- Email: [email protected]
Activation of ERK12 in cardiac failure due to volume overload
NOT REQUIRED FOR MYOCARDIAL ISCHEMIC PRECONDITIONING lPCl IN PIGS Lisa M. Schwartz, Dept of Anatomy, Physiology, Genetics, USUHS, Bethesda, MD, USA.
ACTIVATION OF ERKY2 IN CARDIAC FAILURE DUE TO VOLUME OVERLOAD and
To test the hypothesis that cardioprotection induced by PC is the result of opening mitochondrial &,rp channels, we investigated the effect of channel blockade by 5-hydroxydecanoate (5HD) in barbitalanesthetized open-chest pigs subjected to 30 min complete occlusion of the left anterior descending (LAD) coronary artery and 3 h reflow. PC was elicited by two episodes of 5 min of LAD occlusion followed by IO min of reperfusion before the 30-min occlusion period. 5-HD (5 mglkg, i.v.) was injected 15 min before PC, or pharmacological PC induced by infusion of diazoxide (3.5 mglkg, 1 mllmin, i.v.) Infarct size was determined by triphenyl-tetrazolium chloride macrochemistry and expressed as a percent of the area at risk. Infarct size following 30 min ischemia was 35.1 * 9.9% (n=7). PC markedly limited myocardial infarct size (2.7 * 1.6%, n=7), and 5-HO did not abolish the protective effect (2.4 f 0.9%, n=8). Diazoxide infusion also significantly limited infarct size (14.6 * 7.4%, n=7) and this effect was blocked by 5HD (30.8 + 8.0%, n=7). These results indicate that opening mito y4Tp channels is cardioprotective in pig heart, but do not support the hypothesis that opening of y4Tp channels is critical for the endogenous protection afforded by PC.
LACK OF DYSTROPHIN IN MURINE SLOWTWITCH MUSCLE: ALTERED INTEGRATION BETWEEN MITOCHONDRIA AND ATPASES Evelin E. Seppet, Urmo Braun, Kalju Paju. Margus Eimre, Ehte Orlova, Lumme Kadaja. Sonata Trumbeckaite, Frank N. Gellerich, Stephan Zierz E Enn K. Seppet. Dept of Pathophysiology. University of Tartu. Estonia & Clinic of Neurology, Martin Luther University, HallelSaale, Germany. Mitochondrial function in skinned muscle fibers from dystrophin-deficient (MDXj and wild-type mice was compared. In the myocardium and m. soleus of the MDX mice the coupling of mi-CK to adenine nucleotide translocase was attenuated (decreased effect of creatine on Km for ADP in the reactions of oxidative phosphorylation). In m. soleus, low Km for ADP compared to wild-type counterpart was found that implies increased permeability for ADP across the mitochondrial outer membrane. In normal cardiac fibers 35% of the ADP flux generated by ATPases was not accessible to external ADP -trapping system, which suggests the compartmentalized (direct j channeling of that fraction of ADP to mitochondria. Compared to control. the direct ADP transfer was increased in MDX ventricles. In conclusion, in slow-twitch muscle cells the absence of dystrophin results in rearrangement of the energy and feedback signal transfer systems between mitochondria and ATPases.
A108
Emmanuelle Sentex, Weihua Zhang, Xi Wang & Naranjan S. Dhalla. Institute of Cardiovascular Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. Recent studies have pointed out the role of extracellular signal-regulated kinase (ERK), a member of the mitogenactivated family, as pro- and anti-hypertrophic agent. Since no data are available concerning the status of ERK in cardiac hypertrophy and heart failure due to volume overload, this work investigated changes in ERK1/2 activities and contents in the left and right ventricles (LV, RV) at 2 to 16 wk after the induction of aortocaval shunt (AVS) in rats. Volume overload induced a 45% and 150% increase in cardiac mass after 4 wk and 16 wk in the AVS group. Hemodynamic data showed that cardiac hypertrophy evolve from a compensated stage before 8 wk to a decompensated stage after this point. In the LV, ERK activities were increased by 30,150 and 60% at 4,8 and 16 wk, respectively; the higher activities were associated with an increase in phosphorylated ERKl/2 content. No change in ERK1/2 activities or contents was observed in the RV. These results suggest that an increase in the ERKlR in the LV may be involved in the development of heart failure. (Supported by ClHR Group in Experimental Cardiology)
PRESCRIBING PATTERN OF CALCIUM CHANNEL BLOCKERS BY PRIMARY CARE PHYSICIANS IN BAHRAIN. Reginald P. Sequeira, Khalid A.J. Al Khaja & Vijay S. Mathur. Department of Pharmacology & Therapeutics, Arabian Gulf University, Bahrain. Concern has recently been expressed about the longterm safety of short-acting dihydropyridine calcium channel blockers (CCBs), such as nifedipine, in the management of hypertension. The goal of present study was to determine the extent of CCBs use as antihypertcnsives by primary care physicians in 7 out of 18 Health Centres in Bahrain. A prescription audit showed that: (a) of the 3838 patients with uncomplicated hypertension, 62.9% were treated with a single antihypertensive drug. Among 11.1% treated with a CCB, 5.4% were on short-acting nifedipine; (b) in 432 elderly hypertensives, 20.1% were treated with CCB alone: approximately half of these with a short acting nifedipine; and (c) in 1463 type 2 diabetichypertensives, 17.9% were treated with CCB alone; 8.2% of these were on short-acting nifedipine. Nondihydropyridine CCBs (diltiazem) were rarely used. The tendency tc prescribe short-acting nifedipine as monodmg therapy for hypertension does not conform with International guidelines for the management of hypertension, and should be discouraged.
ACTIVATION OF ERKY2 IN CARDIAC FAILURE DUE TO VOLUME OVERLOAD and
To test the hypothesis that cardioprotection induced by PC is the result of opening mitochondrial &,rp channels, we investigated the effect of channel blockade by 5-hydroxydecanoate (5HD) in barbitalanesthetized open-chest pigs subjected to 30 min complete occlusion of the left anterior descending (LAD) coronary artery and 3 h reflow. PC was elicited by two episodes of 5 min of LAD occlusion followed by IO min of reperfusion before the 30-min occlusion period. 5-HD (5 mglkg, i.v.) was injected 15 min before PC, or pharmacological PC induced by infusion of diazoxide (3.5 mglkg, 1 mllmin, i.v.) Infarct size was determined by triphenyl-tetrazolium chloride macrochemistry and expressed as a percent of the area at risk. Infarct size following 30 min ischemia was 35.1 * 9.9% (n=7). PC markedly limited myocardial infarct size (2.7 * 1.6%, n=7), and 5-HO did not abolish the protective effect (2.4 f 0.9%, n=8). Diazoxide infusion also significantly limited infarct size (14.6 * 7.4%, n=7) and this effect was blocked by 5HD (30.8 + 8.0%, n=7). These results indicate that opening mito y4Tp channels is cardioprotective in pig heart, but do not support the hypothesis that opening of y4Tp channels is critical for the endogenous protection afforded by PC.
LACK OF DYSTROPHIN IN MURINE SLOWTWITCH MUSCLE: ALTERED INTEGRATION BETWEEN MITOCHONDRIA AND ATPASES Evelin E. Seppet, Urmo Braun, Kalju Paju. Margus Eimre, Ehte Orlova, Lumme Kadaja. Sonata Trumbeckaite, Frank N. Gellerich, Stephan Zierz E Enn K. Seppet. Dept of Pathophysiology. University of Tartu. Estonia & Clinic of Neurology, Martin Luther University, HallelSaale, Germany. Mitochondrial function in skinned muscle fibers from dystrophin-deficient (MDXj and wild-type mice was compared. In the myocardium and m. soleus of the MDX mice the coupling of mi-CK to adenine nucleotide translocase was attenuated (decreased effect of creatine on Km for ADP in the reactions of oxidative phosphorylation). In m. soleus, low Km for ADP compared to wild-type counterpart was found that implies increased permeability for ADP across the mitochondrial outer membrane. In normal cardiac fibers 35% of the ADP flux generated by ATPases was not accessible to external ADP -trapping system, which suggests the compartmentalized (direct j channeling of that fraction of ADP to mitochondria. Compared to control. the direct ADP transfer was increased in MDX ventricles. In conclusion, in slow-twitch muscle cells the absence of dystrophin results in rearrangement of the energy and feedback signal transfer systems between mitochondria and ATPases.
A108
Emmanuelle Sentex, Weihua Zhang, Xi Wang & Naranjan S. Dhalla. Institute of Cardiovascular Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. Recent studies have pointed out the role of extracellular signal-regulated kinase (ERK), a member of the mitogenactivated family, as pro- and anti-hypertrophic agent. Since no data are available concerning the status of ERK in cardiac hypertrophy and heart failure due to volume overload, this work investigated changes in ERK1/2 activities and contents in the left and right ventricles (LV, RV) at 2 to 16 wk after the induction of aortocaval shunt (AVS) in rats. Volume overload induced a 45% and 150% increase in cardiac mass after 4 wk and 16 wk in the AVS group. Hemodynamic data showed that cardiac hypertrophy evolve from a compensated stage before 8 wk to a decompensated stage after this point. In the LV, ERK activities were increased by 30,150 and 60% at 4,8 and 16 wk, respectively; the higher activities were associated with an increase in phosphorylated ERKl/2 content. No change in ERK1/2 activities or contents was observed in the RV. These results suggest that an increase in the ERKlR in the LV may be involved in the development of heart failure. (Supported by ClHR Group in Experimental Cardiology)
PRESCRIBING PATTERN OF CALCIUM CHANNEL BLOCKERS BY PRIMARY CARE PHYSICIANS IN BAHRAIN. Reginald P. Sequeira, Khalid A.J. Al Khaja & Vijay S. Mathur. Department of Pharmacology & Therapeutics, Arabian Gulf University, Bahrain. Concern has recently been expressed about the longterm safety of short-acting dihydropyridine calcium channel blockers (CCBs), such as nifedipine, in the management of hypertension. The goal of present study was to determine the extent of CCBs use as antihypertcnsives by primary care physicians in 7 out of 18 Health Centres in Bahrain. A prescription audit showed that: (a) of the 3838 patients with uncomplicated hypertension, 62.9% were treated with a single antihypertensive drug. Among 11.1% treated with a CCB, 5.4% were on short-acting nifedipine; (b) in 432 elderly hypertensives, 20.1% were treated with CCB alone: approximately half of these with a short acting nifedipine; and (c) in 1463 type 2 diabetichypertensives, 17.9% were treated with CCB alone; 8.2% of these were on short-acting nifedipine. Nondihydropyridine CCBs (diltiazem) were rarely used. The tendency tc prescribe short-acting nifedipine as monodmg therapy for hypertension does not conform with International guidelines for the management of hypertension, and should be discouraged.