Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been suggested that central nervous system (CNS) neuroexcitation plays an important role in digitalis-induced cardiac arrhythmias. To elucidate further the role of the CNS in digitalis-induced arrhythmias, the inotropic and toxic effects of a highly polar semisynthetic cardiac glycoside, 3beta-O-(4 amino-4,6 dideoxy-beta-D-galactopyranosyl)-digitoxigenin (ASI-222) were compared to those of digoxin and correlated with plasma and cerebrospinal fluid (CSF) concentrations of each drug. Thirteen dogs anesthetized with sodium pentobarbital were given repeated intravenous doses of digoxin or ASI-222. Ventricular tachycardia was elicited at a mean dose of digoxin of 0.12 mg/kg, compared with 0.09 mg/kg for ASI-222 (not significant). Terminal ventricular fibrillation occurred after 0.18 mg/kg of digoxin, a value significantly larger than the ASI-222 dose (0.14 mg/kg, P less than 0.05) required to produce lethal arrhythmias. Digoxin produced a 21% increase in LV dP/dt at a plasma digoxin concentration of 20.0 +/- 2 ng/ml (mean +/- SEM) 30 minutes after 0.05 mg/kg; the CSF digoxin concentration at this time averaged 0.7 +/- 0.1 ng/ml. At death, the plasma digoxin concentration was 88 +/- 16 ng/ml and CSF digoxin concentration was 5.7 +/- 1.6 ng/ml. ASI-222 produced a similar 25% increase in LV dP/dt 30 minutes after administration of 0.05 mg/kg, with a plasma concentration of 18 +/- 2 ng/ml as determined by a newly developed radioimmunoassay. The plasma ASI-222 concentration at death, 95 +/- 18 ng/ml, was similar to that of digoxin. However, CSF samples at 30 minutes and at death showed no detectable levels of ASI-222. Thus, despite similar inotropic and toxic responses and similar plasma drug concentrations compared to digoxin, ASI-222 was demonstrated to have limited if any access to the CNS as judged by CSF concentrations. These findings suggest that direct CNS stimulation does not play a primary part in the genesis of digitalis-induced cardiac arrhythmias in this experimental model, or that CNS effects are mediated by an area or areas lacking an effective blood-brain barrier.
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PMID:Inotropic and toxic effects of a polar cardiac glycoside derivative in the dog. 70 46

The potential antiarrhythmic efficacy of pharmacologic parasympathetic activation is still controversial. This study assessed the antiarrhythmic effect of saline solution (n = 9) and of the muscarinic agonist oxotremorine (1.5 micrograms/kg administered intravenously) (n = 17) in a feline animal model in which malignant arrhythmias were reproducibly elicited by the combination of acute myocardial ischemia and left stellate ganglion stimulation. Although saline solution had no effect, oxotremorine significantly decreased heart rate, blood pressure, the incidence of ventricular fibrillation from 47% to 0% (p = 0.004), and the incidence of malignant arrhythmias (either ventricular tachycardia or ventricular fibrillation) from 88% to 12% (p less than 0.001). When reduction in heart rate was prevented by means of atrial pacing (n = 15), the incidence of malignant arrhythmias was still significantly reduced from 87% to 27% (p = 0.001). Arrhythmias were also graded as follows: 0 = no premature ventricular contractions; 1 = 1 to 10 premature ventricular contractions; 2 = 11 to 50 premature ventricular contractions; 3 = ventricular tachycardia; 4 = ventricular fibrillation. Arrhythmia severity was 3.29 +/- 0.16 (SEM) in the control trials and was reduced to 0.76 +/- 0.26 (p less than 0.001) by oxotremorine and to 1.53 +/- 0.34 by oxotremorine and pacing (p = 0.002). Therefore a muscarinic agonist can significantly reduce malignant arrhythmias during acute myocardial ischemia and may represent a novel approach to the prevention of sudden cardiac death.
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PMID:Prevention of life-threatening arrhythmias by pharmacologic stimulation of the muscarinic receptors with oxotremorine. 138 85

In 12 open-chest dogs, cardiac sympathetic nervous activity (CSNA) was recorded before and after occlusion of the left anterior descending coronary artery as well as during reperfusion and ventricular fibrillation (VF). In 7 control animals, CSNA did not significantly differ from preocclusion levels when determined 20 min after occlusion (+3.5 +/- 1.5%, mean +/- SEM) and up to 15 min following reperfusion (+1.5 +/- 0.6%). However, VF was associated with a potential increase in CSNA by 106 +/- 15.5% (p less than 0.001). The effect of lidocaine (6 mg/kg) on cardiac sympathetic tone was examined in 5 additional animals. Lidocaine reduced control CSNA by 23 +/- 4.7% (p less than 0.001); subsequent ischemia and reperfusion did not substantially change the level of preocclusion activity. CSNA decreased significantly also during VF (52 +/- 4.2%, p less than 0.001). In conclusion, efferent CSNA was slightly altered in the course of acute myocardial ischemia and reperfusion, but significantly increased during VF. Lidocaine produced marked attenuation of CSNA in anesthetized dogs.
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PMID:Cardiac sympathetic nervous activity during myocardial ischemia, reperfusion and ventricular fibrillation in the dog--effects of intravenous lidocaine. 151 66

To test the hypothesis that angiotensin II (Ang II) in the central nervous system modulates catecholamine-induced cardiac arrhythmias and to determine whether endogenous opioids are operative in this action, arrhythmias were produced in male Wistar rats, by continuous infusion of epinephrine at incremental doses until the development of fatal arrhythmias that were usually ventricular fibrillation. Rats were instrumented with catheters in the lateral cerebral ventricle, femoral vein and femoral artery. Ang II, 0.5 microgram, in the lateral cerebral ventricle (ICV) markedly and significantly (p less than 0.05) increased the epinephrine dose, at the occurrence of ventricular premature beats compared to the control group 228 +/- 11 (SEM) vs 116 +/- 7 micrograms epinephrine/kg and at the onset of fatal arrhythmias 225 +/- 13 vs 185 +/- 9 micrograms epinephrine/kg. Ang II, 0.5 microgram i.v., did not affect arrhythmia threshold. The angiotensin converting enzyme inhibitor captopril, 1 mg/kg, decreased arrhythmia threshold as ventricular arrhythmias were first noted at 106 +/- 4 and fatal arrhythmias occurred at 118 +/- 4 micrograms epinephrine/kg. The Ang II receptor antagonist saralasin 150 micrograms/kg ICV, blunted and 300 micrograms/kg ICV reversed the effect of Ang II. The mu opioids antagonist naloxone and the kappa opioid antagonist MR 2266, 50 micrograms/kg ICV, prevented the effect of Ang II on fatal arrhythmias. The action Ang II on arrhythmias could not be explained by the effects of Ang II on blood pressure or heart rate. These data indicate a role for Ang II within the CNS to modulate cardiac arrhythmias and that this is mediated in part, by endogenous opioids.
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PMID:Angiotensin in the brain suppresses epinephrine-induced cardiac arrhythmias through CNS opioid mechanisms. 165 93

We used isolated rat hearts subjected to coronary artery ligation and reperfusion to study the antiarrhythmic activity of 5-hydroxypropafenone (5OHP) and N-depropylpropafenone (NDPP), major metabolites of propafenone (P) in humans, and of the two enantiomers (R)- and (S)-propafenone. 5OHP suppressed reperfusion arrhythmias similar to the parent drug in a concentration-dependent manner. The concentration of 5OHP needed to prevent ventricular fibrillation in 50% of experiments (EC50) was significantly higher than that of P (0.186 +/- 0.05 vs. 0.153 +/- 0.005 mg/L, mean +/- SEM, p less than 0.05). 5OHP had a relative potency of 80% compared to P. When 5OHP and P were administered together, their antiarrhythmic effect appeared to be supra-additive. The NDPP metabolite showed very little antiarrhythmic potency and was about four times less active than P. The two enantiomers (R) and (S) were equipotent and showed antiarrhythmic activities similar to racemic P.
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PMID:The relative potency of major metabolites and enantiomers of propafenone in an experimental reperfusion arrhythmia model. 168 86

The antiarrhythmic effect of alpha 1-adrenoceptor antagonists during myocardial ischemia and reperfusion remains controversial. The potential antiarrhythmic properties of indoramin, an alpha 1-antagonist, were assessed in the isolated perfused rat heart during regional ischemia and during sustained reperfusion. Coronary artery ligation (CAL) decreased the ventricular fibrillation threshold (VFT) of control hearts from 9.1 +/- 1.3 (pre-CAL, mean +/- SEM) to 2.1 +/- 0.5 mA 15 min post-CAL (p less than 0.0001). Perfusion with indoramin 10(-8) M (alpha 1-receptor antagonistic concentration) started 5 min prior to CAL did not prevent the fall in VFT after CAL. Indoramin 10(-6) M prevented the fall in VFT after CAL relative to the control group. Indoramin 10(-5) M markedly increased the VFT before CAL from 9.9 +/- 1.0 to 28.6 +/- 2.9 mA (p less than 0.0001) and prevented the fall in VFT after CAL. During reperfusion, indoramin 10(-5) M decreased the incidence of spontaneous ventricular fibrillation (VF) to 1 of 6 vs. 6 of 6 in the control group (p less than 0.02). Indoramin 10(-5) M preserved adenosine triphosphate in the reperfused myocardium: 2.82 +/- 0.06 vs. 2.16 +/- 0.21 mumol/g in the control group (p less than 0.05). Specific alpha 1-antagonist properties of indoramin did not appear to be involved in the antiarrhythmic effects.
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PMID:Antiarrhythmic and metabolic effects of indoramin during acute regional ischemia and reperfusion in isolated rat heart. 169 64

The effects of probucol, a lipophilic antioxidant, on the myocardial dysfunction (stunning) observed during reperfusion after 15-min ischemia in rabbit heart were studied. Rabbits received food with or without 1% probucol for 3 weeks. They were then anesthetized and prepared for recording of myocardial segment shortening, arterial blood pressure (BP), left ventricular pressure (LVP), rate of development of LVP (dP/dt), and a lead II ECG. Regional myocardial ischemia was produced by acute occlusion of the first marginal branch of the left coronary artery. Myocardial segment shortening was depressed after reperfusion in control rabbits. In comparison, myocardial segment shortening was significantly greater in probucol-treated rabbits than in control rabbits during reperfusion, indicating a beneficial effect. No hemodynamic or ECG changes measured could explain this difference. The number of premature ventricular contractions was reduced in the probucol-treated group, although the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) were not. Concentrations of probucol in serum and heart of five rabbits were 15.0 +/- 1.2 micrograms/ml and 17.5 +/- 2.5 micrograms/g (mean +/- SEM), respectively. Only probucol concentrations in the serum were positively correlated with the improvement in myocardial segment shortening (r = 0.91, p = 0.03). We conclude that a clinically relevant serum concentration of probucol reduces ischemia-induced myocardial stunning in the rabbit.
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PMID:Probucol reduces myocardial dysfunction during reperfusion after short-term ischemia in rabbit heart. 170 50

It has been reported that agents having the ability to scavenge oxygen-derived free radicals reduce the severity of ventricular arrhythmias that occur after brief coronary occlusion and reperfusion. Superoxide dismutase plus catalase (SOD + CAT) or placebo was administered in a blinded randomized fashion prior to coronary occlusion in rats (n = 25 each group) undergoing a 5-min left coronary occlusion followed by 15 min of reperfusion. During reperfusion, ventricular tachycardia (VT) developed in 96% of animals in both groups. Reperfusion ventricular fibrillation (VF) developed in 60% of the placebo group vs 56% in the SOD + CAT group (p = 1.0). Irreversible VF occurred in 40% of the placebo group vs 20% in the SOD + CAT group (p = 0.22). Atrioventricular block occurred in 12% of placebo and 4% of SOD + CAT animals (p = 0.61). There were no significant difference between groups in duration of VT (85 +/- 15 s (mean +/- SEM) placebo vs 81 +/- 14 s SOD + CAT, p = 0.81), total duration of VT plus VF (391 +/- 76 s placebo vs 256 +/- 64 SOD + CAT, p = 0.45) or numbers of single ventricular ectopic beats (65 +/- 15 placebo vs 97 +/- 18 SOD + CAT, p = 0.18). Heart rate at reperfusion was slightly higher in control than SOD + CAT animals (340 +/- 33 vs 319 +/- 32, p = 0.02). Risk zone size, determined by Monastral blue injection, was equal in both groups (34 +/- 2% of ventricular mass). The occurrence of reperfusion VF in this model could not be predicted by heart rate at reperfusion (331 +/- 33 VF animlas vs 328 +/- 36 no VF, p = 0.77), or by risk zone size (34 +/- 2%, VF and no VF groups).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lack of significant effects of superoxide dismutase and catalase on development of reperfusion arrhythmias. 187 67

We examined the "vascular waterfall" hypothesis, which proposes that coronary flow is unaffected by elevations in outflow pressure until the latter reaches a critical threshold level, in 29 isolated canine hearts. In fibrillating hearts vasodilated with adenosine or carbocromen, coronary flow and the coronary pressure-flow relation were not affected by changes in great cardiac vein pressure (PGCV) below a threshold value of 11 +/- 0.9 (mean +/- SEM) mm Hg. Further elevations of PGCV reduced flow and shifted the pressure-flow relation to the right, increasing its pressure-axis intercept (Pf=0). When vasomotor tone was augmented with vasopressin, threshold PGCV increased to 25 +/- 2.7 mm Hg (p less than 0.001). Once again, the pressure-flow relation was unaffected by changes in PGCV below the threshold value and shifted to the right when this value was exceeded. The amount by which spontaneous values of Pf=0 exceeded threshold values of PGCV was greater when vasomotor tone was augmented than during vasodilation. Pf=0 continued to exceed PGCV when the latter was raised above the threshold level. Both Pf=0 and threshold values of PGCV were less during a long diastole than during ventricular fibrillation. We reached the following conclusions. 1) During changes in PGCV below a threshold value, the coronary circulation exhibits traditional waterfall behavior. 2) The threshold pressure for altering waterfall behavior is affected by vascular tone and mechanical activity. 3) Pf=0 remains above PGCV when the latter is increased above the threshold value needed to alter flow.
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PMID:Tone-dependent waterfall behavior during venous pressure elevation in isolated canine hearts. 199 45

The hemodynamic, electrocardiographic, and coronary flow responses to a psychological test were studied in 13 pigs both in the absence (group 1, n = 8) and the presence (group 2, n = 5) of a transient occlusion of the left anterior descending coronary artery. The psychological test consisted of presenting food to a fasting but restrained animal for 3 minutes. In group 1, stress increased the heart rate from 128 +/- 5 to 176 +/- 8 beats/min (mean +/- SEM) and arterial pressure from 93 +/- 4 to 112 mm Hg. Comparing the individual increase in rate-pressure product with the increase in coronary conductance during the test, a parallel response was found in only two animals, whereas a relatively lower coronary conductance was observed in the remainder, suggesting vasoconstriction. Clinical signs of ischemia or life-threatening arrhythmias were never observed in this group of animals. Each group 2 animal underwent two occlusions of the left anterior descending coronary artery, randomly performed on separate days both in the presence and the absence of the food deprivation stress. When the latter was applied in the presence of occlusion, all animals developed ventricular fibrillation in less than 2 minutes (mean, 81.4 seconds). Conversely, only one animal had ventricular fibrillation when a 3-minute occlusion was performed without exposure to stress. This occurred despite the fact that more severe ischemia (as detected by an increase in left ventricular end-diastolic pressure and decreases in dP/dt and systolic pressure) was recorded at 3 minutes of occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coronary flow and mental stress. Experimental findings. 200 33


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