(-6)M-1 X 10(-4)M) did not affect significantly the contractions of vas deferens induced by noradrenaline (1 X 10(-8)M-1 X 10(-4)M), but decreased in a concentration-dependent manner the contractile effects of noradrenaline on anococcygeal muscle. The EC50 of noradrenaline on the latter preparation was increased 2.6-16.2 times by histamine but the antagonism was of a noncompetitive type. Histamine exerted a biphasic effect on the smooth muscle contractions in response to square wave electrical stimulation with supramaximal voltage (vas deferens--0.1 Hz, 1 sh or 10 Hz, 20 sh; anococcygeal muscle--5 Hz, 8 sh or 10 Hz 20 sh). The lower histamine concentrations (1 X 10(-12)M-1 X 10(-7)M) slightly potentiated the contractions and the higher concentrations (1 X 10(-6)M-1 X 10(-4)M) markedly inhibited the contractions in response to electrical stimulation. The results obtained are consistent with the hypothesis that the modulatory role of histamine for the adrenergic neurotransmission is mediated via presynaptic inhibitory H2--and postsynaptic excitatory H1--histaminergic receptors.