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Aims Antithrombin is an important inhibitor of the coagulation system, additionally exerting specific anti-inflammatory effects on endothelial cells. Healthy vascular endothelium is coated by the endothelial glycocalyx, diminution of which increases capillary permeability, e.g. after ischaemia. Antithrombin is known to infiltrate the glycocalyx, binding to glycosaminoglycans, and to preserve the glycocalyx after application tumour necrosis factor-α. We investigated the influence of antithrombin on glycocalyx subjected to ischaemia/reperfusion. Methods and results Isolated guinea pig hearts were perfused with Krebs–Henseleit buffer (KHB). Antithrombin was applied to achieve physiological levels (1 U/mL) before inducing 20 min of ischaemia (37°C). Hearts were reperfused for 20 min at constant flow (baseline perfusion pressure 70 cmH2O) with KHB or KHB plus 2 g% hydroxyethyl starch (130 kDa). Coronary net fluid filtration was assessed directly by measuring transudate formation on the epicardial surface. Post-ischaemic coronary release of syndecan-1 and heparan sulfate was quantified by ELISA. Hearts were perfusion-fixed to visualize the glycocalyx by electron microscopy. Ischaemia/reperfusion caused degradation of the glycocalyx, enhanced coronary perfusion pressure, and increased vascular permeability. Antithrombin significantly reduced post-ischaemic glycocalyx shedding, coronary perfusion pressure, coronary leak, and tissue oedema formation compared to untreated hearts. Additional application of colloid augmented these actions of antithrombin. Electron microscopy revealed a mostly intact glycocalyx after antithrombin treatment. Conclusion Antithrombin preserves the endothelial glycocalyx, sustaining the vascular barrier function and reducing interstitial oedema. The potentiated effect of colloid in these hearts suggests that the prevention of shedding should be of functional benefit also in vivo .

Objective: : The present study examined the role of nitric oxide (NO) in oxygen demand–supply balance in hypoperfused canine right ventricular myocardium. Methods: : The right coronary artery of anesthetized, open-chest dogs was perfused at pressures of 80, 60, and 40 mm Hg, and right ventricular myocardial oxygen consumption, right coronary blood flow and other hemodynamic and cardiac function variables were measured. Right ventricular mechanical function was indexed as the product of heart rate×peak right ventricular systolic pressure×right ventricular d P /d t max. NO synthesis blocker N ω-nitro-l-arginine methyl ester (l-NAME, 150 μg/min) was infused into the right coronary artery to block NO synthesis. Results: : Neither hypoperfusion nor l-NAME altered right ventricular function. Right ventricular myocardial oxygen consumption fell with coronary perfusion pressure, but less steeply after l-NAME, and at all perfusion pressures was elevated above control. The increase in myocardial oxygen consumption in the absence of NO was met by increased oxygen extraction and by non-NO dependent vasodilation, but the relationship between flow and oxygen consumption was displaced downward after l-NAME. As right coronary perfusion pressure was reduced, the relationship between right ventricular oxygen consumption and right coronary venous PO2 became steeper after l-NAME, and right coronary venous PO2 was significantly reduced. Conclusions: : During right coronary hypoperfusion, right ventricular function is well maintained, but myocardial oxygen consumption falls, reflecting an increase in oxygen utilization efficiency. NO contributes to this adaptation to hypoperfusion by restraining myocardial oxygen consumption, and by promoting coronary vasodilation with less severe reduction in myocardial PO2. NO has an important role in right ventricular oxygen demand–supply balance when right coronary perfusion pressure is reduced.

Objective: The JCR:LA-corpulent rat is a unique animal model of human vascular disease that exhibits a profound insulin resistance, vasculopathy, and cardiovascular dysfunction. We tested the hypothesis that the defects affect endothelial and smooth muscle function of the coronary microvasculature as well as cardiac contractility. Coronary, myocardial and aortic function were assessed in obese (homozygous for the cp gene, cp/cp) and lean (heterozygous or homozygous normal, +/?) littermates aged 7 and 18 weeks. Methods: Coronary endothelial relaxation was examined in isolated perfused hearts by determining the effect of bradykinin (0.1–1000 nmoll−1) on coronary perfusion pressure (CPP), myocardial mechanical function was evaluated in terms of left-ventricular developed pressure (LVDevP), and aortic relaxation with the endothelium-dependent agonist, A 23187 (1–1000 nmoll−1). Results: In rats aged 7 weeks, bradykinin reduced CPP from 133±1 mmHg to 43±1 mmHg (−67%) in lean rats, but only to 64±3 mmHg (−52%) in corpulent rats ( n =6, P

Objective The purpose was to investigate the influence of the 38-amino-acid neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP38), on contractile function and coronary vascular tone in neonatal hearts. Methods Isolated, paced (150 bpm), isovolumically-beating, piglet hearts ( n = 19) underwent retrograde aortic perfusion at constant coronary flow (≈2.5 ml/min/gwet) with an erythrocyte-enriched (Hct 15-0%) solution (37 °C). Agonists were injected into the aortic root of hearts, and the changes in + dP/dtmax and − dP/dtmax (reflecting contractility), and coronary perfusion pressure (reflecting vascular tone) were determined. Responses to PAPCAP38 were compared to isoproterenol, and to the truncated peptide PACAP6–38. Results PACAP38 (0.1 and 0.5 nmol) increased + dP/dtmax from 1387.4 ± 134.6 to 1619.0 ± 118.7, and from 1296.2 ± 93.4 to 1872.2 ± 111.4 mmHg/s ( P < 0.05); changed −dP/dtmax from −1087.6 ± 107.5 to −1206.6 ± 93.6, and from −1025.0 ± 46.8 to −1375.4 ± 80.9 mmHg/s ( P < 0.05) and decreased coronary perfusion pressure from 61.8 ± 2.5 to 51.0 ± 3.8, and from 62.5 ± 1.0 to 45.3 ± 3.3 mmHg ( P < 0.05), respectively. In comparison, isoproterenol (0.1 nmol) increased +dP/dtmax from 1313.6 ± 62.8 to 1679.0 ± 74.4 ( P < 0.05), and −dP/dtmax from −1026.4 ± 54.1 to −1222.6 ± 57.4 mmHg/s ( P < 0.05). PACAP6–38 reduced PACAP38's coronary vasodilatory, but not its contractile, effect. When compared to our previous studies of the the 27-amino-acid neuropeptide PACAP27, PACAP38 had less potent contractile, but similar vasodilatory effects. Conclusions PACAP38 enhanced contractility and produced coronary vasodilation in piglet hearts, which may make PACAP38 a promising cardiotonic agent for the treatment of neonates with heart failure.

Objective: We have previously demonstrated that myocardium is capable of down-regulating its O2 requirements and thus avoiding ischaemia when O2 supply is limited. The present study tested the hypothesis that endogenous adenosine produced this protective response when O2 supply was decreased by moderate coronary hypopertusion or moderate coronary hypoxaemia. Methods: In anaesthetised dogs, hearts were exposed by left thoracotomy and instrumented for measuring intraventricular pressure and regional myocardial segment length. The left anterior descending coronary artery was isolated, cannulated, and extracorporeally perfused. Coronary O2 supply was moderately reduced by lowering coronary perfusion pressure from 100 to 60 mmHg or by lowering coronary arterial O2 content by 50%. Hearts were treated with intracoronary infusions of adenosine, adenosine deaminase to degrade endogenous adenosine or with erythro-9-(2-hydroxy-3-nonyl)-adenine · HC1 (EHNA) to inhibit adenosine degradation by endogenous adenosine deaminase, during β-adrenergic stimulation with isoprenaline. Cardiac power in the left anterior descending perfusion territory was indexed by the product of heart rate · left ventricular peak systolic pressure · percent systolic segment shortening. O2 utilisation efficiency was taken as the ratio of power index/myocardial O2 consumption. Results: Prior to a reduction in O2 supply, isoprenaline did not alter O2 utilisation efficiency. Intracoronary adenosine increased O2 utilisation efficiency during isoprenaline stimulation by 23% ( P

Objective: The aim was to examine the effects of the Na+/H+ exchange inhibitors amiloride and methylisobutyl amiloride (MIA) in buffer perfused rabbit hearts subjected to one hour of normothermic ischaemia (37 °C) followed by reperfusion. Methods: Experiments were carried out in five groups of Langendorff perfused rabbit hearts: (1) control, (2) amiloride, and (3) MIA (agents in both the preischaemic and reperfusion perfusate), (4) amiloride-R and (5) MIA-R (agents added at reperfusion only). Functional evaluation included serial measurement of resting tension, force, rates of ventricular force development and relaxation, and coronary perfusion pressure. Samples of coronary effluent were obtained for creatine kinase assay and hearts were freeze clamped for metabolite assays. Results: Reperfusion resulted in a marked increase in resting tension in group (1) which was statistically significant compared to groups (2) and (3). Groups (2) and (3) also showed significantly improved recovery of ventricular force, rate of force development, and rate of ventricular relaxation. Addition of either agent only during reperfusion failed to produce a significant beneficial effect. There were no significant differences among the groups with respect to postreperfusion creatine kinase release or end reperfusion metabolite levels. Conclusion: This study shows for the first time that both of the Na+/H+ exchange inhibitors amiloride and MIA produce improved recovery of ventricular function in rabbit hearts subjected to ischaemia and reperfusion, although the beneficial effect was not obtained with drug administration at the time of reperfusion only.

Objective: The mechanism by which changes in coronary perfusion alter myocardial oxygen consumption (MVo2; Gregg phenomenon) is controversial. This study examined the effect of coronary perfusion on myocardial contractile force and systolic ventricular stiffness in the intact, ejecting heart. Methods: During selective perfusion of the left anterior descending coronary artery, coronary blood flow was changed with or without concurrent changes in coronary perfusion pressure in 19 α chloralose anaesthetised dogs. Regional myocardial segment length (end diastolic length; end systolic length) and developed force were measured with piezoelectric crystals and with a miniature force transducer, respectively. MVo2 was calculated from coronary flow and arteriovenous O2 difference. The slope of the force-length curve during ejection period (ΔF/ΔSL) was used as an index of systolic myocardial stiffness. Results: When coronary perfusion pressure was varied from 60 to 180 mm Hg (protocol 1, n = 11), maximum developed force (Fmax), ΔF/ΔSL, and MVo2, increased with perfusion pressure while end diastolic length, segmental shortening, and other haemodynamic variables stayed constant. When coronary blood flow was increased at constant perfusion pressure by infusion of either a low dose or a high dose adenosine (protocol 2, n = 8), Fmax, ΔF/ΔSL, and MVo2 increased while end diastolic length, segmental shortening, and other haemodynamic variables stayed constant. MVo2, and ΔF/ΔSL increased more steeply with flow in protocol 1. Conclusions: (1) Increased coronary blood flow enhances myocardial contractile force, systolic ventricular stiffness, and MVo2 in the intact, ejecting heart. (2) Coronary blood flow induced changes in myocardial contractile force and systolic ventricular stiffness, but not end diastolic length, are probably responsible for coronary blood flow related changes in MVo2. Cardiovascular Research 1994; 28 :1331-1336

Objective: The aim was to obtain an estimate of the affinity of glibenclamide binding to ATP sensitive potassium channels of coronary smooth muscle cells in the intact guinea pig heart, in order to assess possible cardiovascular risks for diabetic patients receiving sulphonylurea drugs. Methods: The arrested isolated perfused heart was used as a bioassay for KATP channels in coronary resistance vessels. The decrease of coronary perfusion pressure induced by hypoxia and by various concentrations of the potassium channel opener levcromakalim was measured and the inhibitory effect of glibenclamide on hypoxic and drug induced vasodilatation was analysed. Results: The delay between application of hypoxic solution and half maximum vasodilatation was on average 105(SEM 4) s. It was increased by 17.6(2.0) s in the presence of 5 nM glibenclamide. The dose-response curve of the effects of levcromakalim on coronary perfusion pressure was shifted to the right in the presence of 20 nM to 1 μM glibenclamide. The concentrations of levcromakalim required to produce half maximum vasodilatation in the presence and absence of glibenclamide were determined, and the data were analysed using a Schild plot. The measured concentration ratios could be fitted by a straight line with a slope of 0.93(SD 0.04), which was not significantly different from 1. This is consistent with competitive inhibition of the vasodilator effects of levcromakalim by glibenclamide. The apparent dissociation constant of glibenclamide binding to KATP channels in coronary smooth muscle cells was 35 nM. Conclusions: The KATP channels in coronary resistance arteries are almost as sensitive to inhibition by glibenclamide as the KATP channels in pancreatic β cells. It is likely that the plasma concentrations reached after oral ingestion of glibenclamide may inhibit a fraction of the KATP channels in coronary smooth muscle cells and thus impair hypoxic dilatation of coronary resistance arteries. Cardiovascular Research 1994; 28 :888-893

Objective: Reports of autoregulation in the right coronary vasculature have varied from non-existent to almost perfect. At least some of this discrepancy may be due to failure to account for changes in myocardial metabolism secondary to the method used to vary perfusion pressure. The aim of this study was to determine if the potent autoregulation reported when right coronary perfusion pressure was lowered by opening a large arteriovenous shunt was due to increased right ventricular myocardial oxygen consumption (MVO2) induced by augmented preload and afterload. Methods: Two protocols were used to produce right coronary perfusion pressures of 100, 80, and 60 mm Hg in anaesthetised dogs. In both protocols the right coronary artery was cannulated and supplied with blood from a pressurised chamber. In protocol 1, right coronary perfusion pressure was decreased independently of aortic pressure, and in protocol 2, aortic pressure was decreased in parallel with right coronary perfusion pressure by opening a large arteriovenous shunt. Right coronary blood flow, central venous pressure, and pulmonary arterial pressure were measured, and right ventricular oxygen extraction and MVO2 were calculated at each level of right coronary perfusion pressure. Results: In protocol 1, reducing right coronary perfusion pressure alone resulted in decreased right coronary blood flow and right ventricular MVO2. Central venous pressure (right ventricular preload) and pulmonary arterial pressure (right ventricular afterload) did not change. In protocol 2, opening the arteriovenous shunt increased venous return, as shown by increased central venous pressure and pulmonary arterial pressure. This increased right ventricular MVO2 at the lower right coronary perfusion pressures and maintained right coronary blood flow at the level recorded when right coronary perfusion pressure was 100 mm Hg. Conclusions: This apparently potent autoregulation resulted from the shunt induced increase in oxygen consumption at low right coronary perfusion pressures, in contrast to the decreased right ventricular oxygen consumption and right coronary blood flow observed when right coronary perfusion pressure is selectively decreased. Cardiovascular Research 1993; 27 :748-752

Objective: The aim was to determine whether aging alters coronary vascular responses to cholinergic and α adrenergic stimulation. Methods: Changes in coronary perfusion pressure and myocardial contractility in response to infusion of cholinergic and a adrenergic agonists and antagonists were determined in isolated Langendorff perfused hearts from adult (6-8 months old) and aged (28-30 months old) Fischer 344 rats. Results: In electrically paced hearts (250 beats·min−1), perfused at constant perfusate flow rate, the cholinergic agonist carbachol (10−10 –106M) elicited concentration dependent coronary vasoconstriction. The maximum response and the sensitivity to carbachol were more than twofold greater in the aged than in the adult heart: concentration of carbachol producing 50% increase in coronary perfusion pressure: adult 916(SEM 210) nM; aged 21(7) nM; p

The aim was to study the effects on coronary vascular tone of three inhibitors of nitric oxide (NO) synthesis.Studies were performed on isolated perfused hearts of 74 male New Zealand White rabbits fed normal laboratory diet. Resting coronary perfusion pressure was increased to 40-60 mm Hg with the thromboxane mimetic 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy prostaglandin F2 alpha (U46619). The effects of NG-monomethyl-L-arginine (L-NMMA), N-iminoethyl-L-ornithine (L-NIO), and NG-nitro-L-arginine methyl ester (L-NAME) (0.3-300 microM) on resting coronary perfusion pressure were determined. The effects of these compounds, at concentrations that increased the resting perfusion pressure to a similar extent, on the fall in perfusion pressure induced by acetylcholine (0.1 microM) and glyceryl trinitrate (1 microM) were also investigated. In these studies the resting perfusion pressure was maintained at 40-60 mm Hg by reducing the concentration of U46619.L-NMMA, L-NIO, and L-NAME induced concentration dependent increases in resting coronary perfusion pressure (n = 3-9, p0.05). L-NAME had the greatest potency and efficacy, increasing the resting pressure by 48.0(SEM 9.6) mm Hg at 30 microM. L-NIO and L-NMMA increased perfusion pressure by 27.3(3.0) and 19.5(5.8) mm Hg respectively at the maximum concentration studied (300 microM). However, at concentrations that were equieffective on resting perfusion pressure (15 mm Hg increase), L-NMMA (100 microM), but not L-NIO (25 microM) or L-NAME (4 microM), significantly inhibited the fall in pressure induced by acetylcholine by 57.2(5.0)%, n = 6, p0.05. This effect of L-NMMA++ was attributed to a shorter duration of fall and was reversed by L-arginine (300 microM). L-NMMA (100 microM) and L-NIO (25 microM) potentiated the effect of glyceryl trinitrate by increasing the peak fall in perfusion pressure by 75.6(11.0)% and 68.8(24.1)% respectively (n = 6 for each, p0.05).The differential effects of the three inhibitors on resting coronary perfusion pressure and the acetylcholine induced fall in coronary perfusion pressure suggest that basal and stimulated NO synthesis may be differentially regulated. Reduction in the synthesis of endogenous NO by these compounds potentiates the glyceryl trinitrate induced fall in perfusion pressure, which may have important clinical implications.

Objective : Amitriptyline, one of the most prescribed antidepressants, is reported to claim a large number of human lives due to drug overdose related cardiac arrest. Although amitriptyline poisoning has long been recognized as a frequent and serious fatality in the medical field, few efforts have been made to devise methods for treating its toxicity. To address this issue, phospholipid-based nanosized vesicles (spherulites) were employed to reverse the cardiotoxicity induced by amitriptyline in an isolated heart perfusion model. Methods : The ability of spherulites to efficiently take up amitriptyline was first established in vitro in protein free and albumin-containing buffers. Vesicles bearing an internal pH of 3.0 or 7.4 were then infused into amitriptyline pre-intoxicated isolated rat hearts, and changes in coronary perfusion pressure (CPP), the first derivative of left ventricular pressure (d P /d t max) and heart rate were monitored. Control hearts received no vesicles. Results : Based on the recoveries in CPP observed, the efficacies of the formulations were ranked as follows: control=pH 7.4-spherulites

Objective: The role of nitric oxide (NO) in myocardial ischemia/reperfusion injury remains controversial as both NO donors and NO synthase (NOS) inhibitors have shown to be protective. We generated transgenic (TG) mice that overexpress endothelial NOS (eNOS) exclusively in cardiac myocytes to determine the effects of high cardiac NO levels on ischemia/reperfusion injury and cellular Ca2+ homeostasis. Wild-type (WT) mice served as controls. Methods: Hearts were perfused in vitro and subjected to 20 min of total no-flow ischemia and 30 min of reperfusion ( n =5 per group). Left ventricular function, cGMP levels and intracellular Ca2+ transients (Ca2+i) were determined. Results: Left ventricular pressure was reduced (maximum, −33%) and basal cardiac cGMP was increased (twofold) in TG hearts, and the changes were reversed by NOS blockade with NG-nitro-l-arginine methyl ester (l-NAME). Relative to baseline, recovery of reperfusion contractile function was significantly better in hearts from TG (98%) than WT (51%) mice, and l-NAME abolished this effect. Heart rate and coronary perfusion pressure were not different between groups. Systolic and diastolic Ca2+i concentrations were similar in WT and TG hearts, but Ca2+i overload during early reperfusion tended to be less in TG hearts. Kinetic analysis of pressure curves and Ca2+i transients revealed a faster left ventricular diastolic relaxation and abbreviated aequorin light signals in TG hearts at baseline and during reperfusion. Conclusions: High levels of NO/cGMP strongly protect against ischemia/reperfusion injury, the protection is largely independent of changes in Ca2+i modulation, but relates to reduced preischemic performance. Myocyte-specific NO augmentation may aid in studies of the (patho)physiological roles of cardiac-derived NO.

Objective: The non-specific serine protease inhibitor aprotinin is currently used to reduce blood loss and the need for blood transfusion after cardiopulmonary bypass. We have recently reported that aprotinin impairs endothelium-dependent but not endothelium-independent relaxations in rat thoracic aortic rings due to its inhibitory effect on endothelial nitric oxide (NO) production. In light of these findings, the current study was designed to investigate the effects of aprotinin on coronary endothelial function in isolated rat hearts and on the expression of endothelial NO synthase (eNOS) in cultured rat coronary microvascular endothelial cells (CMEC). Methods: Hearts obtained from Sprague–Dawley rats were perfused on a constant flow Langendorff isolated heart system and coronary perfusion pressure and cardiac parameters were recorded. The coronary relaxant responses to bolus infusions of bradykinin (BK) and sodium nitroprusside (SNP) were recorded in the absence and presence of aprotinin. Total RNA and protein samples were extracted from CMEC incubated with aprotinin or the vehicle, 0.9% NaCl. RT-PCR-Southern blotting and Western analyses were carried out to assess eNOS mRNA and protein levels, respectively. Results: Aprotinin (125 and 250 kIU/ml) increased coronary perfusion pressure without changing the heart rate and cardiac contractility. Aprotinin inhibited BK-induced coronary vasodilatation at 250 kIU/ml, but not at 125 kIU/ml concentrations. The relaxant response to SNP did not change in response to either concentration of the drug. Incubation of CMEC with aprotinin down-regulated eNOS mRNA and protein at 250 kIU/ml, but not at 125 kIU/ml concentration. Conclusion: These data suggest that aprotinin selectively inhibits NO synthesis at higher doses (≥250 kIU/ml) and therefore impairs endothelium-dependent coronary vascular tone. This effect of the drug may contribute to its ‘blood-sparing’ action, but may also account for the increase in the incidence of postoperative graft thrombosis observed in clinical practice during aprotinin therapy.

Objective: Recent evidence suggests a possible role for nitric oxide (NO) in atrial natriuretic peptide-induced blood pressure effects. We tested the hypothesis that C-type natriuretic peptide (CNP)-mediated relaxation of the rat coronary circulation involves NO and activation of soluble guanylyl cyclase. Methods: Rat hearts ( n =6 per group) were perfused in vitro at constant flow and the effect of CNP (0.1–3 μmol/l) on coronary perfusion pressure (a measure of vascular tone) and release of guanosine 3′,5′-cyclic monophosphate (cGMP) was determined in absence and presence of the nitric oxide (NO) synthase inhibitor NG-nitro-l-arginine (l-NNA; 0.2 mmol/l) or the natriuretic peptide receptor antagonist HS-142-1 (50 μg/ml). The involvement of Ca2+-gated and ATP-dependent K+ channels in CNP-induced relaxation was tested with iberiotoxin (30 nmol/l) and glibenclamide (1 μmol/l), respectively. Rings of rat aorta ( n =12) were tested using the organ bath set-up. Results: CNP reduced perfusion pressure from 134±2 mmHg (baseline) to 71±1 mmHg (−48%) and this effect was significantly attenuated by l-NNA (−37%) or HS-142-1 (−19%). In presence of glibenclamide, CNP reduced perfusion pressure to 92±2 mmHg (−32%), in presence of iberiotoxin to 93±1 mmHg (−30% and in their combined presence to 102±2 mmHg (−23%) ( P

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 (Δ F /ΔSL) 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 ( F max), Δ F , and MVO2 decreased linearly, whereas end-diastolic length, ΔSL, 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, F max and Δ F continued to fall, end-diastolic segment length and right atrial pressure increased significantly, ΔSL and RV d P /d t max fell significantly, and Δ F /ΔSL 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 ΔSL 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.

Objective: The aim of this study was to investigate whether cardiodepressant mediators are released after myocardial ischaemia during reperfusion. Methods: Using a double heart model, the effect of the reoxygenated coronary effluent of an isolated guinea pig heart on a sequentially perfused second heart was studied under control conditions and after 10 min ischaemia of the first heart. Investigation of the modulating role of known autacoids took place by using free radical scavengers, an NO synthase inhibitor and adenosine receptor antagonists. In order to identify the chemical nature of cardiac metabolites, the coronary effluent was also subjected to different chemical treatment modes. Results: No haemodynamic changes were observed during sequential perfusion under control conditions. After 10 min of global ischaemia in heart I, a marked decrease in LVP (−22%), LVdP/dtmax (−43%), LVdP/dtmin (−41%) and coronary perfusion pressure (−25%) was measured in heart II during sequential perfusion. The negative inotropic effect was rapid in onset and reversible within 5 min; free radicals, nitric oxide and adenosine were not involved. Storage of the coronary effluent of the first heart up to 24 h, heating, or protease treatment did not modify its cardiodepressant effects on the second sequentially perfused heart. Conclusions: These results suggest the release—from an isolated heart after ischaemia during reperfusion—of a cardiodepressant mediator which induces a potent reversible negative inotropic effect on a sequentially perfused heart. The mediator is stable and in all probability not a protein.

Objective: Since muscles, vessels and interstitial spaces are in close physical proximity in the heart wall, interstitial (i.e., intramyocardial) pressure (IMP) should be affected by the stresses of the vessels and/or the muscular tissue surrounding the interstitial spaces. Thus, we tested the hypothesis that increasing the stresses (or stiffness) of the surrounding tissues by muscle contraction or stretching—produced externally by stretching the LV cavity or internally by increasing coronary perfusion pressure—has a greater effect than LV cavity pressure per se on IMP. Methods: In isolated rabbit hearts we measured IMP with small (

Objective: Angiotensin II (ANG II) has recently been reported to increase inotropy in adult rabbit myocytes by a mechanism of alkalinization and consequent increased myofilament sensitivity to calcium. Accordingly, we tested the hypothesis that ANG II would have a greater inotropic effect during ischemic conditions than it would during normoxia, since ischemia-induced intracellular acidosis contributes to ischemic contractile depression by decreasing myofilament calcium sensitivity. Methods: We studied the effects of ANG II in isolated, red-blood-cell-perfused, isovolumic rat and rabbit hearts during normoxic perfusion conditions and at graded reductions in coronary perfusion pressure (CPP). At each level of perfusion, ANG II was infused at progressively increasing concentrations ranging from 10−11 to 10−5 M. The maximal effective ANG II concentration was 10−7 M. Results: Our studies show that ANG II caused comparable absolute increases in isovolumic LV developed pressure in normoperfused and hypoperfused rabbit hearts. However, since contractile function was markedly depressed in ischemic hearts prior to ANG II administration, the relative inotropic response to ANG II was significantly greater during ischemia than normoxia. Similarly, ANG II had no positive inotropic effect in the rat during normoxia, but increased contractility during ischemia. To assess specifically the potential of ANG II to reverse the negative inotropy of acidosis, normoxic non-ischemic rat hearts were perfused with a hypercarbic acidotic perfusate (pH = 7.1). During the hypercarbic perfusion when contraction was depressed by acidosis, ANG II [10−7]M increased LV developed pressure by 19% and + dP/dt by 27% ( P < 0.05), in contrast to its lack of inotropic effect at a normal pH. The positive inotropic effect observed in rat hearts with ANG II during ischemia was significantly attenuated ( P < 0.001) by concomitant infusion with amiloride, 5-( N -ethyl- N -isopropyl) (EIPA), a Na+/H+ exchange inhibitor. Conclusions: We conclude that during normoxia, ANG II has a different inotropic potency in rabbits from that in rats. In both species, the relative inotropic responsiveness of ANG II is potentiated during low-flow ischemia. These results are consistent with a relative intracellular alkalinization that occurs secondary to ANG II's action to stimulate Na+/H+ exchange.

Objective: Little is known as to whether an increase in coronary perfusion pressure can alter the right ventricular (RV) distensibility and the contractile function as it does in the case of the LV. Methods: In eight isolated isovolumically contracting canine hearts, RV and LV volumes and coronary perfusion were independently controlled. Effects of an increase in coronary perfusion pressure (from 73 ± 1 to 152 ± 6 mmHg) on the end-diastolic and end-systolic pressure-volume relations in both RV and LV were assessed. Results: Following an increase in coronary perfusion, and at a similar volume of the ventricles, end-diastolic pressure was elevated by 2.8 ± 0.8 mmHg in RV and 8.9 ± 2.0 mmHg in LV ( P < 0.01; RV vs LV), and the slope of RV end-systolic pressure-volume relation, Ees, increased by 11 ± 6% ( P < 0.05) and that of the LV Ees by 21 ± 5% ( P < 0.01). The percent change of RV pressure-volume area (PVA) was less than that in LV-PVA (26 ± 9 vs 48 ± 11%; P < 0.05). Conclusions: Accordingly, increases in coronary perfusion pressure and/or flow decreased the RV distensibility and enhanced the RV contractile function, the extent of which, however, was less than that in the LV.

Objective: Washed platelets have been shown to protect isolated buffer perfused rat hearts from injury and dysfunction following ischaemia-reperfusion. This study was designed to investigate whether platelet glutathione redox cycle contributes to the protective effect of platelets. Methods: Isolated rat hearts were perfused with Krebs-Henseleit buffer alone, buffer containing platelets, or buffer containing platelets pretreated with inhibitors of glutathione redox cycle. All hearts were subjected to 40 min of global ischaemia followed by 30 min of reperfusion. Results: Following ischaemia and reperfusion, hearts perfused with buffer alone showed a marked reduction in force of cardiac contraction and heart rate, an increase in coronary perfusion pressure and diastolic tone, and a release of creatine kinase in the coronary effluent. Myocardial creatine kinase, superoxide dismutase activity, and glutathione content all fell. Perfusion of hearts with washed platelets provided significant protection from ischaemia-reperfusion related myocardial injury and dysfunction. The cardioprotective effects of platelets were attenuated when they were preincubated with the glutathione redox cycle inhibitors dehydroepiandros-terone, 1,3-bis (2-chloroethyl)-l-nitrosurea, or l-chloro-2,4-dinitrobenzene. Pretreatment of platelets with glutathione redox cycle inhibitors did not affect the platelet mediated preservation of myocardial superoxide dismutase activity. Conclusions: Platelet glutathione redox cycle contributes in part to the cardioprotective effects of platelets against ischaemia-reperfusion injury and dysfunction in the isolated rat heart. Cardiovascular Research 1994; 28 :1586-1593

Objective: The aim was to investigate the potential for the enhancement of endogenous catalase activity after heat stress to protect the isolated rat myocardium from the injurious effects of exogenous hydrogen peroxide. Methods: Male Sprague-Dawley rats were randomised to either heat stress or sham treatment. At 24 and 48 h after treatment hearts were retrogradely perfused at a constant flow rate of 10 ml·min−1. After a 15 min stabilisation period hearts were perfused with 75 μM hydrogen peroxide for 85 min. Mechanical function was measured by an intraventricular isovolumic latex balloon while coronary perfusate was collected for measurement of lactate dehydrogenase activity. At the end of the perfusion period the glutathione status of the hearts was determined. In separate experiments baseline cardiac catalase activity and glutathione state were measured 24 and 48 h after heat stress or sham treatment. Results: Cardiac catalase activity was increased by 49% at both 24 and 48 h after heat stress in comparison with sham controls. Glutathione concentrations were reduced by 12% 24 h after heat stress but had recovered by 48 h. Perfusion of sham hearts with 75 μM hydrogen peroxide resulted in a progressive decline in mechanical function as evident by a fall in developed pressure and rise in diastolic pressure. Coronary resistance also rose during the perfusion period as shown by a progressive increase of coronary perfusion pressure. Coronary effluent lactate dehydrogenase release was only increased above basal concentrations at the end of the perfusion period, whereas cardiac glutathione concentrations were severely depleted. Hearts taken 24 h after heat stress showed a reduced resistance to the effect of 75 μM hydrogen peroxide on mechanical activity, although there was no difference in the pattern of lactate dehydrogenase release or depletion of glutathione. Perfusion of hearts taken 48 h after heat stress with 75 μM hydrogen peroxide resulted in the same effect on mechanical dysfunction, coronary resistance, lactate dehydrogenase release, and cardiac glutathione depletion as sham controls. Conclusion: The increase in endogenous cardiac catalase activity caused by prior heat stress is insufficient to protect the isolated rat heart from injury induced by exogenous hydrogen peroxide.

Objective: The aim was to study the contribution of ATP sensitive potassium channels (KATP channels) in the coronary vasodilatation produced by prostaglandins I2, E2, and D2 in rats. Methods: Isolated Langendorff rat hearts, perfused under constant flow conditions, and rat aortic rings were used. Dose-response curves to PGE2, PGD2, and iloprost, a PGI2 analogue, were performed before and during KATP channel blockade with glibenclamide. Arachidonic acid was used to increase the formation of endogenous PGI2. Results: Infusions of PGE2, PGD2, and iloprost in isolated hearts induced marked vasodilatation, as reflected by the reduction in coronary perfusion pressure of 27(SEM 7), 30(6), and 43(6)%, for 0.1 μM PGE2, PGD2, and iloprost, respectively. Infusion of glibenclamide (0.3 μM) was accompanied by a 23(3)% increase in coronary perfusion pressure. The vasodilatation induced by levcromakalim (0.1 μM) was completely inhibited in the presence of glibenclamide, whereas that of papaverine (30 μM) was unaffected. Glibenclamide significantly reduced the vasodilatation induced by iloprost (at 3 to 100 nM), PGE2 (30 and 100 nM), and PGD2 (30 and 100 nM), at all concentrations studied. In contrast, glibenclamide (1 μM) had no effect on iloprost induced relaxation of aortic rings. Arachidonic acid infusion (from 0.1 to 3 μM) in isolated hearts induced a pronounced vasodilatation and a significant release of 6-keto-PGF1α into the coronary effluent in a dose dependent fashion. Both responses to arachidonic acid were significantly reduced in the presence of the cyclo-oxygenase inhibitor diclofenac (1 μM). In an additional experimental series, the vasodilatation induced by arachidonic acid infusions was found to be significantly reduced in the presence of glibenclamide. Conclusions: Glibenclamide is a potent inhibitor of the coronary dilator action of prostaglandins I2, E2, and D2. This observation suggests that these prostaglandins may cause vasodilatation by opening KATP channels. Cardiovascular Research 1994; 28 :901-905

Objective: The aim was to evaluate the hypothesis that the oxygen demand of stimulated myocardium is downregulated and ischaemia avoided when oxygen supply is limited. Methods: Isoprenaline stimulation during reduced coronary perfusion pressure or moderate coronary hypoxaemia was studied in relation to myocardial oxygen demand, power, and oxygen utilisation efficiency (O2Effic) in 19 anaesthetised open chest dogs. The left anterior descending coronary artery was perfused with normoxic blood at 100 or 60 mm Hg or with moderately hypoxic blood [CaO2=9.8(SEM 0.2) ml·dl−1] at 100 mm Hg. Myocardial oxygen demand was estimated from oxygen consumption (MVo2), and power index was computed from heart rate, left ventricular pressure, and segment shortening. O2Effic was calculated from power index divided by MVo2. Lactate extraction and contractile function were used as indices of myocardial ischaemia. Results: Isoprenaline under control conditions increased coronary blood flow, MVo2, and power index, but did not alter lactate extraction. Reducing coronary perfusion pressure to 60 mm Hg decreased oxygen delivery by 31.6(5.7)% (p < 0.05). MVo2 fell by 26.6(8.6)% (p < 0.05), but power index and lactate extraction were not reduced. At reduced coronary perfusion pressure, isoprenaline-induced elevation of MVo2 decreased from 26.0(1.5) to 15.7(2.6) ml·min−1·100 g−1 (p < 0.05), but the isoprenaline-induced rise in power index was not significantly lessened, nor was lactate extraction altered. O2Effic was increased by reduced coronary perfusion pressure and by isoprenaline during reduced coronary perfusion pressure. Hypoxaemia increased coronary blood flow but did not alter oxygen delivery, MVo2 or power index. Isoprenaline-induced elevation of MVo2 decreased from 25.2(1.7) to 19.1(0.5) ml·min−1·100 g−1 (p < 0.05), and power index decreased by 33(9.1)% (p < 0.05). O2Effic was not altered by hypoxaemia or by isoprenaline during hypoxaemia. Conclusions: Oxygen demand of isoprenaline stimulated myocardium is downregulated and ischaemia is avoided when oxygen is limited. Downregulation of oxygen demand is achieved by increasing oxygen utilisation efficiency in the presence of reduced coronary perfusion pressure and by decreasing power in the presence of hypoxaemia. Cardiovascular Research 1993; 27 :1542-1550

Objective: The aim of the study was to investigate the ambiguous effect of left ventricular afterload on myocardial work, oxygen consumption, and efficiency. Methods: Myocardial oxygen consumption and mechanical parameters of the left and right ventricle were measured in situ in a modified heart-lung preparation in the rat. Left ventricular afterload was adjusted arbitrarily by means of a Starling resistor mounted in a shunt circuit between the left ventricle and the caudal caval vein. Left and right ventricular pressure and aortic pressure as well as pulmonary flow and the flow in the shunt circuit were measured. The left ventricular pressure and volume values were converted into wall stress and length data assuming a thick walled sphere, and external work was calculated from left ventriculap force and shortening. Results: Left ventricular external work ran through a maximum with decreasing aortic pressure. Left ventricular oxygen consumption per gram and beat correlated linearly with left ventricular peak wall stress, tension-time integral, and maximum rate of stress development. Left ventricular force and shortening, the two components of external work, acted differently: force determined left ventricular oxygen consumption, whereas shortening had no direct effect on myocardial oxygen consumption, but was important in determining left ventricular efficiency. Conclusions: The interplay between left ventricular afterload and coronary perfusion pressure is of special significance for the heart in situ. The decrease in shortening and external work as well as the diminution in efficiency, observed at low aortic pressure values, can be attributed to impaired coronary perfusion. The coronary perfusion pressure must therefore be taken into consideration for the critical examination of the efficiency of the heart in situ. Cardiovascular Research 1992; 26 :886–892

Study objective — The aim was to study coronary pressure-flow, pressure-myocardial wall motion and myocardial wall motion-myocardial oxygen consumption relations in postischaemic myocardium with prolonged myocardial dysfunction (stunned myocardium) in comparison with normal myocardium. Design — Regional myocardial wall thickening was measured with ultrasonic crystals, and postischaemic myocardial dysfunction was achieved by occlusion of a carotid-left anterior descending coronary artery bypass (15 min) and reperfusion (30 min). Coronary perfusion pressure was decreased in 10 mm Hg steps by constricting the bypass before and after producing postischaemic myocardial dysfunction. At each constriction step, coronary flow, regional wall thickening, and regional myocardial oxygen consumption in the area perfused by the left anterior descending artery were measured. Experimental material — 12 anaesthetised open chest mongrel dogs, weighing 12-16 kg, were studied. Measurements and main results — At the basal level, myocardial wall thickening of postischaemic myocardium was depressed compared to normal myocardium, at 18.5(SD 8.9)% v 1.3(7.1)%, p

Study objective – The aim was to determine the site of coronary vasoconstriction induced by endothelin, by investigating the response in terms of retrograde pressure and reactive hyperaemia. Experimental material – Twelve anaesthetised mongrel dogs, 12-14 kg, were used for the studies. Design – The left anterior descending coronary artery was cannulated and perfused with blood through an extracorporeal bypass. The effects of intracoronary endothelin-l (1-500 pmol) on coronary blood flow, coronary flow reserve (the peak reactive flow and the repayment after 15 s coronary occlusion), and retrograde coronary pressure during coronary occlusion were studied (n=7). The retrograde coronary flow was collected from the bypass at each dose (n=5). Measurements and main results – At doses of greater than 20 pmol the coronary flow decreased dose dependently and reached almost zero flow at 500 pmol. The coronary flow reserve also decreased; however, the retrograde pressure was raised dose dependently at doses of greater than 10 pmol. At a dose of 500 pmol, the retrograde pressure was increased to 61 mm Hg [82(SEM 12)% of the coronary perfusion pressure]. Retrograde flow remained unchanged throughout the experiment. Conclusions – The endothelin-1 induced rise in retrograde pressure is in accordance with a dose dependent reduction in coronary flow reserve, and collateral flow was not augmented by endothelin. It is concluded that the effect of endothelin-1 on coronary circulation in situ was mainly due to the constriction of small resistant vessels.

Study objective – The aim was to test the hypothesis that the release of vascular tone with adenosine during constant flow ischaemia alters both transmural function and regional metabolism in a detrimental way. Design – In one group of anaesthetised swine, the effects of graded reductions of flow on segmental left ventricular function, myocardial oxygen consumption (MVo2), and lactate production in the distribution of the left anterior descending coronary artery (LAD) were determined. In a second group, a model of constant flow ischaemia was induced to test how altering vascular tone with adenosine changed the relationship of flow, function, and metabolism. Experimental material – The experiments were performed in 20 open chest, anaesthetised swine. Protocol A consisted of 11 animals and protocol B of nine animals. Measurements and main results – In protocol A, during graded ischaemia, reductions in flow, % systolic wall thickening (WTh), normalised MVo2 and % lactate extraction (%LE) correlated well with reductions in coronary perfusion pressure when fitted with 3rd order polynominal curves (r = 0.78, 0.87, 0.85 and 0.81 respectively; p

STUDY OBJECTIVE - The aim was to study the effects of endothelin on the heart with special attention to an interaction with endothelium derived relaxing factor (EDRF). DESIGN - Bolus injections of various amounts of endothelin (1-300 ng) were given into the coronary circulation of isolated perfused rabbit hearts while coronary flow was held constant at 35 ml.min-1 and coronary perfusion pressure and other physiological variables were measured. The effects of indomethacin and haemoglobin on the responses were examined. EXPERIMENTAL MATERIAL - 15 New Zealand white rabbits, 1.0-1.5 kg, were used for the studies. The animals were anaesthetised and the hearts rapidly excised and perfused in the Langendorff manner. MEASUREMENTS and RESULTS - With coronary flow held constant, bolus injections of endothelin up to 300 ng caused no consistent increase in perfusion pressure, but resulted in a slight increase in left ventricular developed pressure. Indomethacin (10 microM) did not alter the response to endothelin; however, when endothelium dependent dilatation was inhibited by haemoglobin (10 microM), a dose dependent endothelin induced constriction was unmasked, with EC50 of 41 (SEM 15) ng, maximum +46(8) mm Hg. This constrictor response was further augmented by air infusion (0.5 ml), EC50 26(10) ng, maximum +102(12) mm Hg, and endothelin now caused a substantial dose dependent reduction in left ventricular contractile function. Endothelium dependent dilatation was not significantly reduced after air embolisation. CONCLUSIONS - The remarkable ability of the endothelium to protect against vasoconstrictor action of circulating endothelin in the coronary bed may not be due only to EDRF release, but perhaps also to an additional mechanism related to endothelial barrier of metabolic function.

The relation between diastolic dimensions and systolic function was studied in isolated rat hearts exposed to pressure (primary hypertension) and to volume load (hyperthyroidism). The hearts were arrested in diastole and cardiac dimensions analysed. Cardiac function was determined using an anterograde working heart preparation. Both models of cardiac overload produced significant left ventricular hypertrophy, however with different design. One concentric and one eccentric form of left ventricular hypertrophy were found in the spontaneously hypertensive rat obtained from two different breeders. An even more pronounced form of eccentric left ventricular hypertrophy was seen in hyperthyroid rats. The hearts with an eccentric form of hypertrophy had a higher maximal stroke volume when perfused at a high aortic pressure than those with a concentric form. At a low aortic pressure and hence a limited coronary perfusion cardiac performance was diminished in both types of spontaneously hypertensive rats but remained normal in hyperthyroid rats. Furthermore, oxygen consumption was reduced in all hypertrophied hearts compared with non-hypertrophied hearts. These data therefore suggest ( a ) that hearts having an eccentric type of hypertrophy may be in a more favourable situation, delivering a higher stroke volume for a given degree of myocardial fibre shortening; and (b) that the development of coronary vascular structural changes in spontaneously hypertensive rats, thereby increasing vascular resistance, leads to a decrease in left ventricular function at a low coronary perfusion pressure, whereas no such reduction was observed in hyperthyroid hearts, probably owing to a normal vascular resistance.

Relationship of coronary perfusion pressure with total and regional myocardial blood flow in right ventricular free wall was studied in 10 anaesthetised open chest dogs. The right coronary artery was perfused by an autoperfusion system from the carotid artery. Total coronary blood flow into the perfused area was measured by an extracorporeal electromagnetic flow probe. Critical perfusion pressure of the right coronary artery, defined as the lowest pressure level below which the regional wall motion deteriorated, was 39(SEM1) mm Hg. Reactive hyperaemia was noted at 60(2) mm Hg, a level well above the critical perfusion pressure. There was an inverse linear relation between the level of reactive hyperaemia and perfusion pressure. Regional myocardial blood flow was measured by a tracer microsphere technique at control condition, just above and below the critical perfusion pressures and during coronary occlusion. This correlated closely with values obtained by an electromagnetic flow probe (r = 0.94, p less than 0.001) and both values were dependent on the level of perfusion pressure. Endocardial to epicardial flow ratio remained at unity at any level of coronary perfusion pressure. Thus the level of coronary perfusion pressure was a major determinant of the regional myocardial blood flow into the right coronary artery, and autoregulation of the regional myocardial blood flow was not apparent across the wall, despite the presence of a reactive hyperaemia.

The isolated perfused rat heart is an important experimental preparation for both mechanical and biochemical studies. In order to define better the relationship between coronary flow and loading conditions, a new preparation was developed in which the left ventricle ejected through the apex, while the aortic perfusion pressure could be separately controlled at a higher level than the apex afterload. Results were compared with a standard aortic perfused and ejecting preparation. All analyses were made at low calcium concentration (1.6 mmol·litre−1) for reducing cardiac performance. Coronary flow was related to perfusion pressure in the aortic ejecting preparation when the aortic afterload chamber was between 6.0 and 9.3 kPa (45 and 70 mmHg). Coronary autoregulation was demonstrable in the apex ejecting preparation irrespective of the height of the apex afterload chamber and the aortic ejecting preparation when the aortic chamber was between 11.0 and 16.0 kPa (83 and 120 mmHg). Following the addition of 10−6 mol·litre−1 adenosine, there was significant coronary vasodilatation, and flow became pressure dependent in all cases. In the apex-ejecting preparation, with a high aortic pressure, coronary flow remained at relatively fixed level, and increases in oxygen demand were met by increasing oxygen extraction. Thus, in this preparation oxygen extraction was directly related to workload. With abrupt increases in afterload, going from 6.0 to 9.3 kPa (45 to 70 mmHg) to a higher level, there was evidence of transient hypoxia with the aortic ejecting but not the apex ejecting preparation. It is concluded that the apex ejecting heart is a stable preparation in which coronary perfusion pressure and flow can be maintained independent of preload and afterload. The coronary reserve of this preparation provides some advantage for both mechanical and biomedical studies.

The relationship between regional contractile function (ultrasonic crystals) and S-T segment elevation recorded from both endocardial and epicardial electrodes was examined at thoracotomy in dogs with sudden or graded coronary artery occlusion. After sudden occlusion of the left anterior descending artery in 5 dogs, hypokinetic changes were apparent within 10 s. However. S-T segment elevation was first observed in both endocardial and epicardial electrograms at 30 s, synchronous with the onset of dyskinesia. By 5 min after occulsion, endocardial S-T segment elevation (8.6 ± 1.3 mV) and epicardial S-T segment elevation (7.6 ± l.4mV) were essentially identical. In 6 dogs, a carotid-to-coronary shunt was created to perfuse the LAD. A significant reduction in normalised velocity of contraction over the first ⅓ of systole ⅓ (Vn; from 10.1 ± 1.0 to 3.7± 2.5 mm·s−1 cm−1; P < 0.05) was first observed after reduction of coronary perfusion pressure (CPP) to 5.3 kPa (40 mmHg) (P 0.05). Both the end-diastolic segment length and the mean systolic segment length were significantly increased at CPP = 4.0 kPa (30 mmHg). Significant endocardial S-T segment elevation (11.7 ±3.8 mV; P < 0.05) was observed after graded occlusion and reduction of CPP to 6.7 kPa (50 mmHg). Epicardial S-T segment elevation was less than endocardial S-T segment elevation at all levels of CPP and was only significantly increased after reduction of CPP to 4.0 kPa (30 mmHg) (9.0; 1.2 mV; P < 0.05). These data suggest that endocardial S-T segment elevation may be a slightly more sensitive index of ischaemia than is depression of contractile function which, in turn, is more sensitive than epicardial S-T segment elevation.

Nine mongrel dogs were instrumented with left circumflex coronary artery (LCf) flow probes and balloon occluders and the LCf narrowed so that peak hyperaemia following release of a 15 s coronary occlusion was diminished by 40.4±5.9%. Following insertion of a 16-gauge catheter through an LCf branch immediately distal to the stenosis and advancement to the branch's junction with the main vessel, the left anterior descending artery (LAD) was ligated in its middle third. The dogs were studied 7 to 14 days following recovery from surgery. Haemodynamics and myocardial blood flow were measured under control conditions and again during adenosine infusion, 280 to 320 μ g·min−1, through the LCf catheter. After the start of treadmill running measurements before and during adenosine infusion were repeated. At rest the gradient across the LCf stenosis averaged 2.4 kPa. During adenosine infusion there were no detectable systemic haemodynamic effects, but average distal LCf pressure fell from 11.4 to 7.3 kPa in the eight dogs responding to the vasodilator. This decrease in coronary perfusion pressure was associated with a significant decrease in collateral flow. Under control conditions ischaemic LAD flow averaged 60% of normal flow. Adenosine doubled coronary flow to the LCf areas directly perfused with this agent, while the average flow to the collateral-dependent area beyond the LAD stenosis decreased by 20%. The single dog with no increase in LCf flow or fall in distal LCf pressure induced by adenosine also had no change in collateral flow. During exercise LCf flow again double and distal LCf pressure diminished. Ischaemic LAD flow did not change in 3 of 6 exercising animals despite two- to three-fold increases in flow to other left ventricular areas. The fall in ischaemic LAD flow was obscured in three other animals by changes accompanying the exercise state, eg, increased aortic pressure and increased perfusion of collaterals not affected by the coronary steal occurring in the distal LCf vascular bed. Thus, the arteriolar dilating agent adenosine increases coronary flow and decreases perfusion pressure resulting in a coronary flow redistribution, or coronary steal. The metabolic vasodilatation of exercise also creates the haemodynamic milieu for a coronary steal, but other factors accompanying the exercise state may hide the expected decrease in ischaemic flow.

These experiments were performed in order to ascertain whether activation of coronary vascular adrenergic receptors could change the time course of the coronary vasodilatation accompanying increases in myocardial metabolic activity. The left common coronary arteries of dog hearts were perfused in situ with blood at constant flow. Coronary perfusion pressure and coronary sinus blood 02 content were continuously monitored. Norepinephrine was infused into the coronary artery at 0.5 to 5 microgram.min-1. and isoprenaline at 0.5 to 2 microgram.min-1. The amplitude of the vascular resistance change was less with norepinephrine than with isoprenaline infusion for a similar change in oxygen consumption. The time course of coronary vascular resistance, after correction for the effects of vascular transit, lagged significantly behind the time course of coronary sinus 02 content in the case of norepinephrine infusion. On the average, no lag was observed with isoprenaline infusion. It is concluded that stimulation of coronary vascular adrenergic receptors can alter the time course and the magnitude of the coronary vascular response to increases in myocardial metabolic activity resulting from myocardial beta-receptor stimulation.

The coronary vasodilatation that accompanies cardiac stimulation by catecholamines and histamine or exposure to hypoxia is thought to be due to the release of a coronary vasodilator metabolite. Adenosine has been proposed as a likely candidate and this study examines its possible involvement by use of hexobendine, an agent that enhances the effects of adenosine. The force and rate of contraction and coronary perfusion pressure of isolated guinea-pig hearts were recorded. Adenosine exerted dose-dependent negative chronotropic effects and coronary vasodilatation. Both responses were potentiated during perfusion with hexobendine. However, hexobendine did not potentiate the coronary vasodilator responses to isoprenaline, suggesting that adenosine was not involved. Isolated hearts were then perfused in series, the donor heart supplying perfusate to the recipient. Stimulation of donor hearts by isoprenaline or histamine resulted in coronary vasodilator activity appearing in the recipient, which had received the appropriate antagonists of beta-adrenoceptors of histamine H1- and H2-receptors. Exposure of donor hearts to hypoxia also caused vasodilator metabolite release. Infusion of hexobendine into the recipient heats potentiated the vasodilator metabolite release. Infusion of hexobendine into the recipient hearts potentiated the vasodilator responses to exogenous adenosine, however, the responses to vasodilator metabolite released by the three procedures was not affected. Furthermore, there were no negative chronotropic responses accompanying the vasodilator metabolite release as there were with adenosine in a dose that produced equivalent vasodilatation. These results provide evidence that the vasoactive metabolite released by catecholamines, histamine and hypoxia is not adenosine.

The effects of increased pericardial pressure on blood flow to collateral dependent and normal myocardium were investigated and the mechanisms responsible for these effects evaluated in 10 anaesthetised dogs after collateral inducement by gradual occlusion of a coronary artery. Regional myocardial blood flows were measured with radioactive microspheres during control conditions, mild tamponade, severe tamponade, and severe tamponade with aortic blood pressure held at the control value by blood volume expansion. Mild tamponade increased heart rate by 10% and decreased aortic blood pressure by 15%. Left atrial and central venous blood pressures were moderately increased, and indices of cardiac function were reduced. Blood flow to collateral dependent and normally perfused myocardium was not significantly altered, but the endocardial to epicardial flow ratio was significantly decreased in collateral dependent myocardium. Severe tamponade decreased aortic blood pressure by 45% and cardiac index by 62%. Left atrial and central venous blood pressures were appreciably increased and cardiac function indices considerably depressed. Blood flow to collateral dependent and normally perfused myocardium was decreased similarly (by 54-57%), but the endocardial to epicardial flow ratio was decreased by a greater degree in collateral dependent myocardium. During severe tamponade at control aortic blood pressure, left atrial and central venous blood pressures were further increased, but blood flow to collateral dependent and normally perfused myocardium returned to within 84% of control and endocardial to epicardial flow ratios were normal. Total peripheral vascular resistance increased during severe tamponade, but coronary vascular resistance remained constant. Thus blood flow to collateral dependent and normally perfused myocardium varied according to net coronary perfusion pressure. Tamponade induced hypotension is the dominant factor in reducing regional blood flow in hearts with well developed collateral vessels.

The relationship between the magnitude of epicardial ST-segment elevation and intramyocardial oxygen tension after coronary artery ligation was examined in 11 dogs at various coronary perfusion pressures. The ST map significantly reflected local intramyocardial oxygen tension, and the level of coronary perfusion pressure proved to be an important determinant of both local myocardial oxygen balance and the magnitude of ischaemic injury.

To determine whether or not the fall in coronary perfusion pressure after coronary occlusion is the cause of remote myocardial ischaemia, regional myocardial blood flow was measured using radiolabelled microspheres before and after left anterior descending (LAD) occlusion in the presence of a left circumflex artery stenosis in 22 anaesthetised dogs. Aortic pressure was maintained constant at the time of left anterior descending artery occlusion in 13 dogs (group 1) and proximal left circumflex artery pressure was held constant by a servocontrolled pump in nine dogs with a carotid artery-left circumflex artery shunt (group 2). Despite the maintenance of constant mean aortic pressure in group 1, remote posterior bed mean(SEM) endocardial flow fell from 0.69(0.05) to 0.43(0.07) ml.min-1.g-1 (p less than 0.05). In the dogs in which left atrial pressure rose to less than or equal to 9 mmHg after left anterior descending artery occlusion, remote bed endocardial flow did not fall significantly (0.66(0.07) to 0.56(0.11) ml.min-1.g-1; NS). In contrast, remote bed endocardial flow fell from 0.73(0.07) to 0.28(0.06) ml.min-1.g-1 (p less than 0.0001) after left anterior descending artery occlusion in the dogs in which left atrial pressure rose to greater than 9 mmHg. The fall in remote bed endocardial flow was prevented in group 2 dogs by maintaining proximal left circumflex artery pressure constant (0.95(0.08) to 0.86(0.09) ml.min-1.g-1; NS). An important mechanism for the development of remote myocardial ischaemia appears to be the fall in proximal coronary perfusion pressure at the time of coronary occlusion.

The effect of diastolic ventricular hypertension on regional diastolic coronary flow was measured with radioactive microspheres in the canine heart paced at a constant rate and perfused only during diastole with a constant coronary perfusion pressure. Diastolic ventricular hypertension produced an homogenous increase of diastolic flow across the left ventricular wall when the metabolic coronary autoregulation was intact, but produced a decrease in subendocardial diastolic flow when the autoregulation was abolished. These results suggest that diastolic ventricular hypertension produces a higher subendocardial than subepicardial mechanical resistance to diastolic coronary flow.

The effect of intracoronary versus intravenous administration of nitroglycerin (GTN) on the transmural distribution of coronary blood flow (epi/endo) was studied in an isolated canine heart preparation and intact dogs. The distribution of blood flow between epicardium and endocardium of the left ventricle was determined by use of radioactive microspheres (15 micrometer diameter). Intracoronary infusion of GTN in the isolated heart significantly increased epi/endo during a constant coronary blood flow, whereas no change in epi/endo was observed during a constant coronary perfusion pressure. When maximal coronary vasodilatation was produced by chromonar, the epi/endo increased significantly, however intracoronary GTN produced no further vasodilatation and did not improve epi/endo. In contrast, intravenous infusion of GTN in intact hearts significantly decreased epi/endo. These results suggest that intracoronary GTN does not enhance endocardial perfusion and may even produce a coronary steal, whereas intravenous GTN may improve endocardial perfusion via indirect haemodynamic actions.

End tidal PCO2 (PETCO2) has been found to be a good prognostic indicator of successful resuscitation from cardiac arrest. To explore the value of this measurement further, we carried out a series of experiments during cardiac arrest and closed chest resuscitation in 14 mechanically ventilated Sprague-Dawley rats. Ventricular fibrillation (VF) was induced by a 10 mA current delivered to the right ventricular endocardium. After 4 min of VF, precordial compression was begun with a mechanical thumper and defibrillation was attempted 2 min later. PETCO2 decreased abruptly during cardiac arrest to 0.3 mm Hg (0.04 kPa). With precordial compression, it increased to 11 mm Hg (1.5 kPa). Within 3 min of successful defibrillation, there was an overshoot in the PETCO2 to 44 mm Hg (5.8 kPa) with return to baseline levels approximating those of the pre-arrest control measurements over the 60 min that followed restoration of spontaneous circulation. The PETCO2 measurement during precordial compression predicted the success of defibrillation with return of spontaneous circulation. When PETCO2 exceeded 9 mm Hg (1.2 kpA), 7 of 8 animals were successfully resuscitated. When PETCO2 was less than 9 mm Hg during precordial compression, none of six animals were successfully resuscitated. The PETCO2 correlated with the mean aortic (r = 0.71) and coronary perfusion pressure (r = 0.80) generated during precordial compression. In corroboration of previously reported observations on pigs, dogs, and human patients, PETCO2 served as a non-invasive monitor of the effectiveness of precordial compression for maintaining coronary perfusion and therefore cardiac viability during CPR. The PETCO2 was also useful in that it promptly signalled restoration of spontaneous circulation.

A study to analyse the effects of left ventricular diastolic pressure on coronary pressure-flow relations during physiological vasodilatation was carried out in 14 anaesthetised dogs. The left circumflex artery was perfused at controlled pressures via an extracorporeal circuit and vasodilatation induced by 15 s occlusion of coronary flow. The relation between end diastolic coronary perfusion pressure and flow at peak hyperaemia was linear above 40 mmHg (group 1, n = 7) and became curvilinear at perfusion pressures below 40 mmHg (group 2, n = 7). At a mean left ventricular end diastolic pressure of 8.6(0.8) mmHg the mean zero flow intercept (Pint) in group 1 was 22.5(2.3) mmHg. Graded increases in left ventricular end diastolic pressure by infusion of blood resulted in a parallel rightward shift of the vasodilated pressure-flow relation (Pint = 1.06×LVEDP+13.8 mmHg, r = 0.87). The curvilinear relations at low perfusion pressures in group 2 had lower zero flow intercept pressures (Pint = 4.8(0.7) mmHg at left ventricular end diastolic pressure 6.6(1.5) mmHg). As with group 1, graded increases in left ventricular end diastolic pressure caused a rightward shift of the pressure-flow relation, with a direct relation between left ventricular end diastolic pressure and zero flow intercept (Pint = 0.93×LVEDP+3.9 mmHg, r = 0.89). Diastolic coronary pressure-flow relations during physiological vasodilatation are essentially linear at perfusion pressures >40 mmHg but are appreciably curved at lower pressures. Increases in left ventricular end diastolic pressure cause a parallel rightward shift of the linear region of the pressure-flow relation. Left ventricular diastolic pressure appears to be a major determinant of the zero flow intercept extrapolated from the curved low pressure region.

The direct cardiac effects of hydralazine were studied in isolated working rat heart, isolated cat right ventricular papillary muscle, and isolated rabbit right atrium. The haemodynamics, myocardial energetics, and contractility of isolated hearts were measured at hydralazine concentrations of 0.01, 0.1, 0.5, 1.0, 10 and 100 μmol·litre−1. Coronary flow was significantly increased (≥21%, p

Cardiac performance in renal hypertensive animals has been variously reported as normal, increased, or decreased. Because of the many factors that can alter cardiac function in vivo ventricular contractility was investigated in isolated, paced, isovolumic heart preparations (modified Langendorff). Twenty one hypertensive rats (2 kidney, 1 clip Goldblatt) and 21 matched sham operated controls, were studied. Mean(SD) blood pressure and left ventricular weight were significantly higher in the study rats (228(5) vs 125(2) mmHg and 4.16(0.12) vs 2.35(0.04) mg·kg−1respectively). In the first experiment performed at 50 mmHg perfusion pressure left ventricular +dP/dt and myocardial flow rate were lower in 12 study rats (mean(SD) 1782(79) vs 2270(105) mmHg·s−1, 5.8(0.4) vs 14.0(1.0) ml·g−1 LV weight·min−1, respectively) than in the controls. In a second experiment performed at 80 mmHg perfusion pressure (nine study hearts and seven controls) the increased myocardial flow rate resulted in a higher left ventricular +dP/dt in both groups, but the study hearts still had a lower mean(SD) myocardial flow rate than the controls (12.5(0.9) vs 19.8(2.2) ml·g−1 LV weight·min−1; the difference in left ventricular +dP/dt became non-significant (2646(186) vs 2951(136) mmHg·s−1). Similarly, at equal myocardial flow rates (study hearts at 80 mmHg perfusion pressure and controls at 50 mmHg perfusion pressure) ventricular performance was similar in the two groups (mean(SD) left ventricular +dP/dt 2270(105) in controls vs 2646(186) mmHg·s−1 in study hearts). In addition, beta blockade by propranolol (10−7 mol·litre−1) did not affect the results obtained in non-blocked preparations as regards either left ventricular +dP/dt or myocardial flow rate. These results indicate that coronary perfusion pressure significantly influences ventricular contractility and that left ventricular performance in hypertensive left ventricular hypertrophy depends on a balance between left ventricular mass, perfusion pressure, and myocardial flow rate.

Lactate production by the myocardium does not occur during pacing induced tachycardia in a normal circulation unless coronary perfusion pressure drops to unphysiological levels concomitant with maximum oxygen extraction.