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Background and Objective: Vascular endothelial cells play an important role in the control of vascular tone. The reasons for coronary endothelial dysfunction are complex and may involve ischemia/reperfusion injury. We investigated whether endothelial, smooth muscle, and myocardial dysfunction are independent phenomena., Methods: Rabbit hearts were rapidly excised without intermittent ischemia, connected to a modified Langendorff apparatus, and perfused with a modified Krebs-Henseleit solution containing bovine erythrocytes. Normoxic control hearts (n = 16) were perfused for 125 min. Postischemic hearts (n = 15) were perfused for 45 min, submitted to global ischemia (20 min) and reperfused (60 min). Both the normoxic and the postischemic hearts were divided into three groups that received either 0.9% NaCl (placebo), or 3-morpholinosydnonimine (SIN-1; 100 microM),or substance P (SP; 5 nM)., Results: After SIN-1, CBF in the normoxic hearts was increased by maximum 63% and after SP by 62%. 60 min after the onset of reperfusion, the postischemic hearts of both groups had recovered to 95% LVP(max). In the postischemic hearts, SIN-1 increased CBF still by 58%, while the endothelium-dependent vasomotion was impaired: SP improved CBF by only 9%., Summary and Conclusions: The particular protocol permitted differentiation between myocardial and vascular stunning. The results show that, while myocardial function has already recovered, endothelial cells are more severely impaired than smooth muscle cells, and that this injury persists beyond myocardial stunning. Thus, endothelial-dependent dysfunction can still impair vasodilatation while ventricular dysfunction has already resolved.

Myocardial blood flow exhibits considerable heterogeneity. Consequently, oxygen supply to the myocardium is also heterogeneous, as is myocardial metabolism. Many lines of evidence show a close correlation between local flow and local metabolism in the normoxic myocardium. So far, myocardial metabolism has predominantly been assessed indirectly by using labeled substrates. We used the (18)O isotope, permitting analytical separation of H2(18)O from the (18)O isotope, as well as quantification of regional oxidative metabolism by measuring the tissue residue of oxidation water in the rabbit myocardium. Correlation of local flow with oxidative metabolism was significant in the normoxic myocardium. This correlation was lost in the postischemic/reperfused myocardium. Apart from the established mechanisms underlying myocardial stunning, a mismatch between local flow and oxidative metabolism might thus also contribute to the postischemic dysfunction. In the normoxic myocardium, function should correlate with metabolism and blood flow. For technical reasons, function has not been assessed on a very local scale. Nevertheless, some considerations are presented on the heterogeneity of function as well as on the scale on which heterogeneity should be investigated to convey physiologically meaningful information on regulatory cardiac mechanisms.

The endothelins comprise a family of three isopeptides ET-1, ET-2 and ET-3, whereby ET-1 appears to be the most relevant in humans. They act in a paracrine manner on ETA and ETB receptors. ET-1 plays an important role in the cardiovascular system. In addition, it modulates vasomotion and growth processes, and it participates in thrombogenesis and neutrophil adhesion. This review summarizes some of the current literature pertaining to the physiological and pathophysiological significance of ET-1, focusing the assets and drawbacks of elevated ET-1 levels. In this regard, modulation of the endothelin system by either receptor blockade or by inhibition of endothelin converting enzyme is expected to provide novel therapeutic drug strategies.

From available results, the following schematic can be drawn: Reductions in perfusion pressure are not associated with impaired ventricular function as long as they take place within the autoregulatory range. Additional reductions in perfusion pressure that moderately diminish coronary blood flow will result in a particular ischemia with decreased but stable function: perfusion and contraction match, the myocardium hibernates. The process responsible for this new equilibrium could be termed down regulation of function. The trigger inducing hibernation is so far unknown. The strategy, however, is similar to that used by hibernating animals. Likewise, myocardial hibernation is a protective mechanism. As hibernators recover initial function after unfavourable periods are terminated, hibernating myocardium recovers after institution of physiologic perfusion. It is under debate, whether function quickly recovers or remains temporarily depressed. As hibernating animals might finally even die, if unfavourable periods last too long, myocardium might become irreversibly injured due to ischemia lasting too long. Additional reductions in perfusion pressure and oxygen supply below the hibernating range produce ischemia in the more classical sense, because oxygen supply and demand no longer match. Damage will become irreversible in case the situation persists longer than about 20 min. After onset of reperfusion, the myocardial function would remain depressed, however, for a considerable period: myocardial stunning. Considering the regional heterogeneities of myocardial blood flow, distinct differentiation between moderate and severe ischemia is difficult. Ischemia will induce more articulate damage in subendocardial than in subepicardial layers. Similarly, damage in the ischemic core will be more pronounced than in the border zone.(ABSTRACT TRUNCATED AT 250 WORDS)

A possible cause for the decreased function in postischemic reperfused (= stunned) myocardium could be a decrease in Ca++ sensitivity. To test this hypothesis, we used an agent with reportedly Ca++ sensitizing properties (EMD 57033) and performed experiments on a total of 17 isolated rabbit hearts that were perfused with an erythrocyte-containing medium in a modified Langendorff setting (hct = 30%; Ca++ = 2.0 meq/l). The hearts were divided into two groups. In one group (n = 9), the Ca++ sensitizer (30 microM) was administered to nonischemic myocardium, and in a second group (n = 8), the Ca++ sensitizer was administered after 30 min of reperfusion that followed a period of 20 min normothermic, no-flow ischemia. In the nonischemic group, addition of the agent, improved left ventricular (LV) function significantly. In the ischemic group, LV-function was depressed at 30 min reperfusion compared to control. Again, the agent improved LV-function significantly. The increase in systolic and diastolic function was comparable in both groups as well as the oxygen consumption that was significantly increased after administration of the agent. In both groups, the agent neither exhibited significant, positive chronotropic nor arrhythmogenic effects. We summarize that the novel Ca++ sensitizer acts as a potent positive inotropic agent in the isolated blood-perfused rabbit heart. Because of the agent's properties to ameliorate postischemic contractile dysfunction, this general strategy may be useful for treating poorly functioning reperfused myocardium.

Efficiency is defined as the ratio of the energy delivered by a system to the energy supplied to it. Depending on the particular question being addressed, there exist a plethora of definitions of efficiency in medical texts, thus hampering their comparison. If only the ventricular work seen by the arterial system is under investigation, pressure-volume work will serve as a useful numerator. If, on the other hand, external and internal work together, i.e. the total mechanical work, is of interest, the pressure-volume area might be employed. Total myocardial oxygen consumption (MVO2) will be a useful denominator in the case of aerobic energy production. The MVO2 for the unloaded contraction must be assessed if, as in other energy transfer systems, net efficiency is to be addressed. If even smaller steps in the chain of energy transfer are to be investigated MVO2 for the arrested heart must be assessed. With an appropriate therapy, hemodynamic determinants can be varied, to improve cardiac efficiency. Nonetheless, measurement of all variables necessary for the calculation of efficiency remains a challenge, in particular in the clinical setting. Separation of the direct effects of drugs on efficiency is even more difficult, since hemodynamic conditions can hardly be controlled throughout the observation period, and changes in efficiency might be secondary to changes in hemodynamics. Whether the heart by itself employs mechanisms to improve its efficiency is still a matter of discussion: there is evidence that when oxygen supply decreases, the heart can switch from one substrate to a less costly one, or possibly can improve efficiency through better use of oxygen. Moreover, the heart seems to "sense" an even more decreased oxygen supply and reduce function in response. Myocardial stunning could be regarded as a protective mechanism as well, with function remaining depressed and the oxygen supply being normal or close to normal. One may conclude from the decreased efficiency that the excess oxygen consumption is used up for repair processes. The improved efficiency found in hypertrophied hearts represents another adaptive process. The underlying mechanism is unclear: a shift towards isomyosin V3 or some undefined shift in metabolic pathway is discussed. It is also still a moot question towards which objective the efficiency of the heart is adjusted. It has been described that under physiologic conditions, the efficiency of both the left and the right ventricle ought to be maximized.(ABSTRACT TRUNCATED AT 400 WORDS)

Sudden increases in aortic pressure (AoP, mm Hg) are associated with increases in left ventricular (LV) function which persist even after diastolic volume has returned to its initial value (Anrep effect). Likewise, increases in coronary arterial pressure (CAP, mm Hg) are associated with improved LV function (gardenhouse effect). In situ, increases in AoP are paralleled by increases in both CAP and coronary blood flow, i.e., oxygen supply. We investigated the individual contributions of AoP and CAP increases on function (peak systolic pressure: LVPmax, mm Hg; dP/dtmax, mm Hg/s; end-diastolic pressure: LVPed, mm Hg) and end-diastolic geometry (inner diameter: IDed, mm; wall thickness: WTed, mm; sonomicrometry). CAP-induced increases in coronary flow were prevented by admixing dextran to the perfusate. The experiments were performed on isolated, saline-perfused, working rabbit hearts. Increasing CAP from 60 to 80 mm Hg (n = 11) resulted in improved function: LVPmax 89 +/- 3 vs. 94 +/- 3, dP/dtmax 1160 +/- 50 vs. 1250 +/- 50, LVPed 17 +/- 1 vs. 16 +/- 1 (mean +/- SEM). IDed decreased from 9.96 +/- 0.25 to 9.64 +/- 0.33 and WTed increased from 6.02 +/- 0.16 to 6.15 +/- 0.17. In a second series, AoP was increased from 60 to 80 (n = 9). Both LVPmax, dP/dtmax and LVPed increased (90 +/- 4 vs. 97 +/- 3, 1170 +/- 70 vs. 1270 +/- 90 and 18 +/- 1 vs. 19 +/- 1). IDed increased from 9.76 +/- 0.39 to 9.99 +/- 0.37 and WTed decreased from 6.08 +/- 0.22 to 5.86 +/- 0.25. After additionally increasing CAP to 80, function further improved (LVPmax: 101 +/- 3, dP/dtmax: 1310 +/- 80) while LVPed decreased (18 +/- 1). This time, IDed decreased to 9.71 +/- 0.36 and WTed increased to 6.03 +/- 0.26. Increases in CAP improve LV function via the gardenhose effect and likely do not depend on simultaneous increases in coronary flow or oxygen supply. On the other hand, increases in AoP alone improve systolic function via the Frank-Starling mechanism. Increases in both pressures together amplify this effect. Increases in CAP and in AoP have opposing effects on IDed and WTed. In conclusion, the homeometric Anrep effect--at least in part--can be viewed as synergistic action of the Frank-Starling mechanism and the gardenhose effect for this experimental model.

One central hypothesis of cardiovascular physiology has been a balance between myocardial blood flow and contractile function during natural conditions, i.e. supply and demand are matched. This hypothesis was derived from studies relating total coronary blood flow to global ventricular function. The present article examines the relationship between myocardial blood flow and function on a regional level. In normal myocardium, considerable heterogeneity of blood flow exists, indicating similar heterogeneity of metabolic demand and potentially also function. However, when the degree of metabolic coupling between flow and function is questioned, there is no evidence whether or not flow and function are matched on a regional level. One closely related hypothesis of cardiovascular pathology has been an imbalance or mismatch between supply and demand during ischemia. Because myocardial function rapidly declines during early ischemia, residual, regional myocardial blood flow and function may be once again matched on a lower level. Such low-level supply-demand balance may persist over prolonged periods of ischemia and permit the myocardium to remain viable, i.e. the myocardium can "hibernate." Analyzing myocardial blood flow and function on a regional level has generated new insight into strategies of adaptation to the adverse situation of reduced blood flow. Whereas in hibernating (ischemic) myocardium, regional myocardial blood flow and function are matched, flow and function appear to be unmatched in reperfused, dysfunctional, i.e. 'stunned' myocardium. "Stunned myocardium" appears once more as a result of a strategy of adaptation, as the preceding ischemia did not induce irreversible myocardial damage but preserved the ischemic myocardium viable, although functionally impaired.

In a first series, we tested whether the relative ischemia distal to a severe stenosis on the left circumflex coronary (CX) artery increases the activity of cardiac sympathetic (CS) nerves which, in turn, may result in a poststenotic vasoconstriction and an aggravation of ischemia. In 23 anesthetized, vagotomized dogs, an acute stenosis that reduced CX blood flow to 50% of control was produced and maintained for 20 min. The activity of postganglionic CS nerves increased by 23 +/- 4% within 20 min. In parallel, poststenotic coronary resistance increased from 0.48 +/- 0.03 (SEM) to 0.61 +/- 0.03 mm Hg.min.100 g/ml, resulting in a net lactate production after 15 min. The selective alpha 2-adrenoceptor antagonist rauwolscine (0.2 mg/kg i.v.; n = 6) and the calcium antagonist nifedipine (10 micrograms/kg i.v.; n = 6) prevented the progressive increase in poststenotic resistance and the net lactate production, but still permitted an increase in CS activity. Segmental anesthesia of CS nerves with epidural infiltration of procaine at segments C7-T6 (n = 6) prevented the sympathetic activation, the progressive increase in poststenotic resistance and the net lactate production. In six additional dogs with intact vagus nerves, CS activation and a concomitant increase in poststenotic resistance resulting in myocardial ischemia were also found. These data suggest a vicious cycle between poststenotic coronary vasoconstriction and CS activation, resulting in severe myocardial ischemia. In a second series, stimulation of high-threshold somatic afferents (= nociceptive stimulation: NCS) was used to cause reflex CS activation. The superficial peroneal nerve was electrically stimulated in 14 anesthetized, vagotomized dogs. With intact CX arteries, a 1 min stimulation resulted in a pronounced increase in CX blood flow and perfusion pressure. In contrast, NCS in the presence of a severe stenosis on the CX artery increased end-diastolic poststenotic coronary resistance by 96 +/- 15% due to a reflex activation of CS nerve fibers. This activation was markedly reduced after injection of fentanyl (27 micrograms/kg i.v.; n = 6). Injection of naloxone (60 micrograms/kg) restored the original effect. Systolic wall thickening (WT; sonomicrometry) in the CX artery-perfused myocardium was increased during NCS (10.9 +/- 3.9 (SD) vs. 13.6 +/- 5.0%) in additional five dogs with intact coronary arteries. In the presence of a stenosis on the CX artery, systolic WT was reduced to 7.0 +/- 2.5% and was further decreased to 4.6 +/- 2.3% during NCS. The additional deterioration of systolic regional function during NCS was prevented after i.v. injection of fentanyl, as was the increase in poststenotic coronary resistance.(ABSTRACT TRUNCATED AT 400 WORDS)

We previously found that myocardial ischemia/reperfusion (I/R) initiates expression of tumor necrosis factor-α (TNF) leading to coronary endothelial dysfunction. However, it is not clear whether there is a direct relationship between levels of TNF expression and endothelial dysfunction in reperfusion injury. We studied levels of TNF expression by using different transgenic animals expressing varying amounts of TNF in I/R. We crossed TNF overexpression (TNF++/++) with TNF knockout (TNF−/−) mice; thus we have a heterozygote population of mice with the expression of TNF “in between” the TNF−/− and TNF++/++ mice. Mouse hearts were subjected to 30 min of global ischemia followed by 90 min of reperfusion and their vasoactivity before and after I/R was examined in wild type (WT), TNF−/−, TNF++/++ and TNF heterozygote (TNF−/++, cross between TNF−/− and TNF++/++) mice. In heterozygote TNF−/++ mice with intermediate cardiac-specific expression of TNF, acetylcholine-induced or flow-induced endothelial-dependent vasodilation following I/R was between TNF++/++ and TNF−/− following I/R. Neutralizing antibodies to TNF administered immediately before the onset of reperfusion-preserved endothelial-dependent dilation following I/R in WT, TNF−/++ and TNF++/++ mice. In WT, TNF−/++ and TNF++/++ mice, I/R-induced endothelial dysfunction was progressively lessened by administration of free-radical scavenger TEMPOL immediately before initiating reperfusion. During I/R, production of superoxide (O2 ·−) was greatest in TNF++/++ mice as compared to WT, TNF−/++ and TNF−/− mice. Following I/R, arginase mRNA expression was elevated in the WT, substantially elevated in the TNF−/++ and TNF++/++ mice and not affected in the TNF−/− mice. These results suggest that the level of TNF expression determines arginase expression in endothelial cells during myocardial I/R, which is one of the mechanisms by which TNF compromises coronary endothelial function in reperfusion injury. [ABSTRACT FROM AUTHOR]

Brief periods (a few seconds) of cyclic coronary occlusions applied early in reperfusion induce a cardioprotection against infarct size, called postconditioning (PostC) in which B2-bradykinin receptors play a pivotal role. Since angiotensin-converting enzyme (ACE) inhibitors reduce degradation of kinins, we studied the effects of PostC on infarct size and postischemic myocardial dysfunction in both normotensive (WKY) and spontaneously hypertensive rats (SHR) acutely or chronically treated with the ACE inhibitor Captopril. Isolated hearts from SHR and WKY rats were subjected to the following protocols: (a) ischemia for 30- and 120-min reperfusion (I/R); (b) I/R + PostC protocol (5-cycles 10-s I/R); (c) pretreatment with Captopril for 4-weeks before to subject the hearts to I/R with or without PostC maneuvers. Some SHR hearts were treated with Captopril during the 20- or 40-min early reperfusion with or without PostC maneuvers. Cardiac function was assessed in vivo with echocardiography. Left ventricular pressure and infarct size were measured ex vivo. Chronic Captopril significantly reduced left ventricular hypertrophy in SHR, and reduced infarct size in both WKY and SHR hearts. PostC maneuvers significantly reduced infarct size in WKY, but not in SHR hearts. Yet, PostC slightly improved postischemic systolic function in untreated SHR. Captopril given in reperfusion was unable to limit I/R injury in SHR hearts. Data show that PostC protection against infarct size is blunted in SHR and that PostC is unable to add its protective effect to those of chronic Captopril, which per se reduces cardiac hypertrophy and heart susceptibility to I/R insult. [ABSTRACT FROM AUTHOR]

Although it has long been recognized that thyroid hormone is an effective positive inotrope, its efficacy in supporting hemodynamics in the acute setting of ischaemia and reperfusion (R) without worsening reperfusion injury remains largely unknown. Thus, we investigated the effects of triiodothyronine (T3) on reperfusion injury in a Langendorff–perfused rat heart model of 30 min zero-flow ischaemia and 60 min of (R) with or without T3 (40 µg/l) at R, T3-R60, n = 11 and CNT-R60, n = 10, respectively. Furthermore, phosphorylated levels of intracellular kinases were measured at 5, 15 and 60 min of R. T3 markedly improved postischaemic recovery of left ventricular developed pressure (LVDP%); 56.0% (SEM, 4.4) in T3-R60 versus 38.8% (3.1) in CNT-R60, P < 0.05. Furthermore, LDH release was significantly lower in T3-R60. Apoptosis detection by fluorescent probe optical imaging showed increased fluorescent signal in CNT-R60 hearts, while the signal was hardly detectable in T3-R60 hearts. Similarly, caspase-3 activity was found to be 78.2 (8.2) in CNT-R60 vs 40.5 (7.1) in T3-R60 hearts, P < 0.05. This response was associated with significantly lower levels of phospho-p38 MAPK at any time point of R. No significant changes in phospho- ERK1/2 and JNK levels were observed between groups. Phospho–Akt levels were significantly lower in T3 treated group at 5 min and no change in phospho–Akt levels were observed at 15 and 60 min between groups. In conclusion, T3 administration at reperfusion can improve postischaemic recovery of function while limiting apoptosis. This may constitute a paradigm of a positive inotropic agent with anti-apoptotic action suitable for supporting hemodynamics in the clinical setting of ischaemia-reperfusion. [ABSTRACT FROM AUTHOR]

Previous studies have shown that the disruption of the coronary endothelium and the increase in its permeability during ischemia-reperfusion (I/R), are linked to matrix metalloproteinase-2 (MMP-2) activity. Studies from our group have shown that during I/R, activity of MMP-2 in the coronary effluent increases and this increase is associated with cardiac dysfunction, which in turn, can be prevented by MMP inhibitors. Therefore, we hypothesize that inhibiting MMPs reduces the MMP-2 dependent disruption of the coronary endothelium and subsequent protein release during I/R. Isolated rat hearts were perfused in the Langendorff mode at a constant pressure and subjected to 15, 20 or 30 min no-flow ischemia followed by 30 min of reperfusion. The MMP inhibitors, o-phenanthroline (Phen, 100 µM) or doxycycline (Doxy, 30 µM) an inhibitors of MMPs, were added to the perfusion solution 10 min before ischemia and for the first 10 min of reperfusion. The coronary effluents were collected during perfusion for protein analysis. Creatine kinase was measured as an index of cellular damage. Endothelial integrity was assessed by measuring coronary flow and by measuring the levels of serotransferrin and interstitial albumin in the coronary effluent. Additionally, damage to the endothelium was assessed histologically by light microscopy analysis of the cellular structure of the myocardium. MMP-2 activity was measured by zymography in hearts subjected to 15, 20 and 30 min of ischemia without reperfusion. MMP-2 activity was increased in heart tissue at the end of ischemia and was correlated with duration of ischemia. The post-ischemia decrease in coronary flow, and the increase in the release of serotransferrin and albumin were attenuated by Phen. Edema (another indirect marker of endothelial damage) was observed in I/R heart and the edema was abolished in I/R heart treated with MMP inhibitors. MMP inhibition not only reduces cardiac mechanical dysfunction but also reduces endothelial damage resulting from cardiac I/R injury. [ABSTRACT FROM AUTHOR]

Clinical and experimental data support a link between endothelial dysfunction and inflammation. Inflammatory cytokines are important protagonists in formation of atherosclerotic plaque, eliciting effects throughout the atherosclerotic vessel. Importantly, the development of atherosclerotic lesions, regardless of the risk factor, e.g., diabetes, hypertension, obesity, is characterized by disruption in normal function of the endothelial cells. Endothelial cells, which line the internal lumen of the vasculature, are part of a complex system that regulates vasodilation and vasoconstriction, growth of vascular smooth muscle cells, inflammation, and hemostasis, maintaining a proper blood supply to tissues and regulating inflammation and coagulation. Current concepts suggest that the earliest event in atherogenesis is endothelial dysfunction, manifested by deficiencies in the production of nitric oxide (NO) and prostacyclin. The focus of this review is to summarize recent evidence showing the effects of inflammation on vascular dysfunction in ischemic-heart disease, which may prompt new directions for targeting inflammation in future therapies. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effect of coronary flow (CF) changes and inflammatory indices on myocardial microcirculation—assessed by myocardial contrast echocardiography (MCE)—and on left ventricular remodelling, in an experimental ischaemia–reperfusion model. In 15 pigs, weighing 30 ± 5 kg, ligation of the left anterior descending (LAD) coronary artery was performed, followed by reperfusion for 120 min. Peak, mean, duration and volume of systolic and diastolic components of CF distal to the LAD ligation were measured using a butterfly flowmeter and their ratio was calculated. The following two-dimensional echocardiography indices of LV geometry/function were measured from the apical four-chamber view: LV end-systolic (ESD) and end-diastolic (EDD) dimension long- (Ls, Ld) and short-axis (Ss, Sd) and their ratio (Ld/Sd, Ls/Ss, defined as the sphericity index). Interleukin (IL) 1 β, 6, 10 and tumour necrosis factor (TNF) were measured in samples obtained from the LV cavity and coronary sinus. A 0.5 ml/min injection slow bolus over 30 s of SonoVue was made into the left ventricle (LV) in order to assess myocardial perfusion by MCE. Standard apical four-chamber views were digitally acquired and stored for off-line analysis using the Echofit system. The peak intensity (Ac) of the microbubbles at the apex, distally to ligation, was normalised with respect to the peak intensity of the microbubbles in the LV cavity. All parameters were recorded at baseline, immediately after ligation and at 5, 15, 30, 60, 120 min during reperfusion. The percentage changes of CF indices, echocardiographic parameters, interleukins and Ac between baseline and reperfusion were calculated. Mean systolic CF, systolic volume, peak and mean diastolic flow (MDF) changes and epicardial mean CF, Ld/Sd, Ls/Ss changes and coronary sinus IL-6 (IL-6 cs) were inversely correlated with Ac changes during reperfusion. At 5 and 15 min of reperfusion (hyperaemic phase), the greatest median increase of mean diastolic (172% and 86%), and mean systolic CF (713% and 344%) and the greatest reduction of Ac (−41% at 5 min) compared to baseline ( P < 0.05) were observed. The maximum increase of IL-6 cs (40%) was detected at 120 min. ROC analysis showed that of all examined echocardiography indices an increase of mean diastolic CF > 22% was the best predictor of a >25% reduction of Ac with 76% sensitivity and 65% specificity (area 71%, CI 54%–85%, P = 0.02). In addition an >32% increase of IL-6 at 120 min of reperfusion predicted a >25% reduction of Ac with a 76% sensitivity and 65% specificity (area 71% CI 61%–97%, P = 0.01). Changes of mean diastolic CF and IL-6 cs are associated with alterations in myocardial microvascular integrity after ischaemia–reperfusion and may be used as a predictor of myocardial dysfunction. [ABSTRACT FROM AUTHOR]

Endothelin (ET)-1 is an endogenous vasoconstrictor which modulates norepinephrine (NE) release in myocardial ischemia reperfusion. Recent studies have demonstrated the pro- or anti-arrhythmic effects in reperfusion. The present studies were undertaken to test the hypothesis that ET receptors located in sympathetic nerve terminals modulate NE release associated with reperfusion arrhythmias (ventricular fibrillation; VF). Immunohistochemical studies showed that both ETA and ETB receptors exist in the sympathetic nerve varicosities, which were stained positive for tyrosine hydroxylase (TH) in the left ventricular wall in guinea pigs. Isolated guinea pig hearts were subjected to 20 min of normothermic global ischemia followed by 30 min reperfusion. Exogenously applied ET-1 (0.1 and 1 nM) dose-dependently increased NE release and the duration of VF, but these responses were significantly suppressed with the Na+/H+ exchanger inhibitor, 5-(N-ethyl-N-isopropyl)-amiloride (10 μM). The ETA receptor antagonist (BQ123, 1 μM) and nonselective ET receptor antagonist (PD142893, 1 μM) significantly attenuated NE release and VF, whereas the ETB receptor antagonist (BQ788,300 nM) markedly elevated NE release but did not affect VF. These studies provide the first evidence that both ETA and ETB receptors, located in the sympathetic nerve varicosities, modulate NE release, at least in part, in association with reperfusion arrhythmias. [ABSTRACT FROM AUTHOR]

The literature is reviewed on methods to assess heterogeneity of blood flow, substrate uptake and oxidative end energy metabolism in the normal heart, and their interrelations. Even though the factors controlling matching on the regional level remain largely obscure, the evidence that heterogeneous blood flow partially correlates to indicators of metabolism in the normal heart is accumulating, particularly in face of a correlation between acetate metabolism indicative of regional O2 consumption to microsphere blood flow. Moreover, the partial matching cannot be explained by vascular anatomical differences from one region to the other, since, although fractal theory can partially describe the branching patterns of the coronaries, vasodilation is similar among regions upon metabolic stimulation of the heart. It is dissimilar among regions, so that blood flow is redistributed, upon maximum vasodilation with adenosine or hypoxia, denoting regionally different maximum vessel diameter and flow reserve. However, regionally differing tissue composition could also contribute somewhat to regional differences in (the need for) blood flow. It is still unknown, because of technical limitations, how the foregoing measures relate to regional work load. [ABSTRACT FROM AUTHOR]

Myocardial blood flow exhibits the most marked heterogeneity at the microvascular level. Its within-layer spatial distribution can be described from subepi- to subendocardium with resolutions of 0.1 × 0.1 to 1 × 1 mm2 by quantitative digital radiography based on the technique of desmethylimipramine deposition. In the subendocardium, flow heterogeneity is the highest, whereas local flow randomness is the lowest, showing the clustered pattern of high- or low-flow regions. The resolution-dependence of flow heterogeneity is characterized by its fractality, which holds consistently down to the microvascular level through the vascular structural transition from the treelike arteriolar to the non-treelike capillary network. Flow heterogeneity is adjustable in a transmurally different manner to local metabolic changes. The redistribution of flow is considered as a result of adaptive coordination of microperfusion between adjacent microcirculatory units, which are perfused by a single precapillary arteriole. [ABSTRACT FROM AUTHOR]

It is well established that myocardial blood flow is heterogeneous on the local level. During recent years comprehensive studies have been undertaken to assess the relation between myocardial metabolism and spatial blood flow heterogeneity. Based on the type of measurements two major groups of studies have been performed: enzyme activity and tissue metabolite level assessments. Enzyme activity measurements have provided only limited insight into the coupling of local metabolism and flow. This is probably due to the fact that, in addition to estimated Vmax values, local substrate affinity (Km values) and substrate concentrations affect the metabolite fluxes. However, the latter two variables remain normally unknown. In contrast, valuable insight has been obtained concerning flow-metabolism matching from tissue metabolite measurements, especially when connected with mathematical model analyses. The latter permitted the calculation of metabolic flux rates (e.g., production of oxidation water, citric acid cycle flux, glucose uptake, fatty acid uptake) or the translation of the metabolic indexes into physiologically meaningful local metabolite concentrations (e.g., free cytosolic adenosine). The bottom line of the studies reported to date is that the broad range of myocardial flows observed under resting control conditions correlates with local metabolism possibly affected by spatial differences in adrenergic stimulation. Thus, high flow samples exhibit a higher oxidative metabolism than low flow samples. As a result the flow threshold below which local myocardial ischemia ensues is higher in control high flow samples. The importance of these findings with respect to local flow-metabolism matching is underlined by the finding that the probability of developing an infarction following ischemia/reperfusion is related to the functional state of the myocardium under control conditions, i.e., the local level of flow-metabolism matching. [ABSTRACT FROM AUTHOR]

It has previously been shown that endothelin (ET) receptor antagonists limit myocardial ischaemia/reperfusion (I/R) injury. The mechanism behind this effect is still unclear. The aim of this study was to elucidate the possible relationship between cardioprotection by an ETA receptor antagonist and inhibition of neutrophil accumulation or activation in the myocardium determined as myeloperoxidase (MPO) activity during I/R. Anaesthetised pigs were subjected to 45 min ischaemia by ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. Infiltration of MPO-containing cells, presumably neutrophils, into the ischaemic area was confirmed with an immunohistochemical technique using antibodies against porcine MPO. Vehicle (n = 7) or the selective ETA receptor antagonist LU 135252 (LU; n = 7) were given into the LAD during the last 10 min of ischaemia and the first 5 min of reperfusion. There were no significant differences in LAD flow, mean arterial pressure, heart rate, or rate pressure product between the groups during I/R. The area at risk was similar in the two groups. LU reduced the final infarct size to 40 ± 6 % of the area at risk compared to 80 ± 6 % in the vehicle group (P < 0.001). Endothelin-like immunoreactivity increased 2-fold in the ischaemic area in the vehicle group (P < 0.01), but not in the group given LU. MPO activity was higher (2.5x) in the ischaemic than in the non-ischaemic myocardium of the vehicle group. The MPO activity in the ischaemic myocardium was significantly lower in the group given LU (7.0 ± 1.2 units g-1) than in the vehicle group (14.2 ± 1.9 units g-1; P < 0.01). There was a significant correlation between the infarct size and MPO activity (P < 0.01, r = 0.68). In conclusion, local administration of the selective ETA receptor antagonist LU during the last period of ischaemia and early reperfusion reduces the extent of myocardial necrosis and MPO activity. This suggests that LU may exert its cardioprotective effect by inhibiting neutrophil-mediated injury. [ABSTRACT FROM AUTHOR]

Nitric oxide synthase (NOS) inhibitors elicit bradycardias independent of the endothelium (e-NOS) or increases in blood pressure. Therefore, this bradycardia could be mediated by other NOS isoforms, most likely that of the nervous system (n-NOS). If so, heart rate variability (HRV) as a measure of vagal activity should be an indicator of the activity of n-NOS in vagal neurons. To test this, we studied the dose-effect relations of L-NAME (0.3 – 50 mg·kg-1) on heart rate (HR), HRV and systemic vascular resistance (SVR) in seven awake dogs. HRV was analyzed in the time domain as standard deviation of the RR-intervals (SDNN) and in the frequency domain as power in the high (0.15 – 0.5 Hz) and low (0.04 – 0.15 Hz) frequency range. The effects of HR and SDNN reached their maxima at a dose of 3 mg·kg-1 and had their ED50 at 0.27 ± 0.03 mg·kg-1 and 0.43 ± 0.1 mg·kg-1, respectively, whereas SVR had its maximum at 10 mg·kg-1 and ED50 at 0.86 ± 0.11 mg·kg-1 (p < 0.05). HF-power (vagal activity) predominated compared to LF-power (mainly sympathetic activity) during baseline as well as after L-NAME. The effects on HR and HRV were absent after ganglionic blockade (hexamethonium), whereas the effects on SVR remained unchanged. Thus, NO exerts a powerful restraining activity on vagal neurons and plays a key role in the adjustment of heart rate in awake resting animals with prevailing vagal activity. [ABSTRACT FROM AUTHOR]

The present article describes the concept of perfusion-contraction matching originally proposed by Ross, goes on to critically discuss the available techniques to measure both regional myocardial blood flow and function in the experimental and clinical setting, and finally analyzes the available evidence for perfusion-contraction match and mismatch during normoperfusion and various scenarios of myocardial ischemia/reperfusion, including acute and subacute ischemia, coronary microembolization, stunning and hibernation. [ABSTRACT FROM AUTHOR]

The widely accepted theories for the decreased function in the stunned myocardium relate to Ca2+ desensitization and free radical-mediated tissue damage of the myofilaments. The aim of the present study was to examine whether the depressed contractile function and Ca2+ responsiveness of the stunned myocardium may be restored by a new Ca2+ sensitizer (levosimendan), which has been shown to improve the Ca2+ response of the myofilaments. The effects of levosimendan on the left ventricular function and the in vivo protein phosphorylation were examined in both the non-ischemic and the stunned myocardium. Myocardial stunning was induced in Langendorff-perfused guinea pig hearts by suspending the circulation for 8 min, followed by a 20-min reperfusion period. Perfusion of post-ischemic guinea pig hearts with levosimendan (0.03–0.48 μM, 6 min) was associated with dose- and time-dependent increases in both dP/dtmax (contractility) and dP/dtmin (speed of relaxation). When the effectiveness of levosimendan was compared in non-ischemic and post-ischemic hearts, no significant differences were noted in the relative stimulatory effects on contractility and relaxation, at any given time point (time-response curve) or concentration (dose-response curve). Perfusion of the guinea pig hearts with a high (0.3 μM) levosimendan concentration did not reveal any qualitative or quantitative difference in the phosphodiesterase inhibitory potential of the compound (elevation of tissue cyclic AMP levels and characteristics of protein phosphorylation) between the non-ischemic and the post-ischemic myocardium. However, when isoproterenol was adminstered to induce maximal in vivo phosphorylation of cardiac phosphorproteins, an attenuation of the 32P-incorporation into troponin I was noted in the post-ischemic hearts. The decrease in isoproterenol-induced 32P-incorporation into troponin I was associated with similar alterations in the tissue level of this protein. We conclude that the Ca2+ sensitizer levosimendan exerts dose- and time-dependent positive inotropic and lusitropic effects on the postischemic myocardium, lending support to the hypothesis tha Ca2+ desensitization of the myofibrils is involved in myocardial stunning. [ABSTRACT FROM AUTHOR]

Local deposition density of microspheres is heterogeneous in histologically homogeneous myocardium under physiological conditions. The underlying biological heterogeneity must be distinguished from a methodological heterogeneity which depends preferentially on the number of microspheres injected, blood flow to a particular myocardial region and sample mass. As the variables space (spat), time (temp), and the method (meth) are independent of each other, the observed (obs) variability may be approximated using the coefficients of variation (CV) of the individual variables: CVobs=(CV2 spat+CV2 temp+CV2 meth)0.5. Studies in which these different variables have been quantified indicate that the largest fraction of the observed variability of microsphere deposition density is contributed by spatial flow heterogeneity which exists independent of the myocardial layer. Spatial flow heterogeneity increases with decreasing sample mass and decreasing mean flow. Fractal and autocorrelation analyses have shown that adjacent myocardial flows are spatially correlated and nonrandom. Local blood flow was shown to correlate with various metabolic and transport rates, while no differences were found between low and high flow regions with respect to several metabolic markers of tissue hypoxia. In conclusion, the evidence available to date indicates that 1) in histologically homogeneous myocardium there exists a spatial blood flow heterogeneity which 2) is temporally stable, 3) resolution dependent, 4) largely layer-independent, 5) nonrandom, and 6) related to local aerobic metabolism. [ABSTRACT FROM AUTHOR]

We examined and compared the effects of levosimendan, a new myofilament calcium sensitizer with phosphodiesterase inhibiting activity, pimobendan, and milrinone on left ventricular-arterial coupling and mechanical efficiency in 21 experiments performed in open-chest, barbiturate-anesthetized dogs instrumented for measurement of aortic and left ventricular (LV) pressure (micromanometer-tipped catheter), +dP/dt, and LV volume (conductance catheter). Myocardial contractility was assessed with the endsystolic pressure-volume relation (E) and preload recruitable stroke work (M) generated from a series of differentially loaded LV pressurevolume diagrams. LV-arterial coupling and mechanical efficiency were determined by the ratio of E to effective arterial elastance (E; the ratio of end-systolic arterial pressure to stroke volume) and the ratio of stroke work (SW) to pressure-volume area (PVA), respectively. Levosimendan (0.75, 1.5, and 3.0 μg·kg·min) significantly (p<0.05) increased heart rate, +dP/dt, and ejection fraction (EF) and decreased mean arterial pressure (MAP), pressurework index (PWI; an estimate of myocardial oxygen consumption), and LV systolic and end-diastolic pressures (LVSP and LVEDP) and volumes (EDV and ESV). Levosimendan-induced augmentation of myocardial contractility (E, M, and+dP/dt) and reductions in LV afterload (E) caused increases in the E/E ratio (0.61±0.10 during control to 3.3±0.7 during the high dose) consistent with enhancement of LV-arterial coupling. Levosimendan increased SW/PVA (0.48±0.05 during control to 0.84±0.04 during the high dose), indicating this drug improves the transfer of myocardial potential energy to external work. Levosimendan also increased the ratio of SW to PWI (109±18 during control to 255±50 mmHg·min·100g during the high dose), suggesting that myocardial metabolic efficiency was improved as well. Like levosimendan, pimobendan and milrinone (10, 20, and 40 and 1.0, 2.0, and 4.0 μg·kg·min, respectively) increased HR, +dP/dt, EF, E, and M and decreased MAP, LVSP, LVEDP, EDV, ESV, and E. In contrast to levosimendan, neither agent reduced PWI. Pimobendan and milrinone caused dose-related increases in E/E, SW/PVA, and SW/PWI. The results indicate that levosimendan, pimobendan, and milrinone augment myocardial contractility, produce venous and arteriolar vasodilation, and enhance LV-arterial coupling and mechanical efficiency in open-chest, barbiturateanesthetized dogs. [ABSTRACT FROM AUTHOR]