Cardioselective anti-ischemic ATP-sensitive potassium channel openers.
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Adenosine Triphosphate↗
Biomedical subjects
G J Grover
Publications and source records attributed to G J Grover.
Effects of endogenous and exogenous lysophosphatidylcholine in isolated perfused rat hearts.
In isolated Langendorff perfused rat hearts, treatment with exogenous palmitoyl-lysophosphatidylcholine (P-LPC; 3-50 microM) under normoxic conditions, resulted in reduced heart rate (HR), coronary flow (CF) and contractile function. After 30 min Krebs perfusion, following P-LPC infusion, HR and CF remained reduced and contractile function continued to deteriorate. End diastolic pressure (EDP) and lactate dehydrogenase (LDH) release in LPC treated hearts were significantly increased from controls. Myocardial lysophosphatidylcholine (LPC) levels after 25 min global ischemia were significantly higher than controls (463 +/- 10 for control vs 550 +/- 15 nmol/g dry wt for ischemia). Following 30 min reperfusion an increase from control was still observed (475 +/- 11 for control vs. 594 +/- 17 for ischemia+reperfusion). Analysis of molecular species of LPC demonstrated that palmitoyl, oleoyl and stearoyl were increased after 25 min ischemia. After 30 min of reperfusion only palmitoyl and stearoyl were significantly increased. After 25 min treatment with 3 microM P-LPC and 30 min normoxic perfusion, myocardial LPC was three-fold higher than after 25 min ischemia. Treatment with 0.2 microM exogenous P-LPC resulted in myocardial tissue LPC levels (562 +/- 23) equivalent to those seen after 25 min ischemia (550 +/- 15). Compared to time matched controls hearts perfused with 0.2 microM P-LPC displayed no significant reductions in contractile function nor increase in LDH release. Thus, in isolated rat hearts, the increase in LPC seen after 25 min of global ischemia may not solely mediate the contractile dysfunction and LDH release observed.
Animals↗
An explanation for the reported observation that ATP dependent potassium channel openers fail to mimic preconditioning.
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Adenosine Triphosphate↗
The endothelin-1 receptor antagonist BQ-123 reduces infarct size in a canine model of coronary occlusion and reperfusion.
OBJECTIVE: The aim was to determine the effect of the endothelin-1 receptor antagonist, BQ-123, on infarct size in anaesthetised dogs subjected to 90 min of left circumflex coronary artery occlusion and 5 h of reperfusion. METHODS: BQ-123 was given directly into the left circumflex coronary artery at 0.03 or 10 micrograms.kg-1 x min-1 starting 15 min before coronary occlusion and continuing throughout occlusion and reperfusion. Regional myocardial blood flow was determined before, during, and after ischaemia. At the end of the study, infarct size was determined using triphenyltetrazolium chloride staining. RESULTS: Myocardial infarct size was significantly reduced by BQ-123 (40% reduction from vehicle infarct size) at both doses used. This cardioprotection occurred despite a lack of effect of BQ-123 on peripheral haemodynamic status. BQ-123 also had no effect on regional myocardial blood flow in ischaemic and non-ischaemic tissue. Both cardioprotective doses of BQ-123 were found to completely abolish the coronary constrictor effect of intracoronary endothelin-1 administration. CONCLUSIONS: These data indicate that endothelin-1 release during ischaemia may be involved in the pathogenesis of myocardial ischaemia and infarction.
Animals↗
Cardioprotective effects of the cyanoguanidine potassium channel opener P-1075.
P-1075 is a cyanoguanidine ATP-sensitive potassium channel opener (KATP) that relaxes smooth muscle and shortens myocardial action potential duration (APD) at concentrations in the nanomolar range. Most KATP openers have antiischemic potencies in the micromolar range. We wished to determine if the relatively high cardiac potency of P-1075 could be translated into high antiischemic potency. Isolated rat hearts were pretreated with 10-300 nM P-1075 followed by 25-min global ischemia and 30-min reperfusion. Before ischemia, P-1075 had little effect on cardiac function, although it did increase coronary flow. During ischemia, P-1075 significantly increased time to contracture in a concentration-dependent manner (EC25 = 57 nM). P-1075 also improved recovery of contractile function significantly and reduced lactate dehydrogenase (LDH) release during reperfusion (at concentrations > or = 60 nM). Treatment with 75 nM P-1075 both before and after ischemia did not add to the protective effects observed after preischemic treatment. Treatment with P-1075 only during reperfusion was not cardioprotective. The protective effects of P-1075 were completely abolished by the KATP blocker glyburide (100 nM). In addition, P-1075 relaxed methoxamine-constricted aorta with a higher potency relative to antiischemic potency. Thus, P-1075 has cardioprotective effects similar to that of other reference KATP openers, except that P-1075 is approximately 100-fold more potent relative to most other tested KATP openers. These results demonstrate that P-1075 is the first KATP opener that protects ischemic myocardium at nanomolar concentrations.
Animals↗
Protective effect of serotonin (5-HT2) receptor antagonists in ischemic rat hearts.
Serotonin (5-HT) may play a role in exacerbating thrombosis and coronary spasm during myocardial ischemia, but its role in mediating myocardial damage directly is not clear. We determined the effect of the 5-HT2 receptor antagonists cinanserin (0.1-10 microM), ketanserin (0.3-10 microM), and LY 53857 (1-10 microM) on time to contracture, recovery of contractile function, and lactate dehydrogenase (LDH) release after 25-min global ischemia and 30-min reperfusion in isolated rat heart. All 5-HT2 antagonists significantly increased time to contracture in a concentration-dependent manner (EC25 = 1.6, 5.5, and 6.1 microM for cinanserin, ketanserin, and LY 53857, respectively). These compounds also significantly reduced LDH release and improved recovery of contractile function during reperfusion. 5-HT > or = 30 microM significantly reduced time to contracture, indicating a proischemic effect. The proischemic effect of 5-HT was abolished by ketanserin and cinanserin. Inhibition of 5-HT synthesis by parachlorophenylalanine resulted in significant cardioprotection, further indicating the involvement of 5-HT in the pathogenesis of ischemia in this model. Although cinanserin and ketanserin had alpha 1-adrenoceptor blocking effects, LY 53857 was devoid of this activity at concentrations exhibiting cardioprotection. Therefore, 5-HT may exacerbate ischemic injury in rat heart, and this exacerbation appears to be mediated specifically by 5-HT2 receptors.
Animals↗
Cardioprotective effects of a novel calcium antagonist related to the structure of cromakalim.
A novel pyranoquinoline analog (BMS-188107) of the ATP-sensitive potassium channel (KATP) opener cromakalim was previously shown to be devoid of KATP opening activity in nonischemic myocardium and vascular smooth muscle, but appeared to be a relatively potent calcium antagonist. This clear differentiation between channels within a structural series is a novel finding. With the idea that KATP openers are often more active in ischemic relative to nonischemic myocardium, we determined the cardioprotective effects of this agent in isolated rat hearts and whether these anti-ischemic effects are abolished by KATP blockade. Isolated rat hearts were subjected to 25 min of global ischemia and 30 min of reperfusion and the severity of ischemic/reperfusion injury was determined. BMS-188107 was given before ischemia at 0.5 to 10 microM. Pretreatment (before ischemia) with BMS-188107 caused significant cardiodepressant activity and increased coronary flow only at a concentration of 10 microM, although modest negative inotropic effects were observed at the 0.5 and 1 microM concentrations. Significant improvements in postischemic contractile function and reductions in lactate dehydrogenase release were observed with 1 to 10 microM BMS-188107, indicating significant reductions in ischemic/reperfusion injury. Neither the pre- nor the postischemic effects of 1 to 10 microM BMS-188107 were significantly altered by the KATP blockers sodium 5-hydroxydecanoate (100 microM) or glyburide (1 microM). Previous studies did not determine the effect of BMS-188107 on sodium channels and thus, the effect of this agent on maximum upstroke velocity of the action potential was determined.(ABSTRACT TRUNCATED AT 250 WORDS)
Action Potentials↗
The cardioprotective, vasorelaxant and electrophysiological profile of the large conductance calcium-activated potassium channel opener NS-004.
A series of compounds have been reported which open the large conductance calcium activated potassium channel (maxi-K). By utilizing the most potent compound, NS-004 [1-(5-chloro-2-hydroxyphenyl)-5-trifluromethyl-1,3-dihydro-2-be nzimidazol-2- one], we studied the role of maxi-K channels in ischemic myocardium. Isolated rat hearts were pretreated with vehicle or NS-004 (6-36 microM). NS-004 caused a concentration-dependent reduction in left ventricular developed pressure and an increase in coronary flow. In global ischemia (25 min), a concentration-dependent increase in time to contracture was found in NS-004 (6-20 microM)-treated hearts (EC25 = 8.6 microM). Neither iberiotoxin (50 nM), a maxi-K blocker, nor glyburide (1 microM), an adenosine triphosphate-sensitive potassium channel blocker, reversed the preischemic or ischemic effects of 20 microM NS-004. NS-004 relaxed phenylephrine- and KCl- contracted rat aortic smooth muscle (IC50 = 9.2 microM). This relaxation was unaffected by 50 and 200 nM iberiotoxin. Whole cell potassium currents in ventricular myocytes demonstrated no significant increases in outward potassium current after treatment with NS-004 (1-20 microM). A small, but significant, increase in outward potassium current was observed with 50 microM NS-004. When peak inward L-type calcium currents were measured in ventricular myocytes, a concentration-dependent inhibition was observed in the presence of NS-004 (1-50 microM). Iberiotoxin (50 nM) did not alter the inhibition of inward calcium current observed in the presence of NS-004.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The ATP-sensitive potassium channel blocker glibenclamide (glyburide) does not abolish preconditioning in isolated ischemic rat hearts.
Previous studies have indicated that the ATP-sensitive potassium channels blocker glibenclamide (glyburide) can abolish preconditioning in canine models of myocardial ischemia. Recently, an isolated rat heart model of preconditioning has been developed that may be ideal for studying the mechanisms of preconditioning. In the present study, we determined the effect of glyburide on preconditioning in isolated rat hearts. Rat hearts were isolated and retrogradely perfused with oxygenated Krebs'-Henseleit solution. They were then subjected to four periods of total global ischemia of 5-min duration, separated by 5-min reperfusion. The hearts were then subjected to 30-min global ischemia followed by 30-min reperfusion and contractile function and lactate dehydrogenase release determined. Non-preconditioned hearts sustained severe damage. Glyburide (1-100 microM) pretreatment had no effect on the severity of 30-min global ischemia and 30-min reperfusion. Preconditioning caused significant improvements in reperfusion contractile function (25-fold increase in left ventricular developed pressure) and reductions in reperfusion lactate dehydrogenase release and reperfusion end diastolic pressure (contracture). Glyburide had modest preischemic cardiodepressant and vasoconstrictor effects at 1-30 microM, whereas 100 microM caused a 50% reduction in preischemic coronary flow. Despite these effects, none of these concentrations of glyburide affected the efficacy of preconditioning. These studies indicate that preconditioning in isolated rat hearts does not occur via a glyburide- (and thus presumably ATP-sensitive potassium channel) sensitive mechanism.
Adenosine Triphosphate↗
Cardioprotection in ischemic rat hearts with the SH-containing angiotensin-converting enzyme inhibitor zofenopril: possible involvement of the ATP-sensitive potassium channel.
The SH-containing angiotensin-converting enzyme (ACE) inhibitors zofenopril and captopril have been shown to protect the ischemic myocardium independently of ACE inhibition. Zofenopril (30-100 microM) enhanced reperfusion contractile function and reduced lactate dehydrogenase release. The cardioprotective activity of zofenopril was stereoselective in isolated globally ischemic rat hearts (S, S,R stereoisomer of zofenopril was inactive). The role of ATP-sensitive potassium channel (KATP) activation was investigated using two structurally different KATP blockers, 1 microM glyburide and 100 microM sodium 5-hydroxydecanoate. The cardioprotective activity of 100 microM zofenopril was abolished by both KATP blockers. Cardioprotection with the SH-containing compound n-acetyl cysteine (300 microM) was also reversed by glyburide, further demonstrating that ACE inhibition is not a prerequisite. Isobolographic analysis demonstrated that cotreatment with zofenopril and the KATP opener cromakalim resulted in a super-additive response in the ischemic myocardium. KB analysis demonstrated glyburide was a noncompetitive antagonist in the presence of zofenopril and a competitive antagonist in the presence of cromakalim. Zofenopril has been reported to cause relaxation in aortic smooth muscle rings via an endothelium-dependent component. This relaxation was shifted to the right by both glyburide and sodium 5-hydroxydecanoate. Isobolographic analysis of zofenopril and cromakalim in smooth muscle also demonstrated a super-additive response. These results demonstrate for the first time a link between the cardioprotective effects of the SH-containing compounds zofenopril and n-acetyl cysteine and the KATP. The activity appears to be a receptor-mediated event which occurs in a manner different from classical KATP openers such as cromakalim.
Adenosine Triphosphate↗
Quantitation of lysophosphatidylcholine molecular species in rat cardiac tissue.
We have developed a rapid and sensitive procedure for isolation and measurement of 1-acyllysophosphatidylcholine (LPC) species in rat myocardial tissue. Tissues were spiked with heptadecanoyl-LPC internal standard and extracted with chloroform/methanol. The chloroform phase was dried, resuspended in chloroform/propan-2-ol (2/1, v/v), and applied to an aminopropyl-bonded phase (Bond Elut) column. Following stepwise elution with several solvent mixtures, the LPC fraction (ethyl acetate/methanol, 4/6, v/v) was separated by HPLC with direct quantitation of palmitoyl-LPC (P-LPC), oleoyl-LPC (O-LPC), and stearoyl-LPC (S-LPC), using an evaporative light scattering mass detector. Calibration curves were generated for each individual LPC species. Recoveries of added [14C]LPC and of heptadecanoyl-LPC internal standard after extraction and chromatography were 85.8 +/- 1.9% (mean +/- SE, N = 10) and 83.4 +/- 1.8% (N = 15), respectively. This assay showed satisfactory sensitivity, reproducibility, and accuracy for measurement of LPC species in rat myocardial tissue. The major molecular species of LPC in rat myocardium were found to be P-LPC and S-LPC, which were two- to sixfold as abundant as O-LPC. In isolated, crystalloid-perfused rat hearts the time of perfusion was found to significantly influence the content of P-LPC (0 min, 252 +/- 10; 15 min, 178 +/- 10, P less than 0.001, compared with 0 min; 40 min, 131 +/- 4, P less than 0.001; and 70 min, 129 +/- 4, P less than 0.001; nmol/g dry weight), but not the content of O-LPC and S-LPC. The method will be useful for studying the participation of LPC species in physiology, pathophysiology, and therapeutics.
Animals↗
Effects of intracoronary cromakalim on postischaemic contractile function and action potential duration.
OBJECTIVE: The effects of intracoronary cromakalim (1 microgram.kg-1 x min-1) on postischaemic contractile function and monophasic action potential duration at the 95% repolarisation level (APD95) were assessed in a canine model of stunned myocardium. METHODS: Animals (n = 24) were anaesthetised, subjected to a left thoracotomy, and the left anterior descending coronary artery was isolated. Measurements of segmental shortening and monophasic action potential were taken before drug, after drug, during a 15 min occlusion, and at times following reperfusion. RESULTS: Cromakalim significantly improved reperfusion recovery of function. Both preischaemic and postischaemic myocardial blood flows were increased with cromakalim, although there was no significant change in collateral blood flow during ischaemia relative to vehicle. In the absence of ischaemia, cromakalim reduced APD95 by 8%. There was no change in APD95 with vehicle alone. During coronary occlusion, cromakalim significantly reduced APD95 by 27% as compared with 8% in the vehicle group. APD95 values returned to preocclusion levels within minutes of reperfusion and remained there throughout reperfusion (30 min). Glyburide (3.0 mg.kg-1 intravenously), a blocker of ATP sensitive potassium channels, abolished the APD95 effects of cromakalim. One out of six animals given glyburide survived through reperfusion. In contrast, four out of five of the glyburide+cromakalim treated animals survived through reperfusion. CONCLUSIONS: Cardioprotection with cromakalim is likely to be mediated through activation of ATP sensitive potassium channels, measured as a decrease in action potential duration. Shortening of action potential duration with cromakalim was shown to be augmented in the presence of ischaemia. It is suggested that a possible interrelationship between cardioprotection and action potential duration shortening may exist such that the cardioprotective effects of cromakalim may be selective for ischaemic conditions.
Action Potentials↗
Blockade of ischaemic preconditioning in dogs by the novel ATP dependent potassium channel antagonist sodium 5-hydroxydecanoate.
OBJECTIVE: The aims were: (1) to determine if a new ischaemia selective ATP dependent potassium (KATP) channel antagonist, sodium 5-hydroxydecanoate (5-HD), blocks ischaemic preconditioning in dogs; (2) to determine whether a small intracoronary dose of glibenclamide, a classical sulphonylurea KATP channel antagonist, could block ischaemic preconditioning independent of systemic metabolic effects. METHODS: Barbitone anaesthetised dogs were subjected to 60 min of left circumflex coronary artery occlusion followed by 5 h of reperfusion. Preconditioning was produced by a single 5 min left circumflex occlusion followed by 10 min of reperfusion prior to the 60 min occlusion period. 5-HD (150 micrograms.kg-1 x min-1) or vehicle was given by intracoronary infusion into the ischaemic region over 20 min, beginning 15 min prior to the 60 min occlusion period in the presence or absence of preconditioning. Glibenclamide (3 micrograms.kg-1 x min-1) was given by intracoronary infusion into the left circumflex artery during the 5 min preconditioning period or during the first 5 min of occlusion in preconditioned or non-preconditioned dogs. Transmural myocardial blood flow was measured by radioactive microspheres and infarct size determined by triphenyltetrazolium staining and expressed as a percent of the area at risk. RESULTS: There were no differences in haemodynamic variables, myocardial blood flow, area at risk, or blood glucose between groups. Infarct size was markedly reduced in preconditioned dogs compared to control animals, at 7(SEM 2)% v 29(4)%, p < 0.05 The reduction in infarct size by preconditioning was blocked completely by intracoronary 5-HD, or by intracoronary glibenclamide given during preconditioning or during the first 5 min of the prolonged occlusion period. Neither 5-HD nor glibenclamide affected infarct size in the absence of preconditioning at the doses studied. CONCLUSIONS: These results further strengthen the hypothesis that activation of myocardial KATP channels is involved in the mechanism of ischaemic preconditioning in dogs.
Animals↗
Effect of calmodulin and protein kinase C inhibitors on globally ischemic rat hearts.
Several calmodulin inhibitors have been reported to be cardioprotective, but the ability of these compounds to inhibit protein kinase C (PKC) suggests that calmodulin inhibition may not be the sole mechanism responsible. To distinguish between the effects, we determined the cardioprotective activity of several calmodulin inhibitors with differing PKC inhibitory potencies in isolated globally ischemic rat hearts. Twenty-five minutes of global ischemia caused significant myocardial dysfunction, contracture formation, and lactate dehydrogenase (LDH) release on reperfusion in vehicle-treated hearts. The calmodulin inhibitors trifluoperazine, W-7, calmidazolium, W-13, and CGS 9343B improved postischemic contractile function and/or reduced LDH release. They also reduced preischemic cardiac function, although cardioprotection did not appear to be correlated with cardiodepression. Calmodulin inhibitors increased preischemic coronary flow (CF) and decreased heart rate (HR), but controlling these parameters did not affect the cardioprotection. Pretreatment of ischemic hearts with trifluoperazine was associated with preservation of myocardial ATP. Pretreatment of ischemic rat hearts with the PKC inhibitors staurosporine, calphostin C, polymyxin B, and H-7 did not result in cardioprotection. Thus, calmodulin inhibition causes cardioprotection that appears to be independent of PKC inhibition.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Coronary reactive hyperemia and adenosine-induced vasodilation are mediated partially by a glyburide-sensitive mechanism.
The effect of glyburide on coronary reactive hyperemia and dilator responses to adenosine was evaluated in isolated perfused guinea pig hearts and anesthetized dogs. In isolated guinea pig hearts, changes in flow due to increasing concentrations of adenosine were measured, followed by 2 min of global ischemia to produce reactive hyperemia. This procedure was repeated after glyburide treatment. A similar study was performed in anesthetized open chest dogs. In isolated guinea pig hearts, 1 microM glyburide reduced reactive hyperemia with a peak flow reduction of 30.7% and debt repayment reduction of 78.0%, relative to vehicle-treated hearts. The adenosine dose-response curve in these hearts was shifted 20-fold to the right by 1 microM glyburide. Glyburide (3 mg/kg + 0.01 mg/kg/min) in dogs inhibited both the peak flow (from 154 +/- 26 to 105 +/- 22 ml/min) and the percentage of debt repayment (from 756 +/- 243 to 336 +/- 88%) of reactive hyperemia. Additionally, the canine intracoronary adenosine response curve was shifted rightward 100-fold by glyburide. Thus, there is a glyburide-sensitive component influencing the magnitude of both the adenosine and the reactive hyperemia response, suggesting that some of this response involves ATP-sensitive potassium channels.
Adenosine↗
Effect of the potassium channel opener EMD 56431 on globally ischemic rat hearts.
The effect of the ATP-sensitive potassium channel opener EMD 56431 on coronary vasodilation and cardioprotection in isolated rat hearts was investigated. EMD 56431 caused a significant increase in pre-ischemic coronary flow. Time to contracture and reperfusion function were significantly increased at 3, 10 and 30 microM concentrations. LDH release was significantly reduced at 10 and 30 microM concentrations. 1 microM glyburide completely abolished the protective effects found with 10 microM EMD 56431. When given during reperfusion only, 10 microM EMD 56431 showed no cardioprotection. Thus, EMD 56431 appeared to reduce the severity of ischemia/reperfusion injury. The vasorelaxant versus cardioprotective effects for EMD 56431 are similar to other potassium channel openers, such as cromakalim.
Animals↗
Role of myocardial ATP-sensitive potassium channels in mediating preconditioning in the dog heart and their possible interaction with adenosine A1-receptors.
BACKGROUND: A brief period of myocardial ischemia can result in an increased resistance to subsequent, more severe episodes of ischemia. Recent studies have indicated that activation of adenosine A1-receptors may mediate this preconditioning effect. It is also known that A1-activation can lead to ATP-sensitive potassium channel (KATP) opening via a G(i) protein-mediated effect. Thus, we determined whether the KATP blocker glyburide could abolish preconditioning or the protective effects of A1-receptor activation. METHODS AND RESULTS: Anesthetized dogs were subjected to 5 minutes of left circumflex coronary artery (LCx) occlusion (or sham) followed by 10 minutes of reperfusion. The hearts were then subjected to 60 minutes of LCx occlusion and 5 hours of reperfusion. Glyburide (5 micrograms/kg/min) or vehicle was given directly into the LCx 20 minutes before preconditioning or sham preconditioning. Preconditioning resulted in a significantly reduced infarct size compared with nonpreconditioned animals. Glyburide abolished the protective effect of preconditioning. To establish a link between KATP and A1-receptor activation, the effect of the A1-agonist R-PIA with or without glyburide on infarct size was determined. R-PIA (0.4 microgram/kg/min, directly into the LCx) significantly reduced infarct size, and this protective effect was abolished by glyburide. None of the treatments described above had a significant effect on peripheral hemodynamic status or myocardial blood flow. CONCLUSIONS: Preconditioning may be mediated by KATP activation, and this may be linked to A1-receptor stimulation.
Adaptation, Physiological↗
Effect of the phospholipase A2 inhibitors quinacrine and 7,7-dimethyleicosadienoic acid in isolated globally ischemic rat hearts.
Phospholipase A2 (PLA2) activity results in the formation of lysophospholipids and free fatty acids which may contribute to ischemic myocardial dysfunction. We evaluated the cardioprotective activity of two putative PLA2 inhibitors, quinacrine and 7,7-dimethyleicosadienoic acid (DEDA), in isolated globally ischemic rat hearts. Pretreatment with 1, 5 and 50 microM quinacrine before ischemia did not alter coronary flow but did cause significant cardiodepression. Twenty five minutes of global ischemia and 30 min of reperfusion caused severe myocardial dysfunction and lactate dehydrogenase release. Quinacrine significantly improved reperfusion contractile function and reduced lactate dehydrogenase release, indicative of cardioprotection. In contrast, 30 to 100 microM DEDA produced neither preischemic cardiodepression nor cardioprotective activity. PLA2 inhibition was inferred from measurements of the prostacyclin metabolite, 6-keto-prostaglandin F1 alpha in the coronary effluent and myocardial palmitoyl-lysophosphatidylcholine. Quinacrine and DEDA reduced both 6-keto-prostaglandin F1 alpha and palmitoyl-lysophosphatidylcholine by similar degrees. These results suggest that the cardioprotective activity of quinacrine is independent of PLA2 inhibition. A possible role of calcium inhibition was investigated in rat aortic smooth muscle strips. Norepinephrine-, KCl- and BAY K8644-induced contractions were antagonized in the presence of 5 and 50 microM quinacrine, but were unaffected by 30 to 60 microM DEDA. The ability of quinacrine to inhibit calcium was investigated further in cardiac ventricular myocytes. Measurement of mean whole cell calcium currents showed that quinacrine (5 microM) could inhibit this current up to 70%. Thus, these results suggest that quinacrine-induced cardioprotection may not be due to PLA2 inhibition, but may be related to calcium entry blocking activity.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗