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Biomedical subjects

K A Kane

Publications and source records attributed to K A Kane.

At least 55 records · Page 3Linked to original sources
PubMed1994

Characterization of a method for the detection of drugs with free radical scavenging activity using porcine leukocytes.

The effects of a range of free-radical scavenging drugs on luminol-enhanced chemiluminescence (CL) generated by porcine leukocytes, following activation by two nonreceptor-mediated stimulants, phorbol myristate acetate (PMA; a protein kinase activator) and ionomycin (a cation ionophore), and by xanthine plus xanthine oxidase (X-XO), have been examined. Superoxide dismutase (0.1 units/mL) and catalase (50 units/mL) inhibited X-XO, but they were ineffective in leukocyte suspensions except at concentrations 500 times and 20 times higher. Sodium azide (10(-5) to 10(-3) M) caused a marked inhibition in CL production in activated leukocytes, but not of X-XO CL. The antioxidants, glutathione (10(-3) M) and L-ascorbic acid (10(-3) M) were ineffective in activated leukocytes, but caused total inhibition of X-XO-induced CL. Mannitol (100 mM) had no effect on chemiluminescence in either system. Captopril (10(-3) M) produced an inhibition of CL in both systems and this inhibition was significantly modified by pH. Thus, the present study has established a standard screening procedure for the assessment of free-radical scavenging activity using activated porcine leukocytes and xanthine-xanthine oxidase.

Animals↗
PubMed1994

Comparison of the cardiac electrophysiologic effects of NE-10064 with sotalol and E-4031 and their modification by simulated ischaemia.

The electrophysiologic effects of a new anti-arrhythmic agent NE-10064 were compared with known class III drugs, E-4031 and sotalol, in sheep Purkinje fibres paced at 1 Hz under normal and simulated ischaemic conditions. NE-10064 0.3-3 microM and sotalol 0.3-300 microM prolonged action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP) concentration dependently without affecting APD50 under normal conditions. E-4031 0.3-300 microM prolonged APD50, APD90, and ERP concentration dependently. Percentage increases in APD90 of 20 +/- 6, 27 +/- 6, and 33 +/- 9 were calculated for NE-10064 3 microM, sotalol 300 microM, and E-4031 1 microM under normal conditions, respectively. The concentration-response curves for all three drugs were shifted to the right under simulated ischaemic conditions. The shift was more marked for NE-10064 and sotalol. Percentage increases in APD90 of 8 +/- 5, 13 +/- 2, and 23 +/- 4 were observed with NE-10064 3 microM, sotalol 300 microM, and E-4031 1 microM during simulated ischaemia. NE-10064 exhibits electrophysiologic characteristics similar to those of known class III agents. Its ability to prolong APD90 under normal conditions may explain its antiarrhythmic action in vivo.

Animals↗
PubMed1994

Effects of NS-2, a new class 1 antiarrhythmic agent, and AFD-19, its active metabolite, on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats: comparison with disopyramide and mexiletine.

We studied the antiarrhythmic effects of NS-2 (4-diisobutylamino-1,1-diphenyl-1-butanol maleate) and AFD-19 (active metabolite of NS-2) on early stage ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized male rats. These effects were compared with those of disopyramide and mexiletine. Drugs were intravenously administered either before or after coronary occlusion. When administered 5 min before occlusion, 3 mg/kg of NS-2 and AFD-19 exhibited equivalent anti-arrhythmic activity to that of 5 mg/kg of disopyramide and mexiletine, as assessed by reductions in the number of premature ventricular complexes and in the incidences of ventricular tachycardia and ventricular fibrillation. In a dose of 5 mg/kg, the antiarrhythmic effects of NS-2 and AFD-19 were more pronounced. When administered 5 min after coronary artery occlusion, only NS-2 and AFD-19 (in doses of 5 mg/kg) had significant antiarrhythmic effects. None of the drugs influenced the severe ventricular arrhythmias induced by reperfusion when administered 1 min before reperfusion. In conclusion, NS-2 might be effective in reducing the severity of the life-threatening ventricular arrhythmias that occur during acute myocardial infarction.

Amino Alcohols↗
PubMed1994

A characterized model of left ventricular hypertrophy in the rabbit.

A rabbit model of left ventricular hypertrophy is characterized with respect to blood pressure, heart mass and ventricular refractoriness. Hypertension and left ventricular hypertrophy was induced by unilateral nephrectomy plus wrapping of the contralateral kidney in cellophane. Control or sham operated animals were subjected to a similar procedure except that the kidney was not wrapped in cellophane. No change in conscious mean arterial blood pressure was shown in the 11 sham operated animals (75 +/- 2 mmHg before operation and 75 +/- 3 mmHg 4-5 weeks after). Mean arterial pressure was increased from 73 +/- 2 to 99 +/- 3 mmHg by 4-5 weeks and had reached a plateau of 110 +/- 3 mmHg 5-6 weeks after operation in the 16 animals in which the kidney was wrapped. The ratios of left ventricular dry weight to body weight and of whole heart wet weight to body weight were significantly (p < 0.05) higher in the wrap group (0.38 +/- 0.01 and 2.97 +/- 0.12, respectively) than in the sham group (0.29 +/- 0.01 and 2.44 +/- 0.08 respectively). Effective refractory period, recorded from the left side of the arterially perfused interventricular septum, was greater in the wrap (266.1 +/- 8.9 ms) than in the sham group (228.2 +/- 3.5 ms). Linear correlations were shown between mean arterial pressure or effective refractory period vs the ratio of left ventricular dry weight to body weight or ratio of whole heart to body weight. This study has shown that hypertension induced by perinephritis caused left ventricular hypertrophy which was associated with a prolongation in ventricular refractoriness in the rabbit.

Animals↗
PubMed1993

Effects of the xanthine oxidase system on cardiac function in anaesthetised rats.

This investigation aimed to determine whether contractile dysfunction of the myocardium could be produced upon generation of free radicals in the anaesthetised rat. The enzyme xanthine oxidase, combined with its substrate purine and an iron source, was used to generate free radicals in the venous circulation. The suspended form of xanthine oxidase, with substrate, produced a transient, significant depression in the contractile indices dP dt-1 max and dP dt-1 P-1 and arterial blood pressure, 1146 +/- 87 mm Hg s-1, 9 +/- 1 s-1, and 18 +/- 1 mm Hg, respectively. This could not be attenuated by the enzymatic free radical scavengers superoxide dismutase and catalase. Furthermore, the suspended xanthine oxidase alone or its vehicle were able to produce a similar effect to that of the complete free-radical-generating system. The maximum soluble dose of the crystalline form of the enzyme when employed in the generating system had no effect upon administration despite its production of superoxide radicals in vitro. These results suggest that the haemodynamic effects of the free-radical-generating system containing the suspended form of xanthine oxidase were due to the effects of its vehicle and that the free-radical-generating system containing the crystalline form of the enzyme did not produce sufficient free radicals in vivo to modify myocardial contractility.

Animals↗
PubMed1993

Comparison of antiarrhythmic and electrophysiologic effects of diltiazem and its analogue siratiazem.

We compared the abilities of diltiazem and siratiazem to protect the heart against coronary artery occlusion and reperfusion-induced arrhythmias in anaesthetised rats and assessed their effects on cardiac action potentials (APs) recorded in paced sheep Purkinje fibres. Both drugs in the concentration range of 0.5-4 mg kg-1 reduced the number of ventricular ectopic beats and the percentage of incidence of ventricular tachycardia (VT) that occurred during the first 7 min after coronary artery occlusion. The incidence of ventricular fibrillation (VF) on reperfusion was significantly reduced by siratiazem at a concentration of 2 mg kg-1 only. These antiarrhythmic effects were not accompanied by a reduction in mortality but were associated with a marked and sustained bradycardia and a decrease in mean arterial blood pressure (MAP). In sheep Purkinje fibres, diltiazem and siratiazem (10(-6)-10(-5) M) caused concentration-dependent reductions in AP duration measured at both 50 and 90% of repolarisation (APD50 and APD90), in the maximum rate of depolarisation of phase 0 and in AP amplitude (APA). Resting membrane potential (RMP) was not modified by either drug. The antiarrhythmic effects of both diltiazem and siratiazem may be due in part to direct electrophysiologic effects on cardiac tissue to block sodium and calcium channels and in part to an antiischaemic effect associated with bradycardia and vasodepression.

Animals↗
PubMed1993

Attenuation by phentolamine of hypoxia and levcromakalim-induced abbreviation of the cardiac action potential.

1. The effects of phentolamine (5-30 microM) and glibenclamide (10 microM) on action potential characteristics were examined in guinea-pig papillary muscle exposed to either hypoxia or levcromakalim (20 microM). 2. The hypoxia-induced abbreviation of action potential duration (APD) and effective refractory period (ERP) were attenuated but not abolished by glibenclamide (10 microM). Hypoxia reduced APD by 24 +/- 2 vs 65 +/- 4% in glibenclamide- and vehicle-treated tissue, respectively. 3. Phentolamine (10-30 microM) was less effective than glibenclamide in attenuating the hypoxic shortening of APD since APD was reduced by 38 +/- 10, 51 +/- 6% vs 65 +/- 4% in 10 and 30 microM phentolamine and vehicle-treated muscle, respectively. 4. Phentolamine, at concentrations of 10 and 30 microM, also reduced the upstroke velocity of the action potential and at 5 microM it increased the APD from 193 +/- 9 to 221 +/- 12 ms. 5. Glibenclamide completely abolished and phentolamine (30 microM) significantly attenuated levcromakalim-induced changes in duration and ERP. Levcromakalim reduced APD by 71 +/- 2 and 55 +/- 2% in control and phentolamine pretreated muscle, respectively. 6. It is concluded that phentolamine may block KATP channels at concentrations that also block sodium channels.

Action Potentials↗
PubMed1993

The role of endothelium in hypoxic constriction of human pulmonary artery rings.

The aim of the study was to elucidate the mechanism of the contraction produced by hypoxia in human intrapulmonary artery rings. Hypoxia (5 mm Hg) produced a contraction that was greater when the artery rings were precontracted (with endothelin-1) than when recorded under optimal resting force. The contraction was similar in small-diameter (0.38 to 0.68 mm) and in large-diameter (2.2 to 4.5 mm) artery rings under resting force. Removal of the endothelium markedly reduced or abolished the hypoxic contraction in precontracted artery rings (large diameter, 26 +/- 9 to -7 +/- 4 g cm-2) or under optimal resting force. Hypoxia markedly reduced or abolished the acetylcholine-induced relaxation in precontracted artery rings without affecting relaxation produced by sodium nitroprusside. Flurbiprofen caused a slight contraction itself (large diameter, 10 +/- 3 g cm-2) and significantly inhibited the contraction produced by hypoxia both under resting force (8 +/- 2 to 2 +/- 1 g cm-2) and in precontracted artery rings (18 +/- 2 to 1 +/- 1 g cm-2). Verapamil had no significant effect on the hypoxic contraction either under resting force or when precontracted. It is concluded that hypoxic contraction of human pulmonary artery rings depends on the presence of endothelium and is partly due to inhibition of a vasodilator cyclooxygenase product.

Aged↗
PubMed1992

Effects of a combination of acidosis, lactate, and lysophosphatidylcholine on action potentials and ionic currents in guinea pig ventricular myocytes.

The aim of this study was to determine the electrophysiological effects of a combination of factors that are of importance during myocardial ischaemia, i.e., acidosis, lactate, and lysophosphatidylcholine, in ventricular myocytes. Intracellular microelectrode techniques were used to record action potential and ionic currents in ventricular myocytes before, during, and after a 30 min exposure to a salt solution that was acidotic (pH 6.8), and contained lactate (10 mM) and lysophosphatidylcholine (5 microM). Single ventricular myocytes were dissociated enzymatically from guinea pig hearts, and perfused with either normal or modified physiological salt solution. Combined acidosis, lactate, and lysophosphatidylcholine resulted in a reduction in the resting membrane potential and maximum rate of depolarisation of phase 0, and flattening of the plateau but prolongation of the action potential duration at 90% repolarisation. Automatic activity was also induced in about one-third of the cells studied. Under voltage-clamp conditions, this combination of factors reduced the peak inward calcium current, on repolarisation after a depolarising step, reduced the steady-state outward current, and reduced the delayed rectifier current, measured as the tail current at the end of a depolarising clamp step. In some cells, a transient inward current was induced by the modified salt solution. It is concluded that the characteristic alterations in action potential characteristics induced by a combination of acidosis, lactate, and lysophosphatidylcholine are likely to result from reductions in the inward Ca current and the background and delayed rectifier K current.

Acidosis↗
PubMed1992

Modification by hypoxia, hyperkalaemia and acidosis of the cardiac electrophysiological effects of a range of antiarrhythmic drugs.

1. The electrophysiological effects of a series of drugs with Class I antiarrhythmic activity were examined in sheep Purkinje fibres, superfused in vitro with either a normal or hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS). 2. In normal sheep Purkinje fibres, lignocaine, disopyramide, nicainoprol and propranolol all significantly reduced action potential height and the maximum rate of depolarization of phase zero (MRD) and abbreviated the action potential, without modifying resting membrane potential (RMP). 3. Verapamil at the highest concentration studied, 8 microM, significantly reduced MRD with an associated slight membrane depolarization and abbreviated action potential duration measured at 50% repolarization (APD50). 4. Superfusion of sheep Purkinje fibres with a hypoxic, hyperkalaemic and acidotic PSS resulted in marked reductions in resting membrane potential, upstroke and duration of the action potential. 5. In the presence of modified PSS, lignocaine, propranolol and verapamil all reduced MRD to a greater extent than in normal PSS. The effects of nicainoprol on MRD were not affected whereas those of disopyramide were significantly attenuated. 6. Under simulated ischaemic conditions, lignocaine, propranolol and nicainoprol did not produce a concentration-dependent reduction in action potential duration whereas disopyramide and verapamil, respectively, prolonged and abbreviated both APD50 and APD90. 7. The Na+ channel blocking actions of the different subtypes of Class I antiarrhythmic agents studied, as well as their effects on action potential duration, were modified differently by simulated ischaemia.

Acidosis↗
PubMed1992

Antiarrhythmic, electrophysiological and haemodynamic effects of prolonged oral dosing with Org 7797 in the anaesthetized rat.

The antiarrhythmic, electrophysiological and haemodynamic effects of chronic oral administration of Org 7797 ((16 alpha,17 beta)-17-methylamino-oestra-1,3,5(10)-triene-3, 16-diol-(Z)-2-butonedioate) were studied in rats. During dosing (10 mg kg-1 twice a day for 10 days) no effects on the electrocardiogram, monitored in conscious animals, were observed despite modest reductions (15-18%) in the maximum rate of depolarization of papillary muscle excised 1 or 6 h after completion of the dosing regime. Following anaesthesia, Org 7797 reduced the severity of arrhythmias induced by coronary artery occlusion and prevented the accompanying decrease in the ventricular fibrillation threshold (VFT) at 1 h after completion of dosing. By 6 h the effect on VFT had waned but protection against ischaemia-induced arrhythmias was retained despite a substantial decrease in Org 7797 plasma levels. Drug treatment did not modify arterial blood pressure, heart rate or stroke volume. We conclude that Org 7797 given chronically via the oral route exerts antiarrhythmic actions which may, at least in part, be due to sodium-channel block. In addition, our results suggest the presence of an active metabolite. The protective effects of Org 7797 were seen in the absence of electrocardiographic or haemodynamic changes suggesting that multiple oral doses of Org 7797 do not compromise normal cardiac function.

Action Potentials↗
PubMed1991

Pharmacological evidence for the role of mediators in hypoxia-induced vasoconstriction in sheep isolated intrapulmonary artery rings.

The aim of this study was to determine the likely mediator(s) involved in the hypoxic-induced contraction in sheep pulmonary artery rings in vitro by studying the effects of selective receptor antagonists and enzyme inhibitors. Hypoxia caused a contraction in arteries under resting force and when precontracted with 5-hydroxytryptamine (5-HT). Flurbiprofen, a cyclooxygenase inhibitor, reduced the hypoxic contraction in 5-HT-precontracted rings but augmented the first part of the hypoxic contraction under baseline force. Inhibition of nitric oxide by haemolysate increased the hypoxic contraction under resting force. Superoxide dismutase and N-t-butyl-alpha-phenylnitrone (PBN), free radical scavenging agents, and trypsin, a proteolytic enzyme, did not produce any significant effect on hypoxia-induced constriction. Propranolol plus phentolamine, beta- and alpha-adrenoceptor antagonists respectively, did not produce any effect on hypoxic contraction under resting force, whereas these antagonists augmented hypoxic contraction in the presence of 5-HT. This combination of antagonists also caused a reduction of 5-HT contraction which was the result of alpha 2-adrenoceptor blockade. Verapamil, a calcium channel blocking drug, significantly reduced the 5-HT contraction, but did not reduce that caused by hypoxia either under resting force or in precontracted rings. These results suggest that hypoxic constriction in sheep isolated intrapulmonary artery is in part caused by reduced release of vasodilator prostanoids. This contraction does not involve voltage-operated calcium channels and is limited by release of endothelium-derived nitric oxide.

Adrenergic alpha-Antagonists↗
PubMed1991

Effects of hypoxia on isolated intrapulmonary arteries from the sheep.

The effects of hypoxia on contraction of sheep pulmonary artery rings (large = 2.2-4.1 mm diameter, small = 0.32-0.64 mm diameter) has been investigated following precontraction or with the artery rings set at their optimal resting force. Hypoxia (PO2 4 mmHg) caused a marked contraction of pulmonary artery rings precontracted with 5-HT at its EC85 (small arteries 40 +/- 8 g cm-2) but not when precontracted with KCl. At optimal resting force hypoxia caused a small contraction (small arteries 11 +/- 2 g cm-2). Larger artery rings gave a smaller contraction in response to hypoxia at optimal resting force than did small artery rings (2 +/- 0.2 g cm-2 at PO2 = 4 mmHg). Large, unlike the small, artery rings did not contract in response to hypoxia when precontracted with 5-HT at its EC35. Lowering the PO2 to 40 mmHg caused contraction in arteries precontracted with 5-HT at its EC85 but not in arteries at their optimal resting force. Removal of the endothelium abolished all hypoxia-induced contractile responses in sheep pulmonary artery rings. Hypoxia reversibly abolished acetylcholine-induced relaxation and augmented the 5-HT contraction (206 +/- 28 to 255 +/- 34 g cm-2) in small rings. It is concluded that hypoxia may produce contraction in sheep pulmonary artery rings at least, in part, by reducing the output of vasodilator mediators from the endothelium.

Acetylcholine↗
PubMed1991

Effects of components of myocardial ischaemia on cardiac action potentials in vitro.

The aim of this study was to examine the effects of hypoxia (PO2 = 34 mm Hg), acidosis (pH 6.8), lactate (10 mM), glucose removal, hyperkalaemia (8 mM), and lysophosphatidylcholine (5-50 microM), alone and in combination, on paced sheep Purkinje fibre action potentials in an attempt to find a combination that simulated the electrophysiological changes associated with the delayed phase of ischaemia-induced arrhythmias. Modification of the physiological salt solution to produce a combination of acidosis, lactate, and lysophosphatidylcholine (5 microM) reduced the resting membrane potential and the maximum rate of depolarisation and prolonged action potential duration, these effects being stable from 60 to 120 min of superfusion. Hypoxia, glucose removal, or elevation of the extracellular concentration of potassium alone or in combination with the above factors caused action potential shortening. Thus, the electrophysiological changes associated with the delayed phase of ischaemia-induced arrhythmias in vivo can be simulated in vitro by a combination of acidosis, lactate, and lysophosphatidylcholine.

Acidosis↗
PubMed1990

Antagonism by adenosine and ATP of an isoprenaline-induced background current in guinea-pig ventricular myocytes.

A background current induced by isoprenaline, and its modulation by adenosine and ATP, have been studied using the whole cell patch clamp technique in guinea-pig ventricular myocytes. Isoprenaline (1-2000 nM) caused an inward shift of the holding current, in addition to increasing the inward calcium current (ICa). The effect on the background current was maximal earlier than the increase in ICa, but was of shorter duration. The magnitude of the background current was concentration dependent with a EC50 of 8 nM. This current was unaffected by tetrodotoxin 20 microM, Cd 200 microM or verapamil, 10 microM and potassium channel blockade (intracellular Cs, extracellular Cs 20 mM, Ba 2 mM or tetraethylammonium 10 mM). Lowering the chloride content of the electrode solution reduced the magnitude of the background current. The background current was also induced by histamine (1 or 10 microM). Adenosine (10-1000 microM) and and ATP (200 microM) antagonised the isoprenaline induced background current and the increase in ICa. The histamine effects on these currents were also reduced by adenosine. These results suggest that this background current may be carried by chloride ions and may be mediated via an increase in intracellular cyclic AMP concentration. Antagonism of this current may contribute to the antiarrhythmic actions of adenosine and ATP but their mechanisms of action are yet to be determined.

Adenosine↗
PubMed1990

Comparative antifibrillatory effects of d- and dl-sotalol in normal and ischaemic ventricular muscle of the cat.

The aim of this study was to compare the effects of d- and dl-sotalol on the ventricular fibrillation threshold (VFT) and the effective refractory period (VERP) in anaesthetized cats subjected to coronary artery occlusion. Occlusion of the left anterior descending coronary artery caused a decrease in VFT (measured in mA) (1.40 +/- 0.1 to 0.6 +/- 0.1). dl-Sotalol (1 and 5 mg kg-1) increased VFT before the induction of ischaemia (1.7 +/- 0.1 to 33.8 +/- 1.0 and 38, respectively), and the higher dose prevented the ischaemia-induced fall in VFT. d-Sotalol (1 and 5 mg kg-1) caused only small increases in VFT in normal (1.9 +/- 0.3 to 2.3 +/- 0.3 and 2.6 +/- 0.3) and ischaemic (0.8 +/- 0.1 to 1.2 +/- 0.2 and 1.3 +/- 0.2) myocardium. Both d- and dl-sotalol increased VERP measured in normal myocardium. The % changes observed with 1 and 5 mg kg-1 of the racemate (17 +/- 1 and 57 +/- 4) were significantly greater than those with the d-isomer (8 +/- 3 and 16 +/- 2). dl-Sotalol, but not d-sotalol, prevented the haemodynamic responses to 50 ng kg-1 isoprenaline. These results suggest that VFT in anaesthetized cats is markedly increased by beta-adrenoceptor blockade and only marginally increased by the direct class III antiarrhythmic action of d-sotalol.

Adrenergic beta-Antagonists↗