[Hydration products of veratrine-alkamines. 6. Veratrine-Veratrum alkaloids].
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Amino Acids↗
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The 24Na-transport increasing effect of veratrine in frog sartorius muscle influenced by the tonicity, composition and temperature of the external environment.
The influence of tonicity, ionic composition and temperature of the incubating medium on the increasing effect of veratrine on 24Na transport in the frog sartorius muscle has been studied. (1) The effect of veratrine applied during 24Na loading on the rate coefficient for sodium loss depended on the tonicity of the medium. The rate of loss of 24Na from muscles loaded in the presence of veratrine was not affected if the muscles had been equilibrated in hypertonic medium. However, when treating the muscles with veratrine in isotonic medium during 24Na loading, we obtained a twofold increase in the rate coefficient for sodium loss. (2) The effect of veratrine applied during the desaturation period on 24Na efflux was also found to depend on the tonicity of the medium. Veratrine applied during the desaturation period increased the 24Na efflux in muscles equilibrated in isotonic Ringer's solution. However, when the muscles were equilibrated in hypertonic medium, veratrine did not influence 24Na efflux, not even after the rate of 24Na loss had been decreased by ouabain. (3) Hypertonic medium inhibited the Li uptake-enhancing effect of veratrine, while in isotonic medium veratrine had a marked enhancing effect. (4) In hypertonic medium lithium inhibited the otherwise characteristic increasing effect of veratrine on 24 Na uptake. (5) The increase of intracellular sodium concentration as a result of incubation in cold, potassium-free Ringer's solution did not influence the 24Na exchange-increasing effect of veratrine in isotonic medium. (6) The increasing effects of 0.1 and 0.5 mM veratrine on 24Na influx had the same degree at room temperature. However, at 5 degrees C 0.5 mM veratrine increased 24Na influx to a greater extent than 0.1 mM. (7) On the basis of our earlier experiments it has been suggested that the site of action of the 24Na uptake-increasing effect of veratrine could be the neural structures in the muscle equilibrated in hypertonic media. The present experiments confirm this suggestion and at the same time demonstrate that there are substantial differences in the mechanism of the sodium transport of veratrine-treated neural and muscle membranes, which become more apparent in hypertonic medium.
Animals↗
Effects of veratrine and paeoniflorin on the isolated rat aorta.
The interactions and mechanisms between veratrine and paeoniflorin on the isolated rat aorta were studied. Veratrine (1x10(-6) to 1x10(-4) g/ml) could induce contraction on the isolated rat aorta in a concentration-related manner. Paeoniflorin had no effect on the isolated rat aorta. Pretreatment with prazosin (1x10(-6) M) and nifedipine (1x10(-6) M) but not yohimbine (1x10(-5) M) could decrease the tension of contraction induced by veratrine (1x10(-4) g/ml). Sodium nitroprusside (1x10(-4) M) could inhibit the contraction induced by veratrine (1x10(-4) g/ml) with or without endothelium, whereas methylene blue (5x10(-5) M) could increase the contraction induced by veratrine (1x10(-4) g/ml). Treatment with veratrine (1x10(-4) g/ml) could decrease the tension of contraction induced by norepinephrine (1x10(-6) M) or phenylephrine (1x10(-4) M). The inhibition of veratrine on norepinephrine-induced contraction was potentiated by L-arginine (1x10(-4) M) and reversed by L-NAME (1x10(-5) M). Paeoniflorin (1x10(-4) M) could decrease the tension of contraction induced by veratrine (1x10(-4) g/ml) and methylene blue (5x10(-5) M). The inhibition of paeoniflorin on veratrine was more potent on rat isolated aorta with endothelium than without endothelium. Ryanodine (1x10(-5) M) and Ca2+ -free medium could inhibit methylene blue-induced contraction. From the above results, the relaxation of veratrine on the norepinephrine-induced contraction might be related to the increase of NO and cGMP. The contraction of veratrine on the isolated rat aorta was via the increase of intracellular calcium which was inhibited by paeoniflorin.
Animals↗
In vivo mechanisms underlying dopamine release from rat nigrostriatal terminals: I. Studies using veratrine and ouabain.
The in vivo mechanisms underlying the dopamine (DA)-releasing actions of veratrine and ouabain in the striatum of halothane-anaesthetised rats have been investigated using brain microdialysis. Relevant catecholamines and indoleamines were separated and quantified using HPLC combined with an electrochemical detection system. Veratrine (10 micrograms/ml-1 mg/ml) and ouabain (10 microM-1 mM) were added to the medium perfusing the dialysis probes. Both compounds increased dialysate DA content in a dose-related manner. Dialysate levels of the DA metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid and the serotonin metabolite 5-hydroxyindoleacetic acid were reduced by both veratrine and ouabain. Veratrine-induced DA efflux was maximal in the first 20-min sample collected after drug infusion began, whereas the maximal effect of ouabain was not observed until 20-40 min after administration began. Veratrine-induced DA efflux was unaffected by systemic injection of the DA uptake inhibitor nomifensine but was inhibited by either coperfusion of tetrodotoxin (TTX) or removal of calcium from the perfusing buffer. These data suggest that veratrine induces release of DA via a carrier-independent mechanism, perhaps involving an exocytotic release process. In contrast, ouabain-induced DA release was reduced by nomifensine but was inhibited to a lesser degree by calcium depletion and TTX. Detailed analyses of these data suggest that although ouabain initially induces release of DA via a carrier-dependent mechanism, an exocytotic process may also be involved. The finding that ouabain-induced DA efflux exhibits a degree of TTX and calcium sensitivity suggests that membrane depolarisation caused by Na+,K(+)-ATPase blockade opens voltage-gated sodium channels and initiates an exocytotic release of DA. The intracellular pools of DA involved in the release of DA induced by veratrine and ouabain were also examined. Depletion of vesicular pools of DA by pretreatment with reserpine reduced the amount of DA release induced by both agents, although this effect was only significant in the case of veratrine. However, in reserpinised animals the residual amount of DA release induced by veratrine was inhibited by nomifensine, a result suggesting that DA may be released via a carrier-dependent process in the absence of vesicular DA. Newly synthesised pools of DA were also depleted by pretreatment with the DA synthesis inhibitor alpha-methyl-p-tyrosine. Under these conditions, both veratrine- and ouabain-induced DA efflux was reduced.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Histochemical differences in the responses of predominantly fast-twitch glycolytic muscle and slow-twitch oxidative muscle to veratrine.
The aim of this study was to investigate if the Na(+)-channel activating alkaloid veratrine is able to change the oxidative and m-ATPase activities of a fast-twitch glycolytic muscle (EDL, extensor digitorum longus) and slow-twitch oxidative muscle (SOL, soleus) in mice. Oxidative fibers and glycolytic fibers were more sensitive to veratrine than oxidative-glycolytic fibers 15, 30 and 60 min after the i.m. injection of veratrine (10 ng/kg) with both showing an increase in their metabolic activity in both muscles. In EDL, the m-ATPase reaction revealed a significant (p < 0.001) decrease (50%) in the number of type IIB fibers after 30 min while the number of type I fibers increased by 550%. Type I fibers decreased from 34% in control SOL to 17% (50% decrease) in veratrinized muscles, with a 10% decrease in type IIA fibers within 15 min. A third type of fiber appeared in SOL veratrinized muscle, which accounted for 28% of the fibers. Our work gives evidence that the changes in the percentage of the fiber types induced by veratrine may be the result, at least partially, from a direct effect of veratrine on muscle fibers and else from an interaction with the muscle type influencing distinctively the response of a same fiber type. Based on the results obtained in the present study the alterations in EDL may be related to the higher number of Na(+) channels present in this muscle whereas those in SOL may involve an action of veratrine on mitochondria. Although it is unlikely that the shift of enzymes activities induced by veratrine involves genotypic expression changes an alternative explanation for the findings cannot be substantiated by the present experimental approach.
Adenosine Triphosphatases↗
Concentration dependence of the veratrine effect on inducing depolarization and membrane potential oscillation in skeletal muscle.
The concentration dependence of the effect of veratrine in inducing depolarization and membrane potential oscillation in the frog sartorius muscle has been studied. (1) On increasing the veratrine concentration from 0.025 to 1 mM, the latency period of the development of membrane potential oscillation and depolarization is proportionally shortened. (2) On changing the veratrine concentration from 0.025 to 1 mM, the magnitude of depolarization is raised logarithmically. (3) When the veratrine concentration reaches 0.05-0.1 mM, both the amplitude and the frequency of the membrane potential oscillation increase. On rising to 1 mM, a further increase in frequency to eight-fold occurs especially in the later phase of oscillation. At this concentration range, the amplitude of oscillation inversely proportional to the concentration of veratrine. (4) On increasing the veratrine concentration above 0.1 mM, the membrane potential oscillation ceases after a temporary rise of frequency. This inhibitory effect of veratrine is, however, reversible, and oscillations appear again, despite the absence of veratrine in Ringer's solution. This also proves the persistance of the veratrine effect.
Animals↗
The effects of calcium antagonists on calcium overload contractures in embryonic chick myocytes induced by ouabain and veratrine.
1. The protective effects of some calcium antagonists against different forms of calcium overload contracture were investigated in embryonic chick cardiac myocytes. 2. Tetrodotoxin-sensitive sodium currents were recorded from the myocytes by the whole-cell voltage-clamp technique. Although the peak current was attenuated by veratrine, the inactivation process was markedly inhibited, resulting in a large increase in the total inward current. Action potentials were prolonged by veratrine, automaticity was inhibited and the membrane potential depolarized from -79 to around -45 mV. 3. Measurements of contraction were made from aggregates of myocytes using a video edge detection technique which quantified edge movement. Veratrine caused an initial positive inotropism then inhibited automaticity of aggregates with subsequent development of a tonic contracture to around 300% of the twitch contraction. 4. Veratrine-induced contractures were not significantly affected by 10 microM diltiazem or verapamil. Nifedipine (5 microM), nimodipine (5 microM) and ryanodine (5 microM) also had little effect whilst nicardipine and flunarizine caused a concentration-dependent inhibition of veratrine-induced contractures with IC50s of 3 microM and 2 microM respectively. 5. Veratrine-induced contractures were found to be very sensitive to extracellular calcium concentration with an EC50 of 32 microM. Edge movement associated with beating of the myocytes was much less sensitive to calcium (EC50 = 1 mM). Submaximal veratrine contractures in 20-50 microM extracellular calcium were not potentiated by 1 microM Bay K 8644. 6. Tetrodotoxin also inhibited veratrine-induced contractures but did not affect contractions induced by ouabain in the presence of 10 microM diltiazem. 7. Ouabain-induced contractures were also inhibited by nicardipine and flunarizine indicating that these drugs can protect against calcium overload in embryonic chick heart by a mechanism independent of the normal form of voltage-sensitive sodium or calcium channels.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Action and mechanism of action of veratrine on renin secretion from rat kidney slices.
It is well known that norepinephrine released from the renal nerves stimulates the secretion of renin by a beta adrenergic mechanism. In the present experiments, we investigated the effects of renin secretion of veratrine, which depolarizes nerve terminals and thereby causes transmitter release. The rat renal cortical slice preparation was used. Veratrine (10-200 microM) stimulated renin secretion in a concentration-dependent manner. Veratrine-stimulated secretion was antagonized by timolol (0.9 and 9.0 microM) and by tetrodotoxin (0.5 and 5.0 microM), a sodium channel blocker. Neither drug abolished completely the stimulatory effect of veratrine. Moreover, veratrine stimulated renin secretion in slices prepared from previously denervated kidneys; this response was not antagonized by timolol. These results are consistent with the hypothesis that veratrine stimulates renin secretion by at least two mechanisms. One component probably consists of veratrine-induced depolarization of renal nerve terminals, release of norepinephrine and activation of juxtaglomerular cell beta adrenergic receptors; the other component appears to be independent of nerve terminals in the preparation. We conclude that the tetrodotoxin-sensitive component of veratrine-stimulated renin secretion in this preparation is an in vitro model of renal nerve-stimulated renin secretion; it should be useful in investigating substances which affect renin secretion by presynaptic modulation of transmitter release.
Animals↗
Histoenzymological and ultrastructural changes in lateral muscle fibers of Oreochromis niloticus (Teleostei: Cichlidae) after local injection of veratrine.
The effects of veratrine have been investigated in mammalian, amphibian, and crustacean muscle, but not in fish. In this work, the action of veratrine was studied in the lateral muscle of the freshwater teleost Oreochromis niloticus after intramuscular injection. Histoenzymological typing and electron microscopy of muscle fibers before and 15, 30, and 60 min after veratrine injection (10 ng/kg fish) were used to indirectly assess the morphological changes and the oxidative and m-ATPase activities. In some cases, muscles were pretreated with tetrodotoxin to determine whether the ultrastructural changes were the result of Na(+) channel activation by veratrine. Veratrine altered the metabolism of fibers mainly after 30 min. Oxidative fibers showed decreased NADH-TR activity, whereas that of glycolytic and oxidative-glycolytic type fibers increased. There was no change in the m-ATPase activity of the three fiber types, except at 60 min postveratrine, when a novel fiber type, which showed no reversal after acidic and alkaline preincubations, appeared. Ultrastructural damage involved sarcomeres, myofibrils, and mitochondria, but the T-tubules remained intact. Pretreatment with tetrodotoxin (1 ng/ml) prevented the ultrastructural changes caused by veratrine. These results show that in fish skeletal muscle veratrine produces some effects that are not seen in mammalian muscle.
Adenosine Triphosphatases↗
Release of gonadotropin-releasing hormone by veratrine in a hypothalamic-pituitary coincubation.
The effects of veratrine and veratridine on the release of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) from incubations of pituitary alone, hypothalamus alone, and coincubations of hypothalamus and pituitary were examined. Veratrine produced only small increases in LH secretion from pituitaries alone relative to that produced by exogenous GnRH. Veratrine caused a calcium-dependent release of GnRH from the hypothalamus. When a pituitary and hypothalamus were coincubated veratrine produced increases in LH secretion that were much larger than its direct pituitary effects. Veratridine also produced large increases in the release of GnRH and LH from hypothalamic-pituitary coincubations. The direct effect of veratridine on pituitary LH release, however, was greater than that of veratrine. The results indicate that veratrine is capable of releasing hypothalamic GnRH with relatively small direct effects on pituitary LH secretion. Hypothalamic-pituitary coincubations coupled with veratrine depolarization may be quite useful for studying hypothalamus factors controlling pituitary hormone release.
Animals↗
The interactions of paeoniflorin and veratrine on isolated rat atria.
In this study, we attempted to identify the interactions and mechanisms between veratrine and paeoniflorin on isolated rat atria. Paeoniflorin alone showed no effect on the rat atria. Veratrine increased the atrial contraction and induced arrhythmia at 1 x 10(-5) g/ml. Veratrine could directly induce contraction and elicit tetanic contraction at 1 x 10(-4) g/ml in the left atria with or without electric stimulation. Paeoniflorin (4.8 x 10(-6) to 4.8 x 10(-3) g/ml), verapamil (2.2 x 10(-6) g/ml), tetrodotoxin (TTX) (3.2 x 10(-8) g/ml) and quinidine (7.5 x 10(-6) g/ml) inhibited the increase of contraction and delayed the onset of contraction induced by veratrine (1 x 10(-5) g/ml). The inhibitory effect of paeoniflorin combined with verapamil on the contraction induced by veratrine was more potent than that of paeoniflorin or verapamil alone. However, the inhibitory effect of paeoniflorin was not potentiated by TTX or quinidine. From the above results, the contraction evoked by veratrine in the rat atria may be concluded to be caused by the stimulation of Na(+)- and Ca(2+)-ion channels. The inhibition of paeoniflorin on the contraction induced by veratrine may primarily be related to the blockade of Ca2+ channels.
Animals↗
Effects of veratrine and paeoniflorin on isolated mouse vas deferens.
In this study, we attempted to identify the interactions and mechanisms between veratrine and paeoniflorin on isolated mouse vas deferens. Paeoniflorin had no effect on isolated mouse vas deferens. Veratrine (1 x 10(-5) approximately 1 x 10(-3) g/ml) could directly induce contraction of isolated rat and mouse vas deferens. The concentration induced by veratrine (1 x 10(-5) g/ml) was completely inhibited by Ca2+-free solution and verapamil (1 x 10(-5) M), in both the epididymal and the prostatic portions of isolated mouse vas deferens. Naloxone (1 x 10(-5) M) did not alter the contraction induced by veratrine (1 x 10(-5) g/ml) in either the epididymal or the prostatic portions of isolated mouse vas deferens. Paeoniflorin (4.8 x 10(-5) g/ml) inhibited the contraction induced by veratrine (1 x 10(-5) g/ml) in both the epididymal and the prostatic portions of isolated mouse vas deferens. Paeoniflorin (4.8 x 10(-5) g/ml) potentiated norepinephrine (1 x 10(-5) M)-induced phasic contraction in the epididymal portion, but decreased contractions in the prostatic portion. Paeoniflorin (4.8 x 10(-5) g/ml) increased KCI (56 mM)-induced phasic contraction in the epididymal portion, but decreased the tonic contraction in either the epididymal or the prostatic portion. Veratrine (1 x 10(-5) g/ml)-induced contractions could be decreased by pretreatment with ryanodine (1 x 10(-5) M) in both the epididymal and the prostatic portions. Pretreatment with the combination of paeoniflorin (4.8 x 10(-5) g/ml) and ryanodine (1 x 10(-5) M) did not potentiate the inhibition of paeoniflorin in the veratrine-induced contraction in both the epididymal and the prostatic portions of isolated mouse vas deferens.
Animals↗
Veratrine-induced decrease of (Na+ + K+)-adenosine triphosphatase activity in rat brain slices.
The effect of membrane excitability on (Na+ + K+)-adenosine triphosphatase (ATPase) was studied in rat brain slices. The treatment of the brain cortical slices with veratrine for more than 10 min caused a significant decrease of the (Na+ + K+)-ATPase activity. The similar inhibition of the enzyme by veratrine was observed in the hippocampus and hypothalamus, and the veratrine treatment did not affect the sensitivity of the cortical enzyme for ouabain inhibition. These findings suggest that two isozymes of (Na+ + K+)-ATPase are equally inhibited by the treatment. Veratrine inhibited the partial reactions such as Na+-dependent phosphorylation and K+-stimulated phosphatase as well as the specific binding of [3H]ouabain. Agents which increase intracellular Na+ concentration also inhibited the enzyme activity. The effects of veratrine were blocked by Na+-free medium or tetrodotoxin. Low Na+ medium decreased the enzyme activity, and the effect was blocked by amiloride or Ca++-free medium, indicating the involvement of Na+/Ca++ exchange in the inhibition. The decreased activity induced by low Na+ or high K+ medium was restored to the normal level by the subsequent incubation in normal medium. The inhibitory effect of veratrine was dependent on external Ca++, and was blocked by addition of W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide]. A23187 also decreased (Na+ + K+)-ATPase activity in the slices. High Mg++ medium blocked the effect of veratrine but not that of monensin which was not dependent on external Ca++.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Comparison of norepinephrine- and veratrine-induced phosphoinositide hydrolysis in rat brain.
Stimulation of phosphoinositide hydrolysis by depolarization with veratrine was compared to that produced by stimulation of alpha-1 adrenoceptors by norepinephrine. The phosphoinositides in rat cerebral cortex were labeled with [myo-3H]inositol and the effects of the drugs on the formation of the following inositol phosphates were determined: inositol 1-phosphate (IP); inositol 1,4-bisphosphate (IP2); mixture of inositol 1,4,5-trisphosphate and inositol 1,3,4-trisphosphate (IP3). Termination of the hydrolysis by trichloroacetic acid resulted in lower basal levels and more reproducible results than termination by water lysis or a chloroform-methanol mixture (CHCl3-MeOH). The amounts of IP and IP2 formed by a maximal concentration of veratrine were about one half of that formed by a maximal concentration of norepinephrine although the amount of IP3 formed after stimulation by veratrine was only about 10% of that produced by norepinephrine. The increase in IP was linear with time (30 min) for both norepinephrine and veratrine. Stimulation of IP2 and IP3 formation by veratrine reached a maximum at 5 min whereas that produced by norepinephrine continued to increase for 30 min. Blockade of voltage-dependent calcium channels with manganese produced nearly complete antagonism of the veratrine response while only partially antagonizing the norepinephrine response. Norepinephrine-induced IP2 formation was less sensitive to manganese than was formation of IP or IP3. These data suggest that either veratrine and norepinephrine cause hydrolysis of different pools of phosphoinositide or that the hydrolysis occurs by different mechanisms. The data also suggest that IP and IP2 may be produced directly from phosphatidylinositol and phosphatidylinositol 4-phosphate rather than solely as a metabolite of IP3.
Animals↗
Veratrine-induced tetanic contracture of the rat isolated left atrium. Evidence for novel direct protective effects of prazosin and WB4101.
An investigation has been made of the putative direct myocardial protective effects of the alpha 1-adrenoceptor antagonists, prazosin and WB4101, against tetanic contractures of rat isolated left atria following modified Na+ channel function and consequent Ca2+ loading elicited by veratrine. Veratrine evoked concentration-dependent, reversible, tetanic contractures which were critically dependent upon the external Ca2+ concentration. Tetrodotoxin (TTX), prazosin, WB 4101 and R 56865 (0.1-10 microM) prevented tetanic contracture elicited by veratrine (100 micrograms/ml) at concentrations which were significantly lower than those which decreased active tension development. The apparent Hill coefficients (nH) obtained for TTX, prazosin, WB 4101 and R 56865 were comparable (range 0.79-0.93), and are consistent with a single site of action. In contrast, the class 1 antiarrhythmic agents, quinidine and lidocaine, elicited no significant inhibition of veratrine-induced contracture at 30 microM, but almost completely abolished the contractures at 100 microM. The nH values for quinidine and lidocaine were found to be significantly greater than unity (3.1 and 2.6, respectively). The L-type Ca2+ channel blockers, diltiazem, nicardipine, nifedipine and verapamil only weakly prevented tetanic contracture, whilst markedly, and concentration-dependently, decreasing active tension development. Neither atropine (10 microM) nor propranolol (1 microM) significantly modified either veratrine-induced contractures or active tension development. In conclusion, evidence is presented of novel, direct protective effects of prazosin and WB 4101 against tetanic contracture following modified Na+ channel function and Ca2+ loading provoked by veratrine. The precise mechanisms involved are unclear at present, but appear to be distinct from blockade of atrial alpha 1-adrenoceptors or L-type Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Antagonists↗
Unequal depolarization of the membrane of the rat diaphragm muscle fibres caused by veratrine.
The effect produced by veratrine on transmembrane potential was investigated in five distinct regions of the isolated rat diaphragm blocked with either d-tubocurarine or alpha-bungarotoxin. It was found that small (0.4 micrograms/ml) and large (2.0 micrograms/ml) doses of veratrine depolarize only two or three of these regions. With the use of a very large (10.0 micrograms/ml) dose depolarization occurred in all five regions of the diaphragm but the effect was much larger in those areas of the muscle fibre membrane which were selectively depolarized by the smaller ones. These results clearly indicate either an unequal distribution of sodium channels activated by veratrine or differences in sodium channel density in distinct areas of the muscle fibre membrane. Supersensitivity of veratrinized muscles to potassium was confirmed. However, the sensitiveness to the depolarizing action of potassium was only increased in the regions of the diaphragm partially depolarized by veratrine. This suggests that partial depolarization of the muscle fibre membrane was actually the cause of the supersensitivity. The possible involvement of potassium and of the unequal depolarization of the muscle fibre membrane in the veratrine response is considered.
Animals↗
Protective effect of bepridil against veratrine-induced contracture in rat atria.
In isolated stimulated rat atria, superfusion with veratrine caused a marked contracture (VIC) which was absent in calcium-free medium and which was inhibited by tetrodotoxin (IC50VIC of 1.38 microM). Lowering the extracellular calcium concentration from 2.5 to 0.5 or 0.1 mM reduced the veratrine-induced contracture and delayed its onset. Superfusion of bepridil (1-10 microM) for 60 min before and during veratrine exposure markedly slowed the onset of contracture, reduced the maximum response (IC50VIC = 2.11 microM) and facilitated recovery upon washout of the alkaloid. The direct negative inotropic effect (NIE) of bepridil (IC50NIE = 10.96 microM) resulted in an VIC/NIE ratio of 5.19 for this drug. The protective effects of bepridil were rate-independent and were not modified by the presence of atropine (1.4 microM) and propranolol (0.3 microM) in the medium. Diltiazem, verapamil and nifedipine only reduced veratrine-induced contracture at concentrations much higher than those producing a negative inotropic effect, giving them negative NIE/VIC ratios of 0.31, 0.08 and 0.08 respectively. Like bepridil, flunarizine had a positive NIE/VIC ratio (15.87, IC50VIC = 3.71 microM). The lack of effect of the quaternary derivative of bepridil CERM 11888 indicated that intracellular sites of action may be involved in the activity of bepridil on veratrine-induced contracture. Given that veratrine-induced changes may mimic some of the pathological changes occurring in ischaemia, the results suggest that bepridil and flunarizine may be more effective than L-type, slow calcium ion-channel blockers in protecting against calcium overload during ischaemia and reperfusion injury.
Animals↗
Effects of veratrine and veratridine on oxygen consumption and electrical membrane potential of isolated rat skeletal muscle and liver mitochondria.
We have previously shown that veratrine, a mixture of alkaloids known as Veratrum alkaloids, produces skeletal muscle toxicity, and there is evidence that veratrine interferes with the energetics of various systems, including cardiomyocytes and synaptosomes. In this work, we explored the effects of veratrine and veratridine, a component of this mixture, in rat skeletal muscle mitochondria and compared the results with those seen in liver mitochondria. Veratrine and veratridine alkaloids caused a significant concentration-dependent decrease in the rate of state 3 respiration, respiratory control (RCR) and ADP/O ratios in isolated rat skeletal muscle mitochondria (RMM), but not in rat liver mitochondria (RLM) supported by either NADH-linked substrates or succinate. The oxygen consumption experiments showed that RMM were more susceptible to the toxic action of Veratrum alkaloids than RLM. The addition of veratrine (250 microg/ml) to RMM caused dissipation of the mitochondrial electrical membrane potential during succinate oxidation, but this effect was totally reversed by adding ATP. These results indicate that there are chemical- and tissue-specific toxic effects of veratrine and veratridine on mitochondrial respiratory chain complexes. Identification of the specific respiratory chain targets involved should provide a better understanding of the molecular mechanisms of the toxicity of these agents.
Animals↗