Nutrient and metal analyses of Chinese herbal products marketed for veterinary use.

Many Chinese herbs and herbal mixtures are fed to domestic animals for their reputed medicinal properties. These herbs could contribute to the intake of essential nutrients and toxic metals, but their composition is mostly unknown. The purpose of this study was to measure major nutrient (crude protein, crude fat, carbohydrate, fibre) and mineral (Ca, P, Mg, K, Na, Fe, Zn, Cu, Mn, Mo, S, Al, Cd, Ni, Pb) concentrations in samples of fourteen combination formulas labelled for veterinary use and commonly administered to horses and dogs. Three single herbs, Bupleurum chinense, Curcuma zedoaria and Astragalus membranaceus, each obtained from several sources, and Yunnan Baiyao, a proprietary hemostatic mixture, were also analysed. Proximate analyses and some mineral concentrations differed (p < 0.05) among single herbs, and high concentrations of several minerals were detected in some herbal combinations. Those containing the highest concentrations [g/kg dry matter (DM)] of calcium (92.4), iron (2.6) and manganese (0.28) could provide >38%, 142% and 96%, respectively, of recommended allowances in adult dogs, and >13%, 122% and 2%, respectively, of maintenance requirements in horses, at the maximum labelled dose assuming complete availability. Concentrations of cadmium, nickel and lead were below published oral tolerance levels. Aluminium concentrations (median 380, maximum 920 mg/kg DM) were higher than has been previously reported in Chinese herbs. These nutrient analyses suggest that herbal combinations marketed to veterinarians, when fed at the maximal labelled dose, are unlikely to produce clinically relevant changes in the dietary intake of essential nutrients. However, small amounts of non-essential contaminant minerals are present in some formulas, and further research is necessary to understand the significance of this finding.

The effect of capromorelin on glycemic control in healthy dogs.

Capromorelin is a ghrelin-receptor agonist widely used as an appetite stimulant in dogs. Capromorelin disrupts glucose homeostasis in cats but information regarding its effects on canine glucose homeostasis is lacking. The study objective was to evaluate the effect of capromorelin on glucose homeostatic mechanisms in healthy dogs. Eight clinically healthy client-owned adult dogs were enrolled in this prospective, cross-over, placebo-controlled study. Dogs were randomized to receive capromorelin (Entyce, 3 mg/kg) or placebo, q24h for 3 d. A wk later, treatments were crossed over. Interstitial glucose (IG) concentrations were measured using a flash glucose monitoring system throughout. On d 1 of each treatment, blood glucose (BG), insulin, glucagon, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide-1 (GLP-1) concentrations were measured before drug administration, then before and 30-120 min after feeding a glucose-rich diet (Ensure Plus, 21 kcal/kg). Data were analyzed as a 2-period crossover design using generalized least squares estimation. Capromorelin administration increased mean 48 h IG by10% and mean BG by 20% at 90 and 120 min post-prandially (P < 0.0001). Post-prandially, there was a time-by-treatment effect for insulin (P = 0.03) and GIP (P = 0.0002) because capromorelin doubled geometric mean insulin concentrations at 120 min and increased geometric mean GIP concentrations more rapidly than after placebo. There were no differences in glucagon or GLP-1 concentrations between treatment groups. The increase in post-prandial blood glucose was not the result of overt suppression of incretin hormone secretion. There was also no suppressive effect of capromorelin on insulin.

Dietary cation-anion difference may explain why ammonium urate nephrolithiasis occurs more frequently in common bottlenose dolphins () under human care than in free-ranging common bottlenose dolphins.

Ammonium urate nephrolithiasis frequently develops in common bottlenose dolphins () managed under human care but is rare in free-ranging common bottlenose dolphins. In other species, the dietary cation-anion difference (DCAD) can affect ammonium urate urolith formation by increasing proton excretion as ammonium ions. Therefore, differences in diet between the 2 dolphin populations could affect urolith formation, but the DCAD of most species consumed by free-ranging and managed dolphins is unknown. To compare the nutrient composition of diets consumed by free-ranging and managed bottlenose dolphins, samples ( = 5) of the 8 species of fish commonly consumed by free-ranging bottlenose dolphins in Sarasota Bay, FL, and the 7 species of fish and squid commonly fed to managed bottlenose dolphins were analyzed for nutrient content. Metabolizable energy was calculated using Atwater factors; the DCAD was calculated using 4 equations commonly used in people and animals that use different absorption coefficients. The nutrient composition of individual species was used to predict the DCAD of 2 model diets typically fed to managed common bottlenose dolphins and a model diet typically consumed by common bottlenose dolphins in Sarasota Bay. To mimic differences in postmortem handling of fish for the 2 populations of bottlenose dolphins, "free-ranging" samples were immediately frozen at -80°C and minimally thawed before analysis, whereas "managed" samples were frozen for 6 to 9 mo at -18°C and completely thawed. "Free-ranging" species contained more Ca and P and less Na and Cl than "managed" fish and squid species. As a consequence, the DCAD of both model managed dolphin diets obtained using 3 of the 4 equations was much more negative than the DCAD of the model free-ranging bottlenose dolphin diet ( < 0.05). The results imply that managed bottlenose dolphins must excrete more protons in urine than free-ranging bottlenose dolphins, which will promote nephrolith formation. The nutrient composition of the free-ranging bottlenose dolphin diet, determined for the first time here, can be used as a guide for feeding managed bottlenose dolphins, but research in vivo is warranted to determine whether adding more cations to the diet will prevent urolith formation in managed dolphins.

A Targeted Metabolomics Assay to Measure Eight Purines in the Diet of Common Bottlenose Dolphins, Tursiops truncatus.

Bottlenose dolphins managed under human care, human beings and Dalmatian dogs are prone to forming urate uroliths. Limiting dietary purine intake limits urate urolith formation in people and dogs because purines are metabolized to uric acid, which is excreted in urine. Managed dolphins develop ammonium urate nephroliths, whereas free-ranging dolphins do not. Free-ranging dolphins consume live fish, whereas managed dolphins consume different species that have been stored frozen and thawed. Differences in the purine content of fish consumed by dolphins under human care versus in the wild may be responsible for the difference in urolith prevalence. Commercially available purine assays measure only four purines, but reported changes in purines during frozen storage suggest that a wider range of metabolites should be measured when comparing fresh and stored fish. A method using high performance liquid chromatography with tandem mass spectrometry was developed to quantify eight purine metabolites in whole fish and squid commonly consumed by dolphins. The coefficient of variation within and among days was sometimes high for purines present in small amounts but was acceptable (≤ 25%) for guanine, hypoxanthine, and inosine, which were present in high concentrations. This expanded assay identified a total purine content up to 2.5 times greater than the total that would be quantified if only four purines were measured. Assuming additional purines are absorbed, these results suggest that additional purine metabolites should be measured to better understand the associated risk when fish or other purine-rich foods are consumed by people or animals prone to developing uroliths.

Comparison between Urine Protein: Creatinine Ratios of Samples Obtained from Dogs in Home and Hospital Settings.

BACKGROUND: The urine protein:creatinine ratio (UPC) is used to quantify urine protein excretion and guide recommendations for monitoring and treatment of proteinuria. HYPOTHESIS/OBJECTIVES: Home urine samples will have lower UPCs than hospital samples. The objectives were to compare UPCs of samples collected in each setting and to determine whether environment of sample collection might affect staging, monitoring or treatment recommendations. ANIMALS: Twenty-four client-owned dogs. METHODS: Prospective, nonmasked study. Clients collected a urine sample from their dog at home and a second sample was collected at the hospital. Dogs receiving corticosteroids or angiotensin-converting enzyme inhibitors were excluded, as were those with urine samples of inadequate volume, no protein on dipstick analysis, or active urine sediment. Samples were refrigerated after collection, dipstick and sediment evaluations were completed and each sample was frozen at -80°C within 12 hours. UPCs were performed on frozen samples within 2 months. RESULTS: From 81 paired samples, 57 were excluded. Of the remaining 24, 12/24 (50%) had higher hospital sample UPCs, 9/24 (38%) had identical UPCs, and 3/24 (12%) had lower hospital UPCs. The UPCs of hospital samples were higher than home samples for the total population (P = .005) and the subset with UPC > 0.5 (P = .001). CONCLUSIONS: Setting and related circumstances of urine collection in dogs is associated with UPC differences; results are usually higher in hospital than in home samples. This difference has the potential to affect clinical interpretation.

Synthesis and pharmacological studies of 4,4-disubstituted piperidines: a new class of compounds with potent analgesic properties.

A series of 4,4-disubstituted piperidines has been synthesized and evaluated for analgesic activity. Several of these analogues show analgesic potency comparable to morphine in the mouse writhing and tail-flick tests. A number of compounds exhibit high affinity for [3H]naloxone binding sites in rat brain membranes. Among the most potent derivatives are compounds 15 and 48. Although opiate-like, attempts to modify this activity with various substituents have failed to produce antagonistic properties. A few of these analogues also show marked long-lasting serotonin antagonism in the guinea pig serotonin toxicity test and the DL-5-hydroxytryptophan induced head-twitch model in the mouse.

Preliminary investigations of a new beta-adrenoceptive receptor blocking drug, LB46, in man.

1. Preliminary studies in man of a new beta-adrenoceptive receptor blocking drug, DL-4-(2-hydroxy-3-isopropylaminopropoxy)-indole (LB46), are described.2. LB46, 0.5 mg by oral administration, appeared to be of similar potency to propranolol 20 mg in inhibiting isoprenaline-induced and exercise-induced tachycardia.3. In comparable beta-receptor blocking doses LB46 did not show the negative chronotropic property possessed by propranolol.

Reperfusion of inflow-limited myocardium following hypothermic potassium-induced cardioplegia.

Previous studies have shown that transmural reperfusion patterns may be markedly abnormal following periods of ischemia. The present study was done to elucidate the effects of hypothermic potassium cardioplegia on pressure-flow characteristics during reperfusion of myocardial regions with chronically compromised arterial inflow. Prior to cardiopulmonary bypass studies. Ameroid constrictors were placed on the circumflex coronary artery of 10 adult dogs to create a myocardial region subserved by inflow-restricting collaterals. Subsequently, during cardiopulmonary bypass at 80 mm Hg, 10 minutes of ischemic arrest was induced with hypothermic potassium cardioplegia (15 degrees C, pH 7.4, potassium chloride 25 mEq/L). Transmural myocardial flow was measured in normal and collateral-dependent regions during control conditions and at 1, 5, and 10 minutes of reperfusion. Also, retrograde circumflex pressures were monitored as an additional index of perfusion of the collateral regions. A normal endocardial/epicardial flow ratio was maintained in the normal regions at 1, 5, and 10 minutes of reperfusion. In contrast, a marked decrease in endocardial/epicardial flow ratio occurred transiently in the collateral regions at 1 minute of reperfusion (0.28 +/- 0.05). Simultaneously, retrograde circumflex pressures fell from 55 +/- 3.5 mm Hg to 42 +/- 3.0 mm Hg (p less than 0.001). By 5 minutes of reperfusion, retrograde circumflex pressure, mean flow, and transmural endocardial/epicardial ratios returned to normal in collateral regions. These data suggest that, even with optimal myocardial protection, changes in transmural flow occur very early during reperfusion and are exaggerated in inflow-restricted myocardial regions. Mechanisms responsible for these changes may include refilling of epicardial vessels emptied during the cross-clamp period or an early epicardial hyperemic response. Despite these alterations, normal transmural flow patterns are reestablished rapidly. Thus, when detailed attention is paid to adequate myocardial protection, abnormal reperfusion characteristics are obviated, and this is particularly important in myocardium supplied by inflow-compromised coronary vessels.

Partial anomalous pulmonary venous connection to the right side of the heart.

Partial anomalous pulmonary venous connection to the right side of the heart often complicates surgery for atrial septal defects. Between 1964 and 1987, 39 patients, ranging from 2 to 52 years old, underwent repair of partial anomalous pulmonary venous connection. At least one anomalous pulmonary vein arose from the right upper lobe in 38 patients and right middle lobe in 30 patients and connected to the superior vena cava in 28 patients and the right atrium only in 11 patients. An atrial septal defect was present in 32 patients (82%). Patients who had partial anomalous pulmonary venous connection to the superior vena cava-right atrium junction, the right atrium or both were treated by septal translocation (two patients) or patch redirection of the anomalous pulmonary venous flow to the left atrium through a native atrial septal defect (eight patients) or a surgically created atrial septal defect in two patients with intact atrial septum. For partial anomalous pulmonary venous connection to the high superior vena cava (27 patients), the superior vena cava was transected and oversewn above the anomalous veins. The anomalous pulmonary venous flow was redirected through the proximal superior vena cava into the left atrium across a sinus venous atrial septum defect (22 patients) or a surgically created atrial septal defect in five patients with intact atrial septum. The atrial septal defect was coapted to the intracardiac orifice of the superior vena cava, and the distal superior vena cava was anastomosed to the right atrial appendage. One 31-year-old woman with severe pulmonary hypertension died early and was the only death in the series. A technical error early in the series resulted in one symptomatic superior vena cava obstruction. Only one patient remains in sick sinus syndrome late. All patients remain well over long follow-up (1 to 24 years). Postoperative catheterization or echocardiography has revealed no intracardiac defects, pulmonary venous obstruction, or superior vena cava obstruction (except the one technical error). Correction of partial anomalous pulmonary venous connection should be individualized according to the site of connection of the anomalous pulmonary veins and the location of the atrial defect to minimize undesirable postoperative sequelae often associated with other methods of repair.

Diastolic ventricular properties in patients during coronary revascularization. Intermittent ischemic arrest versus cardioplegia.

Left ventricular diastolic properties were examined in 24 patients undergoing coronary revascularization with either 32 degrees C intermittent ischemic arrest (IA) or 4 degrees C potassium cardioplegia (CP) for myocardial protection. The ages, numbers of grafts, and preoperative cardiac function were similar for the two groups of patients. For compliance data, hearts were filled passively during bypass perfusion to diastolic pressures between 0 and 20 mm Hg by clamping the left ventricular vent. Simultaneously, minor axis dimensions were measured with 8 mm epicardial ultrasonic crystals. End-diastolic lengths (EDL), normalized to a Lagrangian strain definition (epsilon), were compared at each pressure (P) by the nonlinear regression equation, P = alpha(e beta epsilon-1). Both elastic constants, alpha and beta, as well as linear regression slopes (k) of pressure-strain data were compared as indices of ventricular stiffness. Prior to determinations, the EDL at 0 mm Hg transmural pressure was defined as l0. At each filling pressure, a leftward shift in the compliance curve developed following IA but not CP. Moreover, shifts in alpha, beta, and k constants occurred with IA alone, l0 did not change in either group. Therefore, stiffening did not occur when CP was used for protection, despite ischemic durations twice those of IA (31 versus 15 minutes). These data confirm CP to be a superior method of cardiac protection during coronary bypass grafting and show diastolic ventricular properties to be a sensitive indicator of subclinical ischemic injury.

Transmural myocardial flow distribution during hypothermia. Effects of coronary inflow restriction.

Hypothermic coronary perfusion and blood cardioplegia have been used clinically to minimize intraoperative myocardial damage. However, pressure-flow characteristics in regions supplied by inflow-limiting collateral coronary arteries have not been investigated during hypothermic conditions. In this study tracer microspheres determined transmural myocardial blood flow distribution during cardiopulmonary bypass in normothermic empty, beating dog hearts (EBH), during hypothermic sanguineous perfusion at 15 degrees C (HP), and after hemodilution of cooled (15 degrees C) hearts to a hematocrit value of 20 vol% (HDL). Animals in Group I (N = 8) had normal hearts. Group II dogs (N = 9) had one region supplied predominantly by narrow collateral vessels (CR) and another nourished by normal coronary arteries (NR). Retrograde circumflex pressures were measured continuously for Group II as an additional index of CR perfusion. Flow characteristics in Group I hearts were always similar to the NR of Group II dogs. With HP, endocardial blood flow in the NR decreased from approximately 0.80 to 0.50 ml/min/gm. Subsequently, following HDL this flow increased to approximately 1.70 ml/min/gm, or over twice control levels. In comparison, flow to CR endocardium decreased even more during HP (0.12 ml/min/gm). Even though control flow levels were reestablished in CR endocardium by adding HDL, an unfavorable endocardial/epicardial ratio persisted. With both HP and HDL, retrograde circumflex pressure never changed from EBH values. These data suggest that a significant endocardial flow defect exists during periods of hypothermic sanguineous perfusion and may become more prevalent in regions subserved by inflow-limiting coronary vessels. Similar flow maldistributions may occur in patients if blood-containing cardioplegic solutions are used and during systemic hypothermia. Significant hemodilution helps minimize these imbalances and permits salutary effects of hypothermia to be delivered more evenly across the ventricular wall.

Effects of phenylephrine on transmural distribution of myocardial blood flow in regions supplied by normal and collateral arteries during cardiopulmonary bypass.

Cardiopulmonary bypass is frequently accompanied by decreased peripheral vascular resistance with resultant hypotension that is unresponsive to increased flow rates. Alpha adrenergic agonists are routinely used to increase peripheral vascular resistance and augment blood pressure. In this study, the effects of the alpha adrenergic stimulant phenylephrine on blood flow distribution during cardiopulmonary bypass in myocardium supplied by normal and collateral arteries were studied in eight mongrel dogs. Microsphere determinations of blood flow were made following augmentation of perfusion pressure with phenylephrine and were compared with intraoperative normotensive and hypotensive control levels. With systemic flow rates held constant, phenylephrine was infused in doses adequate to raise perfusion pressure to normotensive levels following hypotension. In the normal region (NR), blood flow was returned to normotensive control levels with flow favoring the subendocardium. In the region supplied by collateral vessels (CR), however, phenylephrine infusion failed to return flow to the normotensive control level in the subendocardial layer, and the flow imbalance present during hypotension was not corrected. An analogue model of the calculable resistances in the CR is presented, which indicates that phenylephrine increased resistance in the collateral vessels. Associated with this inflow restriction is decreased resistance or vasodilatation of the intramyocardial vessels supplied by collateral coronary arteries.

Preservation of adenosine 5'-triphosphate and mitochondrial function during hypercalcemic reperfusion using verapamil cardioplegia.

Immediate hypercalcemic reperfusion results in ventricular dysfunction and loss of high-energy stores. The purpose of this study was to evaluate the effect of verapamil cardioplegia on the preservation of myocardial energy stores, mitochondrial ultrastructure, and ventricular dysfunction in the postischemic rat heart during immediate hypercalcemic reperfusion. Rats in the control group were subjected to cardioplegia with potassium, while rats in groups 1 to 3 were subjected to the same with verapamil (0.5 mg/L). The control and group 1 rats underwent normocalcemic reperfusion and groups 2 and 3 rats underwent hypercalcemic reperfusion. Myocardial samples were analyzed for adenosine 5'-triphosphate (ATP) content and mitochondrial ultrastructural damage. Hemodynamic parameters of heart rate, aortic flow (AF), and postischemic rate of aortic pressure change (dP/dT) also were evaluated. Data were analyzed using analysis of variance. The ATP stores were preserved at greater than 100% control levels in hearts subjected to verapamil cardioplegia. There was no evidence of irreversible mitochondrial damage. Heart rate, AF, and dP/dT were significantly (p < 0.05) depressed in hearts subjected to verapamil cardioplegia. This study suggests verapamil cardioplegia preserves ATP and mitochondrial function during immediate hypercalcemic reperfusion but does not improve postischemic hemodynamics.

Current management of esophageal impactions.

We analyzed our experience at a university medical center from 1977 to 1990 to assess our success in using esophagoscopy and related treatments for removing esophageal impactions. There were 157 episodes of impaction in 150 patients, consisting of 39 pediatric and 111 adult patients. In the pediatric cases, foreign bodies were most often the cause of impaction, while adult cases were usually caused by food or bones. Esophagoscopy was performed successfully in 32 of 34 pediatric patients in which it was attempted; there was only one complication. Other forms of therapy that were infrequently tried met with variable results. Esophagoscopy was successful in removing the impaction in 104 of 109 attempts in adults. Two perforations occurred, with one resulting in death. Various other methods achieved success in the remaining patients. The data suggest that esophageal impaction can be treated successfully by endoscopy with very low morbidity and mortality.

Regional myocardial dimensions following coronary artery bypass grafting in patients. Relationship of functional deterioration to graft occlusion.

The direct relationship between graft flow and regional midwall myocardial function has not been documented in patients. Therefore, the present study was designed to quantitate the effects of coronary artery bypass grafting on regional myocardial mechanics distal to a coronary artery obstruction. Twenty-one patients with subtotal or total occlusion of the left anterior descending (LAD) coronary artery underwent coronary artery bypass grafting. Following completion of the aortic and coronary anastomoses, two miniature ultrasonic dimension transducers (2.5 mm. diameter) were positioned within the minor axis of the anterior left ventricular free wall and were allowed complete freedom of movement. The transducers were placed at midwall depth, and areas of clinically apparent myocardial fibrosis were not utilized as sites of implantation. During control, 30 minutes following the termination of cardiopulmonary bypass, regional myocardial dimensions, pulmonary artery diastolic pressure, arterial pressure, and heart rate were recorded with all saphenous vein grafts open and after 30 seconds of single vein graft occlusion. These measurements were repeated during atrial pacing at a rate of 128 +/- 4 beats per minute. Data are mean +/- the standard error of the mean. During control, graft occlusion resulted in a regional decrease in systolic excursion from 1.3 +/- 0.1 to 1.0 +/- 0.2 mm. (p less than 0.01), as well as a decrease in the rate of shortening from 8.7 +/- 0.2 to 6.2 +/- 1.1 mm. per second (p less than 0.05); heart rate, mean arterial pressure, and diastolic pulmonary artery pressure remained unchanged. Graft occlusion with atrial pacing resulted in an exaggerated decrease in both regional systolic excursion, from 1.2 +/- 0.2 to 0.6 +/- 0.2 mm. (p less than 0.01), and rate of shortening, from 9.4 +/- 1.5 to 4.4 +/- 0.2 mm. per second (p less than 0.01). For the group of patients studied, end-diastolic lengths were unchanged with graft occlusion during control and atrial pacing. Moreover, with graft occlusion, isolated patients demonstrated regional dyskinesia as evidenced by holosystolic bulging. These studies in patients have documented for the first time that, despite a constant preload, afterload, and heart rate, regional myocardial function following coronary artery bypass grafting is dependent upon adequate graft flow, especially during stress.

Measurement of global ventricular function in patients during cardiac operations using sonomicrometry.

In these studies, we evaluated the applicability of pulse-transit sonomicrometry for measuring changes in global cardiac activity in patients during cardiac operative procedures. In six patients two epicardial ultrasonic crystals (8 mm) were sutured across the left ventricular minor axis. Diastolic pressure-length data were recorded as left ventricles were filled passively to transmural pressures (P) from 0 to 20 mm Hg. Data were collected at the beginning of cardiopulmonary bypass and again 15 minutes following periods of induced global ischemia (29.8 +/- 0.8 minutes). Minor axis length data were normalized to Lagrangian strain (epsilon), and best-fit regression curves were obtained from P-epsilon by computer analysis. Nonlinear elastic constants, alpha and beta, were mathematically derived as additional curve descriptors. Decreases in ventricular compliance were demonstrated as leftward shifts in both computed and measured P-epsilon curves. Global ischemia appeared to effect a decrease in overall ventricular diastolic compliance in all patients studied (p =7E 0.01 at 5, 10, 15, 20 mm Hg). Simultaneously, no statistical change occurred in lo (62.93 +/- 2.80 mm), which represented end-diastolic length (EDL) at 0 mm Hg transmural pressure. Following coronary grafting several patients showed augmented systolic excursion when compared at similar EDL. For those analyses, shortening was compared at specific minor axis EDLs rather than filling pressures. These data indicate that experimentally developed sonomicrometry may safely provide accurate indices of systolic and diastolic ventricular properties during operations necessitating cardiopulmonary bypass. Thus various cardioplegic solutions, ischemic arrest periods, and inotropic agents may be evaluated more objectively.

Correlation of mitochondrial function and ischemic contracture.

Structural and functional changes in the mitochondrium have been described following timed cardiac ischemia. However, mitochondrial abnormalities associated with acute muscular dysfunction have not been well defined. In the present investigation, the isolated rat heart subjected to global ischemia was used to determine the relationship between the biochemical parameters of high-energy phosphate content and mitochondrial function and the physiological event of ischemic contracture. High-energy phosphate content and mitochondrial structure and function were determined under control conditions, at the initiation of ischemic contracture, at the completion of ischemic contracture, and 20 minutes after completion of contracture. Contracture initiation and completion were associated with the anticipated depletion of high-energy phosphate content. Also demonstrated were specific degrees of structural and functional deterioration of the mitochondria associated with specific degrees of contracture. In addition to its prior applications, this model seems well suited for investigation of the interdependence of high-energy phosphate levels, ischemic contracture, and mitochondrial function as affected by specific protective interventions designed to limit ischemic injury.

Metabolic deterioration during global ischemia as a function of time in the intact normal dog heart.

High-energy phosphate content and mitochondrial function were analyzed at the initiation and completion of ischemic contracture in dog hearts exposed to normothermic ischemia while on cardiopulmonary bypass. Contracture initiation and completion were detected by a balloon catheter placed within the left ventricle. In seven dogs, inner and outer layers of the myocardium were assayed for adenosine triphosphate (ATP) and creatine phosphate (CP). ATP and CP content in these two layers were compared prior to ischemia and at contracture initiation and completion. Inner layer ATP levels were 23.88 +/- 0.73 (mean +/- SM) mu moles/gm dry weight prior to ischemia, 5.14 +/- 0.49 at initiation, and 0.73 +/- 0.2 at completion. Inner layer CP content was 41.29 +/- 0.87 prior to ischemia, 3.49 +/- 0.34 at initiation, and 4.06 +/- 0.48 at completion. Mitochondrial respiratory control indices (RCI) were assayed in a second group of seven dogs prior to ischemia, at contracture initiation, and at contracture completion and were, respectively, 11.5 +/- 1.18, 3.1 +/- 0.43 and 1.76 +/- 0.29 (alpha ketoglutarate as substrate). Despite the specific degrees of metabolic deterioration associated with the events of contracture, ischemic time required to develop contracture initiation and completion was variable, ranging from 29.5 to 72 minutes for initiation and 60.25 to 101 minutes for completion. A third group of five dogs had biopsy specimens taken for ATP at fixed ischemic time intervals, and at 45 minutes of ischemia they were found to have greater ranges in ATP values than the ranges associated with contracture initiation. In contrast to ischemic time, the physiological events of ischemic contracture are reliable predictors of the degree of metabolic injury in the intact dog heart exposed to normothermic ischemic arrest during cardiopulmonary bypass.

Characteristics of chronic left ventricular hypertrophy induced by subcoronary valvular aortic stenosis. I. Myocardial blood flow and metabolism.

Using a canine model of subcoronary valvular aortic stenosis, we determined myocardial blood flow, high-energy phosphate content, and mitochondrial function in eight hearts with chronic left ventricular hypertrophy. Fourteen normal hearts were used for control data. Myocardial blood flow was determined by injection of tracer microspheres. During cardiopulmonary bypass, left ventricular transmural biopsy specimens were taken for metabolic analyses. Subepicardial and subendocardial content of adenosine triphosphate (ATP) and creatine phosphate (CP) were assayed. Respiratory control indices for isolated mitochondria were measured by use of NAD-linked and FAD-linked substrates. Endocardial blood flow, subendocardial high-energy phosphate content, and respiratory control indices for NAD-linked substrate in the hearts with chronic left ventricular hypertrophy were significantly lower than the normal values. These data provide insight into the metabolic and myocardial blood flow abnormalities occurring in cardiac hypertrophy and provide a framework for understanding the altered response of hypertrophied hearts to ischemia.