Flecainide inhibits the stimulatory effect of veratridine on the response of airway mechanoreceptors to maintained inflations in rats.

AIMS: the purpose of the present study was to investigate (a) whether maintained inflations result in the inhibition of slowly adapting pulmonary stretch receptor (SAR) discharge to elicit an abrupt change in receptor activity and (b) whether pretreatment with veratridine, a Na(+) channel opener, and/or flecainide, a Na(+) channel blocker, alters the responses of SAR properties to maintained inflations. MAIN METHODS: we measured the properties of SAR activity during maintained inflations at different pressures in 31 anesthetized, artificially ventilated rats with unilateral vagotomy. KEY FINDINGS: During maintained inflations (approximately 5, 10 and 15 cmH(2)O) for about 5s, the procedures did not produce the induction of inhibition of either 16 low-threshold SARs (firing during both inflation and deflation) or 15 high-threshold SARs (firing during inflation only). In these preparations, the excitatory responses of SARs to maintained inflations at three different pressures were markedly enhanced after administration of veratridine (50 µg/kg), but under such conditions, the inhibition of SAR discharges was not observed. In the same SAR preparations, after flecainide treatment (9 mg/kg) sufficient for the blockade of veratridine (50 µg/kg)-induced SAR stimulation, maintained inflations at higher pressures (10 and 15 cmH(2)O) greatly inhibited SAR discharges. Under these conditions, the inhibition of SAR discharges was not observed during maintained inflations at 5 cmH(2)O. SIGNIFICANCE: These results suggest that neither low-threshold SARs nor high-threshold SARs in the rat lung are deactivated during maintained inflations at higher pressures.

Bidirectional modulation of isoflurane potency by intrathecal tetrodotoxin and veratridine in rats.

BACKGROUND AND PURPOSE: Results from several studies point to voltage-gated Na(+) channels as potential mediators of the immobility produced by inhaled anaesthetics. We hypothesized that the intrathecal administration of tetrodotoxin, a drug that blocks Na(+) channels, should enhance anaesthetic potency, and that concurrent administration of veratridine, a drug that augments Na(+) channel opening, should reverse the increase in potency. EXPERIMENTAL APPROACH: We measured the change in isoflurane potency for reducing movement in response to a painful stimulus as defined by MAC (minimum alveolar concentration of anaesthetic required to abolish movement in 50% of subjects) caused by intrathecal infusion of various concentrations of tetrodotoxin into the lumbothoracic subarachnoid space of rats, and the change in MAC caused by the administration of a fixed dose of tetrodotoxin plus various doses of intrathecal veratridine. KEY RESULTS: Intrathecal infusion of tetrodotoxin (0.078-0.63 microM) produced a reversible dose-related decrease in MAC, of more than 50% at the highest concentration. Intrathecal co-administration of veratridine (1.6-6.4 microM) reversed this decrease in a dose-related manner, with nearly complete reversal at the highest veratridine dose tested. CONCLUSIONS AND IMPLICATIONS: Intrathecal administration of tetrodotoxin increases isoflurane potency (decreases isoflurane MAC), and intrathecal administration of veratridine counteracts this effect in vivo. These findings are consistent with a role for voltage-gated Na(+) channel blockade in the immobility produced by inhaled anaesthetics.

Intrathecal veratridine administration increases minimum alveolar concentration in rats.

BACKGROUND: Results from several studies point to sodium channels as potential mediators of the immobility produced by inhaled anesthetics. We hypothesized that the intrathecal administration of veratridine, a drug that enhances the activity or effect of sodium channels, should increase MAC. METHODS: We measured the change in isoflurane MAC caused by intrathecal infusion of various concentrations of veratridine into the lumbothoracic subarachnoid space of rats. We compared these result with those obtained from intracerebroventricular infusion. RESULTS: As predicted, intrathecal infusion of veratridine increased MAC. The greatest infused concentration (25 microM) also produced neuronal injury in the hindlimbs of two rats and decreased the peak effect on MAC. A concentration of 1.6 microM produced the largest (21%) increase in MAC. Intraventricular infusion of 1.6 and 6.4 microM veratridine did not alter MAC. Rats given 25 microM died. CONCLUSIONS: Intrathecal administration of veratradine increases MAC of isoflurane, a finding consistent with a role for sodium channels as potential mediators of the immobility produced by inhaled anesthetics.

Drug assessment based on detection of L-glutamate released from C6 glioma cells using an enzyme-luminescence method.

Monitoring of excitation activity of nerve cells is very useful for not only brain research but also assessment of the effects of various chemicals, including drugs and toxins. We previously reported a novel enzyme-luminescence method for real-time monitoring of l-glutamate release from C6 glioma cells with high levels of sensitivity ( approximately 10 nM) and temporal resolution (<1 s) using a luminescence plate reader. In the present study, we tested the applicability of this novel system for assessment of effects of drugs in vitro. Several drugs (e.g., veratridine and 4-aminopyridine) were administered to C6 glioma cells for inducing glutamate release. Moreover, antagonists of voltage-dependent Ca (2+) channels (e.g., nifedipine, flunarizine, and NiCl 2) and Na (+) channels (e.g., carbamazepine and lidocaine) were applied separately for evaluating the effects of these chemicals on glutamate release from the cells. The combined effect of carbamazepine and lidocaine was also investigated by using our method, and the combined effect was found to be more potent than that of single drug administration. These results indicated that the glutamate release from C6 cells was modulated by these drugs in a way similar to that found by using several conventional analytical techniques. We therefore conclude that the developed monitoring system for real-time detection of dynamic l-glutamate release from cells could be very useful for application to assessment of drugs acting on the nervous system.

Down regulation of sodium channel Na(v)1.1 expression by veratridine and its reversal by a novel sodium channel blocker, RS100642, in primary neuronal cultures.

This study investigated the effects of veratridine-induced neuronal toxicity on sodium channel gene (NaCh) expression in primary forebrain cultures enriched in neurons, and its reversal by a novel sodium channel blocker, RS100642. Using quantitative RT-PCR, our findings demonstrated the expression ratio of NaCh genes in normal fetal rat forebrain neurons to be Na(v)1.2 > Na(v)1.3 > Na(v)1.8 > Na(v)1.1 > Na(v)1.7 (rBII > rBIII > PN3 > rBI > PN1). Veratridine treatment of neuronal cells produced neurotoxicity in a dose-dependent manner (0.25-20 micro M). Neuronal injury caused by a dose of veratridine producing 80% cell death (2.5 micro M) significantly, and exclusively down-regulated the Na(v)1.1 gene. However, treatment of neurons with RS100642 (200 micro M) reversed the down-regulation of the Na(v)1.1 gene expression caused by veratridine. Our findings document for the first time quantitative and relative changes in the expression of various NaCh genes in neurons following injury produced by selective activation of voltage-gated sodium channels, and suggest that the Na(v)1.1 sodium channel gene may play a key role in the neuronal injury/recovery process.

Cardiovascular and respiratory interactions of hyperosmolar saline, scorpion toxin, and veratridine in rats.

This study evaluates the cardiovascular and respiratory effects evoked by hypertonic sodium chloride solution (HSS) and the possible interactions of these effects with scorpion toxin (TX) or veratridine (V). Groups 1 (1 mL/kg, rapid), 2 (4 mL/kg, rapid), and 3 (4 mL/kg, slow) were used for comparison of HSS administered by rapid or slow injection. HSS (4 mL/kg) was injected after bilateral vagotomy (group 4) or administration of atropine (group 5). In groups 6 (1 mL/kg in bolus), 7 (4 mL/kg in bolus), and 8 (4 mL/kg/60 s), HSS was injected 20 min after the administration of TX (250 microg/kg). In group 9, two doses of V (25 microg/kg, i.v.) were injected 10 min apart. Concomitantly with the second dose of V, HSS (4 mL/kg) was injected into the jugular vein. HSS administered by rapid injection (1 mL/kg) resulted in hypotension, hyperventilation, and a slight decrease in heart rate. However, when HSS was administered after TX, only bradypnea was observed. HSS (4 mL/kg, rapid) induced a rapid and marked fall in blood pressure, bradycardia, and apnea. However, when HSS was administered after TX, a more pronounced bradycardia and a smaller reduction in mean arterial pressure were observed. Slow injection of HSS (60 s) evoked hypotension, hyperventilation, and bradycardia. The same dose injected after TX resulted in bradypnea and a smaller reduction in blood pressure. The HSS-induced hypotension was attenuated by previous administration of atropine or by vagotomy, whereas bradycardia was prevented by previous injection of atropine, but not by bilateral vagotomy. Like vagotomy, atropinization prevented the apnea and bradypnea produced by HSS (4 mL/kg in bolus). V evoked a slight bradycardia, hypotension, and apnea. These effects were potentiated when V was injected concomitantly with HSS. The effects of HSS are dependent on both volume and speed of injection, and are affected by previous injection of TX or concomitant injection of V.

Excitatory mechanism of deflationary slowly adapting pulmonary stretch receptors in the rat lung.

The excitatory responses of deflationary slowly adapting pulmonary stretch receptor (SAR) activity to lung deflation ranging from approximately -15 to -25 cm of H(2)O for approximately 5 s were examined before and after administration of flecainide, a Na(+) channel blocker, and K(+) channel blockers, such as 4-aminopyridine (4-AP) and tetraethylammonium (TEA). The experiments were performed in anesthetized, artificially ventilated rats after unilateral vagotomy. The deflationary SARs increased their activity during lung deflation and its effect became more pronounced by increasing the degree of negative pressure. During lung deflation the average values for the deflationary SAR adaptation index (AI) were below 40%. Intravenous administration of veratridine (50 microg/kg), an Na(+) channel opener, stimulated deflationary SAR activity: one maintained excitatory activity mainly during deflation and the other receptors showed a tonic discharge during both deflation and inflation. Despite the difference in deflationary SAR firing patterns after veratridine administration, flecainide treatment (6.0 mg/kg) blocked veratridine-induced deflationary SAR stimulation and also caused strong inhibition of the excitatory responses of deflationary SARs to lung deflation. Under these conditions, the average values for deflationary SAR AI were over 90%. The responses of deflationary SARs and deflationary SAR AI to lung deflation were not significantly altered by pretreatment with either 4-AP (0.7 and 2.0 mg/kg) or TEA (2.0 and 6.0 mg/kg). These results suggest that the excitatory effect of lung deflation on deflationary SAR activity is mediated by the activation of flecainide-sensitive Na(+) channels on the nerve terminals of deflationary SARs.

Corticotropin-releasing hormone and arginine vasopressin: mRNA and secretion are differentially regulated according to the pattern of exposure to noradrenaline in rat hypothalamic neurones.

Hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) are secreted from the median eminence in a pulsatile manner and regulated by noradrenaline during stress. This study investigated the effect of pulsatile noraderanaline on CRH/AVP mRNAs and secretion. Foetal hypothalamic neurones were cultured on plastic coverslips, inserted into perifusion chambers and noraderanaline pulses given at various doses or pulse intervals for 24 h. CRH and AVP release rose in a dose dependant manner; however, maximal increases in mRNAs were seen with an intermediate noraderanaline pulse dose. The effect of noraderanaline pulse frequency was determined by giving noraderanaline pulses at intervals of 15-120 min vs continuous noraderanaline. Both pulsatile and continuous noraderanaline increased CRH and AVP release, but secretion was reduced after 22 h of treatment in the continuous noraderanaline and rapid pulse groups. CRH mRNA levels were maximally increased by medium interval pulses and AVP mRNA by rapid interval pulses. Neither CRH nor AVP mRNAs were stimulated by continuous noraderanaline. To determine noraderanaline specificity, pulses of veratridine (VER; 15-120 min intervals) vs continuous VER were examined. Only pulsatile VER increased CRH and AVP mRNAs, with maximal effects seen with the 60 min pulse interval for both. Thus, noraderanaline pulse pattern regulates CRH and AVP gene expression in both a coordinate and differential manner. Since noraderanaline plays an important role during stress, the pattern of noraderanaline signals may be critical to the observed changes in CRH and AVP expression.

Blood-pressure lowering, positive chronotropy and inotropy by the Veratrum alkaloids germidine and germerine but negative chronotropy by veratridine in mice.

Germidine and germerine, the Veratrum alkaloids lowered blood pressure accompanied with positive chronotropy and inotropy in mice. Germerine was more potent than germidine in both blood-pressure lowering and positive inotropy, whereas veratridine produced negative chronotropy and positive inotropy. An acyl group (an acetyl or a 2-methylbutyroyl group) at 3-O-R1 position and a 2-methylbutyroyl group at 15-O-R2 position in germine were important to produce the positive inotropy and chronotropy. The presence of a veratroyl group at 3-O-R1 position and a free hydroxyl group at 15-O-R2 position may be essential to produce the negative chronotropy by veratridine. The positive inotropy by germidine and veratridine may be due to TTX-resistant Na+ channel activation.

The effects of intracoeliac injections of alpha-adrenergic agonists and veratridine on reticuloruminal motility and the evocation of rumination in sheep.

The ability of alpha-2 adrenoreceptor agonists and veratridine to evoke rumination and to modify reticular motility in adult Suffolk-cross sheep when injected by close-arterial injection into the forestomach was investigated. The specific alpha-2 adrenoreceptor agonists, xylazine and medetomidine, evoked rumination and increased reticular motility. The Na+ channel activator veratridine also evoked rumination and dramatically increased reticular motility. In contrast, injection of the alpha-1 adrenoreceptor agonist, phenylephrine, was ineffectual in evoking rumination and resulted in reduced reticular motility. It is concluded that the evocation of rumination by alpha-2 adrenergic agonists and veratridine is probably due to the activation of sensory nervous receptors (epithelial receptors) located in the reticulorumen.

Effects of veratridine on Na and Ca currents in frog skeletal muscle.

1. Voltage-clamp experiments were performed to determine the effects of veratridine on Na and Ca currents in frog skeletal muscle fibres. 2. Veratridine (1 microM) did not affect the kinetics of the fast Na current but it did induce a slowly inactivating tetrodotoxin-sensitive inward current that was apparent after Na current inactivation. This slow current had a peak amplitude of 6.7 +/- 0.7 microA/cm2 at -20 mV and decayed monoexponentially with a time constant of 606 +/- 77 ms. 3. The slow current had a voltage-dependence for activation that was similar to that of the fast Na current. Single depolarizing prepulses that induced complete inactivation of the fast Na channels, prevented development of the slow current. Trains of brief depolarizations at increasing frequencies increased the amplitude of the slow current. These results suggest that the slow current may be mediated by veratridine modified Na channels that must be in the open position. 4. The low concentration of veratridine (1 microM) did not affect the Ca current, while 100 microM veratridine reversibly suppressed the Ca current and shifted its peak current-voltage relation towards more negative potentials. Thus, veratridine appears not to be a selective fast Na channel modifier as it may also alter Ca channel gating properties in skeletal muscle fibres.

Effects of veratridine and nifedipine on ammonia-induced rapidly adapting pulmonary stretch receptor stimulation in vagotomized rabbits.

We studied the effects of aerosol administration of veratridine (a sodium channel opener) or nifedipine (a calcium channel blocker) on the responses of rapidly adapting pulmonary stretch receptors (RARs) and dynamic lung compliance (Cdyn) to aerosols of 2 and 4% ammonia solutions in anesthetized spontaneously breathing rabbits without intact vagi. The RARs increased their activity following ammonia aerosol, and the increase was concentration-dependent. However, ammonia aerosol did not significantly alter the value of Cdyn. The RARs following aerosol administration of veratridine (about 200 micrograms) showed their characteristic firing pattern with several phases; each phase was characterized by the long high-frequency continuous discharges. Under these conditions, the response was not associated with any significant change in Cdyn. Even though the change in receptor activity produced by veratridine was restored to control level, subsequent aerosol application of ammonia led to similar firing patterns, as veratridine was given by aerosol, but had no significant effect on Cdyn. Following aerosol administration of nifedipine (about 1 and 2 mg) the RAR activity and Cdyn were similar to those during control. Furthermore, the ammonia-induced RAR stimulation was not significantly affected by nifedipine aerosol. These results suggest that the stimulation of RARs by ammonia in vagotomized rabbits is independent of changes in Cdyn and speculate that their excitatory effect is at least in part related to the activation of Na+ influx to the receptive terminals but is not involved in the secondary entry of Ca2+ ions to the receptor membrane, through voltage-dependent calcium channels.

Veratridine blocks voltage-gated potassium current in human T lymphocytes and in mouse neuroblastoma cells.

(i) Effects of veratridine on ionic conductances of human peripheral blood T lymphocytes have been investigated using the whole-cell patch-clamp technique. (ii) Veratridine reduces the net outward current evoked by membrane depolarizations. The reduction originates from block of a 4-aminopyridine-sensitive, voltage-gated K+ current. (iii) Human T lymphocytes do not appear to express voltage-gated Na+ channels, since inward currents are observed neither in control nor in veratridine- and bretylium-exposed lymphocytes. (iv) The effect of veratridine consists of an increase in the rate of decay of the voltage-gated K+ current and a reduction of the peak current amplitude. Both effects depend on veratridine concentration. Half-maximum block occurs at 97 microM and the time constant of decay is reduced by 50% at 54 microM of veratridine. (v) Possible mechanisms of veratridine action are discussed. The increased rate of K+ current decay is most likely due to open channel block. The decrease of current amplitude may involve an additional mechanism. (vi) In cultured mouse neuroblastoma N1E-115 cells, veratridine blocks a component of voltage-gated K+ current, in addition to its effect on voltage-gated Na+ current. This result shows that the novel effect of veratridine is not confined to lymphocytes.

Mutually exclusive action of cationic veratridine and cevadine at an intracellular site of the cardiac sodium channel.

Veratridine modification of Na current was examined in single dissociated ventricular myocytes from late-fetal rats by applying pulses to -30 mV for 50 ms every 2 or 5 s from a holding potential of -100 mV (20 degrees C) and measuring amplitude, Itail, and time constant, tau tail, of the post-repolarization inward tail current induced by the alkaloid. Increasing the pH of a 30 microM veratridine superfusate from 7.3 to 8.3 (which increases the fraction of uncharged veratridine molecules from 0.5 to 5% while decreasing that of protonated molecules from 99.5 to 95%) increased Itail by a factor of 2.5 +/- 0.5 (mean +/- SEM; n = 3). Switching from 100 microM veratridine superfusate at pH 7.3 to 10 microM at pH 8.3 did not affect the size of Itail (n = 4). Intracellular (pipette) application of 100 microM veratridine at pH 7.3 or 8.3 produced small Itail's suggesting transmembrane loss of alkaloid. If this was compensated for by simultaneous extracellular application of 100 microM veratridine at a pH identical to intracellular pH, Itail (measured relative to the maximum amplitude induced by a combination of 100 microM veratridine and 1 microM BDF 9145 in the same cell) at pHi 7.3 did not significantly differ from that at pHi 8.3 (84 +/- 4 vs. 70 +/- 6%; n = 3 each). Results from six control cells and five cells subjected to extra- and/or intracellularly increased viscosity by the addition of 0.5 or 1 molal sucrose showed that increasing intracellular viscosity 1.6- and 2.5-fold increased tau tail 1.5- and 2.3-fold, respectively, while a selective 2.5-fold increase of extracellular viscosity did not significantly affect tau tail.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for two independent mechanisms of gaba release induced by veratridine and glutamate in monolayer cultures of chick embryo retinal cells

GABA is a major inhibitory neurotransmitter in the central nervous system, including the retina. In the present paper we present evidence for the existence of two independent mechanisms for GABA release in cultured retina cells. Eight-day-old chick embryo retinas were dissociated and plated in 35-mm plastic dishes and cultured for 3 or 7 days at 37 grade C. An increase of 3 to 5-fold in GABA release was observed in cultures of 3 or 7 days in vitro preloaded with 0.5 uCi[3H} GABA and stimulated with glutamate (100 uM) or veratridine (100 uM). Tetrodotoxin (1 uM) blocked the release induced by veratridine but not by glutamate. In contrast, the non-N-methyl-D-aspartate (NMDA)glutamate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 100 uM) was able to inhibit GABA release promoted by glutamate but not by veratridine. These results indicate that depolarization of retinal cells byopening of voltage-dependent sodium channels or activation of non-NMDA glutamate receptors can trigger intracellular events that lead to calcium-independent GABA release

Nociception in pigeons is not impaired by capsaicin.

In order to examine the sensitivity of the nociceptive system of birds to capsaicin, the algesic potency of the drug was compared with that of veratridine and mustard oil by instillation into the eye of conscious pigeons and guinea-pigs. In guinea-pigs, 10(-6) g/ml capsaicin provoked severe protective reactions, but even high concentrations of 10(-2) g/ml were insufficient in pigeons. Veratridine and mustard oil induced similar reactions in both species. Close arterial injections of algesic substances revealed that the threshold dose of capsaicin for cardiovascular and nocifensive reactions was 10,000-fold higher in pigeons (200 micrograms) than in guinea-pigs (0.02 micrograms). All other algesic substances tested (bradykinin, 5-HT, veratridine and KCl) had similar thresholds in both species. Slow infusion of a total dose of 600 mg/kg capsaicin into the radial artery of pigeons did not alter the sensitivity to any of the algesic substances tested, which demonstrates that even high concentrations of capsaicin have no desensitizing effect. The demonstrated insensitivity of pigeons to the algesic effect of capsaicin is discussed in the context of the inability of the drug to deplete substance P (SP) from afferent terminals in the spinal cord of the pigeon.

Hind-limb vascular responses in anaesthetized dogs to aortic root injections of veratridine.

In dogs anaesthetized with chloralose we determined the reflex responses of the blood vessels in the vascularly isolated hind limb to injection of veratridine into the aortic root. The presence of a cannula tied in the ascending aorta ensured that responses were due to stimulation of nerves only in the region perfused by the coronary arteries. Injections of veratridine resulted in transient decreases in vascular resistance and in venous resistance in a perfused cutaneous vein. The responses were reduced when carotid perfusion pressure was elevated. The afferent pathway for the reflex lay in the vagus nerves and the efferent pathway to the limb was in the sciatic and femoral nerves, but the vasodilatation was shown to be predominantly non-cholinergic.

Effect of veratridine injected into the aortic root on resistance and capacitance in the abdominal circulation in anaesthetized dogs.

In dogs anaesthetized with chloralose, cardiac receptors were stimulated by injections of veratridine into the aortic root and the effects studied on resistance and capacitance in the vascularly isolated and perfused abdominal circulation. Unless carotid sinus pressure was high, veratridine injections consistently resulted in dilatation of resistance and capacitance vessels. However, at high carotid pressures, the resistance response to veratridine was inhibited and the capacitance response was usually reversed. These results indicate that stimulation of cardiac receptors can affect resistance and capacitance in the abdominal circulation. Further experiments are required to evaluate the physiological role of these responses.

The Bezold-Jarisch-like effect induced by veratridine and its potentiation by scropion toxin in the rat.

The Bezold-Jarisch-like effect (BJE) induced by 2.5 micrograms/100 g of veratridine injected intravenously or into the left ventricle was studied in anesthetized rats. The possible potentiation of the effect by a small dose (10 micrograms/100 g) of a purified scorpion toxin (tityustoxin) was also investigated. Heart rate (HR), electrocardiogram (ECG), mean arterial pressure (MAP) and respiratory rate (RR) were recorded. Intravenous (iv) injection of veratridine induced a BJE consisting of slight bradycardia in 4 out of 8 experiments, fall of MAP (from 107 +/- 3 to 90 +/- 4 mmHg) and apnea. The control RR was 105 +/- 5 insp/min and apnea, after veratridine, lasted 8 +/- 2 s. The BJE evoked by injection of a second dose of veratridine was potentiated 20 min after an iv injection of tityustoxin. The HR decreased from 334 +/- 16 to 108 +/- 17 beats/min, the MAP fell from 110 +/- 5 to 68 +/- 4 mmHg and the control RR of 92 +/- 5 insp/min was followed by a long period of apnea (68 +/- 17 s). Injection of veratridine into the left ventricle (lv) evoked a BJE characterized by slight bradycardia in 5 out of 10 experiments, arterial hypotension (from 110 +/- 6 to 89 +/- 6 mmHg) and tachypnea (from 82 +/- 6 to 102 +/- 7 insp/min). The effects induced by a second dose of veratridine were potentiated 20 min after an lv injection of tityustoxin. The HR decreased from 377 +/- 14 to 119 +/- 18 beats/min, the MAP fell from 119 +/- 5 to 72 +/- 10 mmHg and the RR increased from 80 +/- 6 to 117 +/- 9 insp/min. This tachypnea was followed by bradypnea 20 s later (21 +/- 6 insp/min). The ECG showed that hypotension induced by iv or lv injections of veratridine coincided with a slight sinus bradycardia before tityustoxin (N = 9) and A-V block after the toxin (N = 18). Cervical bilateral vagotomy prevented the cardiac and respiratory effects induced by lv veratridine in tityustoxin-treated rats, but a slight hypotension was still recorded (from 114 +/- 10 to 94 +/- 10 mmHg, P less than 0.05). Injection of veratridine (2.5 micrograms/100 g) into the ascendent aorta evoked a slight hypotension (from 105 +/- 6 to 87 +/- 7 mmHg, P less than 0.05) and tachypnea followed by bradypnea, but bradycardia was not recorded.(ABSTRACT TRUNCATED AT 400 WORDS)

Reflex cardiovascular changes with veratridine in the conscious dog.

The present study was undertaken to examine the reflex responses of activation of cardiac sensory receptors in the conscious dog. Intracoronary (left circumflex coronary artery) injection of veratridine (0.10 micrograms/kg) reduced mean arterial pressure (-40 mmHg, P less than 0.05), heart rate (-34 beats/min, P less than 0.05), and maximum rate of rise of left ventricular pressure (LV dP/dtmax) (-419 mmHg/s, P less than 0.05). Bilateral cervical vagal cold block (BVB) eliminated the depressor and bradycardic responses of veratridine. BVB not only eliminated the negative inotropic response to veratridine but reversed it to a positive inotropic response (LV dP/dtmax increased 313 +/- 76 mmHg/s). Ganglionic blockade abolished all effects of veratridine. The bradycardia and negative inotropic effects caused by veratridine were attenuated by either atropine or metoprolol and completely eliminated by the combination of the two antagonists. Veratridine also produced a decrease in renal artery blood flow but had no effect on renal vascular resistance. In contrast, iliac blood flow was increased with veratridine, and this, combined with the depressor effect, resulted in a decrease in iliac vascular resistance (-37%), P less than 0.05). BVB abolished the changes in renal and iliac blood flow or resistance caused by veratridine. The results indicate that activation of cardiac receptors in the conscious dog elicits inhibitory reflexes to the heart and peripheral circulation that are mediated by vagal afferents. After vagotomy, veratridine elicited a reflex positive inotropic response, which may have resulted from activation of cardiac sympathetic afferent fibers.