Reduction of ischemic damage in isolated rat hearts by the potassium channel opener, RP 52891

Potassium channel activators have been shown to protect ischemic myocardium. We studied the ability of the novel potassium channel activator, RP 52891, to also reduce ischemic damage in isolated globally ischemic rat hearts. RP 52891 (1-100 microM) was given before the hearts were subjected to 25 min of ischemia and 30 min of reperfusion. Before ischemia, RP 52891 reduced contractile function only at the highest concentration (100 microM). Significant reductions in ischemic damage were observed at 3 microM and higher concentrations. RP 52891 improved reperfusion contractile function and reduced lactate dehydrogenase release. Contracture was significantly reduced by RP 52891 during reperfusion. The protective effects of RP 52891 were completely reversed by glyburide and sodium 5-hydroxydecanoate, both blockers of ATP-sensitive potassium channels. Thus, RP 52891 has direct cardioprotective efficacy, which may be related to activation of ATP-sensitive potassium channels.     

K+ Channels and Guinea-pig Trachea: a Possible Functional Modulation by GABAB Receptors

Summary: K⁺ channel activators represent a novel class of smooth muscle relaxant agents. There is now much evidence demonstrating that K⁺ channels, localized to prejunctional neurones and post-junctional smooth muscle membranes, can regulate airway smooth muscle activity, inducing smooth muscle cell membrane hyperpolarization. K⁺ channel activity may be influenced by some neurotransmitters, such as adenosine, serotonin and noradrenaline. More recently, it has been observed that the stimulation of GABA_B receptors influences K⁺ channels in the hippocampus, dorsal rafe and spinal cord neurons. The aim of this study was to investigate the effects of levcromakalim in guinea-pig trachea at pre- and post-junctional sites and to evaluate whether GABA_B receptors may modulate K⁺ channel activation. Levcromakalim (from 1 nM to 1 μM) relaxed guinea-pig trachea (IC₅₀ 10±0.9 nM) previously contracted by KCl (30 mM). This effect was reversed by a pretreatment with tetraethylammonium (10 mM) (IC₅₀ 120±0.7 nM). A 30-min pretreatment with baclofen (1 μM) or phaclofen (1 μM) failed to modify the effects of levcromakalim (IC₅₀ 18±1.0 nM and 14±0.6 nM, respectively). The contractile responses to electrical field stimulation (71.20±5.12% of acetylcholine -100 μM-contraction) was significantly (P<0.05) reduced by a pretreatment with levcromakalim (10 nM) (54.00±6.68%). This reduction was antagonized by tetraethylammonium (10 nM) (72.20±14.27%). A 30-min pretreatment with baclofen (1 μM) significantly (P<0.05) enhanced the effect of levcromakalim on electrical field stimulation, whereas phaclofen (1 μM) significantly (P<0.05) antagonized these responses. These data demonstrate that K⁺ channels may be localized both to prejunctional and post-junctional post-ganglionic sites, and may play an important role in modulating airway responsiveness. In fact, they may act at the prejunctional neurones, inhibiting the release of contractile neurotransmitter, or at the post-junctional sites, hyperpolarizing smooth muscle airway membranes. Moreover, the present study seems to demonstrate that K⁺ channels localized on the prejunctional post-ganglionic nerves may be influenced by GABA^B receptors.     

Modulation of vasodilatation to levcromakalim by hypoxia and EDRF in the rabbit isolated ear: a comparison with pinacidil, sodium nitroprusside and verapamil.

1. We have used an isolated buffer-perfused preparation of the rabbit ear to investigate the effects of hypoxia and inhibition of endothelium-derived relaxing factor (EDRF) synthesis on the vasodilator responses to the potassium channel opener, levcromakalim (the active (-)-enantiomer of cromakalim). The results obtained with levcromakalim have been compared with those for pinacidil, sodium nitroprusside and verapamil. 2. Levcromakalim relaxed preconstricted preparations with an EC50 = 343 +/- 41 nM and Rmax = 80.3 +/- 6.4%. Under hypoxic conditions the concentration-response curve was significantly (P < 0.01) shifted to the left with an EC50 = 118 +/- 16 nM and Rmax = 89.9 +/- 2.7%. Hypoxia did not influence relaxation to either pinacidil, sodium nitroprusside or verapamil. 3. Inhibition of EDRF synthesis with 100 microM NG-nitro-L-arginine methyl ester (L-NAME) also significantly (P < 0.001) increased the vasodilator potency of levcromakalim (EC50 = 56 +/- 5 nM), and caused a similar shift in the concentration-response curve to sodium nitroprusside. It did not influence vasodilation to either verapamil or pinacidil. The potentiation of vasodilator responses to levcromakalim by L-NAME was reversed by an excess of L-arginine. 4. Impairment of oxidative phosphorylation with 400 nM carbonyl cyanide m-chlorophenylhydrazone significantly (P < 0.05) increased the potency of levcromakalim (EC50 = 120 +/- 20 nM) but did not influence vasodilation to pinacidil or endothelium-dependent relaxations to acetylcholine. 5. Vasodilatation to levcromakalim was augmented both by hypoxia and by inhibition of EDRF activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of levcromakalim (BRL 38227) on bladder function in patients with high spinal cord lesions.

The effects of the potassium channel opener levcromakalim (BRL 38227) 7.5 micrograms kg-1 were examined on urodynamic variables and blood pressure during inflow and voiding cystometry in six high spinal cord lesion patients. Levcromakalim administration significantly increased the duration of bladder contraction (197 +/- 128 s to 267 +/- 167 s, P < 0.05) and also reduced blood pressure (126 +/- 13/67 +/- 9 mm Hg to 104 +/- 25/52 +/- 12 mm Hg) but was without effect on other urodynamic parameters. Because of concerns about hypotensive responses, further studies involving higher doses of levcromakalim should be considered only if the drug was administered intravesically.     

Generalization of [DAla2]-enkephalinamide but not of substance P to the morphine cue

Rats were trained to discriminate morphine (7.5 mg/kg, IP) from saline in a two bar positively reinforced lever pressing paradigm on a FR4 schedule. Morphine (IP) showed a naloxone reversible dose-related generalization to the training dose. [DAla²]-Methionine enkephalinamide (DAE) at 1 mg/kg and Substance P (SP) at 0.1 and 0.25 mg/kg showed vehicle appropriate responding after IP injection. DAE (5 mg/kg) disrupted responding completely; SP (0.5 and 0.1 mg/kg) disrupted responding in 50% of the rats. The disruption caused by IP injection of DAE was not naloxone reversible. Intraventricular injection of morphine (5 μg/rat) and DAE (5 μ/rat) produced generalization to the opiate cue. The effect of DAE was reversed by naloxone (1 mg/kg, SC). SP (500 and 750 ng/rat, IVT) produced saline-like responding; 1 μg/rat disrupted responding completely. These data demonstrate that morphine and enkephalin, but not Substance P, share similar discriminative properties.     

Effects of BRL 38227 on neurally-mediated responses in the guinea-pig isolated bronchus.

1. In guinea-pig isolated bronchus treated with indomethacin (2.8 microM), electrical field stimulation (EFS; 10 Hz, 0.5 ms, 60-70 V, for 10 s) evoked a tetrodotoxin (3 microM)-sensitive, biphasic contraction comprising a rapid, atropine (1 microM)-sensitive cholinergic response succeeded by a slowly developing, capsaicin (10 microM)-sensitive, non-adrenergic, non-cholinergic excitatory (NANCe) response. 2. BRL 38227 (0.3-3 microM), salmeterol (0.003-3 microM) and ketotifen (1.0-300 microM) each produced concentration-dependent inhibition of both NANCe and cholinergic responses to EFS in guinea-pig isolated bronchus. 3. Substance P (SP; 1 microM) and neurokinin A (NKA; 0.07 microM) produced contractions equivalent in magnitude to the NANCe response to EFS, which were inhibited by salmeterol (1 microM), but not by BRL 38227 (3 microM) or ketotifen (100 microM). 4. Acetylcholine (ACh; 6 microM) was equi-effective with the electrical activation of cholinergic neurones. BRL 38227 (3 microM) slightly inhibited responses to ACh (6 microM). Salmeterol (1 microM) and ketotifen (100 microM) markedly inhibited responses to ACh (6 microM). 5. In bronchial rings pre-contracted with ACh (100 microM), BRL 38227 (0.1-30 microM), salmeterol (0.001-3 microM) and ketotifen (0.1-100 microM) each produced concentration-dependent relaxation. Unlike ketotifen, BRL 38227 and salmeterol only partially (18.8 +/- 2.1% and 51.8 +/- 3.9% respectively) reversed the ACh-induced contraction. 6. The (+)-analogue of BRL 38227, BRL 38226 (0.3-100 microM), was without effect on responses to EFS and had no effect on the inhibition caused by BRL 38227.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of the Novel Potassium Channel Activator BRL 55834 as an Inhaled Bronchodilator in Guinea-pigs and Rats: Comparison with Levcromakalim and Salbutamol

Summary: The novel potassium channel activator BRL 55834 and the prototype compound levcromakalim have been compared as inhaled bronchodilators in guinea-pigs and rats. Salbutamol was included in the guinea-pig studies. In anaesthetized guinea-pigs, inhaled BRL 55834 [ED₅₀=0.9 (0.5-1.5) μg per animal] was equipotent with salbutamol and about tenfold more potent than levcromakalim as an inhibitor of the increase in airways resistance in response to iv histamine. In anaesthetized rats, BRL 55834 [ED₅₀=0.5 (0.4-0.7) μg] was about eightfold more potent than levcromakalim in inhibiting the response to inhaled methacholine. BRL 55834 had no effect on blood pressure in anaesthetized guinea-pigs or rats, whereas levcromakalim lowered blood pressure in rats at a dose level that had less effect on the airways than one tenth of the highest dose of BRL 55834 used. In conscious guinea-pigs, BRL 55834 (ED₁₀₀=5 μg) was twice as potent as levcromakalim and one sixth as potent as salbutamol in delaying the onset of dyspnoea in response to inhaled histamine. In each model each compound was effective at the earliest time studied, but the peak effect of BRL 55834 tended to be delayed and it was longer acting than levcromakalim or salbutamol. Thus inhaled BRL 55834 is a potent bronchodilator, with a rapid but prolonged duration of action that lacks significant systemic vascular activity.     

Modulation of vasodilatation to levcromakalim by adenosine analogues in the rabbit ear: an explanation for hypoxic augmentation.

1. We have used a rabbit isolated ear, buffered-perfused preparation to investigate the effects of adenosine analogues on the vasodilatation to the potassium channel opener, levcromakalim (the active (-)-enantiomer of cromakalim). We have examined the effects of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 antagonist, on vasodilatation to levcromakalim under hypoxic conditions and also following inhibition of nitric oxide synthesis. 2. Levcromakalim relaxed preconstricted preparations with an EC50 = 369 +/- 48 nM and maximum relaxation of tone (Rmax) = 81.0 +/- 3.2%. In the presence of 1 microM N6-cyclohexyladenosine (CHA) a selective adenosine A1 agonist, there was a significant (P < 0.01) leftward shift in the concentration-response curve with an EC50 = 194 +/- 54 nM and Rmax = 93.2 +/- 2.0%. Conversely, the presence of CHA did not influence vasodilatation to either pinacidil or sodium nitroprusside. 3. Hypoxia also significantly (P < 0.001) increased the vasodilator potency of levcromakalim (EC50 = 134 +/- 22 nM), and this enhancement was completely reversed (EC50 = 380 +/- 107 nM, P < 0.01) by pretreatment of the preparations with 5 microM DPCPX, a selective A1 adenosine antagonist. However, under normoxic conditions DPCPX did not influence vasodilatation to levcromakalim. 4. Inhibition of nitric oxide synthesis with 100 microM NG-nitro-L-arginine methyl ester (L-NAME) caused a significant (P < 0.001) leftward shift in the concentration-response curve to levcromakalim (EC50 = 73.0 +/- 7.6 nM). Pretreatment of preparations with DPCPX partially reversed the increase in potency found in the absence of nitric oxide synthesis (EC50 = 153 +/- 18 nM, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Opposite action of m-chlorophenylpiperazine on avoidance depression induced by trazodone and pimozide in CD-1 mice

m-Chlorophenylpiperazine (CPP) given in doses up to 2 mg/kg did not affect conditioned avoidance responses (CAR) of CD-1 mice pre-trained in a shuttle box. It reversed the inhibitory action of trazodone (10 mg/kg) on CAR, but dose-dependently potentiated the inhibitory effect of pimozide (0.2 and 0.5 mg/kg). Apparently, dopaminergic transmission is important for the attenuating effect of CPP on CAR inhibition.     

Acute malathion toxicosis and related enzymatic alterations in Bubalus bubalis: antidotal treatment with atropine, 2-PAM, and diazepam

Oral administration of malathion (MTH) in sublethal (100 mg/kg) or minimal lethal (125 mg/kg) doses in buffalo calves produced toxicity with an onset within 15-20 min and peak effects including severe tremors and convulsions within 40-60 min. Various antidotal drugs were administered alone or in combination at the time of peak malathion toxicity (within 1 h) and were assessed for their ability to alleviate signs of cholinergic toxicity. Blood cholinesterase and aminotransferases activities were monitored at various times. A combination of atropine sulfate (0.5 mg/kg, 1/4 iv and 3/4 im) and pyridine 2-aldoxime methiodide (2-PAM, 20 mg/kg, iv) reversed the clinical evidence of malathion toxicity within 15 min. The combination of atropine sulfate and diazepam (0.75 mg/kg, iv) prevented death and cholinergic signs of toxicity except for weak muscular fasciculations, which persisted for 30-60 min. Atropine sulfate alone was less effective and also did not reverse malathion-induced biochemical changes. In contrast, administration of either 2-PAM (10-30 mg/kg, iv) or diazepam (0.5-1.0 mg/kg, iv) alone accentuated malathion toxicity. Thus, the combination of atropine sulfate and 2-PAM was the most effective antidotal treatment in acute malathion toxicity.     

Effective Administration Route for the Deleted Form of Hepatocyte Growth Factor To Exert Its Pharmacological Effects

The pharmacokinetics and the pharmacological effects of the deleted form of hepatocyte growth factor (dHGF) after intravenous (iv), subcutaneous (sc), or intramuscular (im) administration (0.25 and 2.5 mg/kg) were studied in rats. After single iv administration (2.5 mg/kg), dHGF in serum rapidly decreased (α‐ and β‐phase half‐life: 3.2 and 26.5 min, respectively). Two to four hours after single sc or im administration (2.5 mg/kg), the serum level of dHGF reached a maximum and then gradually declined (half‐life: 2.7 h). The serum levels were not changed by repetitive iv administration, but were dramatically decreased by repetitive sc or im administration. Liver weight and serum levels of total protein, albumin, and HDL‐cholesterol were significantly increased by iv administration of dHGF (twice daily for 4 days at 0.25 mg/kg). Sc or im administration of dHGF did not increase these parameters at the same dose, but did significantly at 2.5 mg/kg. These observations suggest that iv administration is the most effective in exerting the pharmacological effects of dHGF among three administration routes. dHGF after iv administration was distributed mainly and rapidly into liver (53.6% of the injected dHGF within 5 min) and was sustained at a higher level in the liver than in plasma. In infusion (0.5 mg/kg/3 h), dHGF level in plasma and liver reached a steady‐state 15 and 60 min after starting the infusion, respectively. The steady‐state level of dHGF was 7‐ to 9‐fold higher in liver than in plasma, and the higher level in liver was sustained beyond the steady‐state.     

Reduction of the Amplitude of Preovulatory LH and FSH Surges and of the Amplitude of the In Vitro GnRH-induced LH Release by Substance P. Reversal of the Effect by RP 67580

The effects of Substance P (SP) and of a specific nonpeptide antagonist of the NK1 receptor (RP 67580) on preovulatory gonadotropin surges and on the in vitro GnRH induced LH surge were investigated in cycling female rats. A subcutaneous injection of SP (0.5 mg/kg body weight) at 12.00h on the proestrous day significantly decreased the LH preovulatory surge. RP 67580 (1.5 mg/kg) significantly increased this LH surge. However, when SP and its antagonist were administered together, LH preovulatory surge was normal. The FSH preovulatory surge at 18.00h and also at 19.00h was significantly inhibited by SP administration. RP 67580 alone had no effect on the FSH preovulatory surge. When SP and RP 67580 were both administered, there was no diminution of FSH plasma levels at 18.00h and 19.00h. In vitro perifusions of anterior pituitaries showed that SP inhibits GnRH-induced LH release via a NK1 receptor. Thus, SP inhibits the LH preovulatory surge via NK1 receptors and SP modulation of gonadotropin surges is at least partly exerted at the pituitary. © 1997 Elsevier Science Ltd. All rights reserved.     

Activation by levcromakalim and metabolic inhibition of glibenclamide-sensitive K channels in smooth muscle cells of pig proximal urethra.

1. The effects of levcromakalim (BRL 38227) on ionic currents recorded from pig proximal urethra were investigated by use of tension measurement and patch clamp techniques (conventional whole-cell configuration, nystatin perforated patch, and cell-attached configuration). 2. Levcromakalim (1 microM) caused a relaxation in the resting tone. This levcromakalim-induced relaxation was inhibited by the pretreatment with 1 microM glibenclamide. 3. The resting membrane potential recorded from single cells in current-clamp mode was-36.1 +/- 4.4 mV (n = 5). 4. Levcromakalim induced a concentration-dependent hyperpolarization with a maximum (at > or = 10 microM) close to the theoretical equilibrium potential of potassium (EK). The membrane hyperpolarization caused by 1 microM levcromakalim (24.7 +/- 5.8 mV, n = 4) was abolished by 1 microM glibenclamide. 5. Levcromakalim (100 microM) caused an outward K current in whole-cell recordings which was unaffected by iberiotoxin (300 nM) but abolished by glibenclamide (10 microM). 6. In cell-attached patches, levcromakalim activated a 43 pS K channel which was inhibited by the application of glibenclamide. 7. The metabolic poison, cyanide (CN), also activated a 43 pS K channel which was suppressed by the application of 10 microM glibenclamide. 8. These results indicate that levcromakalim and metabolic inhibition activate the same 43 pS K channel in pig proximal urethra. The resultant urethral hyperpolarization might reduce the usefulness of K channel openers in the treatment of detrusor instability, but be of value in treating outflow obstruction.     

General pharmacology of SDZ WAG 994, a potent selective and orally active adenosine A1 receptor agonist

The pharmacological properties of 6-cyclohexyl-2′-0-methyladenosine (SDZ WAG 994)—a potent, selective, and orally active adenosine A₁ receptor agonist—are described. SDZ WAG 994 is a potent (K_D 23 ± 2 nM, n = 5) and selective (1,090-fold vs. A_2A receptors) displacer of binding to pig striatal A₁ receptors and behaves as a full agonist at the A₁ receptors coupled negatively to adenylate cyclase in rat adipocytes (pEC₅₀ 6.4 ± 0.2, n = 3), those which induce contraction of rat spleen (pEC₅₀ 7.1 ± 0.1, n = 13) and those which suppress the response to autonomic nerve stimulation in guinea-pig ileum (pIC₅₀ 6.6 ± 0.1, n = 4) and rat kidney (pIC₅₀ 6.0 ± 0.1, n = 6). The compound has negligible affinity (pEC₅₀ < 4, n = 5) for the A_2B receptor which mediates relaxation of guinea-pig aorta. In spontaneously hypertensive (SH) rats SDZ WAG 994, 0.05–0.5 mg/kg (0.14–1.4 μmol/kg) po, caused dose-related and sustained (> 5 h) falls in blood pressure (BP) and heart rate (HR) and suppressed plasma renin activity (PRA); the cardiovascular effects could be immediately and fully reversed by an intravenous injection of 8-(p-sulphophenyl)theophylline, 20 mg/kg (56.4 μmol/kg). SDZ WAG 994 given via the food at 0.4 and 1.2 mg/kg/day (1.1 and 3.3 μmol/kg/day) for 7 or 14 days, respectively, induced dose-related hypotension and bradycardia which were well maintained throughout the treatment periods. In the conscious, normotensive dog, SDZ WAG 994, 1 and 3 mg/kg (2.8 and 8.3 μmol/kg) po, induced substantial, sustained falls in BP which were accompanied by tachycardia. In salt depleted squirrel monkeys, SDZ WAG 994, 0.1–0.3 mg/kg (0.28–0.83 m?mol/kg) iv or 0.2–0.6 mg/kg (0.56–1.7 μmol/kg) po caused dose-related and sustained (> 5 h) bradycardia and suppression of PRA but no change in BP. In rhesus monkeys, SDZ WAG 994, 0.1–1.2 mg/kg (0.28–3.3 μmol/kg) po induced sustained bradycardia and suppression of PRA and the plasma free fatty acid and triglyceride concentrations. The data establish SDZ WAG 994 as a potent, selective, and orally active adenosine A₁ receptor agonist with therapeutic potential in certain cardiovascular and/or metabolic disease states. © 1995 Wiley-Liss, Inc.     

Regional and species differences in glyburide-sensitive K+ channels in airway smooth muscles as estimated from actions of KC 128 and levcromakalim.

1. The purpose of the present experiments was to elucidate the differences in actions of two K+ channel openers, KC 128 and levcromakalim, on the carbachol-induced contraction, membrane potential and 86Rb+ efflux of the dog tracheal and bronchial smooth muscles. Furthermore, we compared the effects of these agents on guinea-pig and human airway smooth muscles. 2. In the dog tracheal and bronchial smooth muscle tissues, levcromakalim induced a concentration-dependent relaxation of the carbachol-induced contraction. The IC50 values were 0.35 microM (pIC50: 6.46 +/- 0.10, n = 9) and 0.55 microM (pIC50: 6.26 +/- 0.07, n = 5), respectively. KC 128 relaxed bronchial smooth muscles precontracted by carbachol with an IC50 value of 0.19 microM (pIC50: 6.73 +/- 0.10, n = 7). However, KC 128 had almost no effect on the contraction evoked by carbachol in the trachea (IC50 > 10 microM). The relaxations induced by levcromakalim and KC 128 were antagonized by glyburide (0.03-1 microM) but not by charybdotoxin (100 nM). 3. Levcromakalim (1 microM) hyperpolarized the membrane of both dog tracheal and bronchial smooth muscle cells, whereas KC 128 (1 microM) hyperpolarized the membrane of bronchial but not of tracheal smooth muscle cells. 4. Levcromakalim (10 microM) increased 86Rb+ efflux rate from both tracheal and bronchial smooth muscle tissues but KC 128 (10 microM) increased 86Rb+ efflux rate only from bronchial and not tracheal smooth muscle tissues. Glyburide (1 microM) prevented the hyperpolarization and the 86Rb+ efflux induced by these agents at the same concentration as observed for mechanical responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Similar anticonvulsant,but unique,behavioural effects of opioid agonists in the seizure-sensitive mongolian gerbil

Opioid agonists were used to investigate the modulation of seizures mediated by μ, κ and σ opiate receptors in the seizure-sensitive Mongolian gerbil. Morphine (1.0–25 mg/kg, s.c.) ketocyclazocine (0.15–25 mg/kg, s.c.) and N-allylnormetazocine (0.1–25 mg/kg, s.c.) were used as prototypic agonists for μ, κ and σ opiate receptors. Each opioid decreased the incidence and severity of the seizure as compared to control values. The anticonvulsant effects of morphine (10 mg/kg, s.c.) and ketocyclazocine (0.5 mg/kg, s.c.) were reversed by naloxone (1.0 mg/kg, s.c.), while the anticonvulsant effects of N-allylnormetazocine (2 mg/kg, s.c.) were not significantly changed by naloxone. Additionally, abnormal behavior was observed following administration of the opioids. Morphine (10 mg/kg, s.c.) produced excitation and hyperresponsiveness with intermittent cataleptic-like states. Ketocyclazocine (10 mg/kg, s.c.) predominantly produced a stuporous, immobile state, accompanied by some loss of posture. N-allylnormetazocine (10 mg/kg, s.c.) produced ataxia and Stereotypie side-to-side head nodding. Naloxone was able to reverse the behavioral effects produced by morphine and ketocyclazocine but not those produced by N-allylnormetazocine. The data presented are consistent with earlier studies which demonstrated the anticonvulsant effects of β-endorphin in the gerbil. This study further suggests that opioids have a protective role against seizure activity in the gerbil and the opioid anticonvulsant effect is not specific to one type of opioid agonist.     

Interaction of clonidine and morphine with lidocaine in mice and rats

Morphine and clonidine both elevated plasma levels of lidocaine to the same extent in mice while slowing lidocaine metabolism to deethylated products. The effects of clonidine on lidocaine disposition were reversed by yohimbine. Mice given morphine, 20 mg/kg sc, or clonidine, 0.2 mg/kg sc, had similar, 30-50%, elevation of plasma lidocaine levels at 15 min after lidocaine, 15 mg/kg iv, when compared to saline-treated animals. Despite similarity of effect on plasma lidocaine, mice treated with morphine were much more susceptible to lethal effects of lidocaine than were mice given clonidine. At iv doses of 22 mg/kg or higher, lidocaine caused death in nearly all morphine-treated mice, while even 32 mg/kg lidocaine caused only 11% mortality after saline or clonidine. Clonidine, 0.5 mg/kg sc, and morphine, 20 mg/kg sc, both raised plasma lidocaine levels in rats, but only morphine depressed respiration, causing hypoxia, hypercapnia, and acidosis and increasing lidocaine lethality. These data suggest that potentiation of lidocaine toxicity by morphine is due primarily to changes in blood gases rather than to elevation in lidocaine levels.     

In vivo and in vitro pharmacological studies of a new hypotensive compound (QF0301B) in rat: comparison with prazosin,a known alpha1-adrenoceptor antagonist

In this work, we studied the in vivo and in vitro pharmacological effects of the novel compound QF0301B (2-[2-(N-4-o-methoxyphenyl-N-1-piperazinyl)ethyl]-1-tetralone) and compared with those of prazosin. In anaesthetized normotensive rats, both QF0301B and prazosin (0.1-0.2 mg/kg iv) caused a pronounced and prolonged fall in mean arterial blood pressure accompanied by bradycardia. Neither QF0301B nor prazosin (0.2 mg/kg iv) significantly modified the cardiovascular effects of either 5-hydroxytryptamine (serotonin, 5-HT, 75 microg/kg iv) or the selective alpha(2)-adrenoceptor agonist B-HT 920 (0.2 mg/kg iv), but both markedly inhibited the hypertensive effect of noradrenaline (5 microg/kg iv), a nonselective alpha-adrenergic receptor agonist. In isolated rubbed rat aorta rings, QF0301B and prazosin showed marked alpha(1)-adrenoceptor blocking activity, with pA(2) values of 9.00+/-0.12 and 9.75+/-0.14, respectively. In addition, QF0301B reversed and competitively antagonized the inhibitory action produced by clonidine in electrically stimulated rat vas deferens and inhibited the force and rate of contraction in rat isolated atria (pA(2)=5.91+/-0.43), competitively antagonized the contractile effect of 5-HT in rat aorta (pA(2)=6.75+/-0.06) and in rat stomach fundus (pA(2)=7.13+/-0.48) and the contractions induced by histamine in isolated guinea pig longitudinal ileal muscle (pA(2)=7.40+/-0.40). QF0301B showed noncompetitive low action in 5-HT(3), muscarinic and nicotinic receptors, or as Ca(2+) antagonist. These results indicate that a alpha(1)-adrenoceptor blocking lead has been obtained with a new chemical structure and interesting pharmacological properties, which only alpha(1)-adrenoceptor blocking activity seems to be responsible for its cardiovascular effects.     

槐定碱抗心律失常作用及其机理

槐定碱(Sop)明显对抗由乌头碱、BaCl_2、CaCl_2、肾上腺素和哇巴因诱发的心律失常,提高家兔左心室电致颤阈。Sop减慢大鼠和家兔的正常心率,延长P-R和校正Q-T间期;减慢离体家兔右心房自发频率。Sop使异丙肾上腺素加速离体心房自发频率的量效曲线右移并抑制最大反应。Sop 40μM使离体豚鼠心室乳头肌细胞动作电位零相去极化最大上升速率V_(max)明显减慢,有效不应期(ERP)和动作电信时程(APD)显著延长。提示Sop具有奎尼丁样作用,阻滞钠通道是其抗心律失常的主要作用机理。