A hospital at home case report: Prolonged amphotericin B therapy via elastomeric pump.

PURPOSE: Hospital at home is an alternative means of providing inpatient care for a patient requiring prolonged liposomal amphotericin B therapy. SUMMARY: Hospital at home is a unique care model that allows patients to receive inpatient hospital care within the comfort of their home and can be seen as an alternative care site for patients with complex treatment regimens that may require prolonged hospitalization. Hospital systems have increasingly begun incorporating hospital at home programs into their inpatient service lines. We present the case of a patient with disseminated histoplasmosis requiring a prolonged course of intravenous liposomal amphotericin B therapy. Because of the complex administration and stability of this medication, care is often provided in an inpatient setting. The Vanderbilt University Medical Center Hospital at Home team was able to coordinate resources and services to allow for this patient to receive acute hospital care at home and continue to receive amphotericin B infusion. CONCLUSION: This experience spotlights how hospital at home can be considered for patients requiring ongoing inpatient care for prolonged intravenous treatment courses.

Correlation analysis of Shiga toxin-producing Escherichia coli shedding and faecal bacterial composition in beef cattle.

AIMS: The objectives of this study were to investigate the correlations between Shiga toxin-producing Escherichia coli (STEC) shedding and faecal microflora in beef cattle and to identify functional species that might be used for STEC control. METHODS AND RESULTS: Faecal samples were collected from 110 calves and 92 dams. The number and prevalence of STEC were determined using CHROMagar™ STEC; denaturing gradient gel electrophoresis (DGGE) was employed to analyse faecal bacterial composition. Six-month-old calves had the highest STEC shedding levels (3.03 ± 1.41 Log CFU g(-1)) and prevalence (95.5%). Both the number and prevalence decreased significantly as the calf age increased (P < 0.05). The DGGE analysis showed that faecal bacterial diversity increased, while cattle ages increased and STEC shedding levels decreased. Significant correlations between STEC shedding, cattle age and bacterial compositions were observed by redundancy analysis (P < 0.05). T-value biplots and sequencing results indicated that butyrate-producing bacteria (BPB) negatively correlated with STEC shedding. CONCLUSIONS: Higher STEC shedding levels and prevalence were associated with younger cattle age, lower faecal bacterial diversity and lower BPB levels. SIGNIFICANCE AND IMPACT OF THE STUDY: Butyrate-producing bacteria in GI tract might serve as an option for the future development of STEC shedding control strategy.

Age, cell signalling and cardioprotection.

For many years investigators have been researching methods of preconditioning the myocardium against ischaemia-induced damage; however, a majority of this research has been carried out in young animals and cells. Normal ageing is accompanied by changes in the human myocardium that decrease its capacity to tolerate and respond to various forms of stress. Also, the likelihood of experiencing an ischaemic stress and other cardiovascular complications increases as an individual ages; therefore, an aged population would benefit most from cardioprotective treatments. Methods currently known to provide cardioprotection (or preconditioning) include exercise, heat stress, oxidative stress, brief ischaemia, stretch and certain pharmacological interventions. It is unclear whether the aged myocardium can adapt to a preconditioning stimulus; however, many researchers have observed age-related alterations in the expression and activation of proteins key to the cardioprotective process. These proteins include heat shock protein 70 (HSP70), nitric oxide synthase (NOS), the sodium-hydrogen exchanger (NHE), and the mitogen-activated protein (MAP) kinases c-Jun N-terminal Kinase (JNK), extracellular signal-regulated kinase (ERK), and p38. Therefore, the purpose of the current review will be to outline the current knowledge of these cardioprotective agents in an aged myocardium. Interactions among the cardioprotective agents outlined herein suggest that age-related changes in the myocardium will need to be better understood before cardioprotective interventions that have been proved effective in young animals can be applied to an aged human population.

Effects of body temperature during exercise training on myocardial adaptations.

This study determined the role of body temperature during chronic exercise on myocardial stress proteins and antioxidant enzymes as well as functional recovery after an ischemic insult. Male Sprague-Dawley rats were exercised for 3, 6, or 9 wk in a 23 degrees C room (3WK, 6WK, and 9WK, respectively) or in a 4-8 degrees C environment with wetted fur (3WKC, 6WKC, and 9WKC, respectively). The colder room prevented elevations in core temperature. During weeks 3-9 the animals ran 5 days/wk up a 6% grade at 20 m/min for 60 min. Myocardial heat shock protein 70 (HSP 70) increased 12.3-fold (P < 0.05) in 9WK versus sedentary (SED) rats but was unchanged in the cold-room runners. Compared with SED rats, alphaB-crystallin was 90% higher in 9WKC animals, HSP 90 was 50% higher in 3WKC and 6WKC animals, and catalase was 23% higher in 3WK animals (P < 0.05 for all). Cytosolic superoxide dismutase increased and mitochondrial SOD decreased (P < 0.05) in 3WK and 6WK rats compared with 3WKC and 6WKC rats. Antioxidant enzymes returned to SED values in all runners by 9 wk. No differences were observed among any of the groups for glucose-regulated protein 75, heme oxygenase-1, or glutathione peroxidase. Mechanical recovery of isolated working hearts after 22.5 min of global ischemia was enhanced in 9WK (P < 0.05) but not in 9WKC rats. We conclude that exercise training results in dynamic changes in cardioprotective proteins over time which are influenced by core temperature. In addition, cardioprotection resulting from chronic exercise appears to be due to increased HSP 70.

Exogenous GSH protection during hypoxia-reoxygenation of the isolated rat heart: impact of hypoxia duration.

The objective of this study was to determine the interaction between duration of myocardial hypoxia and presence of exogenous glutathione (GSH) on functional recovery upon subsequent reoxygenation. Isolated perfused rat hearts were subjected to 20, 30, 40, or 50 min hypoxia (HYP), which resulted in a progressive decline in the amount of contractile recovery (% of normoxic rate-pressure product (RPP) and developed pressure) during 30 min reoxygenation. Supplementation with 5 mM GSH throughout normoxia, hypoxia, and reoxygenation significantly improved contractile recovery during reoxygenation after 20 and 30 min hypoxia (p < 0.05), but had no effect after longer durations of hypoxia when contractile recovery was typically below 40% of RPP and significant areas of no-reflow were observed. ECG analysis revealed that GSH shifted the bell-shaped curve for reperfusion ventricular fibrillation to the right resulting in attenuated fibrillation after 20 and 30 min hypoxia then increased incidences after 40 min when Control hearts were slow to resume electrical activity. ECG conduction velocity was well preserved in all hearts after 20 and 30 min hypoxia, but GSH administration significantly attenuated the decline that occurred with longer durations. GSH supplementation did not attenuate the 35% decline in intracellular thiols during 30 min of hypoxia. When 5 mM GSH was added only during 40 min of hypoxia, RPP recovery after reoxygenation was improved compared to unsupplemented Controls (73% vs. 55% of pre-hypoxia value, p < 0.05). Administration of GSH only during reoxygenation following 40 min of hypoxia did not alter RPP recovery compared to Control hearts. We conclude that cardioprotection by exogenous GSH is dependent on the duration of hypoxia and the functional parameter being evaluated. It is not due to an enhancement of intracellular GSH suggesting that exogenous GSH acts extracellularly to protect sarcolemmal proteins against thiol oxidation during the phase of hypoxia when oxidative stress is a major contributor to cardiac dysfunction. Furthermore, if enough damage accrues during oxygen deprivation, supplementing with GSH during reoxygenation will not impact recovery.

Neutrophilic myeloperoxidase-macrophage interactions perpetuate chronic inflammation associated with experimental arthritis.

Rheumatoid arthritis is a systemic disease of unknown etiology. The purpose of this study was to elucidate an unrecognized interaction between neutrophilic myeloperoxidase (MPO) and macrophages (Mphi) which could perpetuate the inflammatory response associated with arthritis. A monoarticular arthritis was induced by intra-articular injection of group A streptococcus cell wall fragments (PG-APS) into the ankle joint of female Lewis rats. After swelling/erythema subsided, joints were reinjected with either recombinant MPO or enzymatically inactive MPO (iMPO). Joint measurements were made daily and arthritis was confirmed by histology. Neither iMPO nor MPO could initiate "clinical" arthritis; however, either form of the enzyme injected after PG-APS induced a dose-dependent increase in erythema and swelling. Mannans, which block the binding of MPO to Mo, ablated clinical symptoms. Also, the presence of tumor necrosis factor alpha was observed only in diseased joints using immunocytochemistry.

Acute exercise can improve cardioprotection without increasing heat shock protein content.

The aim of this study was to determine the effects of acute bouts of exercise on myocardial recovery after ischemia and heat shock protein expression. Adult female Sprague-Dawley rats were divided into five groups: 1) 1-day run (1DR; n = 6) and 2) 3-day run (3DR; n = 7), in which rats ran for 100 min at a speed of 20 m/min up a 6 degrees grade for 1 or 3 consecutive days; 3) 1-day cold run (1CR), in which rats ran the same as 1DR but with wet fur at 8 degrees C, which prevented an elevation of core temperature (n = 8); 4) heat shock sedentary (HS), in which rats had their core temperatures raised to 42 degrees C one time for 15 min (n = 5); and 5) sedentary control (n=15). Cardiac function was analyzed 24 h after the last treatment using an isolated, working heart model. Nonpaced hearts were initially perfused under normoxic conditions, then underwent 17 min of global, normothermic (37 degrees C) ischemia, and, finally, were allowed to recover for 30 min under normoxic conditions. The concentration of the 72-kDa heat shock protein (HSP 72) was measured in each left ventricle. Compared with that in the sedentary group, recovery of cardiac output x systolic pressure (CO x SP) was enhanced (P < 0.05) in all treatment groups when the postischemic value was covaried with the preischemic value. No differences in CO x SP were found (P > 0.05) between the following groups: 1DR vs. 3DR, 1DR vs. HS, and 1DR vs. 1CR. Heat shock protein concentration was significantly greater (P < 0.05) than that in the sedentary controls in HS, 1DR, and 3DR groups, but not for 1CR. The concentration of HSP 72 was not significantly correlated with postischemic CO x SP (R2 = 0.197, P > 0.05). We conclude that acute bouts of exercise can produce cardioprotective effects without an elevation of HSP 72.

Vitamin E concentration in rat skeletal muscle and liver after exercise.

The purpose of this study was to determine whether submaximal exercise significantly changes the concentration of vitamin E (alphaToc) in rat liver and skeletal muscle and to establish a time course for the return to basal levels. Male Sprague-Dawley rats, age 8 to 10 weeks, were randomly divided into sedentary control (Con) (n = 7) and exercise (n = 17) groups. Exercised animals ran 100 min on a motorized treadmill at approximately 70% VO2max for 3 consecutive days. They were then sacrificed immediately postexercise (0Post), 24 hr post (24Post), or 72 hr post (72Post). The gastrocnemius, red vastus lateralis (RV), white vastus lateralis (WV), and liver were excised and analyzed for alphaToc concentration by high-performance liquid chromotography utilizing electrochemical detection. We found that after 3 consecutive days of exercise, alphaToc was reduced in RV and WV at 0Post and 24Post but returned to control values by 72Post. Liver alphaToc content was not changed at 0Post but was significantly reduced at 24Post and 72Post. No significant changes in alphaToc were observed in the gastrocnemius in response to exercise. The data indicate that following an exercise-related decrease, skeletal muscle vitamin E concentration requires more than 24 hr to return to the preexercise concentration, and that the replenishment process may involve redistribution of vitamin E from liver to muscle.

Effects of chronic moderate and heavy ethanol consumption on myocardial recovery from ischemia.

The purpose of this study was to determine the effects of chronic moderate and heavy ethanol consumption on myocardial ischemia/ reperfusion injury. Three groups (n = 18) of 6-month-old female Sprague-Dawley rats were fed a nutritionally balanced liquid diet. Control, moderate alcohol, and heavy alcohol groups consumed 0%, 20%, and 35% of their calories from ethanol, respectively. After 10 weeks of feeding, hearts were isolated and subjected to 21.5 min of ischemia alone, or 21.5 min of ischemia followed by 30 min reperfusion. Hearts were evaluated for hemodynamic characteristics and high-energy phosphate content. Hearts from animals exposed to moderate and heavy amounts of ethanol recovered significantly less (30.61% and 29.45%, respectively) of their preischemic cardiac external work than control hearts (65.52%). Postischemic diastolic stiffness was increased approximately 7-fold, and high-energy phosphate content, both creatine phosphate and adenosine triphosphate, decreased >25% by both chronic moderate and heavy ethanol consumption. In conclusion, both chronic moderate and heavy ethanol consumption exacerbate myocardial ischemia/reperfusion injury. The ethanol-induced reduction in postischemic energy status may be the mechanism of increased diastolic stiffness and subsequent reduced cardiac external work.

Inhibition of tumor necrosis factor and subsequent endotoxin shock by pirfenidone.

Tumor necrosis factor-alpha (TNF) is an extremely potent cytokine which is involved in the pathogenesis of a number of diseases. Interruption of its synthesis can result in a reduction of inflammation and subsequent pathology. A new experimental drug pirfenidone (5-methyl-L-phenyl-2-(1H)-pyridone, trade name: Deskar) has been reported to have beneficial effects for the treatment of certain fibrotic diseases. The present study describes the inhibition of TNF in vitro as well as the inhibition of circulating TNF in vivo by pirfenidone. Isolated, thioglycollate-induced peritoneal macrophages (Mphi) from C57BL/6 mice were exposed to either lipopolysaccharide (LPS) or mannosylated bovine serum albumin then incubated with 0.1-0.9 mg/ml of pirfenidone. This substance inhibited the production of TNF in a dose-dependent manner as measured by ELISA. One i.p. injection of either 100 or 200 mg/kg pirfenidone inhibited the induction of circulating TNF following a single i.v. injection of LPS. Endotoxin shock was induced in mice using an i.p. injection of galactosamine and LPS. The higher dose of pirfenidone (200 mg/kg) completely inhibited shock and subsequent mortality. Lower doses of pirfenidone or administration either prior to or post challenge only partially inhibited symptoms. These results indicate that pirfenidone is able to inhibit both TNF induction and subsequent endotoxin shock. Additional studies are warranted to establish this drug as a potential treatment for diseases where TNF plays a major role.

Cosubstrates involved in the reduction of cytosolic glutathione disulfide in rat heart.

The functionality of glutathione (GSH), which is present in separate mitochondrial and cytosolic pools, hinges on a steady supply of reducing equivalents, provided by NADPH, to convert glutathione disulfide (GSSG) to GSH. It is believed traditionally that glucose 6-phosphate (G6-P) via the pentose phosphate pathway is the main cellular source of NADPH. The current study examined the ability of NADH- and NADPH-linked cosubstrates to support cardiac cytosolic GSSG reduction. Exogenous NADP+ was added to the incubation mixtures because of the loss of this nucleotide during homogenization. Exogenous GSSG was added to all samples to levels that were approximately 60% of total glutathione. In both the 500 x g (with mitochondria) and 10,000 x g (without mitochondria) rat heart supernatants, isocitrate supported reduction of approximately 90% of available GSSG within 10 min. Malate, pyruvate and palmitoyl carnitine did not support GSSG reduction in either supernatant. G6-P yielded GSH levels within 10 min equal to 77% of total glutathione in the 1,0000 x g supernatant and 47% in the 500 x g supernatant. The current data indicate: (1) The pentose phosphate pathway, alone, is less efficient than isocitrate at supplying reducing equivalents for cytosolic GSSG reduction; and (2) some confounding factor(s) occur in the 500 x g and reconstituted 500 x g supernatants whereby G6-P-supported GSSG reduction is attenuated.

Myocardial injury after hypoxia in immature, adult and aged rats.

We evaluated the abilities of isolated perfused hearts from immature (IM) (2.5-3 months), ADULT (11-13 months) and OLD (24-26 months) Fischer 344 rats to tolerate and recover from oxygen deprivation. Hearts were perfused at 60 mmHg for a 30-minute prehypoxic period with oxygenated buffer supplemented with 10 mM glucose (+insulin) and 2 mM acetate, then 30 minutes with substrate-free, hypoxic buffer gassed with 95% N2:5% CO2, and finally reoxygenated for an additional 45 minutes with the same buffer used during the prehypoxic period. During prehypoxia, all groups were similar in ventricular mechanical function, glycogen content, high-energy phosphates (HEP), reduced glutathione (GSH), Ca+2 content, and mitochondrial state 3 rates. At the end of the hypoxic period, glycogen levels were similar and almost completely depleted in all groups, HEP were lower (p < 0.05) in ADULT vs other groups, mitochondrial state 3 rates were decreased (24%, p < 0.05) only in ADULT, and GSH was depleted by 34% in IM vs only 13% in OLD (p < 0.05). After 45 minutes of reoxygenation, IM and OLD had recovered 48% and 45% of their respective prehypoxic function which was two-fold greater than the 23% recovery by ADULT. Loss of cytosolic enzymes, an indicator of sarcolemmal damage, was estimated by measuring lactate dehydrogenase (LDH) release. LDH release and Ca+2 content during reoxygenation in IM were only about half of that observed in ADULT or OLD. We conclude that immature and aged hearts tolerate and recover from hypoxia better than hearts from adults, and that the sarcolemmal membranes of immature rat hearts are less susceptible to damage from hypoxic stress than those of either older group.

Exogenous glutathione attenuates stunning following intermittent hypoxia in isolated rat hearts.

An isolated rat heart model of intermittent hypoxia was used to investigate the impact of exogenous supplementation of glutathione and two thiol delivery vehicles on functional recovery during reoxygenation and whether efficacy was dependent on enhanced intracellular thiol concentration. Hearts from F344 rats were perfused in the Langendorff mode and exposed to three, 5 minute bouts of global, substrate free, normothermic hypoxia separated by 5 minute reoxygenation periods. Changes in coronary flow, heart rate, systolic and diastolic pressure, and rate pressure product were evaluated throughout in control hearts and compared with hearts in which one of the following was provided during the hypoxic periods: reduced glutathione (GSH, 1 or 10 mM), 10 mM GSH mono-ethyl ester (GSHMEE), or 1 mM L-2-oxothiozolidine-4-carboxylate (OZT). After three hypoxic periods plus reoxygenation, rate pressure product in control hearts was approximately 60% of pre-hypoxic values. Exposing hearts to 1 or 10 mM GSH, 10 mM GSHMEE, or 1 mM OZT significantly (p < 0.05) enhanced post-hypoxic recovery of rate pressure product and attenuated the rise in diastolic pressure during hypoxia. This improvement in function was not associated with an elevated intracellular thiol concentration in treated hearts. Cumulative oxidative changes may occur during intermittent hypoxia via a mechanism localized on or near the sarcolemmal membrane. These changes appear to precede the appearance of significant intracellular oxidative stress and may be due to alterations in the reduced status of critical membrane bound proteins. Exogenously administered thiols attenuate protein alterations via a localized increase in thiol availability without an increase in gross measures of intracellular thiol or glutathione content.

Intrinsic myocardial function and oxidative stress after exhaustive exercise.

The purposes of this study were to determine the effect of an exhaustive running bout on intrinsic myocardial function by using the isolated working rat heart and to determine whether exhaustive exercise resulted in measurable oxidative stress in the myocardium. Untrained familiarized male rats were run at 18 m/min on a 0% grade until exhausted. Run time to exhaustion was approximately 75 min. Postexhaustion isolated heart measurements of cardiac output, rate-pressure product at low and high workloads, maximum left ventricular pressure, or 50-min performance at 85% of peak rate-pressure product were not different from those of nonexercised perfused control hearts. Exhaustive exercise resulted in a significant decline (174 vs. 224 nmol/g wet wt; P < 0.05) in nonprotein nonglutathione sulfhydryls, a thiol fraction indicative of oxidative stress. However, the magnitude of this measure of oxidative stress appears insufficient to cause alterations in intrinsic myocardial performance. We conclude that healthy untrained rats subjected to exhaustive exercise fail to demonstrate accumulation of a functionally significant level of myocardial oxidative stress.

Exercise training improves metabolic response after ischemia in isolated working rat heart.

Hearts from treadmill-trained and sedentary rats were perfused in the working heart mode. Mechanical and metabolite status was evaluated before ischemia, after 25 min of global ischemia, and after 30 min of retrograde reperfusion. After reperfusion, hearts from trained rats were found to have better recovery of contractile function, lower diastolic stiffness, greater efficiency of work, and greater extracellular calcium responsiveness than hearts from sedentary rats. Training had no significant impact on bioenergetic status before or at the end of ischemia. However, after reperfusion, both phosphocreatine and ATP were significantly higher in hearts from trained rats than from sedentary control rats. Mitochondrial function in both subsarcolemmal and intermyofibrillar subpopulations was unaffected by ischemia-reperfusion. 45Ca2+ uptake during reperfusion was significantly higher in hearts from sedentary rats than from exercise-trained rats. No differences were found in free radical production or tolerance due to training. Therefore, hearts from exercise-trained rats demonstrated an increased metabolic tolerance to ischemic-reperfusion damage, which may contribute to the improved postischemic functional recovery.

Introduction to respiratory control in skeletal muscle.

It is well known that a linear relationship exists for submaximum exercise intensity and oxygen consumption. Most of the increase in oxygen consumption is by skeletal muscle mitochondria for the purpose of producing enough ATP to match the energy needs of the muscle. The control of mitochondrial ATP production in muscle when workload is varied is a complex process and remains a very active area of research. Thus, the purpose of this symposium is to discuss the factors involved in the coupling between increases in work and increased oxygen consumption by muscle. The program will begin with a consideration of the challenges faced by skeletal muscle when attempting to meet its energy demands and the intracellular strategies that have evolved to optimize energy delivery. Next the major control theories for mitochondrial respiration will be discussed. Finally, experiments will be presented that are designed to determine which of these theories are best suited for specific skeletal muscle fiber types. It is hoped that the information presented will increase our awareness of different energy supply-demand strategies among fiber types and how supply-demand strategies are optimized by endurance training.

Exercise training improves cardiac function after ischemia in the isolated, working rat heart.

The aim of this study was to determine whether exercise training produces a myocardium intrinsically more tolerant to ischemic-reperfusion injury. Male Fischer 344 rats were treadmill trained for 11-16 wk at one of the following intensities: LOW (20 m/min, 0% grade, 60 min/day), moderate (MOD; 30 m/min, 5% grade, 60 min/day) or intensive (INT; 10 bouts of alternating 2-min runs at 16 and 60 m/min, 5% grade). Cardiac function was evaluated both before and after 25 min of global, zero-flow ischemia in the isolated, working heart model. Compared to hearts from sedentary (SED) rats, postischemic cardiac output (CO) and work were significantly higher in all trained groups. Percent recovery of CO (relative to preischemia) was 36.0 +/- 7.1 in SED and 61.2 +/- 6.5, 68.1 +/- 9.3, and 73.2 +/- 5.0 in LOW, MOD, and INT, respectively. Postischemic increases in stroke volume with increased preload and cardiac work at high work load were significantly higher in INT compared with SED. Coronary flow during initial retrograde reperfusion was significantly enhanced with training and correlated with subsequent recovery of CO (R2 = 0.613). Furthermore, trained hearts had higher phosphocreatine (P less than 0.05) and ATP (P less than 0.01) contents after 45 min reperfusion. It is concluded that exercise training results in an intrinsic myocardial adaptation, allowing greater recovery of cardiac pump function after global ischemia in the isolated rat heart.

Exogenous fructose-1,6-bisphosphate is a metabolizable substrate for the isolated normoxic rat heart.

Isolated rat hearts were perfused by the recirculating Langendorff mode under normoxic conditions for 60 min. The Krebs-Ringer buffer was supplemented with 10 mM glucose + 12 IU/l insulin and either [U-14C]-fructose-1,6-bisphosphate (together with 5 mM cold fructose-1,6-bisphosphate) or [U-14C]-fructose (together with 5 mM cold fructose). At the end of perfusion, gaseous 14CO2, 14CO2 trapped in the perfusates, 14C-lactate output and tissue 14C-lactate were assayed in both groups of hearts. Analysis of high-energy compounds, glycogen, lactate, and pyruvate was also performed on the neutralized perchloric acid extracts of the freeze-clamped hearts. Data obtained from the 14C catabolites, originating from the metabolism of the radiolabeled substrates, indicated that the isolated normoxic rat heart metabolizes an 8.5 times higher amount of fructose-1,6-bisphosphate (7.07 mumoles/min/g d.w.) than of fructose (0.83 mumoles/min/g d.w.). CrP, CrP/Cr, glycogen, and total lactate in both tissue and perfusate were significantly higher in fructose-1,6-bisphosphate-perfused hearts. The overall indication is that fructose-1,6-bisphosphate can be taken up in its intact form by myocytes and successively metabolized to support their energy demand, and that its effects on myocardial performance and metabolism should be attributed to the molecule itself rather than to its eventual degradation products.

Effect of perfusion pressure at reoxygenation on reflow and function in isolated rat hearts.

The effect of coronary perfusion pressure during reoxygenation on recovery of endocardial flow, arrhythmogenesis, and mechanical function was investigated in the isolated rat heart. Hearts were subjected to 30 min of substrate-free hypoxia followed by 30 min reoxygenation at either 80 or 150 cmH2O perfusion pressure. No flow areas were quantified by 0.3% phthalocyanine blue injection after 30 min of hypoxia, 30 min reoxygenation at 80 cmH2O, or 30 min reoxygenation at 150 cmH2O. After hypoxia, 31 +/- 2% of the myocardium was unperfused. After 80 cmH2O reoxygenation, 13 +/- 4% of the heart remained unperfused. Ten of 12 (83%) 80-cmH2O hearts were in sustained fibrillation after 10 min of reoxygenation. Reoxygenation at 150 cmH2O resulted in complete reperfusion of the myocardium. Fibrillation was absent in all hearts reoxygenated at this higher pressure. Functional recovery after 30 min reoxygenation (% of normoxic heart rate x left ventricular developed pressure) was significantly (P less than 0.05) higher in 150 cmH2O vs. 80 cmH2O (60 +/- 5 vs. 42 +/- 8%). Elevating perfusion pressure upon reoxygenation appears to counter the vascular compression caused by contracture and leads to a more rapid and homogeneous restoration of coronary flow during the transition from the hypoxic to the normoxic state.