Activation of cardiac muscarinic receptor and ischemic preconditioning effects in in situ rat heart

Activation of cardiac muscarinic receptors by vagal stimulation decreases cardiac work, which may have a protective effect against ischemic injury. To determine whether cardiac muscarinic receptors contribute to the mechanisms of preconditioning effects, we examined the effect of carbachol on ischemia/reperfusion damage and the effect of vagotomy on cardioprotection induced by ischemic preconditioning. Rats were subjected to 30 min of left coronary artery occlusion followed by 30-min reperfusion in situ. Pre-conditioning was induced by three cycles of 2-min coronary artery occlusion and, subsequently by 5 min of reperfusion. The incidence of ischemic arrhythmias, such as ventricular tachycardia (VT) and ventricular fibrillation (VF), and the development of myocardial infarction were markedly reduced by the preconditioning. Carbachol infusion (4 micrograms/kg per min) delayed the occurrence of VT and VF during ischemia and reduced the infarct size. Compared with non-ischemic left ventricle, the cyclic guanosine monophosphate (GMP) content in the ischemic region of the left ventricle was decreased by ischemia/reperfusion, whereas the cyclic adenosine monophosphate (AMP) content of this region was increased. These changes were reversed by preconditioning. Similar changes in cyclic GMP and AMP content in the ischemic region were seen in rats undergoing carbachol treatment. These results suggest the possible contribution of muscarinic receptor stimulation to preconditioning. Vagotomy prior to preconditioning diminished the antiarrhythmic effects, whereas it did not block the anti-infarct effect afforded by pre-conditioning. Vagotomy abolished the preconditioning effect on the tissue cyclic GMP, but it did not attenuate the decrease in tissue cyclic AMP. The results suggest that muscarinic stimulation exerts preconditioning-mimetic protective effects in ischemic/reperfused hearts, but that a contribution of reflective vagal activity to the mechanism for preconditioning is unlikely.     

The reaction mechanism of phosphomannomutase in plants

It was established that selective ligands of the mu-opioid receptors DAGO and DALDA exhibit antiarrhythmic activity on a model of CACl2-induced arrhythmias when infused intravenously in a dose of 0.2 mg/kg. The autonomic nervous system does not take part in realization of the antiarrhythmic effect of DAGO and DALDA. It is supposed that this effect of DAGO and DALDA is associated with activation of cardiac mu-opioid receptors.     

Antiarrhythmic action of the new calcium antagonist [1,2,5-trimethyl-4-phenyl-4-beta-(N-cyanoethyl-N-4'-methoxybenzyl) -ethylamino]piperidine dihydrochloride

Arrhythmias induced by coronary artery ligation in cats, by CaCl2 and epinephrine in rats, and by ouabain in guinea-pigs were used as experimental models for studying the effects of a new calcium antagonist AR-1 ([1,2,5-trimethyl-4-phenyl-4-beta-(N-cyanoethyl-N-4'-methoxybenzyl) -ethylamino]piperidine, calcium channel blocker and calmodulin antagonist) on ventricular arrhythmias. Coronary ligation caused 90% lethality (ventricular fibrillation) with 12.5 min in untreated control cats, which was prevented by administration of AR-1 (4 mg/kg body weight (b.w.) before or after arrhythmia induction. Pretreatment with AR-1 afforded protection in a dose-related fashion. A dose of 1.5 mg/KG b.w. increased survival to 45%, and all cats dosed with 3 to 5 mg/Kg b.w. survived. CaCl2 (180 mg/Kg b.w., i.v.) induced ventricular fibrillation and 100% lethality. These effects were completely prevented by an anti-arrhythmic dose of AR-1 (3 mg/kg b.w.). Epinephrine-induced ventricular arrhythmias were also prevented by the same dose of AR-1. AR-1 (5 mg/kg b.w.) did not prevent ouabain (0.5 mg/kg b.w.)-induced arrhythmias that caused death within 17 +/- 3.7 min, but displayed protective effects during 67 +/- 7.7 min. The results from these animal studies, in conjunction with previously studies demonstrating coronarodilatory and anti-platelet efficacy of this compound, collectively suggest that AR-1 has a potential to become a useful antianginal and antiarrhythmic therapeutic agent.     

The effects of the novel benzodiazepine receptor inverse agonist Ru 34000 on ethanol-maintained behaviors

(1) In vagotomized, anaesthetized rats, effects of stimulation of cardiac N. vagus (2-25 Hz) on cardiac and circulatory functions were studied: we recorded transient reductions in heart rate (HR), in left-ventricular systolic pressure (LV Ps), in maximal change in left-ventricular pressure development (dp/dt)max and in mean arterial pressure (MAP, A. femoralis). (2) Bolus injection of angiotensin II (AII, 2.5-100 microg/kg body weight) caused (a) transient increases in HR, LV Ps and MAP (pressor effects, maximal changes occurred within 3 min after injection), and (b) dose-dependently reduced effects of vagus stimulation (non-pressor effects, recorded 10 min after injection). Due to fast breakdown of All in the circulatory system, all observed vagus stimulation effects were completely recovered within 1 h after injection. (3) Plasma concentration of AII was recorded with a highly specific radioimmunoassay: 10 min after AII injection (non-pressor range), plasma concentration was clearly higher than physiological levels in all experiments with 10 microg AII/kg at least. (4) Treatment with propranolol (beta-adrenoceptor blocker, 1 mg/kg body weight) did not reduce the vagus effects alone, but decreased the modulatory AII effects. This result hints at the activation of sympathetic beta-adrenergic receptors by AII counteracting the parasympathetic cardiac control.     

Effects of arachidonic, linoleic, linolenic and oleic acid on experimental arrhythmias in cats, rabbits and guinea-pigs

Antiarrhythmic effects of the Prostaglandin (PG) precursors arachidonic and Linoleic acid were demonstrated on three models of experimental arrhythmias, whereas the fatty acids linolenic and oleic acid proved to be ineffective in these models. In ouabain-induced arrhythmias infusions of arachidonic acid (1, 0 mg/kg/min) caused a strong antiarrhythmic effect in 80 percent of the animals. On the same model linoleic acid showed a maximum effct in 40 percent of the animals. BaCl2-induced arrhythmias were abolished by arachidonic and linoleic acid in 60 percent and 66 percent of the rabbits, respectively. Pretreatment by indomethacin reduced the antiarrhythmic effects of linoleic acid from 40 percent to 9 percent on ouabain-induced arrhythmias in cats. The results suggest a participation of PG synthesis in the antiarrhythmic effect of PG precursors.     

Transient kinetics and thermodynamics of anthroylouabain binding to Na/K-ATPase

In this study the antiarrhythmic and the proarrhythmic activities of almokalant, a selective class III antiarrhythmic agent, were compared. The antiarrhythmic effect of the drug was tested in pentobarbital-anaesthetised rabbits. Arrhythmia was evoked by occluding and releasing the left circumflex coronary artery. Almokalant in a dose of 250 nmol/kg i.v., significantly decreased the incidence of reperfusion induced ventricular fibrillation (21% vs. 75% in the control group) and increased the proportion of surviving animals during reperfusion (86% vs. 42%). The proarrhythmic effect of almokalant was examined during alpha1-adrenoceptor stimulation in chloralose-anaesthetised rabbits. Almokalant (75 nmol/kg per min) triggered torsade de pointes arrhythmias in 8 animals out of 11. The dose of almokalant (mean+/-S.E.M.) required to produce this effect was 1181+/-519 nmol/kg. It is concluded that, although almokalant is an effective antiarrhythmic agent against ischaemia-reperfusion induced arrhythmias, it has marked proarrhythmic activity during alpha1-adrenoceptor stimulation.     

Sympatholytic action of intravenous amiodarone in the rat heart

BACKGROUND: Amiodarone is a commonly used antiarrhythmic agent with complex pharmacological effects. Although ventricular arrhythmias can be suppressed soon after intravenous amiodarone, the mechanisms responsible for this action are unclear. We studied the effects of acute treatment with amiodarone on the metabolism and release of norepinephrine (NE) in intact rats and in perfused rat hearts. METHODS AND RESULTS: Experiments were performed in anesthetized rats and in perfused, innervated hearts with amiodarone administered intravascularly. NE release was induced by electrical stimulation of the sympathetic ganglion. Concentrations of NE and its intraneuronal metabolite dihydroxyphenylglycol (DHPG) in hearts, plasma, and coronary venous effluent were measured by high-performance liquid chromatography. Acute administration of amiodarone induced dose-dependent increases in DHPG concentrations in plasma (5 mg/kg, +48%; 15 mg/kg, +84%; and 50 mg/kg, +467%) and in coronary venous effluent (1 mumol/L, +37%; 3 mumol/L, +510%; and 10 mumol/L, +1100%) together with an unchanged basal overflow of NE. In perfused hearts, NE release evoked by nerve stimulation was inhibited by infusion of amiodarone (1 mumol/L, -16%; 3 mumol/L, -24%; and 10 mumol/L, -64%) or by intravenous amiodarone (50 mg/kg) given 1 hour before heart perfusion (-70%), and the extent of this suppression correlated well with levels of DHPG overflow present immediately before nerve stimulation. When given in vitro and in vivo, amiodarone also significantly reduced NE and increased DHPG content in the heart, leading to a raised DHPG/NE ratio. All these effects of amiodarone were similar to those found with reserpine but less potent. In contrast, oral amiodarone produced none of these effects. CONCLUSIONS: Acute administration of amiodarone in perfused hearts or intact rats induces partial NE depletion in the heart by interfering with vesicular NE storage and enhancing intraneuronal NE metabolism, effects associated with an impaired NE release during sympathetic activation. Oral dosing with amiodarone has no such effect. Further study is required to test whether this novel sympatholytic effect of amiodarone contributes to its antiarrhythmic action after intravenous administration.     

The relative importance of dopamine and noradrenaline receptor stimulation for the restoration of motor activity in reserpine or alpha-methyl-p-tyrosine pre-treated mice

Two animal models of Parkinsonism have been employed to investigate the role of noradrenaline in the motor effects of levodopa. Pretreatment with reserpine or alpha-methyl-p-tyrosine (AMPT) causes cerebral amine depletion and reduction of motor activity, which can be reversed by levodopa. The effect of inhibitors of noradrenaline (NA) synthesis and antagonists of NA and dopamine (DA) receptors on the action of levodopa have been studied. For comparison, the effects of such treatments on apomorphine action has been investigated. Reversal of reserpine (10 mg/kg) induced akinesia in mice by levodopa (200 mg/kg) plus the peripheral decarboxylase inhibitor MK 486 (L-alpha-methyl-dopahydrazine; 25 mg/kg) was inhibited by prior administration of phenoxybenzamine (20 mg/kg), haloperidol (1 mg/kg), pimozide (1 mg/kg) or the dopamine-beta-hydroxylase inhibitor FLA-63 (bis [4-methyl-l-homopiperazinylthiocarbonyl] disulphide; 15 or 25 mg/kg). Apomorphine (2 mg/kg) reversal of reserpine akinesia was similarly inhibited by haloperidol (1 mg/kg) and pimozide (2 mg/kg) but not by phenoxybenzamine (20 mg/kg) or FLA-63 (25 mg/kg). Apomorphine (5 mg/kg) reversal of reserpine akinesia was enhanced by simultaneous administration of the noradrenergic agonist clonidine (1 mg/kg) and this effect was not significantly altered by prior administration of FLA-63. Clonidine, however, reversed the FLA-63 induced inhibition of the levodopa effect on reserpine akinesia. Levodopa reversal of akinesia induced by AMPT (200 mg/kg) was also inhibited by FLA-63, pimozide and haloperidol. Phenoxybenzamine, however, was without effect, but produced a different pattern of behaviour. Similarly, pimozide and haloperidol blocked apomorphine reversal of AMPT induced akinesia; FLA-63 was without effect but phenoxybenzamine produced marked inhibition. The results suggest that full restoration of motor activity in reserpine or AMPT pretreated animals requires stimulation of both DA and NA receptors.     

Antiarrhythmic effect related to the plasma concentration of pentisomide in vivo and the antiarrhythmic-concentration relationship in vitro

Pentisomide, 2-(2-diisopropylaminoethyl)-4-methyl-2-(pyridyl)- pentanamide, is a novel antiarrhythmic agent structurally related to disopyramide. Using a glass bead arrhythmic model, the authors studied the antiarrhythmic effect of pentisomide in dogs by monitoring the plasma concentrations. When pentisomide was infused at 1 mg/kg/min for 20 min, the ventricular tachycardia was significantly reduced at 5 min after starting the infusion; the arrhythmias were reduced to less than 5% at the end of the 20 min infusion. The plasma-free concentration of pentisomide was about 3 micrograms/ml at 5 min; it increased to about 10 micrograms/ml at the end of 20 min infusion. With 0.3 mg/kg/min infusion, the arrhythmias were reduced to about 60% but were not significant at 20 min of infusion. The plasma-free concentration of pentisomide did not reach 3 micrograms/ml until 20 min of infusion. The 3 micrograms/ml plasma-free concentration for pentisomide seems to be a critical concentration in inducing a significant antiarrhythmic effect. Pentisomide dose-dependently inhibited ischaemia-reperfusion arrhythmia at doses of 30 microM and higher concentrations in vitro. In conclusion, pentisomide inhibits arrhythmias dependent with the plasma concentration or with the concentration of the external solution. The critical plasma-free concentration for inhibition of arrhythmias was 3 micrograms/ml (not equal to 10 microM) and the in vitro effect also had a similar concentration. Therefore, the in vivo and in vitro antiarrhythmic concentrations were well correlated.     

The role of the opioid system in body adaptation and protection of the heart in stress

Literary data and the results of our own studies on the role of opioid neuropeptides in the adaptation of organism and heart protection under the action of extreme factors were analysed. The data on the cardioprotective, antiarrhythmic, neurohumoral, antistressor effects of enkephalins are grown. Possible mechanisms and the role of various populations of opiate receptors in the realisation of opioid peptides' adaptation effects are studied. The key role of endogenous opiate system in the mechanism of cardioprotective effects of natural adaptogens and adaptation is established.     

Differential response of arteries and vein grafts to blood flow reduction

BACKGROUND: Because the relative efficacy of antiarrhythmic agents on halothane-epinephrine arrhythmias has not been well characterized, this study was undertaken to comparatively evaluate the antiarrhythmic action of Na(+)-, K(+)- and Ca(2+)-channel blockers on epinephrine-induced ventricular arrhythmias during halothane anesthesia in rats. METHODS: Rats were anesthetized at random with either halothane (1.5%), isoflurane (2.0%), or pentobarbital (50 mg/kg intraperitoneally), and the lungs were mechanically ventilated with oxygen. The rats were studied in three consecutive protocols. Protocol I determined the arrhythmogenic thresholds of epinephrine during the three types of anesthesia in 33 rats. Protocol II determined the arrhythmogenic thresholds of epinephrine during halothane anesthesia in 64 rats receiving saline (control) or one of five antiarrhythmic agents. Protocol III measured the duration of epinephrine-induced arrhythmias during halothane anesthesia in 42 rats receiving saline (control) or one of five antiarrhythmic agents. RESULTS: In protocol I, the arrhythmogenic doses of epinephrine during halothane, isoflurane, or pentobarbital anesthesia were 1.7 +/- 3.2, 11.1 +/- 0.6, and 39.0 +/- 3.9 micrograms/kg, respectively, and the corresponding plasma concentrations were 4.3 +/- 0.8, 103.7 +/- 9.2, and 246.7 +/- 28.9 ng/ml, respectively. In protocol II, the arrhythmogenic doses were similar in rats receiving saline and in those receiving lidocaine. The arrhythmogenic doses in rats receiving verapamil, flecainide (Na(+)- and K(+)-channel blocker), E-4031 (K(+)-channel blocker), or amiodarone(K(+)-channel blocker with Na(+)-, Ca(2+)-, and beta-blocking activity) increased significantly, i.e., 4.2, 4.2, 5.5, and 31.7 times control (P < 0.01). In protocol III, lidocaine had no effect on the duration of arrhythmias. Flecainide, E-4031, and verapamil markedly reduced the duration of arrhythmias induced by epinephrine, 8 micrograms/kg intravenously (P < 0.01), whereas only amiodarone markedly reduced the duration of arrhythmias induced by epinephrine, 16 micrograms/kg intravenously (P < 0.01). CONCLUSIONS: It was concluded that agents with K(+)-channel blocking properties were the most effective in preventing halothane-epinephrine arrhythmias in rats.     

Ischemia/reperfusion-induced arrhythmias in anaesthetized rats: a role of Na+ and Ca2+ influx

We hypothesized that by limiting the Na+ and Ca2+ loading by a blocker/inhibitor of the Na+ channel (lidocaine), Na+ overload (R56865: N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]-N-methyl-2-benzothiazo lamine), Ca2+ channel (verapamil), Na+ -H+ exchange (ethylisobutyl amiloride) or of Na+ -Ca2+ exchange (No. 7943: 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate), it should be possible to reduce ischemia/reperfusion-induced arrhythmias. To test this hypothesis, we used anaesthetized rats subjected to 5 min of coronary artery occlusion followed by 10 min of reperfusion to study antiarrhythmic effects of above compounds on reperfusion-induced ventricular premature beats, ventricular tachycardia, and reversible and irreversible ventricular fibrillation. Compound or saline was administered as an intravenous bolus injection at 5 min before ischemia. Pretreatment with lidocaine (5 mg/kg), verapamil (0.63 mg/kg), R56865 (0.63 mg/kg) or ethylisobutyl amiloride (1.25 mg/kg) significantly reduced or abolished all types of ventricular arrhythmias. However, pretreatment with verapamil was associated with second or third degree heart block in 3 out of 12 animals. Pretreatment with No. 7943 did not significantly influence the ischemia/reperfusion-induced ventricular arrhythmias. The present results suggest that both intracellular Na+ -and Ca2+ -loading play important roles in reperfusion-induced ventricular arrhythmias and the inhibition of Na+ -Ca2+ exchange to limit Ca2+ loading probably does not play any important role in ischemia/reperfusion-induced arrhythmias in anaesthetized rats.     

Release of somatostatin and its role in the mediation of the anti-inflammatory effect induced by antidromic stimulation of sensory fibres of rat sciatic nerve

1. The effect of antidromic stimulation of the sensory fibres of the sciatic nerve on inflammatory plasma extravasation in various tissues and on cutaneous vasodilatation elicited in distant parts of the body was investigated in rats pretreated with guanethidine (8 mg kg(-1), i.p.) and pipecuronium (200 microg kg(-1), i.v.). 2. Antidromic sciatic nerve stimulation with C-fibre strength (20 V, 0.5 ms) at 5 Hz for 5 min elicited neurogenic inflammation in the innervated area and inhibited by 50.3 +/- 4.67% the development of a subsequent plasma extravasation in response to similar stimulation of the contralateral sciatic nerve. Stimulation at 0.5 Hz for 1 h also evoked local plasma extravasation and inhibited the carrageenin-induced (1%, 100 microl s.c.) cutaneous inflammation by 38.5 +/- 10.0% in the contralateral paw. Excitation at 0.1 Hz for 4 h elicited no local plasma extravasation in the stimulated hindleg but still reduced the carrageenin-induced oedema by 52.1 +/- 9.7% in the paw on the contralateral side. 3. Plasma extravasation in the knee joint in response to carrageenin (2%, 200 microl intra-articular injection) was diminished by 46.1 +/- 12.69% and 40.9 +/- 4.93% when the sciatic nerve was stimulated in the contralateral leg at 0.5 Hz for 1 h or 0.1 Hz for 4 h, respectively. 4. Stimulation of the peripheral stump of the left vagal nerve (20 V, 1 ms, 8 Hz, 10 min) elicited plasma extravasation in the trachea, oesophagus and mediastinal connective tissue in rats pretreated with atropine (2 mg kg(-1), i.v.), guanethidine (8 mg kg(-1), i.p.) and pipecuronium (200 microg kg(-1), i.v.). These responses were inhibited by 37.8 +/- 5.1%, 49.7 +/- 9.9% and 37.6 +/- 4.2%, respectively by antidromic sciatic nerve excitation (5 Hz, 5 min) applied 5 min earlier. 5. Pretreatment with polyclonal somatostatin antiserum (0.5 ml/rat, i.v.) or the selective somatostatin depleting agent cysteamine (280 mg kg(-1), s.c.) prevented the anti-inflammatory effect of sciatic nerve stimulation (5 Hz, 5 min) on a subsequent neurogenic plasma extravasation of the contralateral paw skin. The inhibitory effect of antidromic sciatic nerve excitation on plasma extravasation in response to vagal nerve stimulation was also prevented by somatostatin antiserum pretreatment. 6. Cutaneous blood flow assessment by laser Doppler flowmetry indicated that antidromic vasodilatation induced by sciatic nerve stimulation was not inhibited by excitation of the sciatic nerve of the contralateral leg (1 Hz, 30 min) or by somatostatin (10 microg/rat, i.v.) injection. 7. Plasma levels of somatostatin increased more than 4 fold after stimulation of both sciatic nerves (5 Hz, 5 min) but the stimulus-evoked increase was not observed in cysteamine (280 mg kg(-1), s.c.) pretreated rats. 8. These results suggest that somatostatin released from the activated sensory nerve terminals mediates the systemic anti-inflammatory effect evoked by stimulating the peripheral stump of the sciatic nerve.     

Principal modifications of the Duhamel procedure in the treatment of Hirschsprung''s disease. Analysis based on results of an international retrospective study of 2,430 patients

The present study was undertaken to investigate the effects of losartan, a non-peptide angiotensin II subtype 1 (AT1) receptor antagonist, on both the pressor responses elicited by stimulation of afferent vagal nociceptive fibres and the involvement of the sympathetic nervous system (evaluated by plasma levels of noradrenaline and its co-neurotransmitter neuropeptide Y) in dogs. Electrical stimulation of the afferent fibres of the vagus (1, 5, 10 and 20 Hz) elicited a frequency-dependent increase in blood pressure and heart rate. Plasma noradrenaline levels only increased after stimulation at frequencies of 10 and 20 Hz. Plasma neuropeptide Y levels did not change. Losartan (10 mg/kg i.v.) induced both a decrease in resting blood pressure and an increase in basal plasma levels of noradrenaline and neuropeptide Y. Losartan failed to modify the magnitude of the electrically-evoked pressor and positive chronotropic responses. The angiotensin AT1 receptor antagonist elicited a fall in plasma noradrenaline values after a 1 Hz stimulation and abolished the increase in plasma noradrenaline levels induced by the 10 (but not 20) Hz stimulation. The data suggest that angiotensin AT1 receptors are not directly involved in acute pressor responses induced by stimulation of afferent vagal fibres. Moreover, the results show that, besides its sympatho-inhibitory effect, losartan can exert a sympatho-excitatory action as shown by the increase in the plasma levels of both noradrenaline and its coneurotransmitter, neuropeptide Y.     

MS-551 and KCB-328, two class III drugs aggravated adrenaline-induced arrhythmias

We investigated the proarrhythmic effects of MS-551 and KCB-328, class III antiarrhythmic drugs using adrenaline-induced arrhythmia models in halothane anaesthetized, closed-chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 microg/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non-inducing dose. After MS-551 or KCB-328 administration, the adrenaline injection was repeated and the interval between the injection and the occurrence of arrhythmia (latent interval), the changes in arrhythmic ratio (as calculated by dividing the number of ventricular premature contraction by the number of the total heart rate) and the severity of arrhythmia were observed. MS-551 infusion, 1 mg/kg/30 min, decreased the heart rate (HR) by 16% (P<0.01) and prolonged the QTc interval by 20% (P<0.01). During the 30 min of MS-551 infusion, arrhythmias occurred in three out of seven dogs (torsades de pointes (TdP) type VT in one dog). After these arrhythmias disappeared, MS-551 decreased the latent interval of the adrenaline arrhythmias produced by the inducing dose (30+/-2 s compared with 43+/-3 s of the control interval, P < 0.05), increased the arrhythmic ratio (P<0.05) and induced arrhythmias by non-inducing adrenaline doses (P<0.05). Effect of a new class III drug KCB-328 infusion, 0.3 mg/kg/30 min, was compared witih MS-551 using the same model. KCB-328 decreased the HR by 21% (P<0.01) and prolonged the QTc interval by 25% (P<0.01). During the 30 min of infusion, arrhythmias occurred in five out of seven dogs (TdP in two dogs). KCB-328 also decreased the latent interval of the adrenaline arrhythmias produced by the inducing doses (31+/-3 s compared with 49+/-7 s of the control period, P<0.05), but did not significantly alter the arrhythmic ratio. Adrenaline induced TdP only after MS-551 or KCB-328 was administered, i.e. after MS-551, 1 mg/kg/30 min, 3/7 versus 0/7 in the control; KCB, 0.3 mg/kg/30 min, 3/7 versus 0/7 in the control. To examine the direct arrhythmogenic effect of MS-551 and whether an adrenergic mechanism plays some role on this arrhythmogenesis, a bolus injection of MS-551, 3 mg/kg, was injected either without pre-treatment or after pre-treatment with propranolol 0.3 mg/kg. MS-551 induced arrhythmias in five out of seven dogs (TdP in one dog). Also in the propranolol pre-treated dogs, MS-551 induced arrhythmias in five out of seven dogs (TdP in 1 dog). In conclusion, these observations indicate that MS-551 and KCB-328 induced arrhythmias and intensified proarrhythmic effects of adrenaline, MS-551 being stronger than KCB-328 at the same QTc prolonging doses. The direct arrhythmogenic effect of MS-551 was not influenced by beta-blocker treatment.     

Effects of berberine on delayed afterdepolarizations in ventricular muscles in vitro and in vivo

The effects of berberine on delayed afterdepolarizations in ventricular muscles in vitro and in vivo were investigated to help explain the mechanisms for its antiarrhythmic action. Berberine 3 mumol reduced the amplitude of delayed afterdepolarizations induced by ouabain or posthypoxic reoxygenation and abolished subsequent triggered activity in isolated guinea pig right ventricular papillary muscles. At 30 mumol, it decreased the incidence of delayed afterdepolarizations, associated with a further decrease in the amplitude of delayed afterdepolarizations. In rabbit left ventricular (LV) muscles in vivo, berberine 1 mg/kg intravenously (i.v.) decreased the amplitude of delayed afterdepolarizations evoked by ouabain and calcium gluconate from 9.6 +/- 1.9 to 6.8 +/- 0.8 mV and left stellate ganglion stimulation from 9.4 +/- 2.1 to 6.2 +/- 0.7 mV and blocked ventricular arrhythmias. After a 4-mg/kg i.v. bolus, the drug inhibited and even completely abolished development of delayed afterdepolarizations, yet still reduced maximal velocity of depolarization in isolated and in vivo ventricular muscles. Therefore, one of the important mechanisms for antiarrhythmic action of berberine may be suppression of delayed afterdepolarizations, which may be attributable in part to a decrease in Na+ influx.     

Convergence properties of solitary tract neurons responsive to cardiac receptor stimulation in the anesthetized cat

The convergence pattern of cardiac receptors, pulmonary C-fibers, carotid chemoreceptor, and baroreceptor afferents onto neurons within the nucleus of the solitary tract (NTS) was studied in the anesthetized (pentobarbitone sodium, 40 mg/kg,) paralyzed and artificially ventilated cat. Extra- and intracellular recordings were made from NTS neurons while stimulating both cardiac receptors by aortic root injections of veratridine (1-3 micrograms/kg) and pulmonary C-fibers by a right atrial injection of phenylbiguanide (10-20 micrograms/kg). The ipsilateral carotid body was stimulated by using arterial injection of CO2-saturated bicarbonate solution, whereas inflation of the ipsilateral carotid sinus was used to activate baroreceptors. The ipsilateral cardiac vagal branch, cervical vagus, and carotid sinus nerves were stimulated electrically (1 Hz, 0.2-1 ms, 1-35 V). In 78 NTS neurons recorded either extracellularly (n = 47) or intracellularly (n = 31), electrical stimulation of the cardiac branch of the vagus nerve evoked synaptic potentials (spikes and/or excitatory postsynaptic potentials) with an onset latency between 4 and 220 ms. Some neurons displayed both short and long latency inputs(15.5 +/- 1.8 and 160.0 +/- 8.5 ms; n = 14). Of these 78 neurons, 24 responded to veratridine stimulation of cardiac receptors (i.e., cardioreceptive neurons) by exhibiting an augmenting-decrementing discharge of 37 +/- 4 s in duration with a peak frequency of 30 +/- 5 Hz. Convergence from other cardiorespiratory receptors was noted involving either carotid chemoreceptors (n = 7) or pulmonary C-fibers (n = 4) or from both carotid chemoreceptors and pulmonary C-fibers (n = 6). In contrast, only one cardioreceptive NTS neuron was activated by distension of the carotid sinus. Recording sites recovered were confined to the medial NTS at the level of the area postrema and extended caudally into the commissural subnucleus. Our results indicate a convergence of carotid chemoreceptor and pulmonary C-fiber afferent inputs to cardioreceptive NTS neurons. With the paucity of baroreceptor inputs to these neurons it is suggested that sensory integration within the NTS may reflect regulatory versus defensive or protective reflex control.     

Effects of EGb 761 on nitric oxide and oxygen free radicals, myocardial damage and arrhythmia in ischemia-reperfusion injury in vivo

The cardioprotective effects of EGb 761 on the release of nitric oxide (NO), the concentration of serum thiobarbituric acid reaction substance (TBARS), the activity of creatine kinase (CK) and the incidence of ventricular arrhythmias were investigated in myocardial ischemia-reperfusion injury in vivo. Using sodium nitrite (NaNO2) as standard source of nitric oxide (NO), we compared the correlation coefficients of the three measuring methods used currently in the determination of NOFe2+(DETC)2 complex with that of the measuring method suggested in this study. The result showed that measuring the whole height of three splitting signals is the best linear correlation to the concentration of NO comparing with other methods in this system. Using this method, we observed the effects of EGb 761 on NOFe2+(DETC)2 complex in myocardial ischemia-reperfusion injury in vivo. The hearts of the Wistar rats were subjected to 30 min of ischemia and 10 min of reperfusion in vivo. Different doses of EGb 761 (25, 50, 100, 200 mg/kg i.p.), superoxide dismutase (SOD, 10(4) U/kg), l-arginine (50 mg/kg i.p.) and nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine (NNA, 50 mg/kg i.p.) were administered to the ischemia-reperfusion rats. EGb 761 under the dose of 100 mg/kg increased the signal intensity of NOFe2+(DETC)2 complex, while EGb 761 at 200 mg/kg showed an effect of decreasing the signal intensity of NOFe2+(DETC)2 complex. EGb 761 inhibited the formation of TBARS, the release of CK, and mitigated the incidence of ventricular arrhythmias in a dose dependent way. Both l-arginine and SOD increased the signal intensity of NOFe2+(DETC)2 complex and inhibited the formation of TBARS, the leakage of CK and the incidence of ventricular arrhythmia. NNA not only had no protective effects on myocardial injury, but also increased the incidence of reperfusion-induced arrhythmia. In conclusion, EGb 761 has cardiovascular protective effects by means of adjusting the level of NO and inhibiting oxygen free radicals induced lipid peroxidation in myocardial ischemia-reperfusion injury in vivo.     

Effects of the NMDA-antagonist, MK-801, on stress-induced alterations of dopamine dependent behavior

The effects of pretreatment with the non-competitive NMDA antagonist (+)MK-801 on the behavioral alterations induced by repeated restraint stress were investigated. Repeatedly stressed (restraint stress 2 h a day x 10 days) mice showed enhanced sensitivity to the inhibitory effects of a low dose of direct dopamine agonist, apomorphine (0.25 mg/kg), on climbing behavior. On the other hand, no changes were observed for the stimulatory effect of the high dose of apomorphine (3 mg/kg) on this behavioral response. Mice pretreated with MK-801 (0.15 mg/kg) before the stressful experience did not show altered response to the low dose of apomorphine (0.25 mg/kg). Finally, ten daily injections with 0.15 mg/kg MK-801 did not affect the behavioral response to the low dose of apomorphine, but enhanced the stimulatory effect of the high dose of the dopaminergic agonist on climbing behavior. Therefore, it is possible that the protective action of MK-801 against stress-induced behavioral alteration is due to changes in sensitivity of postsynaptic receptors.     

Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism

A standard electrical stimulus applied to the posterior hypothalamus evoked cardiac arrhythmogenic responses in the spontaneously hypertensive rat. Isolated premature ventricular beats or doublets and nonsustained ventricular tachycardic salvos were observed. This effect was associated with a large rise in blood pressure (79 +/- 3 mm Hg). The same stimulus in normotensive Wistar-Kyoto rats produced no significant cardiac arrhythmias, and the rise in blood pressure was smaller (36 +/- 2 mm Hg). We investigated the influence of baclofen, a GABAB receptor agonist, and two N-methyl-D-aspartate receptor antagonists on the arrhythmogenic response to hypothalamic stimulation. Intravenous baclofen (3 mg/kg) had no effect in the normotensive Wistar-Kyoto rats, but in the spontaneously hypertensive rats it enhanced the adjusted mean value of the number of extrasystoles from 0.5 +/- 0.5 to 18 +/- 1 (P < .001). This value was also increased (from 3 +/- 1 to 17 +/- 1, P < .001) by an intracisternal injection of baclofen (1 micrograms/kg). This facilitatory effect of baclofen was prevented by treatment with atenolol (0.5 mg/kg). Two glutamate receptor antagonists, ketamine (7.5 mg/kg IV) and kynurenic acid (200 micrograms/kg intracerebroventricularly), prevented both the arrhythmogenic response to the hypothalamic stimulation and its facilitation by baclofen. The study confirms that hypothalamic stimulation facilitates the development of arrhythmias through a sympathetic drive and that these arrhythmias are easier to induce in spontaneously hypertensive rats than in normotensive Wistar-Kyoto rats. Both the central GABAergic and the glutamatergic systems are implicated in the development of these ventricular arrhythmias, since baclofen could disinhibit the glutamatergic central pathway. These results could account for the ability of the spontaneously hypertensive rats to develop ventricular arrhythmias of central origin.