American Journal of Physiology-heart and Circulatory Physiology, 2004
Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve develo... more Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve development of tolerance to repeated episodes of ischemia. Not all preconditioning stimuli use identical signaling pathways, and because patients likely experience varying numbers of episodes of preinfarct angina of different degrees and durations, it is important to know whether myocardium tolerant to a particular preconditioning stimulus can still be protected by stimuli employing alternative signaling pathways. We tested the hypothesis that development of tolerance to a particular stimulus does not affect cardioprotection by stimuli that employ different signaling pathways. Anesthetized rats underwent classical, remote or pharmacological preconditioning. Infarct size (IS), produced by a 60-min coronary artery occlusion (CAO), was determined after 120 min of reperfusion. Preconditioning by two 15-min periods of CAO (2CAO15, an adenosine-dependent stimulus) limited IS from 69 +/- 2% to 37 +/- 6%, but when 2CAO15 was preceded by 4CAO15, protection by 2CAO15 was absent (IS = 68 +/- 1%). This development of tolerance coincided with a loss of cardiac interstitial adenosine release, whereas two 15-min infusions of adenosine (200 microg/min i.v.) still elicited cardioprotection (IS = 40 +/- 4%). Furthermore, cardioprotection was produced when 4CAO15 was followed by the adenosine-independent stimulus 3CAO3 (IS = 50 +/- 8%) or the remote preconditioning stimulus of two 15-min periods of mesenteric artery occlusion (IS = 49 +/- 6%). In conclusion, development of tolerance to cardioprotection by an adenosine-dependent preconditioning stimulus still allows protection by pharmacological or ischemic stimuli intervention employing different signaling pathways.
Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve develo... more Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve development of tolerance to repeated episodes of ischemia. Not all preconditioning stimuli use identical signaling pathways, and because patients likely experience varying numbers of episodes of preinfarct angina of different degrees and durations, it is important to know whether myocardium tolerant to a particular preconditioning stimulus can still be protected by stimuli employing alternative signaling pathways. We tested the hypothesis that development of tolerance to a particular stimulus does not affect cardioprotection by stimuli that employ different signaling pathways. Anesthetized rats underwent classical, remote or pharmacological preconditioning. Infarct size (IS), produced by a 60-min coronary artery occlusion (CAO), was determined after 120 min of reperfusion. Preconditioning by two 15-min periods of CAO (2CAO15, an adenosine-dependent stimulus) limited IS from 69 +/- 2% to 37 +/- 6%, but when 2CAO15 was preceded by 4CAO15, protection by 2CAO15 was absent (IS = 68 +/- 1%). This development of tolerance coincided with a loss of cardiac interstitial adenosine release, whereas two 15-min infusions of adenosine (200 microg/min i.v.) still elicited cardioprotection (IS = 40 +/- 4%). Furthermore, cardioprotection was produced when 4CAO15 was followed by the adenosine-independent stimulus 3CAO3 (IS = 50 +/- 8%) or the remote preconditioning stimulus of two 15-min periods of mesenteric artery occlusion (IS = 49 +/- 6%). In conclusion, development of tolerance to cardioprotection by an adenosine-dependent preconditioning stimulus still allows protection by pharmacological or ischemic stimuli intervention employing different signaling pathways.
We tested in the in vivo rat heart the hypothesis that although ischemic preconditioning can empl... more We tested in the in vivo rat heart the hypothesis that although ischemic preconditioning can employ different signal transduction pathways, these pathways converge ultimately at the level of the mitochondrial respiratory chain. Infarct size produced by a 60-min coronary artery occlusion (69%+/-2% of the area at risk) was limited by a preceding 15-min coronary occlusion (48%+/-4%). Cardioprotection by this stimulus was triggered by adenosine receptor stimulation, which was followed by protein kinase C and tyrosine kinase activation and then mitochondrial K(+)(ATP)-channel opening. In contrast, cardioprotection by 3 cycles of 3-min coronary occlusions (infarct size 27%+/-5% of the area at risk) involved the release of reactive oxygen species, which was followed by protein kinase C and tyrosine kinase activation, but was independent of adenosine receptor stimulation and K(+)(ATP)-channel activation. However, both pathways decreased respiratory control index (RCI; state-3/state-2, using succinate as complex-II substrate) from 3.1+/-0.2 in mitochondria from sham-treated hearts to 2.4+/-0.2 and 2.5+/-0.1 in hearts subjected to a single 15-min and triple 3-min coronary occlusions, respectively (both P<0.05). The decreases in RCI were due to an increase in state-2 respiration, whereas state-3 respiration was unchanged. Abolition of cardioprotection by blockade of either signal transduction pathway was paralleled by a concomitant abolition of mitochondrial uncoupling. These observations are consistent with the concept that mild mitochondrial uncoupling contributes to infarct size limitation by various ischemic preconditioning stimuli, despite using different signal transduction pathways. In conclusion, in the in vivo rat heart, different ischemic preconditioning (IPC) stimuli can activate highly different signal transduction pathways, which seem to converge at the level of the mitochondria where they increase state-2 respiration.
It is unknown how cardiac stimulation by Ca2+ sensitization modulates the cardiovascular response... more It is unknown how cardiac stimulation by Ca2+ sensitization modulates the cardiovascular response to exercise when left ventricular (LV) function is chronically depressed following a myocardial infarction. We therefore investigated the effects of EMD 57033 at rest and during exercise and compared these to those of the mixed Ca2+-sensitizer/phosphodiesterase-III inhibitor pimobendan.Pigs were chronically instrumented for measurement of cardiovascular performance. At the time of instrumentation, infarction was produced by coronary artery ligation (MI, n=12). Studies in MI were performed in the awake state, 2 – 3 weeks after infarction.MI were characterized by a lower resting cardiac output (18%), stroke volume (30%) and LVdP/dtmax (18%), and a doubling of LV end-diastolic pressure, compared to normal pigs (N, n=13).In 11 resting MI, intravenous EMD 57033 (0.2 – 0.8 mg kg−1 min−1) increased LVdP/dtmax (57±5%) and stroke volume (26±6%) with no effect on heart rate, LV filling pressure, and myocardial O2-consumption, similar to N.In MI, the effects of EMD 57033 (0.4 mg kg−1 min−1, IV) on stroke volume and LVdP/dtmax were maintained during treadmill exercise up to 85% of maximal heart rate, while heart rate was lower compared to control exercise (all P<0.05). In contrast, the effects of EMD57033 gradually waned in N at increasing intensity of exercise.Compared to N, the cardiostimulatory effects of pimobendan (20 μg kg−1 min−1, IV) were blunted in MI both at rest and during exercise compared to N.In conclusion, the positive inotropic actions of the Ca2+ sensitizer EMD 57033 are unmitigated in resting and exercising MI compared to N, while those of the mixed Ca2+-sensitizer/phosphodiesterase-III inhibitor pimobendan are blunted.It is unknown how cardiac stimulation by Ca2+ sensitization modulates the cardiovascular response to exercise when left ventricular (LV) function is chronically depressed following a myocardial infarction. We therefore investigated the effects of EMD 57033 at rest and during exercise and compared these to those of the mixed Ca2+-sensitizer/phosphodiesterase-III inhibitor pimobendan.Pigs were chronically instrumented for measurement of cardiovascular performance. At the time of instrumentation, infarction was produced by coronary artery ligation (MI, n=12). Studies in MI were performed in the awake state, 2 – 3 weeks after infarction.MI were characterized by a lower resting cardiac output (18%), stroke volume (30%) and LVdP/dtmax (18%), and a doubling of LV end-diastolic pressure, compared to normal pigs (N, n=13).In 11 resting MI, intravenous EMD 57033 (0.2 – 0.8 mg kg−1 min−1) increased LVdP/dtmax (57±5%) and stroke volume (26±6%) with no effect on heart rate, LV filling pressure, and myocardial O2-consumption, similar to N.In MI, the effects of EMD 57033 (0.4 mg kg−1 min−1, IV) on stroke volume and LVdP/dtmax were maintained during treadmill exercise up to 85% of maximal heart rate, while heart rate was lower compared to control exercise (all P<0.05). In contrast, the effects of EMD57033 gradually waned in N at increasing intensity of exercise.Compared to N, the cardiostimulatory effects of pimobendan (20 μg kg−1 min−1, IV) were blunted in MI both at rest and during exercise compared to N.In conclusion, the positive inotropic actions of the Ca2+ sensitizer EMD 57033 are unmitigated in resting and exercising MI compared to N, while those of the mixed Ca2+-sensitizer/phosphodiesterase-III inhibitor pimobendan are blunted.British Journal of Pharmacology (2001) 134, 553–562; doi:10.1038/sj.bjp.0704292
American Journal of Physiology-heart and Circulatory Physiology, 2004
Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve develo... more Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve development of tolerance to repeated episodes of ischemia. Not all preconditioning stimuli use identical signaling pathways, and because patients likely experience varying numbers of episodes of preinfarct angina of different degrees and durations, it is important to know whether myocardium tolerant to a particular preconditioning stimulus can still be protected by stimuli employing alternative signaling pathways. We tested the hypothesis that development of tolerance to a particular stimulus does not affect cardioprotection by stimuli that employ different signaling pathways. Anesthetized rats underwent classical, remote or pharmacological preconditioning. Infarct size (IS), produced by a 60-min coronary artery occlusion (CAO), was determined after 120 min of reperfusion. Preconditioning by two 15-min periods of CAO (2CAO15, an adenosine-dependent stimulus) limited IS from 69 +/- 2% to 37 +/- 6%, but when 2CAO15 was preceded by 4CAO15, protection by 2CAO15 was absent (IS = 68 +/- 1%). This development of tolerance coincided with a loss of cardiac interstitial adenosine release, whereas two 15-min infusions of adenosine (200 microg/min i.v.) still elicited cardioprotection (IS = 40 +/- 4%). Furthermore, cardioprotection was produced when 4CAO15 was followed by the adenosine-independent stimulus 3CAO3 (IS = 50 +/- 8%) or the remote preconditioning stimulus of two 15-min periods of mesenteric artery occlusion (IS = 49 +/- 6%). In conclusion, development of tolerance to cardioprotection by an adenosine-dependent preconditioning stimulus still allows protection by pharmacological or ischemic stimuli intervention employing different signaling pathways.
Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve develo... more Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve development of tolerance to repeated episodes of ischemia. Not all preconditioning stimuli use identical signaling pathways, and because patients likely experience varying numbers of episodes of preinfarct angina of different degrees and durations, it is important to know whether myocardium tolerant to a particular preconditioning stimulus can still be protected by stimuli employing alternative signaling pathways. We tested the hypothesis that development of tolerance to a particular stimulus does not affect cardioprotection by stimuli that employ different signaling pathways. Anesthetized rats underwent classical, remote or pharmacological preconditioning. Infarct size (IS), produced by a 60-min coronary artery occlusion (CAO), was determined after 120 min of reperfusion. Preconditioning by two 15-min periods of CAO (2CAO15, an adenosine-dependent stimulus) limited IS from 69 +/- 2% to 37 +/- 6%, but when 2CAO15 was preceded by 4CAO15, protection by 2CAO15 was absent (IS = 68 +/- 1%). This development of tolerance coincided with a loss of cardiac interstitial adenosine release, whereas two 15-min infusions of adenosine (200 microg/min i.v.) still elicited cardioprotection (IS = 40 +/- 4%). Furthermore, cardioprotection was produced when 4CAO15 was followed by the adenosine-independent stimulus 3CAO3 (IS = 50 +/- 8%) or the remote preconditioning stimulus of two 15-min periods of mesenteric artery occlusion (IS = 49 +/- 6%). In conclusion, development of tolerance to cardioprotection by an adenosine-dependent preconditioning stimulus still allows protection by pharmacological or ischemic stimuli intervention employing different signaling pathways.
We tested in the in vivo rat heart the hypothesis that although ischemic preconditioning can empl... more We tested in the in vivo rat heart the hypothesis that although ischemic preconditioning can employ different signal transduction pathways, these pathways converge ultimately at the level of the mitochondrial respiratory chain. Infarct size produced by a 60-min coronary artery occlusion (69%+/-2% of the area at risk) was limited by a preceding 15-min coronary occlusion (48%+/-4%). Cardioprotection by this stimulus was triggered by adenosine receptor stimulation, which was followed by protein kinase C and tyrosine kinase activation and then mitochondrial K(+)(ATP)-channel opening. In contrast, cardioprotection by 3 cycles of 3-min coronary occlusions (infarct size 27%+/-5% of the area at risk) involved the release of reactive oxygen species, which was followed by protein kinase C and tyrosine kinase activation, but was independent of adenosine receptor stimulation and K(+)(ATP)-channel activation. However, both pathways decreased respiratory control index (RCI; state-3/state-2, using succinate as complex-II substrate) from 3.1+/-0.2 in mitochondria from sham-treated hearts to 2.4+/-0.2 and 2.5+/-0.1 in hearts subjected to a single 15-min and triple 3-min coronary occlusions, respectively (both P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). The decreases in RCI were due to an increase in state-2 respiration, whereas state-3 respiration was unchanged. Abolition of cardioprotection by blockade of either signal transduction pathway was paralleled by a concomitant abolition of mitochondrial uncoupling. These observations are consistent with the concept that mild mitochondrial uncoupling contributes to infarct size limitation by various ischemic preconditioning stimuli, despite using different signal transduction pathways. In conclusion, in the in vivo rat heart, different ischemic preconditioning (IPC) stimuli can activate highly different signal transduction pathways, which seem to converge at the level of the mitochondria where they increase state-2 respiration.
It is unknown how cardiac stimulation by Ca2+ sensitization modulates the cardiovascular response... more It is unknown how cardiac stimulation by Ca2+ sensitization modulates the cardiovascular response to exercise when left ventricular (LV) function is chronically depressed following a myocardial infarction. We therefore investigated the effects of EMD 57033 at rest and during exercise and compared these to those of the mixed Ca2+-sensitizer/phosphodiesterase-III inhibitor pimobendan.Pigs were chronically instrumented for measurement of cardiovascular performance. At the time of instrumentation, infarction was produced by coronary artery ligation (MI, n=12). Studies in MI were performed in the awake state, 2 – 3 weeks after infarction.MI were characterized by a lower resting cardiac output (18%), stroke volume (30%) and LVdP/dtmax (18%), and a doubling of LV end-diastolic pressure, compared to normal pigs (N, n=13).In 11 resting MI, intravenous EMD 57033 (0.2 – 0.8 mg kg−1 min−1) increased LVdP/dtmax (57±5%) and stroke volume (26±6%) with no effect on heart rate, LV filling pressure, and myocardial O2-consumption, similar to N.In MI, the effects of EMD 57033 (0.4 mg kg−1 min−1, IV) on stroke volume and LVdP/dtmax were maintained during treadmill exercise up to 85% of maximal heart rate, while heart rate was lower compared to control exercise (all P<0.05). In contrast, the effects of EMD57033 gradually waned in N at increasing intensity of exercise.Compared to N, the cardiostimulatory effects of pimobendan (20 μg kg−1 min−1, IV) were blunted in MI both at rest and during exercise compared to N.In conclusion, the positive inotropic actions of the Ca2+ sensitizer EMD 57033 are unmitigated in resting and exercising MI compared to N, while those of the mixed Ca2+-sensitizer/phosphodiesterase-III inhibitor pimobendan are blunted.It is unknown how cardiac stimulation by Ca2+ sensitization modulates the cardiovascular response to exercise when left ventricular (LV) function is chronically depressed following a myocardial infarction. We therefore investigated the effects of EMD 57033 at rest and during exercise and compared these to those of the mixed Ca2+-sensitizer/phosphodiesterase-III inhibitor pimobendan.Pigs were chronically instrumented for measurement of cardiovascular performance. At the time of instrumentation, infarction was produced by coronary artery ligation (MI, n=12). Studies in MI were performed in the awake state, 2 – 3 weeks after infarction.MI were characterized by a lower resting cardiac output (18%), stroke volume (30%) and LVdP/dtmax (18%), and a doubling of LV end-diastolic pressure, compared to normal pigs (N, n=13).In 11 resting MI, intravenous EMD 57033 (0.2 – 0.8 mg kg−1 min−1) increased LVdP/dtmax (57±5%) and stroke volume (26±6%) with no effect on heart rate, LV filling pressure, and myocardial O2-consumption, similar to N.In MI, the effects of EMD 57033 (0.4 mg kg−1 min−1, IV) on stroke volume and LVdP/dtmax were maintained during treadmill exercise up to 85% of maximal heart rate, while heart rate was lower compared to control exercise (all P<0.05). In contrast, the effects of EMD57033 gradually waned in N at increasing intensity of exercise.Compared to N, the cardiostimulatory effects of pimobendan (20 μg kg−1 min−1, IV) were blunted in MI both at rest and during exercise compared to N.In conclusion, the positive inotropic actions of the Ca2+ sensitizer EMD 57033 are unmitigated in resting and exercising MI compared to N, while those of the mixed Ca2+-sensitizer/phosphodiesterase-III inhibitor pimobendan are blunted.British Journal of Pharmacology (2001) 134, 553–562; doi:10.1038/sj.bjp.0704292
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