American Journal of Physiology - Heart and Circulatory Physiology, 2003
Pharmacological preconditioning with κ-opioid receptor agonists is proarrhythmic and exerts antip... more Pharmacological preconditioning with κ-opioid receptor agonists is proarrhythmic and exerts antipreconditioning effects in rats. In swine, it is unknown whether κ-opioid receptor stimulation plays a role in pharmacological preconditioning. Swine were preconditioned with 1) saline (controls), 2) [d-Ala2,d-Leu5]enkephalin (DADLE), 3) morphine, 4) pentazocine, 5) norbinaltorphimine (nor-BNI), 6) DADLE + nor-BNI, 7) morphine + nor-BNI, or 8) pentazocine + nor-BNI before occlusion (45 min) and reperfusion (180 min) of the left anterior descending coronary artery. Infarct size to area at risk (IS), regional (systolic shortening) and global (pressures and flows) myocardial function, and arrhythmia occurrence were assessed. Only DADLE + nor-BNI preconditioning significantly decreased infarct size compared with controls (47 ± 13 vs. 65 ± 5%, P < 0.05); morphine preconditioning was not cardioprotective with or without κ-opioid receptor blockade (nor-BNI). DADLE preconditioning significantl...
A link between the cardioprotective benefits of pharmacological preconditioning and natural mamma... more A link between the cardioprotective benefits of pharmacological preconditioning and natural mammalian hibernation is considered to involve the cellular activation of opioid receptors and subsequent opening of K(ATP) channels. In previous studies, we have demonstrated the protective effects of specific delta-opioid agonists against porcine cardiac ischemia/reperfusion injury. We hypothesize here that preincubation with hibernation induction trigger (HIT) should confer a similar protection in skeletal muscles. Therefore, muscle bundles from swine were pretreated with plasma from hibernating woodchucks (HWP) for 30 min, then exposed to hypoxia for 90 min and reoxygenation for 120 min. Stimulated twitch forces were assessed. The functional effects of pretreatment with nonhibernation (summer) woodchuck plasma, a K(ATP) blocker, or opioid antagonist were also studied. During the reoxygenation period, significantly greater force recoveries were observed only for bundles pretreated with HWP; this response was blocked by naloxone (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;lt; 0.05). We conclude that HIT pretreatment could be used to confer protection against hypoxia/reperfusion injury of skeletal muscles of nonhibernators; it could potentially be utilized to prevent injury during surgical procedures requiring ischemia.
Sheng li xue bao : [Acta physiologica Sinica], Jan 25, 2007
Normal rhythm in a healthy human heart originates from the natural biological pacemaker, the sino... more Normal rhythm in a healthy human heart originates from the natural biological pacemaker, the sinoatrial (SA) node which locates in the right atrium. SA node dysfunction or atrial-ventricular (AV) conduction block causes improper heart rate (bradycardia). Such dysfunction, if severe enough, is currently treated by implanting an electronic pacemaker which has been well established technically, but there are some limitations and inadequacies. Recently, progress in developing engineered cardiac biopacemakers with use of genes or cells has been made in experimental animal models. The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channel (pacemaker channel) modulates cardiac automaticity via the hyperpolarization-activated cation current (I(f)). HCN genes have been delivered to animal myocardium via viral vectors or HCN-transferred cells for recreating biological pacemakers. Approaches with non-HCN genes or transplantation of beating cells are also novel and have been inve...
Handbook of Cardiac Anatomy, Physiology, and Devices, 2009
Page 1. Chapter 13 Cardiac and Vascular Receptors and Signal Transduction Daniel C. Sigg and Ayal... more Page 1. Chapter 13 Cardiac and Vascular Receptors and Signal Transduction Daniel C. Sigg and Ayala Hezi-Yamit Abstract Cellular physiological functions are regu-lated via signaling mechanisms in essentially any cell type of any organ. ...
Parametric instabilities have long been studied as a potentially limiting effect in high-power in... more Parametric instabilities have long been studied as a potentially limiting effect in high-power interferometric gravitational wave detectors. Until now, however, these instabilities have never been observed in a kilometer-scale interferometer. In this Letter, we describe the first observation of parametric instability in a gravitational wave detector, and the means by which it has been removed as a barrier to progress.
Proceedings of the National Academy of Sciences of the United States of America, Jan 23, 2014
Excitation-evoked Ca(2+) influx is the fastest and most ubiquitous chemical trigger for cellular ... more Excitation-evoked Ca(2+) influx is the fastest and most ubiquitous chemical trigger for cellular processes, including neurotransmitter release, muscle contraction, and gene expression. The voltage dependence and timing of Ca(2+) entry are thought to be functions of voltage-gated calcium (CaV) channels composed of a central pore regulated by four nonidentical voltage-sensing domains (VSDs I-IV). Currently, the individual voltage dependence and the contribution to pore opening of each VSD remain largely unknown. Using an optical approach (voltage-clamp fluorometry) to track the movement of the individual voltage sensors, we discovered that the four VSDs of CaV1.2 channels undergo voltage-evoked conformational rearrangements, each exhibiting distinct voltage- and time-dependent properties over a wide range of potentials and kinetics. The voltage dependence and fast kinetic components in the activation of VSDs II and III were compatible with the ionic current properties, suggesting that...
A decrease of 1-2 degrees C core temperature provides protection against cerebral ischemia. Howev... more A decrease of 1-2 degrees C core temperature provides protection against cerebral ischemia. However, shivering usually prevents reduction in core temperature in unanesthetized patients. Therefore, it was tested whether facial and airway heating increases the shivering threshold and enables core cooling in unanesthetized patients. Nine trials were performed on seven healthy male volunteers. Each subject was positioned supine on a circulating-water mattress (8-15 degrees C) with a convective-air coverlet (15-18 degrees C) extending from the neck to the feet. A dynamic study protocol governed by individualized physiological responses was used. Focal facial (and airway) warming was employed to suppress involuntary motor activity (muscle tensing, shivering) and, thereby, enabling noninvasive cooling to lower the core temperature. The following parameters were monitored: 1) heart rate, 2) blood pressure, 3) core temperature (tympanic, axilla, and rectal), 4) cutaneous temperatures, and 5) a subjective shiver index (scale 1-10). In three, electromyograms and infrared thermographs were also obtained. Upon cooling without facial and airway warming, involuntary motor activity increased until it was widespread. This vigorous motor activity prevented any significant lowering of core temperature or caused it to slightly increase. Subsequently, in all subjects, within seconds after the application of facial focal warming, motor activity was suppressed almost completely, and within minutes core temperatures significantly decreased. Preliminary studies described here indicate that focal facial warming applied during active whole body cooling to initiate mild hypothermia might minimize the need to pharmacologically suppress involuntary motor activity. Such a procedure might be useful for initiating as soon as possible (such as during emergency transport), cerebral mild hypothermia in order to maximize protection and thus improve outcome in neurologically injured patients (head trauma, stroke).
An in situ versus in vitro comparison of relative dose-dependent effects of halothane on cardiac ... more An in situ versus in vitro comparison of relative dose-dependent effects of halothane on cardiac performance was investigated, including ventricular systolic/diastolic function. Such comparative studies may be of interest to individuals working on heart failure models, cardiac device testing, or xenotransplantation. Normal swine (n=9) received halothane at levels of 0.25, 0.5 and 1 MAC (minimum alveolar concentration) for 30 min each. Parameters assessed included: 1) heart rate; 2) arterial blood pressure; 3) pulmonary artery, central venous, left and right ventricular pressures; 4) cardiac output; 5) end-expiratory CO(2) and halothane levels; 6) cardiac temperature; and 7) arterial blood gases. Hearts were removed using standard cardioplegic procedures and reperfused in four-chamber working mode (n=8); again the effects of increasing halothane concentrations on cardiac performance were analyzed. When comparing biventricular depressive effects (negative inotropic, negative lusitropic) of halothane in vivo and in vitro, there were distinct quantitative differences. The negative lusitropic effects were less pronounced in vitro; this was especially true for the right ventricle. Yet, in vitro, halothane at all doses induced more pronounced decreases in left heart output compared to the right. The large mammalian isolated four-chamber working heart model allows for novel assessment of pharmacodynamics and/or evaluation of cardiac devices under a range of hemodynamic performances. Halothane, a cardiodepressive agent, induced direct myocardial depressive effects in vitro similar to those recorded in vivo; hence additional systemic effects are considered to play a minor role in ultimate performances, e.g., compensatory responses due to autonomic controls.
Isolated mammalian hearts have been used in numerous studies that have led to many important disc... more Isolated mammalian hearts have been used in numerous studies that have led to many important discoveries in cardiac physiology, pharmacology, and surgery. Multiple methods of perfusion have been described including retrograde and/or antegrade flows and crystalloid or blood perfusates. Furthermore, multiple species have been utilized for such studies including the following: rat, rabbit, guinea pig, canine, and swine. The objective of this study was to describe a unique isolated heart preparation, utilizing human hearts not viable for transplant, which allows for physiologic perfusion and endocardial imaging. Utilizing standard cardiac transplantation procedures, 12 human hearts deemed not viable for transplant were explanted to an isolated heart apparatus. A clear, modified Krebs-Henseleit buffer was used as a blood substitute, which allowed for endocardial imaging utilizing 6.0 mm endoscopic video cameras inserted into the cardiac chambers. The hearts were perfused in Langendorff (retrograde) and/or working (physiologic) mode. Eleven of 12 hearts achieved the following performance in working mode: peak left ventricular pressure of 21.5 to 75.8 mm Hg, with an average of 42.7 +/- 19.9 mm Hg. Intracardiac anatomical imaging was possible in all hearts, providing unique views of normal and pathological endocardial anatomy as well as biomedical device-heart interactions. We have described a unique isolated heart preparation with which we have successfully reanimated 11 human hearts deemed not viable for transplant, perfused them by working mode, and performed intracardiac anatomical imaging. This approach provides a novel means for obtaining images of functional human cardiac anatomy and various types of unique biomedical assessments.
A decrease of 1 or 2 degrees C in core temperature may provide protection against cerebral ischem... more A decrease of 1 or 2 degrees C in core temperature may provide protection against cerebral ischemia. However, during corporeal cooling of unanesthetized patients, the initiation of involuntary motor activity (shiver) prevents the reduction of core temperature. The authors&#39; laboratory previously showed that focal facial warming suppressed whole-body shiver. The aim of the current study was to determine whether the use of hand warming alone could suppress shiver in unanesthetized subjects and hence potentiate core cooling. Subjects (n = 8; healthy men) were positioned supine on a circulating water mattress (8-15 degrees C) with a convective-air coverlet (14 degrees C) extending from their necks to their feet. A dynamic protocol was used in which focal hand warming was used to suppress involuntary motor activity, enabling noninvasive cooling to decrease core temperatures. The following parameters were monitored: (1) heart rate; (2) blood pressure; (3) core temperature (rectal, tympanic); (4) cutaneous temperature and heat flux; (5) subjective shiver level (SSL scale 0-10) and thermal comfort index (scale 0-10); (6) metabolic data (n = 6); and (7) electromyograms. During cooling without hand warming, involuntary motor activity increased until it was widespread. After subjects reported whole-body shiver (SSL &gt; or = 7), applied hand warming, in all cases, reduced shiver levels (SSL &lt; o r= 3), decreased electromyographic root mean square amplitudes, and allowed core temperature to decrease from 37.0 +/- 0.2 to 35.9 +/- 0.5 degrees C (measured rectally). Focal hand warming seems to be valuable in minimizing or eliminating the need to suppress involuntary motor activity pharmacologically when it is desired to induce or maintain mild hypothermia; it may be used in conjunction with facial warming or in cases in which facial warming is contraindicated.
American Journal of Physiology - Heart and Circulatory Physiology, 2003
Pharmacological preconditioning with κ-opioid receptor agonists is proarrhythmic and exerts antip... more Pharmacological preconditioning with κ-opioid receptor agonists is proarrhythmic and exerts antipreconditioning effects in rats. In swine, it is unknown whether κ-opioid receptor stimulation plays a role in pharmacological preconditioning. Swine were preconditioned with 1) saline (controls), 2) [d-Ala2,d-Leu5]enkephalin (DADLE), 3) morphine, 4) pentazocine, 5) norbinaltorphimine (nor-BNI), 6) DADLE + nor-BNI, 7) morphine + nor-BNI, or 8) pentazocine + nor-BNI before occlusion (45 min) and reperfusion (180 min) of the left anterior descending coronary artery. Infarct size to area at risk (IS), regional (systolic shortening) and global (pressures and flows) myocardial function, and arrhythmia occurrence were assessed. Only DADLE + nor-BNI preconditioning significantly decreased infarct size compared with controls (47 ± 13 vs. 65 ± 5%, P < 0.05); morphine preconditioning was not cardioprotective with or without κ-opioid receptor blockade (nor-BNI). DADLE preconditioning significantl...
A link between the cardioprotective benefits of pharmacological preconditioning and natural mamma... more A link between the cardioprotective benefits of pharmacological preconditioning and natural mammalian hibernation is considered to involve the cellular activation of opioid receptors and subsequent opening of K(ATP) channels. In previous studies, we have demonstrated the protective effects of specific delta-opioid agonists against porcine cardiac ischemia/reperfusion injury. We hypothesize here that preincubation with hibernation induction trigger (HIT) should confer a similar protection in skeletal muscles. Therefore, muscle bundles from swine were pretreated with plasma from hibernating woodchucks (HWP) for 30 min, then exposed to hypoxia for 90 min and reoxygenation for 120 min. Stimulated twitch forces were assessed. The functional effects of pretreatment with nonhibernation (summer) woodchuck plasma, a K(ATP) blocker, or opioid antagonist were also studied. During the reoxygenation period, significantly greater force recoveries were observed only for bundles pretreated with HWP; this response was blocked by naloxone (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;lt; 0.05). We conclude that HIT pretreatment could be used to confer protection against hypoxia/reperfusion injury of skeletal muscles of nonhibernators; it could potentially be utilized to prevent injury during surgical procedures requiring ischemia.
Sheng li xue bao : [Acta physiologica Sinica], Jan 25, 2007
Normal rhythm in a healthy human heart originates from the natural biological pacemaker, the sino... more Normal rhythm in a healthy human heart originates from the natural biological pacemaker, the sinoatrial (SA) node which locates in the right atrium. SA node dysfunction or atrial-ventricular (AV) conduction block causes improper heart rate (bradycardia). Such dysfunction, if severe enough, is currently treated by implanting an electronic pacemaker which has been well established technically, but there are some limitations and inadequacies. Recently, progress in developing engineered cardiac biopacemakers with use of genes or cells has been made in experimental animal models. The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channel (pacemaker channel) modulates cardiac automaticity via the hyperpolarization-activated cation current (I(f)). HCN genes have been delivered to animal myocardium via viral vectors or HCN-transferred cells for recreating biological pacemakers. Approaches with non-HCN genes or transplantation of beating cells are also novel and have been inve...
Handbook of Cardiac Anatomy, Physiology, and Devices, 2009
Page 1. Chapter 13 Cardiac and Vascular Receptors and Signal Transduction Daniel C. Sigg and Ayal... more Page 1. Chapter 13 Cardiac and Vascular Receptors and Signal Transduction Daniel C. Sigg and Ayala Hezi-Yamit Abstract Cellular physiological functions are regu-lated via signaling mechanisms in essentially any cell type of any organ. ...
Parametric instabilities have long been studied as a potentially limiting effect in high-power in... more Parametric instabilities have long been studied as a potentially limiting effect in high-power interferometric gravitational wave detectors. Until now, however, these instabilities have never been observed in a kilometer-scale interferometer. In this Letter, we describe the first observation of parametric instability in a gravitational wave detector, and the means by which it has been removed as a barrier to progress.
Proceedings of the National Academy of Sciences of the United States of America, Jan 23, 2014
Excitation-evoked Ca(2+) influx is the fastest and most ubiquitous chemical trigger for cellular ... more Excitation-evoked Ca(2+) influx is the fastest and most ubiquitous chemical trigger for cellular processes, including neurotransmitter release, muscle contraction, and gene expression. The voltage dependence and timing of Ca(2+) entry are thought to be functions of voltage-gated calcium (CaV) channels composed of a central pore regulated by four nonidentical voltage-sensing domains (VSDs I-IV). Currently, the individual voltage dependence and the contribution to pore opening of each VSD remain largely unknown. Using an optical approach (voltage-clamp fluorometry) to track the movement of the individual voltage sensors, we discovered that the four VSDs of CaV1.2 channels undergo voltage-evoked conformational rearrangements, each exhibiting distinct voltage- and time-dependent properties over a wide range of potentials and kinetics. The voltage dependence and fast kinetic components in the activation of VSDs II and III were compatible with the ionic current properties, suggesting that...
A decrease of 1-2 degrees C core temperature provides protection against cerebral ischemia. Howev... more A decrease of 1-2 degrees C core temperature provides protection against cerebral ischemia. However, shivering usually prevents reduction in core temperature in unanesthetized patients. Therefore, it was tested whether facial and airway heating increases the shivering threshold and enables core cooling in unanesthetized patients. Nine trials were performed on seven healthy male volunteers. Each subject was positioned supine on a circulating-water mattress (8-15 degrees C) with a convective-air coverlet (15-18 degrees C) extending from the neck to the feet. A dynamic study protocol governed by individualized physiological responses was used. Focal facial (and airway) warming was employed to suppress involuntary motor activity (muscle tensing, shivering) and, thereby, enabling noninvasive cooling to lower the core temperature. The following parameters were monitored: 1) heart rate, 2) blood pressure, 3) core temperature (tympanic, axilla, and rectal), 4) cutaneous temperatures, and 5) a subjective shiver index (scale 1-10). In three, electromyograms and infrared thermographs were also obtained. Upon cooling without facial and airway warming, involuntary motor activity increased until it was widespread. This vigorous motor activity prevented any significant lowering of core temperature or caused it to slightly increase. Subsequently, in all subjects, within seconds after the application of facial focal warming, motor activity was suppressed almost completely, and within minutes core temperatures significantly decreased. Preliminary studies described here indicate that focal facial warming applied during active whole body cooling to initiate mild hypothermia might minimize the need to pharmacologically suppress involuntary motor activity. Such a procedure might be useful for initiating as soon as possible (such as during emergency transport), cerebral mild hypothermia in order to maximize protection and thus improve outcome in neurologically injured patients (head trauma, stroke).
An in situ versus in vitro comparison of relative dose-dependent effects of halothane on cardiac ... more An in situ versus in vitro comparison of relative dose-dependent effects of halothane on cardiac performance was investigated, including ventricular systolic/diastolic function. Such comparative studies may be of interest to individuals working on heart failure models, cardiac device testing, or xenotransplantation. Normal swine (n=9) received halothane at levels of 0.25, 0.5 and 1 MAC (minimum alveolar concentration) for 30 min each. Parameters assessed included: 1) heart rate; 2) arterial blood pressure; 3) pulmonary artery, central venous, left and right ventricular pressures; 4) cardiac output; 5) end-expiratory CO(2) and halothane levels; 6) cardiac temperature; and 7) arterial blood gases. Hearts were removed using standard cardioplegic procedures and reperfused in four-chamber working mode (n=8); again the effects of increasing halothane concentrations on cardiac performance were analyzed. When comparing biventricular depressive effects (negative inotropic, negative lusitropic) of halothane in vivo and in vitro, there were distinct quantitative differences. The negative lusitropic effects were less pronounced in vitro; this was especially true for the right ventricle. Yet, in vitro, halothane at all doses induced more pronounced decreases in left heart output compared to the right. The large mammalian isolated four-chamber working heart model allows for novel assessment of pharmacodynamics and/or evaluation of cardiac devices under a range of hemodynamic performances. Halothane, a cardiodepressive agent, induced direct myocardial depressive effects in vitro similar to those recorded in vivo; hence additional systemic effects are considered to play a minor role in ultimate performances, e.g., compensatory responses due to autonomic controls.
Isolated mammalian hearts have been used in numerous studies that have led to many important disc... more Isolated mammalian hearts have been used in numerous studies that have led to many important discoveries in cardiac physiology, pharmacology, and surgery. Multiple methods of perfusion have been described including retrograde and/or antegrade flows and crystalloid or blood perfusates. Furthermore, multiple species have been utilized for such studies including the following: rat, rabbit, guinea pig, canine, and swine. The objective of this study was to describe a unique isolated heart preparation, utilizing human hearts not viable for transplant, which allows for physiologic perfusion and endocardial imaging. Utilizing standard cardiac transplantation procedures, 12 human hearts deemed not viable for transplant were explanted to an isolated heart apparatus. A clear, modified Krebs-Henseleit buffer was used as a blood substitute, which allowed for endocardial imaging utilizing 6.0 mm endoscopic video cameras inserted into the cardiac chambers. The hearts were perfused in Langendorff (retrograde) and/or working (physiologic) mode. Eleven of 12 hearts achieved the following performance in working mode: peak left ventricular pressure of 21.5 to 75.8 mm Hg, with an average of 42.7 +/- 19.9 mm Hg. Intracardiac anatomical imaging was possible in all hearts, providing unique views of normal and pathological endocardial anatomy as well as biomedical device-heart interactions. We have described a unique isolated heart preparation with which we have successfully reanimated 11 human hearts deemed not viable for transplant, perfused them by working mode, and performed intracardiac anatomical imaging. This approach provides a novel means for obtaining images of functional human cardiac anatomy and various types of unique biomedical assessments.
A decrease of 1 or 2 degrees C in core temperature may provide protection against cerebral ischem... more A decrease of 1 or 2 degrees C in core temperature may provide protection against cerebral ischemia. However, during corporeal cooling of unanesthetized patients, the initiation of involuntary motor activity (shiver) prevents the reduction of core temperature. The authors&#39; laboratory previously showed that focal facial warming suppressed whole-body shiver. The aim of the current study was to determine whether the use of hand warming alone could suppress shiver in unanesthetized subjects and hence potentiate core cooling. Subjects (n = 8; healthy men) were positioned supine on a circulating water mattress (8-15 degrees C) with a convective-air coverlet (14 degrees C) extending from their necks to their feet. A dynamic protocol was used in which focal hand warming was used to suppress involuntary motor activity, enabling noninvasive cooling to decrease core temperatures. The following parameters were monitored: (1) heart rate; (2) blood pressure; (3) core temperature (rectal, tympanic); (4) cutaneous temperature and heat flux; (5) subjective shiver level (SSL scale 0-10) and thermal comfort index (scale 0-10); (6) metabolic data (n = 6); and (7) electromyograms. During cooling without hand warming, involuntary motor activity increased until it was widespread. After subjects reported whole-body shiver (SSL &gt; or = 7), applied hand warming, in all cases, reduced shiver levels (SSL &lt; o r= 3), decreased electromyographic root mean square amplitudes, and allowed core temperature to decrease from 37.0 +/- 0.2 to 35.9 +/- 0.5 degrees C (measured rectally). Focal hand warming seems to be valuable in minimizing or eliminating the need to suppress involuntary motor activity pharmacologically when it is desired to induce or maintain mild hypothermia; it may be used in conjunction with facial warming or in cases in which facial warming is contraindicated.
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