Potent Antifibrillatory Effect of Combined Blockade of Calcium Channels and 5-HT2 Receptors with Nexopamil During Myocardial Ischemia and Reperfusion in Dogs: Comparison to Diltiazem

Q4 · MEDICINE

Article

Author: Verrier, Richard L. ; Hutter, Jon J. ; Nearing, Bruce D.

The need for novel antifibrillatory therapy is underscored by clinical trials indicating that the incidence of sudden cardiac death is increased by sodium or potassium channel blockade and is only partially reduced by beta-blockade. We examined the efficacy of nexopamil, which possesses the unique combination of calcium channel and 5-HT2 receptor blockade, in preventing ventricular tachycardia (VT) and fibrillation (VF) and reducing T-wave alternans magnitude during coronary artery occlusion and abrupt reperfusion in dogs. The results were compared with L-type calcium channel blockade alone with diltiazem. The effect of nexopamil was tested during a 10-min period of left anterior descending (LAD) coronary artery occlusion and release in chloralose-anesthetized dogs. T-wave alternans magnitude was assessed by complex demodulation. The drug reduced the incidence of VT during occlusion (from 5 of 6 to 0 of 6, p < 0.03) and VT/VF during abrupt reperfusion (from 5 of 6 to 0 of 6, p < 0.03) and suppressed the T-wave alternans magnitude increase induced by occlusion (from 14.62 +/- 3.96 to 1.39 +/- 0.34 mV x ms, p < 0.01) and reperfusion (from 17.33 +/- 4.67 to 2.34 +/- 0.77 mV x ms, p < 0.01). When 30-s left stellate ganglion stimulation (10 V, 5-ms pulses, 10 Hz) was superimposed on occlusion, nexopamil reduced the VT/VF incidence (from 8 of 11 to 4 of 11, p < 0.05) and T-wave alternans magnitude (from 24.80 +/- 5.05 to 15.81 +/- 5.09 mV x ms, p < 0.05). Calcium channel blockade alone with diltiazem decreased the incidence of ventricular tachyarrhythmias (from 5 of 10 to 1 of 10, p < 0.05) and T-wave alternans magnitude (from 16.75 +/- 3.06 to 2.87 +/- 1.23 mV x ms, p < 0.05) during coronary artery occlusion. During reperfusion, diltiazem's reduction in arrhythmia incidence (from 5 of 8 to 2 of 8) was not statistically significant, although the decrease in T-wave alternans (from 28.60 +/- 3.43 to 8.27 +/- 3.73 mV x ms, p < 0.05) was significant. Therefore, nexopamil was superior to diltiazem in protecting against reperfusion-induced arrhythmias. Nexopamil's significant antifibrillatory effect during both coronary artery occlusion and abrupt reperfusion is reliably tracked by T-wave alternans magnitude. Because the major component of the protection could be reproduced by blockade of the L-type calcium channel with diltiazem, nexopamil's antiarrhythmic action appears to be due mainly to blockade of this channel. Nexopamil's antiplatelet action through blockade of 5-HT2 receptors may confer additional protection against reperfusion arrhythmias.

04 Mar 1995·Fundamental & Clinical PharmacologyQ3 · MEDICINE

The effect of LU‐49938 (nexopamil) on the activation by serotonin of mesangial cells

Q3 · MEDICINE

Article

Author: M Reverte ; J M López-Novoa ; A Rodríguez-López ; A Montero

Summary— Intraglomerular platelet activation may release vasoactive agents such as serotonin (5‐hydroxytryptamine, 5‐HT) that may affect local hemodynamics and promote mesangial proliferation, eventually leading to glomerular sclerosis. The main purpose of this study is to analyze whether nexopamil, a verapamil derivative, with the property of blocking simultaneously calcium channels and 5‐HT2 receptors, could modify the contractile and mitogenic effects of serotonin on cultured rat mesangial cells. Serotonin caused a concentration‐dependent increase in [3H]thymidine incorporation into DNA, and mesangial cell proliferation. The effects of 5‐HT on thymidine uptake and cell proliferation were blocked by the selective 5‐HT2 receptor blocker ketanserin 10−5 M. Nexopamil abolished in a concentration‐dependent way the serotonin‐induced [3H]thymidine incorporation into DNA, and the serotonin‐induced increase in number of cells. Using 5‐HT 10−4 or 10−5 M, nexopamil had significant effects at concentration above 10−7 M. Serotonin induced a concentration‐ and time‐dependent reduction of planar cell surface area. This effect was also completely blocked by ketanserin. Nexopamil partially blocked the serotonin‐induced mesangial cell contraction, in a dose‐dependent manner. All these data suggest that nexopamil inhibits both 5‐HT‐induced mesangial cell contraction and proliferation by blocking 5‐HT2 receptors and the voltage‐operated Ca2+ channels.

01 Jan 1995·Cardiovascular ResearchQ1 · MEDICINE

The combined 5-HT2 receptor and calcium channel inhibitor LU49938 restores endothelium dependent responses in the regenerated endothelium of the porcine coronary artery

Q1 · MEDICINE

Article

Author: Vanhoutte, Paul M. ; Park, Seung-Jung ; Lee, John J. ; Boulanger, Chantal M. ; Kirchengast, Michael

OBJECTIVEThe aim was to evaluate the effect of the combined 5-hydroxytryptamine-2 (5-HT2) receptor antagonist and calcium channel inhibitor LU49938 ((2S)-5-[N-methyl-N-(n-hexyl)] amino-2-isopropyl-2(3.4.5-trimethoxyphenyl)-valeronitrilhydrochloride ) on the endothelium dependent responsiveness of porcine coronary arteries with native and regenerated endothelium.METHODSMale Yorkshire pigs were assigned randomly to one of four groups: (1) controls; (2) pigs receiving LU49938 daily (5 mg.kg-1) for four weeks; (3) pigs undergoing balloon de-endothelialisation of the left anterior descending coronary artery; and (4) pigs undergoing balloon de-endothelialisation and receiving LU49938 daily. At four weeks, quantitative coronary angiography, organ chamber experiments, and morphometric studies of the tissues were performed.RESULTSTreatment with LU49938 did not affect the endothelium dependent responses in native porcine coronary arteries. Intracoronary injection of serotonin caused significantly greater coronary vasoconstriction in group 3 compared with group 4. The cross sectional area of the intima and media of previously de-endothelialised left anterior descending coronary artery increased significantly in group 3, but not in group 4. In arteries with regenerated endothelium, augmented endothelium dependent contractions were noted not only in response to serotonin, but also in response to platelets, noradrenaline, and endothelin-1. The endothelium dependent relaxations to platelets, serotonin, and UK14304 were impaired in the regenerated endothelium, but not those to adenosine diphosphate and SIN-1. However, following four weeks of treatment with LU49938, the pertussis toxin sensitive endothelium dependent responses were restored. The augmented endothelium dependent contraction to endothelin-1 was not altered by the treatment.CONCLUSIONSChronic treatment with LU49938 restores endothelium dependent, pertussis toxin sensitive, G protein mediated responses in the regenerated endothelium of the porcine coronary artery, and inhibits the intimal thickening following arterial injury.

100 Deals associated with Nexopamil

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Indication	Highest Phase	Country/Location	Organization	Date
Angina Pectoris	Phase 2	EU	-	-
Angina Pectoris	Phase 2	-	AbbVie, Inc.	-
Arrhythmias, Cardiac	Phase 2	US	-	-
Hypertension	Phase 2	DE	Abbott Laboratories	-
Myocardial Ischemia	Phase 2	DE	Abbott Laboratories	-
Thrombosis	Phase 2	DE	Abbott Laboratories	-

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