Nicardipine is a potent coronary and systemic vasodilator without depression of ventricular function. We investigated the changes in local myocardial perfusion (LMP) according to the nicardipine administration after coronary reperfusion in a beating canine model. A Doppler probe was placed around the left anterior descending coronary artery (LAD) and thermal diffusion microprobe was implanted in the myocardium perfused by the exposed LAD. To define the nicardipine effects, we compared the two groups (control group, n=7 vs nicardipine group, n=7). In nicardipine group, 5 microgram/kg/min nicardipine was infused continuously. After the release of the LAD occlusion, LAD blood flow were increased compared to the baseline of both groups. However, there was no difference between groups in the LAD blood flow. The LMP after LAD reperfusion did not recover to the baseline level until 30 min after LAD reperfusion in control group (74%, 52% and 70% at 10, 20 and 30 min after LAD reperfusion, respectively). In nicardipine group, however, the LMP recovered to the baseline level at 20 min (99%), and increased more than the baseline level at 30 min (141%) after LAD reperfusion. Our findings suggest that the nicardipine augments the LMP following the release of a coronary occlusion.
Animals ; Coronary Circulation/drug effects* ; Dogs ; Drug Evaluation, Preclinical ; Myocardial Reperfusion* ; Myocardial Reperfusion Injury/prevention & control* ; Nicardipine/pharmacology* ; Nicardipine/therapeutic use ; Vasodilator Agents/pharmacology* ; Vasodilator Agents/therapeutic use

BACKGROUND: Cytosolic Ca2+ overload and oxygen derived free radicals may contribute to stunned myocardium. The pnt study was aimed to investigate the effects of nicardipine and sodium nitroprusside (SNP) on the functional recovery of postischemic reperfused myocardium. METHODS: Fifty-seven halothane-anesthetized dogs were subjected to 15 minutes of 1eft anterior descending coronary artery (LAD) occlusion and 3 hours of reperfusion. They were randomly assigned to receive either intracoronary nicardipine (n=11) or SNP (n=10) alone or both (nicardipine plus SNP, n=10). Eleven dogs that received saline i.c. served as the controL Regional myocardial contractility was evaluated by systolic shortening (%SS), the preload recruitable stroke work slope (Mw), and intramyocardial pressure (IMPs). Diastolic function was assessed by time constant of myocardial relaxation (IMP-tau) and postsystolic shortening (%PSS), LAD blood flow was measured by a Doppler flowmeter as well. RESULTS: LAD occlusion produced a significant reduction in systolic as well as diasto1ic functions to similar degrees in all groups. However, %SS was significantly higher in the nicardipine, SNP and nicardipine-SNP groups (67%, 56%, and 68% of baseline values, respectively) than in the controls (20%) at 3 hours of reperfusion. Furthermore, Mw recovered to the baseline with the onset of reperfusian in the three experimental groups. IMP-tau was restored to the baseline during early nperfusion in the SNP-treated groups but was significantly prolonged in the control and nicardipine poups throughout the seperfusion. LAD blood flow during reperfusion was higher in the SNP-treated groups in comparison to the control group. CONCLUSIONS: Treatment with either nicardipine or SNP enhances the recovery of mgional contractile function in the canine model of myocardial stunning. SNP not nicardipine is also beneficial in attenuation of early diastolic dysfunction. Nicardipine combined with SNP improved systolic as well as early diastolic functions more significantly when compared to either nicardipine or SNP alane.
Animals ; Coronary Vessels ; Cytosol ; Dogs* ; Flowmeters ; Free Radicals ; Heart ; Myocardial Stunning* ; Myocardium ; Nicardipine* ; Nitroprusside* ; Oxygen ; Pharmacology ; Relaxation ; Reperfusion ; Sodium* ; Stroke

We present accidental findings that potassium channel blockers, such as tetraethyl-ammonium (TEA) or 4-aminopyridine (4-AP), inhibit the sustained tonic contraction induced by carbachol in rat detrusor muscle strips. The relatively lower concentrations (<2 mM) of TEA and 4-AP inhibited phasic and tonic contractions induced by 5 micrometer carbachol, whilst the relatively higher concentrations of TEA and 4-AP (>5 mM) potentiated phasic contractions. The potentiation of phasic contraction was not observed in nicardipine pretreated condition. In nicardipine pretreated condition, the concentration-response curves for the negative inotropic effect of potassium channel blockers were shifted to the right by the increasing concentration of carbachol from 0.5 micrometer to 5 micrometer. IC50 was changed significantly from 0.19 to 0.64 mM (TEA) and from 0.21 to 0.96 (4-AP). Such inhibitory effects were also observed in Ca2+ depleted condition, where 0.1 mM EGTA and 1 micrometer thapsigargin were added into Ca2+ free solution. In conclusion, inhibitory effects of potasssium channel blockers on carbachol-induced contraction may be ascribed to the direct inhibition of receptor-agonist binding.
4-Aminopyridine/pharmacology ; Animals ; Bladder/metabolism ; Calcium/chemistry/metabolism ; Calcium Channel Blockers/pharmacology ; Carbachol/*pharmacology ; Dose-Response Relationship, Drug ; Female ; Guinea Pigs ; Inhibitory Concentration 50 ; Male ; Mice ; Muscle Contraction/*drug effects ; Muscles/drug effects/metabolism/*pathology ; Nicardipine/pharmacology ; Potassium Channel Blockers/*pharmacology ; Protein Binding ; Rabbits ; Rats ; Rats, Sprague-Dawley ; Support, Non-U.S. Gov't ; Tetraethylammonium/pharmacology ; Vasodilator Agents/pharmacology

AIMTo investigate the antiepileptic effect of dizocilpine (MK-801) on amygdala kindling models in rats and the effects of its combination with general antiepileptic drugs.

METHODSTo establish amygdala kindling models in rats and observe the effect of dizocilpine on kindling models and its combination with general antiepileptic drugs (phenobarbital, valproate and nicardipine) at ineffective dose. The influence of dizocilpine on convulsions induced by semicarbazide (SCZ) in mice were also observed.

RESULTSDizocilpine (0.1-0.25 mg.kg-1, i.p.) was shown to dose-dependently inhibit amygdala kindled seizure, shorten the after discharge duration (ADD) and reduce the Racine's stage (P < 0.01). The combination of dizocilpine with phenobarbital, valproate, nicardipine at ineffective dose shortened ADD or reduced Racine's stages (P < 0.01). Dizocilpine (0.1-0.25 mg.kg-1, i.p.) significantly prolonged the latency and reduced the rate of convulsions and death in mice.

CONCLUSIONDizocilpine inhibits the seizure of the amygdala kindling and improve the antiepileptic activity of phenobarbital, valproate and nicardipine, indicating that these combination may provide a new approach for treating epilepsy.

Amygdala ; drug effects ; physiopathology ; Animals ; Anticonvulsants ; pharmacology ; therapeutic use ; Dizocilpine Maleate ; pharmacology ; therapeutic use ; Electric Stimulation ; Epilepsy ; chemically induced ; drug therapy ; Female ; Kindling, Neurologic ; drug effects ; Male ; Mice ; Nicardipine ; pharmacology ; Phenobarbital ; pharmacology ; Random Allocation ; Rats ; Rats, Wistar ; Semicarbazides ; Valproic Acid ; pharmacology