Effects of AN-132 and quinidine, antiarrhythmic agents, on plasma digoxin concentrations in rats

The effects of AN-132, 3-(diisopropylaminoethyl-amino)-2',6'-dimethylpropionanilide.2H 3PO4, on chloroform-induced arrhythmias and plasma digoxin concentrations have been compared with those of quinidine in rats. AN-132 (0.01-3 mg kg-1) administered orally significantly inhibited the incidence of cardiac arrhythmias in a dose-related fashion. A single dose of digoxin (1 mg kg-1) given orally for 7 consecutive days was followed, on day 8, orally by digoxin alone, or together with AN-132 (50, 100 and 200 mg kg-1) or quinidine (25 and 50 mg kg-1). The AUC0-24 and Cmax of plasma digoxin were enhanced significantly by co-administration of quinidine, but not by AN-132.     

Protective effects of the antianginal agent nicorandil on arachidonate-induced sudden death in rats: comparison with several antianginal agents and cyclooxygenase inhibitors

In anesthetized rats, intra-carotid injections of arachidonate . Na (20 mg/kg) elicited a marked pressor response, producing death within 10 min in untreated rats. The antianginal agents (nicorandil, nitroglycerin and diltiazem) and cyclooxygenase inhibitors (indomethacin and aspirin), applied i.v. or p.o., effectively protected the rats from death. In the surviving rats, these drugs significantly prevented intravascular thrombosis in cerebral vessels and the marked pressor response to arachidonate . Na. The protective mechanism of the antianginal agents tested seems to be different from that of cyclooxygenase inhibitors.     

Cardiovascular effects of nicorandil and nitroprusside in furosemide plus digoxin pretreated dogs

In support of human congestive heart failure (CHF) trials, the cardiovascular effects of the vasodilators nicorandil (NIC) and nitroprusside (NP) were examined in anesthetized and conscious dogs pretreated with the diuretic furosemide (FURO) and the cardiac glycoside digoxin (DIG). In anesthetized control dogs, iv NP (2–19 μg/kg/min) and NIC (24–105 μg/kg/min) maximally reduced mean arterial pressure (MAP) by 43 and 40 mmHg, respectively, with moderate increases in heart rate (HR). These hypotensive responses to NP and NIC were unmodified by iv FURO (2.65 mg/kg) + DIG (0.075 mg/kg) pretreatment (PT). FURO + DIG reduced central venous pressure (CVP) BY 3 mmHg, masking the separate effects of NP and NIC. In a third group, FURO's fluid volume depletion and DIG's plasma concentrations were unaffected by adjunctive NIC infused for 2.5 h at a mean 17 μg/kg/min iv. No untoward interactions were seen with any combination. In conscious dogs, the hypotension and tachycardia seen with iv NP (2–20 μg/kg/min) and NIC (20–160 μg/kg/min) were also unchanged after 5 days of oral FURO (5 mg/kg/day) and DIG (0.0125 mg/kg/day), with no intolerance. Repeated oral NIC (7.5 mg/kg/day × 3 days) in these chronic FURO + DIG dogs ws consistently hypotensive but steadily more tachycardiac. This study offers a prototype of 3-way CHF drug interaction, demonstrates that NIC and NP can be safely combined with acute and chronic FURO and DIG, and shows that these CHF agents minimally affect the cardiovascular responses to NIC and NP in dogs.     

PK 10139 and quinidine: interactions with digoxin concentrations in rats and dogs

Quinidine induced an increase in digoxin plasma concentrations in rats and dogs. PK 10139, an antiarrhythmic agent 10 times more potent than quinidine, did not change digoxin plasma concentrations in these species. The results indicate that PK 10139 could be associated with digoxin without risk of side-effects.     

Reduction of size of myocardial infarction with nicorandil, a new antianginal drug, after coronary artery occlusion in dogs

The effects of nicorandil, a new antianginal drug, on size of myocardial infarction were studied in anesthetized, open-chest dogs after left anterior descending coronary artery occlusion. To quantify the extent of the hypoperfused zone, 99mTc-albumin microspheres were injected into the left atrium 1 min after occlusion. Fifteen minutes after occlusion, dogs were randomly assigned to a control group or a nicorandil-treated group that received immediately after assignments 100 micrograms/kg of nicorandil followed by a continuous infusion of 30 micrograms/kg/min for 6 h. Six hours after occlusion, the left ventricle was cut into 3 mm thick slices for triphenyltetrazolium chloride staining and autoradiography. The extent of the hypoperfused zone (26.1% +/- 3.1% of the left ventricle in the control vs. 23.2% +/- 3.7% in the treated group, mean +/- SEM) was not different between the two groups. The ratio of the extent of myocardial necrosis to the extent of the hypoperfused zone was significantly smaller in the treated group (64.3% +/- 7.2%, n = 7, p less than 0.05) than in the control group (92.6% +/- 9.2%, n = 7). Thus, nicorandil administered early after coronary artery occlusion reduced the size of myocardial infarction by 31%.     

Effects of amlodipine on steady-state digoxin concentrations and renal digoxin clearance

The effect of oral amlodipine on steady-state digoxin concentrations and renal clearance was studied in 21 healthy male subjects. After 2-week digitalization (digoxin, 0.375 mg/day), they were randomized in a single-blind crossover protocol to receive either placebo or amlodipine (5 mg/day) in combination with digoxin for the following two 2-week periods. Mean (+/- SD) digoxin concentrations of 0.64 +/- 0.19 ng/ml after 2-week digoxin monotherapy and 0.61 +/- 0.23 ng/ml during placebo were not altered by amlodipine (0.60 +/- 0.18 mg/ml). Renal digoxin clearance was 202 +/- 44 ml/min on placebo and 207 +/- 55 ml/min during amlodipine coadministration. No change in pharmacologic effect of digoxin was noted during amlodipine coadministration, nor was blood pressure or heart rate changed. These data indicate that oral amlodipine does not significantly influence steady-state digoxin concentrations in healthy subjects.     

Effects of standard cigarette and nicotine-less cigarette smoke inhalings on nicorandil plasma levels in rats

The influence of cigarette smoke on nicorandil plasma levels at a dose of 10 mg/kg administered orally was investigated in rats. The animals were exposed to standard and nicotine-less cigarette smoke for 8 min using a 'smoking machine'. In nonsmoking control rats, nicorandil plasma levels increased rapidly and reached the maximum (approx. 7.6 micrograms/ml) after 1 h and then decreased gradually. On the other hand, nicorandil plasma levels in the rats inhaling standard cigarette and nicotine-less cigarette smoke reached the maximum (approx. 4.7 and 4.9 micrograms/ml, respectively) after 1-2 h. These results suggest that nicorandil plasma levels after oral administration are influenced not only by standard cigarette smoke but also by nicotine-less cigarette smoke.     

Hypotensive, antianginal action and pharmacokinetics of glyceryl-1-nitrate in rats and dogs

The antianginal and hypotensive activity and the pharmacokinetic properties of glyceryl 1-nitrate (G-1-N) were examined in the rat and in the dog. The level and duration of antianginal and hypotensive activity were the same after single or repeated oral dosage of G-1-N to the anaesthetized rat. The haemodynamic activity of intravenously administered G-1-N in the anaesthetized and thoracotomized dog was dose-dependent. A bolus injection of G-1-N or glyceryl trinitrate (GTN, Nitro Mack) antagonized the cardiovascular activity of intravenously injected dihydroergotamine (DHE) in the anaesthetized and thoracotomized dog. The bioavailability of G-1-N in the rat and in the dog is practically 100%. After intravenous or oral administration to the rat the concentrations of G-1-N in the walls of the vena cava caudalis were markedly higher and in the aorta abdominalis somewhat higher than in the blood or in the other organs examined. G-1-N was eliminated more slowly from the walls of the animals veins than from the walls of the aorta abdominalis or from the blood.     

Hemodynamic actions of nicorandil, a new antianginal agent, in the conscious dog

We studied the hemodynamic effects of nicorandil (SG-75) and nitroglycerin in conscious dogs before and after beta-adrenergic receptor blockade. Nicorandil (25-300 micrograms/kg/min) and nitroglycerin (5-60 micrograms/kg/min) produced increases in heart rate and decreases in aortic and left ventricular pressures. In the doses studied, nicorandil caused greater decreases in aortic and left ventricular systolic pressure than nitroglycerin; however, nitroglycerin reduced left ventricular end-diastolic pressure to a greater degree. Nicorandil but not nitroglycerin produced an increase in cardiac output secondary to an increase in heart rate. Global contractility (peak positive dP/dt) was increased in a dose-related manner during nicorandil infusion before beta-blockade. In spite of marked hypotensive responses to higher doses, mean coronary blood flow and coronary conductance were increased by nicorandil. In contrast, both parameters were reduced during nitroglycerin infusion. The effects of nicorandil on coronary blood flow were unaltered by beta-adrenergic blockade, suggesting that metabolic autoregulation is not an important mediator of the response. Nicorandil (75-300 micrograms/kg/min) produced a dose-related increase in transmural myocardial blood flow with the greatest increases in perfusion occurring in the subepicardium and midmyocardium. The results of the present study demonstrate that despite structural similarities, nicorandil and nitroglycerin have varying hemodynamic spectra.     

Effects of EDTA and verapamil on renin release in dogs

EDTA or verapamil was infused into the renal artery of the anesthetized dog, and the effects on renin release and renal function were examined in an attempt to elucidate the role and action site of calcium ion in the renin secretory system. Both EDTA (25 mg/min) and verapamil (50 micrograms/min) increased RSR and RBF with a concomitant increase of urine flow, although there was no change in systemic arterial pressure. An infusion of verapamil in combination with ouabain produced a significant increase in RBF which was similar to that seen with verapamil alone. Urine flow and urinary excretion of electrolytes were also increased, but these changes did not differ from those seen with ouabain infusion alone. Ouabain alone did not affect RSR, but its infusion combined with verapamil resulted in a significant increase in RSR. Therefore, the effects of EDTA and verapamil on renin release may reflect the action of both drugs on the vascular component of the juxtaglomerular apparatus. If a change in calcium movement similar to the one in vascular smooth muscle occurs in the juxtaglomerular cells, the altered concentration of calcium may be considered to induce, in part, the stimulation of renin release by EDTA or verapamil.     

Effects of nicorandil on large epicardial coronary artery in conscious dogs

The effect of 2-nicotinamidoethyl nitrate (nicorandil, SG-75, Sigmart) on coronary circulation was studied in conscious dogs, instrumented previously under sterile condition with sonomicrometers for the external coronary diameter measurement, and an electromagnetic flow plobe on the left circumflex coronary artery and a catheter into the thoracic aorta. Intravenous administration of nicorandil in doses of 10, 30, 100 and 300 micrograms/kg increased coronary blood flow dose-relatedly by 13 +/- 2, 24 +/- 3, 144 +/- 18 and 309 +/- 36%, respectively. Nicorandil also increased the diameter of the large epicardial coronary artery by 38 +/- 6, 71 +/- 11, 150 +/- 24 and 173 +/- 26 microns in doses of 10, 30, 100 and 300 micrograms/kg, respectively. To eliminate flow-dependent dilation of the coronary artery, the external diameter of the large epicardial coronary artery was measured during fixing the amount of coronary blood flow constant by a cuff occluder after intravenous administration of nicorandil, however, the degree of coronary diameter increase was not attenuated. Thus, nicorandil dilates both large and small coronary arteries in conscious dogs, the former dilation being independent from changes in coronary blood flow.     

Improved recovery of myocardial segment function following a short coronary occlusion in dogs by nicorandil, a potential new antianginal agent, and nifedipine

The effects of nicorandil [SG-75, 2-nicotinamidoethyl nitrate (ester)] and nifedipine on the recovery of myocardial segment shortening were compared to a vehicle-treated group following a short occlusion (15 min) of the left anterior descending coronary artery (LAD) and reperfusion (5 h). The relationship between myocardial blood flow and myocardial segment shortening was examined by means of the radioactive microsphere technique and sonomicrometry. Nicorandil (100 micrograms/kg followed by 25 micrograms/kg/min, i.v.) or nifedipine (3 micrograms/kg followed by 1 microgram/kg/min, i.v.) was administered 10 min prior to and throughout the occlusion period. Both drugs produced similar decreases in mean arterial pressure (approximately 25 mm Hg) during LAD occlusion. Similar degrees of ischemia (flow deprivation) were produced in the vehicle, nicorandil, and nifedipine groups; however, nicorandil produced a significantly greater decrease in the heart rate-left ventricular systolic pressure product during coronary occlusion. During reperfusion of the LAD there was no difference in the hemodynamics of the vehicle, nicorandil, or nifedipine groups. Neither drug altered myocardial blood flow to the ischemic region during the occlusion or reperfusion period when compared to the vehicle-treated group; however, both nicorandil and nifedipine pretreatment significantly improved recovery of percentage of segment shortening of the ischemic region. Nicorandil improved the recovery of function (percentage of segment shortening) to a greater extent than did nifedipine throughout the reperfusion period, most likely because of the greater decrease in afterload produced by nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diltiazem and verapamil elevate plasma phenytoin concentrations in the rat

The effects of the calcium channel blockers, diltiazem and verapamil on the pharmacokinetics of phenytoin were investigated in rats. Animals were given phenytoin alone or phenytoin together with either diltiazem or verapamil and the plasma samples were collected at different time intervals. The concentration of phenytoin was measured using a high performance liquid chromatographic method (HPLC). Diltiazem and verapamil significantly (p < 0.05) increased the area under the curve (AUC), the maximum plasma concentration (C_max) and elimination half+life (t_1:2) of phenytoin. These results suggest that a potentially harmful drug-drug interaction may occur if phenytoin is administered concurrently with either diltiazem or verapamil.     

Effects of cromakalim, pinacidil and nicorandil on cardiac refractoriness and arterial pressure in open-chest dogs

The cardiac electrophysiologic effects of the potassium channel activators cromakalim, pinacidil and nicorandil were determined in anesthetized open-chest normotensive dogs using conventional surface electrogram recording techniques. Intravenous administration of cromakalim (0.025-0.5 mg/kg), pinacidil (0.1-2.0 mg/kg) and nicorandil (0.1-2.5 mg/kg) produced large dose-dependent decreases in arterial blood pressure accompanied by smaller reductions of atrial and ventricular effective refractory periods. The shortening of refractoriness was more pronounced in the atrium than in the ventricle and was similar for all three compounds at a given level of hypotension. Effects on other electrophysiological parameters were minimal. Atrial arrhythmias could be induced during electrical pacing at doses of cromakalim and pinacidil producing excessive (greater than or equal to 40%) decreases in mean arterial pressure. No arrhythmias were observed with nicorandil. Induction of the arrhythmias appeared to be closely coupled to the extrastimuli (S2) used to determine refractory periods and was associated with a significant reduction in atrial refractory period (greater than or equal to 30%). No ventricular arrhythmias were observed in this study with any of the compounds tested. Although the plasma levels reached in this study are likely to be higher than those seen clinically, the results nevertheless suggest the potential for cardiac electrophysiologic effects by these agents.     

Effects of digoxin on acetylcholine and norepinephrine concentrations in rat myocardium

The influence of digoxin on the autonomic nervous system was studied in rats by examining its effects on the levels of acetylcholine (Ach), a parasympathetic marker, and norepinephrine (NE), a sympathetic marker, in the rat myocardium. Ach and NE were measured by high performance liquid chromatography with electrochemical detection (HPLC-ECD). Digoxin was injected subcutaneously every day for 4 weeks. The administration of 0.35, 0.75, and 2.5 mg/kg of digoxin reduced Ach concentrations in the right atrium to about 80-90% of the control value. However, there was no change in the activity of choline acetyltransferase (ChAT) or acetylcholinesterase (AchE), or in the concentration of choline (Ch). Injection of 0.1 mg/kg of digoxin had no significant effect on Ach concentration. When 0.75 and 2.5 mg/kg of digoxin were injected, there was a significant increase in NE concentration in the right atrium. Neither 0.1 nor 0.35 mg/kg caused any changes. Digoxin (0.75 and 2.5 mg/kg) increased heart rate to about 110% of the control values. Thus, high doses of digoxin increase the NE concentration but decrease the Ach concentration in the rat heart, and these changes might be related to functional changes in the autonomic nervous system.     

Differential effects of the antianginal drug nicorandil on canine arteries and veins.

Nicorandil, a potent coronary vasorelaxant used in the treatment of angina, has differential effects on arteries and veins in vivo. To explain this phenomenon, experiments were designed to characterize the relaxant and inhibitory actions of this compound on canine isolated arteries and veins. Paired rings of canine coronary, femoral, and saphenous arteries and saphenous veins were suspended at optimal length for isometric tension recording in organ chambers containing physiologic salt solution at 37 degrees C and gassed with 95% O2-5% CO2. In certain experiments, one ring of each pair was denuded of the endothelium. Removal of the endothelium did not affect nicorandil-induced relaxations of contracted blood vessels. Nicorandil exerted a differential relaxant effect on arteries and veins contracted with KCl (order of potency: saphenous vein greater than coronary artery greater than femoral artery). No difference in sensitivity to nicorandil was observed in arteries and veins contracted with prostaglandin F2 alpha. Contractions of saphenous arteries and veins to norepinephrine (NE) were equally sensitive to the inhibitory action of nicorandil. However, contractions of saphenous veins induced by sympathetic nerve stimulation were more sensitive to nicorandil than were contractions of saphenous arteries. Furthermore, nicorandil did not affect contractions to phenylephrine in saphenous veins, although contractions to B-HT 920 were virtually abolished by the compound. Saphenous veins contracted with St 587 were more sensitive to the relaxant action of nicorandil than when contracted with phenylephrine. These results suggest that nicorandil inhibits preferentially contractions of canine arteries and veins mediated by alpha 2- rather than alpha 1-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of lignocaine on plasma protein binding and pharmacokinetics of verapamil in dogs

The effect of lignocaine (lidocaine) on the plasma protein binding of verapamil has been studied in-vitro and in-vivo in dogs. The binding of verapamil was ca 85%. In-vitro addition of lignocaine at therapeutic concentrations displaced verapamil from its plasma binding sites. Lignocaine in this regard was equipotent with tris(2-butoxyethyl)phosphate, suggesting an interaction at the level of alpha 1-acid glycoprotein binding sites. On in-vivo administration of 4 mg kg-1 in a bolus to dogs in which steady state concentrations of verapamil were present, the free fraction of verapamil increased transiently. During the lignocaine maintenance infusion, it then decreased to a level higher than that before administration of the local anaesthetic. The free verapamil concentrations increased suddenly upon the administration of the lignocaine loading dose, and then returned to values slightly higher than those before lignocaine. After a bolus injection of verapamil during a lignocaine infusion, the verapamil total plasma concentrations were lower than during a saline infusion, but the free concentrations were not different. The volume of distribution of verapamil was increased, whereas the blood clearance had not changed; the lignocaine infusion did not change the hepatic blood flow, as measured by indocyanine green clearance. These results show that lignocaine displaces verapamil in-vitro and in-vivo from its plasma protein binding sites, but the ensuing pharmacokinetic changes do not lead to significant changes in free verapamil concentrations.