Erratum to: "Anxiety and neurometabolite levels in the hippocampus and amygdala after prolonged exposure to predator-scent stress".

Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2019;23(5):582-587 (in Russian) Page 587, in Acknowledgements instead of The animals and behavioral testing are supported by the budget project (No. 0324-2019-0041). The MRI study is supported by the budget project (No. 0259-2019-0004). All studies are implemented using the equipment of Center for Genetic Resources of Laboratory Animals at ICG SB RAS, supported by the Ministry of Education and Science of Russia (Unique ID# of the project: RFMEFI62117X0015). should read The animals and behavioral testing are supported by the budget project (No. 0324-2019-0041). The MRI study is supported by the budget project (No. 0259-2019-0004). All studies are implemented using the equipment of Center for Genetic Resources of Laboratory Animals at ICG SB RAS, supported by the Ministry of Education and Science of Russia (Unique ID# of the project: RFMEFI62117X0015). The study was conducted within the basic part of the state task of the Ministry of Science and Higher Education of the Russian Federation (No. 17.7255.2017/8.9). The original article can be found under DOI 10.18699/VJ19.528.

Physical Fatigue and Morphofunctional State of the Myocardium in Experimental Chronic Stress.

The relationship between the development of skeletal muscle fatigue of a specific type in male Wistar rats and morphofunctional alterations in the myocardium in the posttraumatic stress disorder (PTSD) model has been investigated for the first time. The aggravation of oxidative stress in the cardiomyocytes and the related transformation of the cell structural components and the depletion of energy reserves in PTSD has been identified as one of the main factors that accelerate the onset of musculoskeletal fatigue.

[Effect of adaptation to hypoxia on expression of NO synthase isoforms in rat myocardium].

Previously we have shown that adaptation to hypoxia (AH) is cardio- and vasoprotective in myocardial ischemic and reperfusion injury and this protection is associated with restriction of nitrosative stress. The present study was focused on further elucidation of NO-dependent mechanisms of AH by identifying specific NO synthases (NOS) that could play the major role in AH protection. AH was performed in a normobaric hypoxic chamber by breathing hypoxic gas mixture (9.5-10% O2) for 5-10 min with intervening 4 min normoxia (5-8 cycles daily for 21 days). Expression of neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) protein was measured in the left ventricular myocardium using Western blot analysis with respective antibodies. AH educed iNOS protein expression by 71% (p < 0.05) whereas eNOS protein expression tended to be reduced by 41% compared to control (p < 0.05). nNOS protein expression remained unchanged after AH. Selective iNOS inhibition can mimic the AH-induced protection. Therefore protective effects of AH could be at least partially due to restriction of iNOS and, probably, eNOS expression.

[Vasoprotective effect of adaptation to hypoxia in myocardial ischemia and reperfusion injury].

Adaptation to hypoxia is known to be cardioprotective in ischemic and reperfusion (IR) injury of the myocardium. This study was focused on investigating a possibility for prevention of endothelial dysfunction in IR injury of the rat heart using adaptation to intermittent hypoxia, which was performed in a cyclic mode (5-10 min of hypoxia interspersed with 4 min of normoxia, 5-8 cycles daily) for 21 days. Endothelial function of coronary blood vessels was evaluated after the in vitro IR of isolated heart (15 min of ischemia and 10 min of reperfusion) by the increment of coronary flow rate in response to acetylcholine. Endothelium-dependent relaxation of isolated rat aorta was evaluated after the IR myocardial injury in situ (30 min of ischemia and 60 min of reperfusion) by a relaxation response of noradrenaline-precontracted vessel rings to acetylcholine. The following major results were obtained in this study: 1) IR myocardial injury induced endothelial dysfunction of coronary blood vessels and the aorta, a non-coronary blood vessel, remote from the IR injury area; and 2) adaptation to hypoxia prevented the endothelial dysfunction of both coronary and non-coronary blood vessels associated with the IR injury. Therefore, adaptation to hypoxia is not only cardioprotective but also vasoprotective in myocardial IR injury.

Right ventricular oxygen supply/demand balance in exercising dogs.

This is the first investigation of right ventricular (RV) myocardial oxygen supply/demand balance in a conscious animal. A novel technique developed in our laboratory was used to collect right coronary (RC) venous blood samples from seven instrumented, conscious dogs at rest and during graded treadmill exercise. Contributions of the RV oxygen extraction reserve and the RC flow reserve to exercise-induced increases in RV oxygen demand were measured. Strenuous exercise caused a 269% increase in RV oxygen consumption. Expanded arteriovenous oxygen content difference (A-V(Delta)O2) provided 58% of this increase in oxygen demand, and increased RC blood flow (RCBF) provided 42%. At less strenuous exercise, expanded A-V(Delta)O2 provided 60-80% of the required oxygen, and increases in RCBF were small and driven by increased aortic pressure. RC resistance fell only at strenuous exercise after the extraction reserve had been mobilized. Thus RC resistance was unaffected by large decreases in RC venous PO2 until an apparent threshold at 20 mmHg was reached. Comparisons of RV findings with published left ventricular data from exercising dogs demonstrated that increased O2 demand of the left ventricle is met primarily by increasing coronary flow, whereas increased O2 extraction makes a greater contribution to RV O2 supply.

Endogenous nitric oxide modulates myocardial oxygen consumption in canine right ventricle.

The role of endogenous nitric oxide (NO) in modulating myocardial oxygen consumption (MVO2) is unclear, in part because of systemic and coronary hemodynamic effects of blocking NO release. This study evaluated the effect of NO on right ventricular MVO2 under controlled hemodynamic conditions. In 12 open-chest dogs, N(omega)-nitro-L-arginine methyl ester (L-NAME, 150 microg/min), a NO synthase (NOS) blocker, was infused into the right coronary artery. Heart rate and mean aortic pressure were constant. Right coronary blood flow and right ventricular MVO2 were measured at normal and elevated right coronary perfusion pressures (RCP) before and after L-NAME. To avoid effects of NO synthesis blockade on right coronary blood flow, which might have altered right ventricular MVO2, experiments, were conducted during adenosine-induced maximal coronary vasodilation. L-NAME did not affect right coronary blood flow (P = 0.51). However, L-NAME significantly increased right ventricular MVO2 (6% at RCP 100 mmHg, and 21% at RCP 180 mmHg). Right coronary blood flow varied with perfusion pressure (P < 0.02), and the elevation of MVO2 produced by L-NAME increased at higher flows (P < 0.04), consistent with the greater shear stress-mediated release of NO. These findings indicate that endogenous NO limits right ventricular MVO2.

Dobutamine enhances both contractile function and energy reserves in hypoperfused canine right ventricle.

Although the beta(1)-adrenergic agent dobutamine is used clinically to provide inotropic support to the failing myocardium, it could jeopardize the myocardium by depleting energy reserves. This investigation delineated the contractile and energetic effects of low versus high dobutamine doses in the hypoperfused right ventricular (RV) myocardium. The right coronary artery (RCA) of anesthetized dogs was cannulated for controlled perfusion with arterial blood, and regional RV contractile function was measured. RCA perfusion pressure was lowered from 100 mmHg baseline to 40 mmHg, and flow fell by 54%. At 15-min hypoperfusion, dobutamine was infused into the RCA at either 0.01 (low-dose dobutamine) or 0.06 microgram. kg(-1). min(-1) (high-dose dobutamine) for 15 min. Regional power (systolic segment shortening x isometric developed force x heart rate) stabilized at 63% of baseline during hypoperfusion. Low-dose dobutamine restored power to baseline but did not increase RV myocardial O(2) consumption (MVO(2)) and thus increased myocardial O(2) utilization efficiency (O(2)UE:power/MVO(2)). At 5 min, high-dose dobutamine enhancement of power was similar to that of low-dose dobutamine, but by 15 min, power and O(2)UE fell to untreated levels. Remarkably, low-dose dobutamine tripled cytosolic phosphorylation potential; in contrast, high-dose dobutamine lowered phosphorylation potential to 45% of the untreated value. Analyses of glucose uptake and glycolytic intermediates revealed sustained enhancement of glycolysis by low-dose dobutamine, but glycolysis became limited at glyceraldehyde 3-phosphate dehydrogenase during high-dose dobutamine treatment. In summary, low-dose dobutamine improved mechanical performance and efficiency of the hypoperfused RV myocardium while increasing myocardial energy reserves, but high-dose dobutamine failed to sustain improved function and depleted energy reserves. Dobutamine is capable of improving both contractile function and cellular energetics in the hypoperfused RV myocardium, but dosage should be carefully selected.

Hyperlipidemia with hypoglycemia reduces myocardial oxygen utilization efficiency but not contractile function during coronary hypoperfusion.

This study was designed to determine changes in myocardial contractile function and fuel selection during moderate coronary hypoperfusion in the presence of elevated plasma free fatty acid (FFA) at normal and reduced blood glucose concentrations. Coronary perfusion pressure (CPP) was sequentially lowered from 100 to 60, 50, and 40 mmHg in the left anterior descending coronary artery (LAD) of anesthetized, open-chest dogs. Regional glucose uptake (GU), fatty acid uptake (FAU), percentage segment shortening (%SS), and oxygen consumption (MV O(2)) were determined with normal arterial plasma FFA concentrations (Group 1) or with elevated FFA concentrations (Groups 2 and 3). In Group 3, glucose in the coronary perfusate blood was reduced from 3.53+/-0.36 to 0.15+/-0.03 m M by hemodialysis. In Group 1, FAU fell by 85% as CPP was lowered to 60 mmHg and remained depressed as CPP was reduced further; GU did not fall significantly. Hyperlipidemia in Group 2 did not alter GU at any CPP, but maintained FAU at baseline levels until CPP was lowered to 40 mmHg. At 40 mmHg CPP, myocardial function and metabolic variables were similar in Groups 1 and 2. In Group 3 at 40 mmHg, FAU increased four-fold and MV O(2)doubled v Groups 1 and 2, and GU fell to zero. Despite these metabolic changes, %SS in Group 3 was unchanged relative to Group 2. Addition of glucose to the dialysate prevented the effects of dialysis on FAU, GU, and MV O(2). Thus, preferential glucose oxidation sustains myocardial oxygen utilization efficiency [(heart rate x %SS x maximum left ventricular pressure)/MV O(2)] during hypoperfusion. Blocking preferential glucose oxidation by combined hyperlipidemia and hypoglycemia lowers oxygen utilization efficiency, but does not compromise myocardial contractile function.

Myocardial oxygen consumption modulates adenosine formation by canine right ventricle in absence of hypoxia.

Myocardial adenosine formation varies with myocardial oxygen consumption (MVO(2)), but whether concurrent hypoxia is required for adenosine formation is uncertain. Changes in right coronary (RC) perfusion pressure (RCP) produce directionally similar alterations in right ventricular (RV) MVO(2)and in RC venous P O(2)(P(v)O(2)), an index of myocardial P O(2). RCP was varied in 10 anesthetized, open chest dogs to determine if, under these conditions, RV formation of adenosine would increase with MVO(2)in absence of myocardial hypoxia. Dialysis probes were implanted in the mid myocardium of RV free wall for collecting dialysate samples for HPLC analyses to estimate interstitial adenosine and other purines. Coronary venous blood was sampled from a superficial vein draining the RC artery (RCA) perfusion territory. At 115+/-3 mmHg baseline RCP, RC blood flow (RCBF)=0.51+/-0.04 ml/min/g, MVO(2)=4.6+/-0.5 ml/min/100 g, P(v)O(2)=34+/-1.5 mmHg, and dialysate adenosine=0. 27+/-0.03microM. When RCP was lowered to 61+/-1 mmHg by adjusting an occluder on the proximal RCA, RCBF decreased to 0.36+/-0.03 ml/min/g, MVO(2)fell to 3.7+/-0.4 ml/min/100 g, lactate uptake remained positive, P(v)O(2)fell to 30+/-1.7 mmHg, and dialysate adenosine decreased to 0.20+/-0.03microM. Reactive hyperemia of 1.25+/-0.13 ml/min/g was observed when the RCA constriction was released, although dialysate adenosine had fallen. When RCP was elevated to 164+/-2 mmHg by inflating a balloon catheter in the descending aorta, RCBF increased to 0.70+/-0.06 ml/min/g, MVO(2)increased to 5.8+/-1. 0 ml/min/100 g, P(v)O(2)rose to 39+/-2.3 mmHg, and dialysate adenosine increased to 0.33+/-0.04microM. These data indicate that (1) RV oxygen demand varies with RCP; (2) if RV ischemia is absent, myocardial adenosine formation is modulated by MVO(2), with no requirement for hypoxia; (3) pressure-flow autoregulation is relatively ineffective in the RC circulation, where adenosine does not mediate and may even blunt autoregulation.

Vascular endothelial growth factor is increased following coronary artery occlusion in the dog heart.

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible factor expressed into several molecular forms in mammalian tissues of which VEGF 120, VEGF 164, and VEGF 188 are the major isoforms. While VEGF 164 is the predominant isoform in most tissues, VEGF 188 has been reported to be dominant in cardiac tissues such as that in guinea pig, rat, and mouse. In the dog heart, an important model for studies of myocardial ischemia and angiogenesis, the expression of VEGF remains to be established. We investigated the expression of the various isoforms of VEGF in normal and ischemic dog heart tissues using Reverse transcription-Polymerase chain reaction, Ribonuclease Protection Assay and Western blotting. The nucleotide sequences of the major isoforms of VEGF were also determined using homology cloning techniques. Our study showed that the nucleotide sequences of dog VEGF were highly homologous to human VEGF especially in the c-terminal region spanning exons 58. A single amino acid-deletion (Glu5 in human VEGF), similar to that reported in other animal species, was observed in the major isoforms resulting in monomers of 120, 164, and 188 amino acids. A novel splice site similar to that in human VEGF183 was also identified in the dog heart, resulting in the 182 amino acid-containing isoform (VEGF 182). Moreover, VEGF 164 was expressed at a higher level as compared with VEGF 182 or VEGF 188 in both normal and ischemic tissues. The identification of the nucleotide sequences of VEGF isoforms in the dog heart should prove useful in investigating the molecular expression of VEGF in canine tissues.

A method for producing regional hypoglycemia in blood perfused tissue.

Numerous studies have focused on the metabolic contributions of glucose and other substrates in isolated tissue preparations by examining the effects of eliminating glucose from the physiologic perfusate or bath solution. To date, however, an effective method of glucose removal from the blood supply to selected tissue in the whole animal model has not been available. We have developed a method for blood glucose removal by continuous flow dialysis. This method was used to generate isolated coronary hypoglycemia for an investigation of myocardial metabolic substrate selection during hypoperfusion in open-chest, anesthetized dogs. Arterial blood was passed through the dialysis system against an isotonic and physiologic dialysate solution prior to controlled coronary perfusion. During normal perfusion pressure (100 mmHg), with a coronary blood flow of 32+/-4 ml/min, arterial blood glucose was reduced from 3.26+/-0.31 to 0.54+/-0.14 mM. When blood flow was reduced to 12+/-3 ml/min with lower perfusion pressure (40 mmHg), dialysis reduced arterial glucose from 3.53+/-0.36 to 0.15+/-0.03 mM. We conclude that this is an effective method for producing regional hypoglycemia.

Right coronary pressure modulates right ventricular systolic stiffness and oxygen consumption.

OBJECTIVE: The low transmural pressure of the thin right ventricular (RV) wall may render it responsive to right coronary (RC) pressure-induced changes in systolic stiffness and account for the dependence of RV MVO2 on RC pressure (RCP). METHODS: In eight dogs anesthetized with pentobarbital and fentanyl, RCP was lowered from the baseline to 30 mmHg in 10 mmHg steps by adjusting an occluder on the proximal RC. Myocardial segment length and isometric developed force were measured, and the slope of the force-length curve during ejection period (delta F/ delta SL) was used as an index of systolic myocardial stiffness. MVO2 was calculated from RC flow and arteriovenous O2 difference. RESULTS: As RCP was varied from 120 to 40 mmHg with positive lactate uptake, RC flow, maximum developed force (Fmax), delta F, and MVO2 decreased linearly, whereas end-diastolic length, delta SL, and other hemodynamic variables stayed constant. Thus, RV systolic stiffness fell linearly with RC pressure. When RCP was further lowered from 40 to 30 mmHg, Fmax and delta F continued to fall, end-diastolic segment length and right atrial pressure increased significantly, delta SL and RV dp/dtmax fell significantly, and delta F/delta SL reached its lowest value. RV systolic stiffness was 22% of previously reported left ventricular systolic stiffness for coronary perfusion pressure at 100 mmHg, and varied less steeply with coronary pressure. CONCLUSIONS: (1) Reductions in RV systolic stiffness preserve delta SL as coronary pressure is reduced over a wide range. (2) The resulting increase in RV efficiency reduces oxygen demand as oxygen supply is reduced, so ischemia is avoided. (3) RV systolic stiffness is much less than left ventricular stiffness, consistent with their anatomical and functional differences.

A method for collecting right coronary venous blood samples from conscious dogs.

This report describes for the first time a technique to collect right coronary venous blood samples from conscious dogs. Catheters, prepared from Micro-Renathane tubing, were surgically implanted in right ventricular superficial veins of three anesthetized dogs. Also implanted were an arterial catheter, a right coronary flow transducer, and a right coronary artery constrictor. The coronary catheter was introduced at a venous bifurcation so that its side holes were positioned above the bifurcation; both ends of the catheter were exteriorized. Heparinized saline was continuously infused through the venous catheter by a battery-powered pump. The dogs were maintained for 10-13 days after surgery, and all catheters remained patent. Multiple right coronary venous samples were collected from each dog. These samples were analyzed for venous oxygen tension (PvO2) under baseline conditions, with right coronary pressure reduced to 50 mmHg, and during the reactive hyperemia after release of the right coronary artery constriction. PvO2 was 27.7 +/- 1.0 mmHg at baseline, 23.4 +/- 1.0 mmHg during coronary artery constriction, and 34.3 +/- 1.5 mmHg during reactive hyperemia. These data and the position of the catheter at autopsy demonstrated that coronary venous blood had been sampled.

Insulin improves cardiac contractile function and oxygen utilization efficiency during moderate ischemia without compromising myocardial energetics.

Insulin improves myocardial contractile function during moderate ischemia, but the mechanism is unknown. To determine effects of insulin on myocardial oxygen utilization efficiency (O2UE) and energetics, regional left coronary perfusion pressure (CPP) was lowered sequentially from 100 to 60, 50, and 40 mmHg in 24 anesthetized, open-chest dogs. Regional power index (PI), myocardial oxygen consumption (MVO2), and O2UE index (PI/MVO2) were determined in untreated and insulin treated (4 U/min, i.v.) hearts. Biopsies were obtained from six untreated and six insulin-treated hearts at CPP=40 mmHg for determining high energy phosphates and the cytosolic phosphorylation potential. Measurements were compared with data from normal, untreated myocardium (n=11). MVO2 fell (P<0.05) in all hearts as CPP was lowered to 40 mmHg, and was unaffected by insulin treatment. PI decreased 32 and 75% in untreated hearts at CPP=50 and 40 mmHg, respectively (P<0.05). In insulin treated hearts, PI was not significantly depressed at CPP>40 mmHg, and fell only 26% at CPP=40 mmHg. O2UE increased (P<0.05) in all hearts at CPP=60 mmHg. In insulin treated hearts, O2UE was greater (P<0.05) at CPP=50 and 40 mmHg than at CPP=100 mmHg, and greater (P<0.05) than in untreated hearts at CPP=40 mmHg. Reducing CPP to 40 mmHg produced similar metabolic changes in all hearts. Compared to normal myocardium, ATP content of untreated and treated hearts was unchanged, creatine phosphate content decreased 21 and 14%, creatine content increased 24 and 30%, inorganic phosphate concentration increased 108 and 140%, and phosphorylation potential decreased 80 and 77%. We conclude that insulin markedly improves PI and O2UE without altering cytosolic energetics during moderate myocardial ischemia.

Downregulation of ventricular contractile function during early ischemia is flow but not pressure dependent.

The mechanism responsible for the abrupt fall in myocardial contractile function following coronary artery obstruction is unknown. The "vascular collapse theory" hypothesizes that the fall in coronary perfusion pressure after coronary artery obstruction is responsible for contractile failure during early ischemia. To test the role of vascular collapse in downregulating myocardial contractile force at the onset of ischemia, coronary flow of isolated rat hearts was abruptly decreased by 50, 70, 85, and 100% of baseline, and subsequent changes in coronary perfusion pressure and ventricular function were recorded at 0.5-s intervals. At 1.5 s after flow reductions ranging from 50 to 100%, decreases in contractile function did not differ, although perfusion pressure varied significantly from 45 +/- 1 to 20 +/- 2 mmHg. When function fell to 50% of baseline, perfusion pressures ranged from 35 +/- 0.5 to 2.5 +/- 1 mmHg for flow reductions ranging from 50 to 100%. Identical contractile function at widely differing coronary perfusion pressures is incompatible with the vascular collapse theory.

Effect of ethanol on myocardial infarct size in a canine model of coronary artery occlusion-reperfusion.

This study was conducted to determine if elevated blood alcohol prior to acute coronary artery occlusion affects myocardial infarct size in an in vivo canine model. Seven pentobarbital anesthetized open-chest dogs received 10 min iv infusion of ethanol (0.08 g/kg/min). Ten min after ethanol, the left anterior descending coronary artery (LAD) was occluded distal to its first major branch for 60 min. The LAD was then reperfused for 5 h. Following electrically induced ventricular fibrillation, the area at risk of infarction was delineated with dye. The area of infarction was identified by staining with triphenyl tetrazolium chloride. Eleven untreated control experiments were also conducted. Mean blood ethanol concentration was 155+/-26 mg/dl just prior to LAD occlusion and 47+/-3 mg/dl after 4 h reperfusion. Ethanol infusion had no effect on systemic hemodynamic variables during ischemia. In ethanol treated animals, the area at risk was 19.7+/-3.0% of the left ventricle, and the infarct size was 20.9 +/-4.8% of the area at risk. In control experiments, the area at risk was 23.0+/-4.1% of the left ventricle (p > 0.05), and the infarct size was 21.6+/-3.8% of the area at risk (p > 0.05). Collateral blood flow to ischemic region did not differ between the two groups, and the relationships between infarct size and collateral flow were similar for control and untreated hearts. Acute ethanol exposure prior to coronary artery occlusion and subsequent reperfusion does not affect myocardial infarct size in the heart of the anesthetized dog.

Right coronary autoregulation in conscious, chronically instrumented dogs.

Right coronary (RC) autoregulation and right ventricular (RV) function were assessed in conscious dogs, chronically instrumented to measure RC flow and RC pressure (RCP) as a hydraulic occluder on the RC was inflated. Dogs were then anesthetized, and RC autoregulation and RV function were again assessed. In the conscious state, moderate RC autoregulation was present with closed loop gains (Gc) of 0.59-0.27 as RCP was reduced from 100 to 40 mmHg. In the anesthetized state, Gc was not significantly less than in the conscious state at RCP >50 mmHg. The range and potency of RV autoregulation were greater in both groups than for previously reported findings in anesthetized dogs with RC perfused by an extracorporeal system. RV contractile function was well maintained in conscious and anesthetized dogs at RCP >45 mmHg. We conclude the following: 1) modest RC autoregulation is present in the conscious dog, 2) anesthesia limits the range but not the degree of RC autoregulation, 3) extracorporeal perfusion systems appear to depress RC autoregulation, and 4) RV contractile function remains constant in both conscious and anesthetized dogs until RCP falls below 50 mmHg.

Insulin improves contractile function during moderate ischemia in canine left ventricle.

This study determined the effects of insulin on myocardial contractile function and glucose metabolism during moderate coronary hypoperfusion. Coronary perfusion pressure (CPP) was lowered from 100 to 60, 50, and 40 mmHg in the left anterior descending coronary artery of anesthetized, open-chest dogs. Regional glucose uptake (GU), lactate uptake, myocardial O2 consumption, and percent segment shortening (%SS) were measured without (n = 12) or with intravenous (4 U/min, n = 12) or intracoronary insulin (4 U/min, n = 6). Glucose metabolites were also measured in freeze-clamped biopsies of control heart (n = 6) and hearts treated with intravenous insulin (n = 6) at the completion of the protocol (40 mmHg CPP). GU increased with intravenous and intracoronary insulin (P < 0.01). In all groups, GU was unaffected by reduced CPP, although lactate uptake decreased significantly (P < 0.01). Myocardial O2 consumption fell (P < 0.05) as CPP was lowered in all groups and was not altered significantly by intravenous or intracoronary insulin treatment. Without insulin, %SS decreased 72% (P < 0.05) at 40 mmHg CPP, but in hearts treated with intravenous and intracoronary insulin, %SS was not reduced (P > 0.05). Myocardial glycogen, alanine, lactate, and pyruvate contents were not significantly different in untreated hearts and hearts treated with intravenous insulin. Thus, in moderately ischemic canine myocardium, insulin markedly improved regional contractile function and did not appreciably increase the products of anaerobic glucose metabolism.

Elevated right atrial pressure does not reduce collateral blood flow to ischemic myocardium.

Right atrial pressure (RAP) may become substantially elevated during heart failure and has been reported to reduce collateral flow to the ischemic myocardium of isolated hearts. The effect of elevated RAP on blood flow to collateral-dependent and normal myocardium of in situ hearts was studied in 20 open-chest anesthetized dogs with acute occlusion of the left anterior descending coronary artery. Regional myocardial blood flow was measured with radioactive microspheres while RAP was elevated by restricting right ventricular (RV) outflow with constant aortic pressure. Increasing RAP from 3.8 +/- 0.5 to 21.5 +/- 0.8 and then to 34.3 +/- 0.9 mmHg did not reduce blood flow to any transmural region of LV normal or collateral-dependent myocardium. Further elevation of RAP to 49.3 +/- 1.1 mmHg reduced subepicardial but not subendocardial collateral flow. Blood flow to normal RV increased. Retrograde flow and peripheral coronary pressure increased as RAP was elevated. Previously injected 11-micron microspheres were present in the retrograde flow when RAP was elevated; thus retrograde capillary flow contributed to the retrograde flow. The results explain discrepancies among previous reports, and they are consistent with a waterfall phenomenon in the coronary collateral circulation.

Correlation between myocardial contractile force and cytosolic inorganic phosphate during early ischemia.

To test the role of inorganic phosphate (Pi) in downregulation of myocardial contractile force at the onset of ischemia, Pi of rat hearts was determined with 31P nuclear magnetic resonance spectroscopy. Forty cycles of brief hypoperfusion (30% of baseline flow for 33 s) were used to achieve a time resolution of 0.512 s for comparing dynamic changes in Pi and contractile force. Initial control values of left ventricular developed pressure (LVP), heart rate, and oxygen consumption were 136 +/- 11 mmHg, 236 +/- 4 beats/min, and 95 +/- 3 microl O2 x min(-1) x g(-1); these values were unchanged at the end of the experiment. During the first 10 s of hypoperfusion, Pi increased at a rate (percentage of the total observed change) faster than the decrease in LVP; Pi and LVP then changed at the same rate during the remainder of the hypoperfusion. ADP did not change in advance of LVP. Intracellular pH did not change. The results indicate that Pi plays an important role in initiating the downregulation of myocardial contractile force at the onset of ischemia. Perfusion pressure also declined faster than LVP at the onset of ischemia, indicating potential importance of vascular collapse in contractile downregulation during early ischemia.