Journal of Cardiovascular Pharmacology, Jul 1, 1999
The efficacy of the temporary oxygen carrier perflubron emulsion (PFC) in maintaining oxygen deli... more The efficacy of the temporary oxygen carrier perflubron emulsion (PFC) in maintaining oxygen delivery, tissue oxygenation, high-energy phosphates (HEPs), and myocardial function was investigated during low-flow ischemia. Perfusion rate, oxygen tensions, and cardiac function were measured during stabilization (5 min), controlled-flow (22 ml/min x 20 min), and low-flow (0.22 ml/min x 120 min) periods in isolated rabbit hearts. Hearts were perfused with Krebs-Henseleit (KH) solution (Control), or 10 or 20% PFC (vol/vol; n = 8 per group) 5 min before and throughout the low-flow period. Myocardial tissue was then frozen for biochemical and metabolic measurements. Myocardial oxygenation was measured at incremental flow rates by using 20% PFC (n = 4) or KH (n = 6). In PFC hearts, oxygen delivery and intramyocardial tissue Po2 were improved at all evaluated time points and flow rates, respectively (p < 0.05). In Control hearts, left ventricular end-diastolic pressure was elevated at 60, 90, and 120 min of low-flow ischemia (p < 0.05). Tissue lactate was higher (p < 0.05) and HEPs lower (p < 0.05) in Control hearts during low-flow ischemia. These results indicate that PFC treatment improves myocardial oxygenation, maintains HEPs, prevents ischemic contracture, and may increase the margin of safety during low-flow ischemia in isolated rabbit hearts.
The cardiovascular effects of acute aquatic (AE) and treadmill (TE) exercise were determined in u... more The cardiovascular effects of acute aquatic (AE) and treadmill (TE) exercise were determined in untrained adult male Sprague-Dawley rats. Animals were exercised to exhaustion or for a maximum of 5 min with either exercise mode and data collected during the last minute of exercise were compared to preexercise rest data. Heart rate and cardiac output increased only with TE; arterial pressure remained stable during both protocols. Regional blood flow was determined by the radioactive microsphere technique. Coronary flow increased only with TE. Skeletal muscle flow, determined in six muscle groups, increased more with TE (97 to 587%) than with AE (-44 to 260%) (flow in the quadriceps group decreased during AE). Flow to the skin and splanchnic regions decreased; cerebral flow increased in both groups. Blood gas data suggest lactic acidosis and hyperventilation only with TE. These data indicate that 1) the cardiovascular effects of acute, exhaustive bouts of AE and TE in the rat are not comparable, and 2) the hemodynamic changes occurring with exhaustive TE in rat, as in man, involve a shunting of blood to the regions of demand and away from the nonessential circulations.
Biomedical instrumentation & technology / Association for the Advancement of Medical Instrumentation
Partial Liquid Ventilation (PLV), a promising method for the treatment of acute lung failure, has... more Partial Liquid Ventilation (PLV), a promising method for the treatment of acute lung failure, has been evaluated in many animal studies. It has recently progressed to the point of controlled clinical trials in which patients of all ages on conventional mechanical ventilation (CMV) have their lungs substantially filled with a perfluorochemical (PFC) liquid, perflubron (PFB). During PLV, it is desirable to both maintain humidification and minimize the evaporation of PFB in order to maintain a desired dose in the lung and to reduce dose consumption and redosing effort. Heat-and-moisture exchangers (HMEs) have been used for years as a passive means of minimizing water vapor loss from the respiratory tract during CMV support of intensive care and surgical patients. In the current study, research was undertaken to leverage the operating principles of existing HMEs such that specialized "fluorophilic" HMEs (FHMEs), devices optimized for both water and PFB conservation, could be r...
Biomedical instrumentation & technology / Association for the Advancement of Medical Instrumentation
Patients undergoing Partial Liquid Ventilation (PLV) with the perfluorochemical liquid perflubron... more Patients undergoing Partial Liquid Ventilation (PLV) with the perfluorochemical liquid perflubron (PFB) continuously evaporate the drug from the lung during ventilatory expiration. In this study, two infrared (IR) devices, a modified industrial analyzer ("experimental prototype") and a custom-designed device suitable for use in a clinical environment ("clinical prototype"), were calibrated and validated on the bench to measure a range of PFB concentrations (CPFB) in a gas stream. PFB loss from the lung (area under the CPFB-vs-time-curve) could be correlated during PLV simulation with changes in tidal volume, breathing rate, and variable CPFB-vs-time profiles. The two IR devices produced nearly identical measurements for the same CPFB standards (maximum deviation = 1.5%). The experimental IR prototype was tested in 17 anesthetized, paralyzed, and ventilated swine (42-53 kg) to quantify the total amount and rate of evaporate loss of PFB over 12 hours of PLV, both w...
Journal of Cardiovascular Pharmacology, Mar 1, 1988
The purpose of this study was to characterize the cardiocirculatory effects of bepridil hydrochlo... more The purpose of this study was to characterize the cardiocirculatory effects of bepridil hydrochloride (BP) in the normal, conscious rat. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive-microsphere technique was used to measure regional blood flow and cardiac output before (control) and during intravenous (i.v.) infusion of either BP at three dosage levels (3.0, 6.0, 12.0 mg/kg) or vehicle (VH) at infusion rates matching those of the BP protocol (0.0408 ml/min). The predominant effects of BP (cumulative dose = 9.0 mg/kg i.v.) in the conscious rat were reduced coronary vascular resistance and heart rate. BP showed selectivity for the coronary circulation since systemic vascular resistance was not significantly reduced until a cumulative i.v. dosage of 21.0 mg/kg was administered. BP had few effects on other regions of the peripheral circulation. BP (21 mg/kg) reduced blood flow and increased vascular resistance in the arterial circulations of four of six skeletal muscles studied although opposite effects occurred in two of six muscles studied. BP had no significant effect on blood flow or vascular resistance in the other major arterial circulations. The results of this study show that BP is a selective coronary vasodilator that also reduces the primary indices of myocardial oxygen demand. These results suggest that the clinical therapeutic antianginal efficacy of BP occurs through a combined effect to increase myocardial oxygen supply and to reduce myocardial oxygen demand.
The relative ability of acetylcholine and 5-hydroxytryptamine (5-HT) to contract the vascular smo... more The relative ability of acetylcholine and 5-hydroxytryptamine (5-HT) to contract the vascular smooth muscle of bovine ventricular coronary arteries by mobilizing extracellular calcium was investigated. Methysergide and atropine specifically inhibited contractions to 5-HT and acetylcholine, respectively. Acetylcholine produced a sustained increase in calcium influx and a relatively sustained contraction. Contractions produced by 5-HT have previously been shown to be more transient than those by acetylcholine, and 5-HT increases calcium influx only transiently. The contraction produced by acetylcholine, but not that produced by 5-HT, was inhibited by 1 microM diltiazem to a level not different from that produced in Ca-free physiological saline solution. Verapamil at 0.1 microM did not inhibit an acetylcholine contraction. Steady-state tension produced by KCl was greatly inhibited by 1 microM diltiazem and 0.1 microM verapamil. Force produced in a calcium-free medium by acetylcholine and 5-HT was not additive. After depletion of the agonist-releasable intracellular calcium pool, however, force produced by acetylcholine plus 5-HT in the presence of extracellular calcium was additive. Likewise, calcium influx produced by both agents together was significantly greater than that produced by either agent alone. These results suggest that, in the smooth muscle of bovine ventricular coronary arteries, 5-HT and acetylcholine do not operate the same calcium channels.
The purpose of this study was to determine the effects of the putative cerebral vasodilator, mefe... more The purpose of this study was to determine the effects of the putative cerebral vasodilator, mefenidil hydrochloride (MF), on cardiocirculatory dynamics and the total distribution of cardiac output in the conscious rat. The radioactive microsphere technique was used to measure regional blood flow and cardiac output before (control) and during intravenous infusion of either MF (2.5, 5.0, 10.0 mg/kg) or vehicle (VH; saline, 0.0204, 0.0408. 0.0816 ml/min, respectively). Neither MF nor VH were found to have significant effects on cerebral blood flow or vascular resistance in conscious rats. MF significantly increased cerebral blood flow and lowered cerebral vascular resistance compared to VH in anesthetized animals without having significant effects in other circulatory regions.
American Journal of Physiology-heart and Circulatory Physiology, Sep 1, 1985
Calcium (Ca) influx in vascular smooth muscle is routinely measured in untethered preparations no... more Calcium (Ca) influx in vascular smooth muscle is routinely measured in untethered preparations not under passive stretch, and Ca influx data are correlated with data for steady-state isometric tension obtained under parallel conditions from tethered preparations under passive stretch. The validity of this method was tested by simultaneous measurement of Ca influx and tension in tethered rings of rabbit thoracic aorta. Ca influx (45Ca 3-min pulse) and tension were measured at 3 and 30 min after norepinephrine (NE) or KCl and under control (no agonist) conditions. Active tension was significantly altered by variations in passive tension. Ca influx was unaffected by passive tension under control, NE, or KCl conditions, and results were similar at 3 and 30 min. The results confirm the validity of correlating Ca influx data from untethered rings with steady-state contractile response data obtained from tethered rings under similar experimental conditions.
The Journal of pharmacology and experimental therapeutics, 1985
The effects of the new calcium blocker (CAB), bepridil hydrochloride (BP), on calcium influx and ... more The effects of the new calcium blocker (CAB), bepridil hydrochloride (BP), on calcium influx and isometric tension development resulting from activation of both the potential-dependent (60 mM KCl) and the receptor-operated (10 microM norepinephrine) calcium channel were studied in rings of rabbit thoracic aorta. BP was compared to nifedipine (NF), verapamil hydrochloride (VP) and diltiazem hydrochloride (DZ). The effects of the CABs were compared to those of alpha-1 adrenergic receptor blocker, prazosin (0.01, 0.1 and 10.0 microM), and to those of the inorganic nonspecific calcium channel blocker, lanthanum chloride (0.1, 1.0 and 5.0 mM). All organic CABs tested between 0.1 and 10.0 microM significantly inhibited potential-dependent activity with respect to both calcium influx and development of isometric tension (NF greater than BP = VP greater than DZ). However, only BP additionally inhibited both aspects of receptor-operated activity in a concentration-dependent fashion. In an is...
Journal of Cardiovascular Pharmacology, Jul 1, 1999
The efficacy of the temporary oxygen carrier perflubron emulsion (PFC) in maintaining oxygen deli... more The efficacy of the temporary oxygen carrier perflubron emulsion (PFC) in maintaining oxygen delivery, tissue oxygenation, high-energy phosphates (HEPs), and myocardial function was investigated during low-flow ischemia. Perfusion rate, oxygen tensions, and cardiac function were measured during stabilization (5 min), controlled-flow (22 ml/min x 20 min), and low-flow (0.22 ml/min x 120 min) periods in isolated rabbit hearts. Hearts were perfused with Krebs-Henseleit (KH) solution (Control), or 10 or 20% PFC (vol/vol; n = 8 per group) 5 min before and throughout the low-flow period. Myocardial tissue was then frozen for biochemical and metabolic measurements. Myocardial oxygenation was measured at incremental flow rates by using 20% PFC (n = 4) or KH (n = 6). In PFC hearts, oxygen delivery and intramyocardial tissue Po2 were improved at all evaluated time points and flow rates, respectively (p < 0.05). In Control hearts, left ventricular end-diastolic pressure was elevated at 60, 90, and 120 min of low-flow ischemia (p < 0.05). Tissue lactate was higher (p < 0.05) and HEPs lower (p < 0.05) in Control hearts during low-flow ischemia. These results indicate that PFC treatment improves myocardial oxygenation, maintains HEPs, prevents ischemic contracture, and may increase the margin of safety during low-flow ischemia in isolated rabbit hearts.
The cardiovascular effects of acute aquatic (AE) and treadmill (TE) exercise were determined in u... more The cardiovascular effects of acute aquatic (AE) and treadmill (TE) exercise were determined in untrained adult male Sprague-Dawley rats. Animals were exercised to exhaustion or for a maximum of 5 min with either exercise mode and data collected during the last minute of exercise were compared to preexercise rest data. Heart rate and cardiac output increased only with TE; arterial pressure remained stable during both protocols. Regional blood flow was determined by the radioactive microsphere technique. Coronary flow increased only with TE. Skeletal muscle flow, determined in six muscle groups, increased more with TE (97 to 587%) than with AE (-44 to 260%) (flow in the quadriceps group decreased during AE). Flow to the skin and splanchnic regions decreased; cerebral flow increased in both groups. Blood gas data suggest lactic acidosis and hyperventilation only with TE. These data indicate that 1) the cardiovascular effects of acute, exhaustive bouts of AE and TE in the rat are not comparable, and 2) the hemodynamic changes occurring with exhaustive TE in rat, as in man, involve a shunting of blood to the regions of demand and away from the nonessential circulations.
Biomedical instrumentation & technology / Association for the Advancement of Medical Instrumentation
Partial Liquid Ventilation (PLV), a promising method for the treatment of acute lung failure, has... more Partial Liquid Ventilation (PLV), a promising method for the treatment of acute lung failure, has been evaluated in many animal studies. It has recently progressed to the point of controlled clinical trials in which patients of all ages on conventional mechanical ventilation (CMV) have their lungs substantially filled with a perfluorochemical (PFC) liquid, perflubron (PFB). During PLV, it is desirable to both maintain humidification and minimize the evaporation of PFB in order to maintain a desired dose in the lung and to reduce dose consumption and redosing effort. Heat-and-moisture exchangers (HMEs) have been used for years as a passive means of minimizing water vapor loss from the respiratory tract during CMV support of intensive care and surgical patients. In the current study, research was undertaken to leverage the operating principles of existing HMEs such that specialized "fluorophilic" HMEs (FHMEs), devices optimized for both water and PFB conservation, could be r...
Biomedical instrumentation & technology / Association for the Advancement of Medical Instrumentation
Patients undergoing Partial Liquid Ventilation (PLV) with the perfluorochemical liquid perflubron... more Patients undergoing Partial Liquid Ventilation (PLV) with the perfluorochemical liquid perflubron (PFB) continuously evaporate the drug from the lung during ventilatory expiration. In this study, two infrared (IR) devices, a modified industrial analyzer ("experimental prototype") and a custom-designed device suitable for use in a clinical environment ("clinical prototype"), were calibrated and validated on the bench to measure a range of PFB concentrations (CPFB) in a gas stream. PFB loss from the lung (area under the CPFB-vs-time-curve) could be correlated during PLV simulation with changes in tidal volume, breathing rate, and variable CPFB-vs-time profiles. The two IR devices produced nearly identical measurements for the same CPFB standards (maximum deviation = 1.5%). The experimental IR prototype was tested in 17 anesthetized, paralyzed, and ventilated swine (42-53 kg) to quantify the total amount and rate of evaporate loss of PFB over 12 hours of PLV, both w...
Journal of Cardiovascular Pharmacology, Mar 1, 1988
The purpose of this study was to characterize the cardiocirculatory effects of bepridil hydrochlo... more The purpose of this study was to characterize the cardiocirculatory effects of bepridil hydrochloride (BP) in the normal, conscious rat. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive-microsphere technique was used to measure regional blood flow and cardiac output before (control) and during intravenous (i.v.) infusion of either BP at three dosage levels (3.0, 6.0, 12.0 mg/kg) or vehicle (VH) at infusion rates matching those of the BP protocol (0.0408 ml/min). The predominant effects of BP (cumulative dose = 9.0 mg/kg i.v.) in the conscious rat were reduced coronary vascular resistance and heart rate. BP showed selectivity for the coronary circulation since systemic vascular resistance was not significantly reduced until a cumulative i.v. dosage of 21.0 mg/kg was administered. BP had few effects on other regions of the peripheral circulation. BP (21 mg/kg) reduced blood flow and increased vascular resistance in the arterial circulations of four of six skeletal muscles studied although opposite effects occurred in two of six muscles studied. BP had no significant effect on blood flow or vascular resistance in the other major arterial circulations. The results of this study show that BP is a selective coronary vasodilator that also reduces the primary indices of myocardial oxygen demand. These results suggest that the clinical therapeutic antianginal efficacy of BP occurs through a combined effect to increase myocardial oxygen supply and to reduce myocardial oxygen demand.
The relative ability of acetylcholine and 5-hydroxytryptamine (5-HT) to contract the vascular smo... more The relative ability of acetylcholine and 5-hydroxytryptamine (5-HT) to contract the vascular smooth muscle of bovine ventricular coronary arteries by mobilizing extracellular calcium was investigated. Methysergide and atropine specifically inhibited contractions to 5-HT and acetylcholine, respectively. Acetylcholine produced a sustained increase in calcium influx and a relatively sustained contraction. Contractions produced by 5-HT have previously been shown to be more transient than those by acetylcholine, and 5-HT increases calcium influx only transiently. The contraction produced by acetylcholine, but not that produced by 5-HT, was inhibited by 1 microM diltiazem to a level not different from that produced in Ca-free physiological saline solution. Verapamil at 0.1 microM did not inhibit an acetylcholine contraction. Steady-state tension produced by KCl was greatly inhibited by 1 microM diltiazem and 0.1 microM verapamil. Force produced in a calcium-free medium by acetylcholine and 5-HT was not additive. After depletion of the agonist-releasable intracellular calcium pool, however, force produced by acetylcholine plus 5-HT in the presence of extracellular calcium was additive. Likewise, calcium influx produced by both agents together was significantly greater than that produced by either agent alone. These results suggest that, in the smooth muscle of bovine ventricular coronary arteries, 5-HT and acetylcholine do not operate the same calcium channels.
The purpose of this study was to determine the effects of the putative cerebral vasodilator, mefe... more The purpose of this study was to determine the effects of the putative cerebral vasodilator, mefenidil hydrochloride (MF), on cardiocirculatory dynamics and the total distribution of cardiac output in the conscious rat. The radioactive microsphere technique was used to measure regional blood flow and cardiac output before (control) and during intravenous infusion of either MF (2.5, 5.0, 10.0 mg/kg) or vehicle (VH; saline, 0.0204, 0.0408. 0.0816 ml/min, respectively). Neither MF nor VH were found to have significant effects on cerebral blood flow or vascular resistance in conscious rats. MF significantly increased cerebral blood flow and lowered cerebral vascular resistance compared to VH in anesthetized animals without having significant effects in other circulatory regions.
American Journal of Physiology-heart and Circulatory Physiology, Sep 1, 1985
Calcium (Ca) influx in vascular smooth muscle is routinely measured in untethered preparations no... more Calcium (Ca) influx in vascular smooth muscle is routinely measured in untethered preparations not under passive stretch, and Ca influx data are correlated with data for steady-state isometric tension obtained under parallel conditions from tethered preparations under passive stretch. The validity of this method was tested by simultaneous measurement of Ca influx and tension in tethered rings of rabbit thoracic aorta. Ca influx (45Ca 3-min pulse) and tension were measured at 3 and 30 min after norepinephrine (NE) or KCl and under control (no agonist) conditions. Active tension was significantly altered by variations in passive tension. Ca influx was unaffected by passive tension under control, NE, or KCl conditions, and results were similar at 3 and 30 min. The results confirm the validity of correlating Ca influx data from untethered rings with steady-state contractile response data obtained from tethered rings under similar experimental conditions.
The Journal of pharmacology and experimental therapeutics, 1985
The effects of the new calcium blocker (CAB), bepridil hydrochloride (BP), on calcium influx and ... more The effects of the new calcium blocker (CAB), bepridil hydrochloride (BP), on calcium influx and isometric tension development resulting from activation of both the potential-dependent (60 mM KCl) and the receptor-operated (10 microM norepinephrine) calcium channel were studied in rings of rabbit thoracic aorta. BP was compared to nifedipine (NF), verapamil hydrochloride (VP) and diltiazem hydrochloride (DZ). The effects of the CABs were compared to those of alpha-1 adrenergic receptor blocker, prazosin (0.01, 0.1 and 10.0 microM), and to those of the inorganic nonspecific calcium channel blocker, lanthanum chloride (0.1, 1.0 and 5.0 mM). All organic CABs tested between 0.1 and 10.0 microM significantly inhibited potential-dependent activity with respect to both calcium influx and development of isometric tension (NF greater than BP = VP greater than DZ). However, only BP additionally inhibited both aspects of receptor-operated activity in a concentration-dependent fashion. In an is...
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