82
Letter to the Editor Calcium antagonists and the stunned myocardium: a role during ischaemia? A role during reperfusion? In the current issue of Ccirdioi~ascvl~ir Resetrrch, Professor Heusch provides a comprehensive overview of the effects
explanation for the improvement in function following delayed administration of these agents. It could be argued that calcium antagonists may enhance recovery of wall motion simply by reducing afterload and/or increasing myocardial blood flow following reperfusion. This was no doubt a contributing factor when the agents were given intravenously, yet ( I iwirked irtipro~~emrnt in segrnent shortetiirig N Y I S achievecl in the (ib.setice of‘ coronury iicrsodilLittrtioti or m y crpprreiit systertiic hcreinodyiiritiii(. effect wheri s r i i ~ i l liiitrtrcoroiiary dosrs of tliftrlipiilr ( 1 - 3 x lo-‘ ~ng.kg-’.i7lili-’/ )(’ere ir[firsed directly into the stunnec/ region.‘ We cannot exclude the possibility that the improved function, even with low dose intracoronary nifedipine, may have been a result of increased contractility due to a decrease in peripheral vascular resistance but without a significant fall in blood pressure. However, it is important to note that one index of global contractility, dP/dt, was similar both before and during nifedipine infusion. In addition, we cannot exclude the possibility that intracoronary nifedipine may have increased a component of microvascular perfusion not detected by the radiolabelled microsphere technique used to measure myocardial blood flow. However, recent evidence indicates that an increase in myocardial perfitsion per se (ie, not achieved by pharmacological intervention) has little influence on contractile function of the stunned myocardium.” A second explanation is that nifedipine (or verapamil) given after reperfusion exerted as yet unknown “direct” effects on the stunned niyocytes. In addition to calcium gain upon reperfusion (see Opie, p 20). an increase in intracellular calcium transients has been described in isolated buffer perfused hearts following ischaemidreflow.“’ In this stage I of the two stage hypothesis, verapamil’ and nisoldipine‘ given at the moment of reflow may have enhanced recovery of function by attenuating calcium influx through the calcium channels (see Opie, p 20), or
Downloaded from by guest on March 23, 2016
of calcium antagonists on the stunned myocardium (p 14). As summarised by Heusch, there is no doubt that calcium antagonists attenuate postischaemic contractile dysfunction if treatment is initiated before the onset of ischaemia. Furthermore, there is no doubt that the beneficial effects of these agents cannot be explained solely on the basis of favourable alterations in systemic haemodynamic variables or myocardial blood flow either during ischaemia or following reperfusion. The question which remains controversial is: does “delayed” treutiiieiif “ith calciurn uritugonists (that is, given at or ojter reperjusion) u l s o iinprove fiinctioti .f the stutitied tnyocurdium :) We were somewhat surprised to find that verapamil, given at or after reperfusion in the anaesthetised open chest canine model. restored segment shortening in the ischaemicheperfused tissue to 65% of baseline values.’ These results were not as impressive as the 100% recovery of function observed when verapamil was given before coronary occlusion, yet wall motion following delayed treatment was significantly greater than that observed in the control group. Even more striking results were obtained when nifedipine was given at 30 minutes after reperfusion: segment shortening recovered to 90- 100% of baseline values following either sublingual administration,’ intravenous infusion.’ or infusion of small doses directly into the stunned region of the heart.’ In addition to this improvement in systolic function, intravenous or intracoronary infusion of nifedipine also attenuated the abnormalities in diastolic function (ie, the paradoxical shortening during early diastole and prolonged diastolic relaxation time) observed following a 15 min transient coronary occlusion in the canine model.‘
This improved recovery of function with delayed calcium antagonist treatment particularly with nifedipine - is not without precedent. Higgins and Blackburn.’ found that nifedipine given only during reflow enhanced the recovery of mechanical performance in isolated rat hearts subjected to 30 min global ischaemia. Delayed treatment with verapamil and diltiazem, however, did not improve postischaemic function.5 More recently, du Toit et nl reported that nisoldipine given during the first five minutes of reperfusion attenuated postischaemic dysfunction in isolated rat hearts stunned by 20 min of ischaemia.‘ Interestingly, however, nisoldipine did not attenuate postischaemic dysfunction if treatment was initiated “late”; that is, at 15 min following reflow.’ This has led to the “two stage” hypothesis for the role of calcium in the stunned myocardium. eloquently summarised by Opie in this issue (p 20). In contrast, other studies have failed to document any salutary effect following delayed administration of calcium antagonists. For example, Ferrari and colleagues found that nifedipine given during reperfusion had no protective effect on postischaemic recovery following a 60 min period of ischaemia in the isolated rat heart.’ This result is not surprising, as the prolonged duration of ischaemia no doubt resulted in profound and irreversible tissue injury. Of greater interest and relevance to the issue of stunned myocardium is the recent preliminary report by Boehm, Heusch and colleagues conducted in the open chest canine model’: although pretreatment with nisoldipine attenuated postischaemic dysfunction, nisoldipine given either during coronary artery occlusion or at four minutes after reperfusion did not alter wall thickening following reflow. Two obvious questions arise from these apparently disparate results. First, why did delaved treatineiit with verupamil atid nifedipine attenuute postischaemic dy.sjiuiiction? Heusch aptly describes our observations as “mysterious”: we readily acknowledge that we cannot provide a definitive
abnormalities in calcium homeostasis were accompanied by asynchronous contraction. I' Considerable evidence indicates that many cardiovascular drugs including calcium antagonists - have antioxidant properties. For example, using a model of sarcolemmal lipid peroxidation. Weglicki and colleagues have shown that nifedipine, verapamil. and diltiazem all have antiperoxidative activity, with nifedipine being the most potent of these three agents." That is, in contrast to the comments of Heusch, there are d i ~ e r e i i c e scitiinng the cciIciiit?i cintcigonists, at least i n terms of their antioxidant properties. These data, combined with the recent evidence of sustained free radical production after reperfusion, make it tempting to speculate that nifedipine or verapamil in our protocols attenuated postischaemic dysfunction by blunting lipid peroxidation following reflow. The important criticism of this concept raised by Heusch, Opie and others is that the concentrations of nifedipine and other agents required to demonstrate an antioxidant effect in the in llitro preparations exceed the therapeutic in vivo plasma concentrations of these drugs. However, the highly lipophilic nature of calcium antagonists results in a markedly increased (>30-fold) accumulation of these agents in cell membranes.15 In addition, these agents may show altered binding to ischaemid reperfused membranes. In fact, data obtained by Herbaczynska-Cedro and Gordon-Majszak indicate that therapeutic doses of nisoldipine given before coronary artery occlusion significantly attenuated the peroxidation of membrane lipids in the in v i v o porcine model.'" At present we have only piecemeal and suggestive evidence for a possible antioxidant effect with delayed administration of calcium antagonists: direct in vivo confirmation is obviously required. We believe, however, that the potential antioxidant properties of these agents cannot be dismissed until direct evidence to the contrary is provided. The second question to arise from this controversy is: why cliel clelriyecl trecitiiient with tiisokl'ipitie ,fiiil to citteiiimte postisc~~zcietiiic dystiitictioti ,yx According to the "two stage" model
proposed by Opie, nisoldipine given four minutes after reperfusion would be expected to attenuate postischaemic dysfunction by inhibition of calcium ion entry by either directly blocking the calcium channel, or by altering oxidant mediated calcium influx.' It could be argued that nisoldipine may differ from nifedipine or verapamil in terms of its antioxidant properties: the relative lipophilicity and antioxidant potency of nisoldipine relative t o these other two agents remains to be determined. However, as mentioned previously, indices of lipid peroxidation were attenuated by the 10 (*.g.kg-ldose of nisoldipine used by Herbaczynska-Cedro and GordonMajszak in the porcine model of coronary artery occlusion.lh This raises the possibility that the 5 (*.g.kg-l intravenous bolus given by Boehm, Heusch and colleagues after reperfusion8 may have been too small to elicit an effect on the stunned myocytes. Thus there is no question that calcium antagonists can enhance contractile function of the stunned myocardium. especially when treatment is initiated "early" - that is, before ischaemia. The issue which remains controversial is whether these agents are effective if given at or after reperfusion: some evidence indicates that delayed treatment with calcium antagonists can attenuate postischaemic dysfunction if given at the appropriate ti me,'-' whereas other evidence indicates that delayed treatment is of no benefit to the stunned myocardium.' ' These apparently disparate results are, indeed, "mysterious". However, this mystery alluded to by Heusch does not lie in the data per se. Rather. the mystery lies i n our inability to interpret these intriguing results, and provides a challenge to find a plausible and definitive solution to this complex puzzle. KAKlN PRZYKLENK KOHkKT A K L O N E R
Heart Institute. Hospital of the Good Samaritan and Section of Cardiology. University of Southern California. 616 South Witnier Street, Los Angeles, CA 90017. USA
Downloaded from by guest on March 23, 2016
by altering calcium flux within intracellular pools - a concept which remains to be confirmed. Although nifedipine is considered to be "vascular selective" (see Heusch, p 14) (an issue which confounds the notion of a direct effect of this agent on the myocytes) calcium antagonists of the dihydropyridine class have clearly been shown to modulate calcium uptake in isolated myocytes." Stage I1 of the model described by Opie is based on the premise that later, following established reperfusion. cytosolic calcium in the stunned myocytes may be diminished. Thus calcium antagonists given at this time might actually exacerbate postischaemic dysfunction." How can we reconcile this hypothesis with the improved recovery of function observed when verapamil and nifedipine were given at 30 minutes after reflow in our in vivo canine model? It is possible that the timing and transition of stage I to stage 11 may differ in the isolated buffer perfused rat heart v the in vivo blood perfused dog heart. Alternatively. calcium antagonists (particularly nifedipine) may have exerted other "direct" effects on the stunned myocytes independent of their calcium channel blocking activity. Numerous studies suggest that free radicals contribute to the phenomenon of the stunned myocardium. In fact, electron spin resonance spectroscopy has revealed a burst of free radical production during the initial minutes following restoration of blood flow," and, perhaps more importantly, increased free radical production during a later time (at 20-30 min) following reperfusion." This sustained production of free radicals, thought to represent the products of lipid peroxidation rather than the generation of primary oxygen radicals,'' may play an important role in the slow recovery of function following reperfusion. It is especially interesting to note that free radical production can precipitate alterations in calcium homeostasis: Burton and colleagues'' observed that exposure of isolated myocytes to oxygen free radicals resulted in an initial subtle increase, followed by diminution, in calcium transients. Furthermore, exposure to oxygen radicals and the resultant
84 I Przyklenk K, Kloner RA. Effect of verapamil on postischemic stunned mvocardium: imoortance of the timine of treatment. J hi Coll Ctrrdiol l k ; l1:614-23. 2 Przyklenk K. Kloner RA. Nifedipine administered postreperfusion ablates the phenomenon of the stunned myocardium (abstract). Circulurion 1987;76(suppl IV): IV-198. 3 Przyklenk K. Ghafari GB. Eitznian DT, Kloner RA. Nifedipine administered after reperfusion ablates systolic contractile dysfunction of postischemic stunned niyocardium. J Am Coll Cnrdiol 1989;13: I 176-83. 4 Przyklenk K. Kloner RA. Calcium antagonists and the stunned myocardium. J Curdiovusc Phurmtrcol 1991;18(suppl 10): s93-101. 5 Higgins AJ, Blackburn KJ. Prevention of reperfusion damage in working rat hearts by calcium antagonists and calmodulin antagonists. J Mol Cell Curdid 1984:16: 427-38. 6 du Toit E. Owen P. Opie LH. Attenuated reperfusion stunning with a calciuni channel
7
8
9
10
II
antagonist or internal calcium blocker in the isolated perfused rat heart (abstract). J Mol Cell Cardiol 1990;22(supplIII):S.S8 Ferrari F, Albertini A, Curello S . er trl. Myocardial recovery during postischemic reperfusion: effects of nifedipine, calcium and magnesium. J Mol Cell Ctrrtliol 1986;18:487-98. Boehm M, Ehring T, Heusch G. Nisoldipine improves the functional recovery of stunned myocardium only when given before ischemia (abstract). Circrrltrfion I99 I ;84 (SUPPI 11):11-656. Miller WP. Eggleston A, Whitesell L. The effect of increased coronary perfusion on the function of stunned myocardium (abstract). Circirlurion 199 1 ;84(suppl 11 ):II-657. Kusuoka H. Koretsune Y. Chacko VP. Weisfeldt ML. Marban E. Excitationcontraction coupling in postischemic mvocardium. Does failure of activator Ca" trinsients underlie stmning? ~ i r c R ~ 1990:66:1268-76. Marsh JD, Dionne MAM. Chiu M. Smith TW. A dihydropyridine calcium channel blocker with phosphodiesterase inhibitor activity: effects on cultured vascular smooth
muscle and cultured heart cells. J Mol Cell Curdiol 1988;20:1141-50.
12 Bolli R. Patel BS, Jeroudi MO. Lai EK.
13
14
15 S
16
McCay PB. Demonstration of free radical generation in stunned myocardium of intact dogs with the use of the spin trap u-phenyl N-tert-butyl nitrone. J Clir7 Imwt 1988: 82:476-85. Mergner GW. Weglicki WB. Kramer JH. Postischemic free radical production in the venous blood of the regionally ischemic swine heart: effect of deferoxaniine. Cirrirlrtiori I99 I ;84:2079-90. Burton KP, Morris AC. Massey KD, Buja LM, Hagler HK. Free radicals alter ionic calcium levelk and membrane phospholipid& in cultured rat ventricular niyocytes. J M d Cell Ctrrdid 1990:22:1035-47. Weglicki WB. Mak IT, Simic MG. Mechanisms of cardiovascular drugs ax antioxidants. J h4d Cell Cmdiol I99O:22: 1 199-208. Herbaczynska-Cedro K. Gordon-Majszak W. Nisoldipine inhibits lipid peroxidation induced by coronary occlusion in pig myocardium. Crrrtiioi~usc Res 1990;24: 683-7.
Downloaded from by guest on March 23, 2016
Letter to the Editor Calcium antagonists and the stunned myocardium: a role during ischaemia? A role during reperfusion? In the current issue of Ccirdioi~ascvl~ir Resetrrch, Professor Heusch provides a comprehensive overview of the effects
explanation for the improvement in function following delayed administration of these agents. It could be argued that calcium antagonists may enhance recovery of wall motion simply by reducing afterload and/or increasing myocardial blood flow following reperfusion. This was no doubt a contributing factor when the agents were given intravenously, yet ( I iwirked irtipro~~emrnt in segrnent shortetiirig N Y I S achievecl in the (ib.setice of‘ coronury iicrsodilLittrtioti or m y crpprreiit systertiic hcreinodyiiritiii(. effect wheri s r i i ~ i l liiitrtrcoroiiary dosrs of tliftrlipiilr ( 1 - 3 x lo-‘ ~ng.kg-’.i7lili-’/ )(’ere ir[firsed directly into the stunnec/ region.‘ We cannot exclude the possibility that the improved function, even with low dose intracoronary nifedipine, may have been a result of increased contractility due to a decrease in peripheral vascular resistance but without a significant fall in blood pressure. However, it is important to note that one index of global contractility, dP/dt, was similar both before and during nifedipine infusion. In addition, we cannot exclude the possibility that intracoronary nifedipine may have increased a component of microvascular perfusion not detected by the radiolabelled microsphere technique used to measure myocardial blood flow. However, recent evidence indicates that an increase in myocardial perfitsion per se (ie, not achieved by pharmacological intervention) has little influence on contractile function of the stunned myocardium.” A second explanation is that nifedipine (or verapamil) given after reperfusion exerted as yet unknown “direct” effects on the stunned niyocytes. In addition to calcium gain upon reperfusion (see Opie, p 20). an increase in intracellular calcium transients has been described in isolated buffer perfused hearts following ischaemidreflow.“’ In this stage I of the two stage hypothesis, verapamil’ and nisoldipine‘ given at the moment of reflow may have enhanced recovery of function by attenuating calcium influx through the calcium channels (see Opie, p 20), or
Downloaded from by guest on March 23, 2016
of calcium antagonists on the stunned myocardium (p 14). As summarised by Heusch, there is no doubt that calcium antagonists attenuate postischaemic contractile dysfunction if treatment is initiated before the onset of ischaemia. Furthermore, there is no doubt that the beneficial effects of these agents cannot be explained solely on the basis of favourable alterations in systemic haemodynamic variables or myocardial blood flow either during ischaemia or following reperfusion. The question which remains controversial is: does “delayed” treutiiieiif “ith calciurn uritugonists (that is, given at or ojter reperjusion) u l s o iinprove fiinctioti .f the stutitied tnyocurdium :) We were somewhat surprised to find that verapamil, given at or after reperfusion in the anaesthetised open chest canine model. restored segment shortening in the ischaemicheperfused tissue to 65% of baseline values.’ These results were not as impressive as the 100% recovery of function observed when verapamil was given before coronary occlusion, yet wall motion following delayed treatment was significantly greater than that observed in the control group. Even more striking results were obtained when nifedipine was given at 30 minutes after reperfusion: segment shortening recovered to 90- 100% of baseline values following either sublingual administration,’ intravenous infusion.’ or infusion of small doses directly into the stunned region of the heart.’ In addition to this improvement in systolic function, intravenous or intracoronary infusion of nifedipine also attenuated the abnormalities in diastolic function (ie, the paradoxical shortening during early diastole and prolonged diastolic relaxation time) observed following a 15 min transient coronary occlusion in the canine model.‘
This improved recovery of function with delayed calcium antagonist treatment particularly with nifedipine - is not without precedent. Higgins and Blackburn.’ found that nifedipine given only during reflow enhanced the recovery of mechanical performance in isolated rat hearts subjected to 30 min global ischaemia. Delayed treatment with verapamil and diltiazem, however, did not improve postischaemic function.5 More recently, du Toit et nl reported that nisoldipine given during the first five minutes of reperfusion attenuated postischaemic dysfunction in isolated rat hearts stunned by 20 min of ischaemia.‘ Interestingly, however, nisoldipine did not attenuate postischaemic dysfunction if treatment was initiated “late”; that is, at 15 min following reflow.’ This has led to the “two stage” hypothesis for the role of calcium in the stunned myocardium. eloquently summarised by Opie in this issue (p 20). In contrast, other studies have failed to document any salutary effect following delayed administration of calcium antagonists. For example, Ferrari and colleagues found that nifedipine given during reperfusion had no protective effect on postischaemic recovery following a 60 min period of ischaemia in the isolated rat heart.’ This result is not surprising, as the prolonged duration of ischaemia no doubt resulted in profound and irreversible tissue injury. Of greater interest and relevance to the issue of stunned myocardium is the recent preliminary report by Boehm, Heusch and colleagues conducted in the open chest canine model’: although pretreatment with nisoldipine attenuated postischaemic dysfunction, nisoldipine given either during coronary artery occlusion or at four minutes after reperfusion did not alter wall thickening following reflow. Two obvious questions arise from these apparently disparate results. First, why did delaved treatineiit with verupamil atid nifedipine attenuute postischaemic dy.sjiuiiction? Heusch aptly describes our observations as “mysterious”: we readily acknowledge that we cannot provide a definitive
abnormalities in calcium homeostasis were accompanied by asynchronous contraction. I' Considerable evidence indicates that many cardiovascular drugs including calcium antagonists - have antioxidant properties. For example, using a model of sarcolemmal lipid peroxidation. Weglicki and colleagues have shown that nifedipine, verapamil. and diltiazem all have antiperoxidative activity, with nifedipine being the most potent of these three agents." That is, in contrast to the comments of Heusch, there are d i ~ e r e i i c e scitiinng the cciIciiit?i cintcigonists, at least i n terms of their antioxidant properties. These data, combined with the recent evidence of sustained free radical production after reperfusion, make it tempting to speculate that nifedipine or verapamil in our protocols attenuated postischaemic dysfunction by blunting lipid peroxidation following reflow. The important criticism of this concept raised by Heusch, Opie and others is that the concentrations of nifedipine and other agents required to demonstrate an antioxidant effect in the in llitro preparations exceed the therapeutic in vivo plasma concentrations of these drugs. However, the highly lipophilic nature of calcium antagonists results in a markedly increased (>30-fold) accumulation of these agents in cell membranes.15 In addition, these agents may show altered binding to ischaemid reperfused membranes. In fact, data obtained by Herbaczynska-Cedro and Gordon-Majszak indicate that therapeutic doses of nisoldipine given before coronary artery occlusion significantly attenuated the peroxidation of membrane lipids in the in v i v o porcine model.'" At present we have only piecemeal and suggestive evidence for a possible antioxidant effect with delayed administration of calcium antagonists: direct in vivo confirmation is obviously required. We believe, however, that the potential antioxidant properties of these agents cannot be dismissed until direct evidence to the contrary is provided. The second question to arise from this controversy is: why cliel clelriyecl trecitiiient with tiisokl'ipitie ,fiiil to citteiiimte postisc~~zcietiiic dystiitictioti ,yx According to the "two stage" model
proposed by Opie, nisoldipine given four minutes after reperfusion would be expected to attenuate postischaemic dysfunction by inhibition of calcium ion entry by either directly blocking the calcium channel, or by altering oxidant mediated calcium influx.' It could be argued that nisoldipine may differ from nifedipine or verapamil in terms of its antioxidant properties: the relative lipophilicity and antioxidant potency of nisoldipine relative t o these other two agents remains to be determined. However, as mentioned previously, indices of lipid peroxidation were attenuated by the 10 (*.g.kg-ldose of nisoldipine used by Herbaczynska-Cedro and GordonMajszak in the porcine model of coronary artery occlusion.lh This raises the possibility that the 5 (*.g.kg-l intravenous bolus given by Boehm, Heusch and colleagues after reperfusion8 may have been too small to elicit an effect on the stunned myocytes. Thus there is no question that calcium antagonists can enhance contractile function of the stunned myocardium. especially when treatment is initiated "early" - that is, before ischaemia. The issue which remains controversial is whether these agents are effective if given at or after reperfusion: some evidence indicates that delayed treatment with calcium antagonists can attenuate postischaemic dysfunction if given at the appropriate ti me,'-' whereas other evidence indicates that delayed treatment is of no benefit to the stunned myocardium.' ' These apparently disparate results are, indeed, "mysterious". However, this mystery alluded to by Heusch does not lie in the data per se. Rather. the mystery lies i n our inability to interpret these intriguing results, and provides a challenge to find a plausible and definitive solution to this complex puzzle. KAKlN PRZYKLENK KOHkKT A K L O N E R
Heart Institute. Hospital of the Good Samaritan and Section of Cardiology. University of Southern California. 616 South Witnier Street, Los Angeles, CA 90017. USA
Downloaded from by guest on March 23, 2016
by altering calcium flux within intracellular pools - a concept which remains to be confirmed. Although nifedipine is considered to be "vascular selective" (see Heusch, p 14) (an issue which confounds the notion of a direct effect of this agent on the myocytes) calcium antagonists of the dihydropyridine class have clearly been shown to modulate calcium uptake in isolated myocytes." Stage I1 of the model described by Opie is based on the premise that later, following established reperfusion. cytosolic calcium in the stunned myocytes may be diminished. Thus calcium antagonists given at this time might actually exacerbate postischaemic dysfunction." How can we reconcile this hypothesis with the improved recovery of function observed when verapamil and nifedipine were given at 30 minutes after reflow in our in vivo canine model? It is possible that the timing and transition of stage I to stage 11 may differ in the isolated buffer perfused rat heart v the in vivo blood perfused dog heart. Alternatively. calcium antagonists (particularly nifedipine) may have exerted other "direct" effects on the stunned myocytes independent of their calcium channel blocking activity. Numerous studies suggest that free radicals contribute to the phenomenon of the stunned myocardium. In fact, electron spin resonance spectroscopy has revealed a burst of free radical production during the initial minutes following restoration of blood flow," and, perhaps more importantly, increased free radical production during a later time (at 20-30 min) following reperfusion." This sustained production of free radicals, thought to represent the products of lipid peroxidation rather than the generation of primary oxygen radicals,'' may play an important role in the slow recovery of function following reperfusion. It is especially interesting to note that free radical production can precipitate alterations in calcium homeostasis: Burton and colleagues'' observed that exposure of isolated myocytes to oxygen free radicals resulted in an initial subtle increase, followed by diminution, in calcium transients. Furthermore, exposure to oxygen radicals and the resultant
84 I Przyklenk K, Kloner RA. Effect of verapamil on postischemic stunned mvocardium: imoortance of the timine of treatment. J hi Coll Ctrrdiol l k ; l1:614-23. 2 Przyklenk K. Kloner RA. Nifedipine administered postreperfusion ablates the phenomenon of the stunned myocardium (abstract). Circulurion 1987;76(suppl IV): IV-198. 3 Przyklenk K. Ghafari GB. Eitznian DT, Kloner RA. Nifedipine administered after reperfusion ablates systolic contractile dysfunction of postischemic stunned niyocardium. J Am Coll Cnrdiol 1989;13: I 176-83. 4 Przyklenk K. Kloner RA. Calcium antagonists and the stunned myocardium. J Curdiovusc Phurmtrcol 1991;18(suppl 10): s93-101. 5 Higgins AJ, Blackburn KJ. Prevention of reperfusion damage in working rat hearts by calcium antagonists and calmodulin antagonists. J Mol Cell Curdid 1984:16: 427-38. 6 du Toit E. Owen P. Opie LH. Attenuated reperfusion stunning with a calciuni channel
7
8
9
10
II
antagonist or internal calcium blocker in the isolated perfused rat heart (abstract). J Mol Cell Cardiol 1990;22(supplIII):S.S8 Ferrari F, Albertini A, Curello S . er trl. Myocardial recovery during postischemic reperfusion: effects of nifedipine, calcium and magnesium. J Mol Cell Ctrrtliol 1986;18:487-98. Boehm M, Ehring T, Heusch G. Nisoldipine improves the functional recovery of stunned myocardium only when given before ischemia (abstract). Circrrltrfion I99 I ;84 (SUPPI 11):11-656. Miller WP. Eggleston A, Whitesell L. The effect of increased coronary perfusion on the function of stunned myocardium (abstract). Circirlurion 199 1 ;84(suppl 11 ):II-657. Kusuoka H. Koretsune Y. Chacko VP. Weisfeldt ML. Marban E. Excitationcontraction coupling in postischemic mvocardium. Does failure of activator Ca" trinsients underlie stmning? ~ i r c R ~ 1990:66:1268-76. Marsh JD, Dionne MAM. Chiu M. Smith TW. A dihydropyridine calcium channel blocker with phosphodiesterase inhibitor activity: effects on cultured vascular smooth
muscle and cultured heart cells. J Mol Cell Curdiol 1988;20:1141-50.
12 Bolli R. Patel BS, Jeroudi MO. Lai EK.
13
14
15 S
16
McCay PB. Demonstration of free radical generation in stunned myocardium of intact dogs with the use of the spin trap u-phenyl N-tert-butyl nitrone. J Clir7 Imwt 1988: 82:476-85. Mergner GW. Weglicki WB. Kramer JH. Postischemic free radical production in the venous blood of the regionally ischemic swine heart: effect of deferoxaniine. Cirrirlrtiori I99 I ;84:2079-90. Burton KP, Morris AC. Massey KD, Buja LM, Hagler HK. Free radicals alter ionic calcium levelk and membrane phospholipid& in cultured rat ventricular niyocytes. J M d Cell Ctrrdid 1990:22:1035-47. Weglicki WB. Mak IT, Simic MG. Mechanisms of cardiovascular drugs ax antioxidants. J h4d Cell Cmdiol I99O:22: 1 199-208. Herbaczynska-Cedro K. Gordon-Majszak W. Nisoldipine inhibits lipid peroxidation induced by coronary occlusion in pig myocardium. Crrrtiioi~usc Res 1990;24: 683-7.
Downloaded from by guest on March 23, 2016
