Search

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.

Under physiologic circumstances, cardiac function determines myocardial oxygen consumption and consequently coronary perfusion. Surprisingly, in a reverse direction, improved coronary perfusion also increased myocardial oxygen consumption and contractile function. This experimental finding, now 40 years old, is termed the Gregg phenomenon. Some 10 years later, in experiments by Arnold and co-workers, an isolated increase in perfusion pressure improved ventricular function. In this context, the term 'gardenhose effect' was coined, implying a hydraulic explanation of the Gregg phenomenon. In the following, we attempt to distinguish the Gregg phenomenon from the gardenhose effect and to critically evaluate them.

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.

In the following, three newer concepts are brought together: myocardial hibernation, heterogeneity in myocardial blood flow and oxidative metabolism, and effects of hibernating animal serum on non-hibernators. Myocardial hibernation is viewed as a protective mechanism that helps to maintain myocardial integrity and viability by down-regulating contractile function as an adaptation to reduced blood flow. Myocardial flow is considerably heterogeneous. Consequently, oxygen supply to the myocardium is also heterogeneous. Many lines of evidence show a close correlation between regional flow and regional metabolism. In low-flow/low-metabolism areas, myocardial function must be reduced, since the myocardium would otherwise undergo necrosis. Thus, others and we hypothesize that function must be down-regulated to induce hibernation in low-flow areas. Because no regional histologic differences exist (the mitochondria are uniformly distributed within the myocardium), the pattern of heterogeneity seems to shift over time. Hence, we hypothesize that such very regional hibernation presents an evolutionary, protective mechanism, permitting subsequent myocardial areas to rest within the ceaselessly working heart. We also hypothesize that this mechanism ensures the down-regulation of function following myocardial ischemia in order to induce myocardial hibernation on a broader level. Surprisingly, a substance (opioid in nature) contained in hibernator serum both induced hibernation-like state in non-hibernators and suppressed myocardial oxygen consumption. Thus, we lastly hypothesize that myocardial hibernation is a remnant of the early stages of evolution and is closer to physiologic hibernation than traditionally viewed.

Beside wall tension and contractility, heart rate is a major determinant of myocardial oxygen consumption. Therefore, a decrease in heart rate could prevent ischemia or reduce its consequences. We examined the effect of a new bradycardic agent of the benzazepinone-type (DK-AH 269) on eight isolated, saline-perfused rabbit hearts, bradycardia resulted from a specific blockade of i(f)-channels in sinus node cells. After control measurements (C), the substance was added in three increasing concentrations (D1: 10(-8) M, D2: 10(-7) M, D3: 10(-6) M). We observed a dose-dependent reduction in heart rate (C: 206 +/- 25, D1: 195 +/- 30, D2: 77 +/- 41, D3: 154 +/- 48/min). In the highest dosage, the duration of diastole was increased by 100%. To characterize systolic function, we measured stroke volume (SV), peak left ventricular pressure (LVPmax) and its first derivative (dP/dtmax). Aortic flow was slightly decreased whereas SV increased to 108% of control after initial reduction at the two lower dosages. LVPmax remained unchanged, and dP/dtmax was dose-dependently reduced to 91, 81, and 70% of control (C: 1885 +/- 376, D1: 1721 +/- 525, D2: 1526 +/- 504, D3: 1327 +/- 337 mm Hg/s); dP/dtmin as a measure of early relaxation was also reduced. The coronary flow per beat did not change compared with control in the presence of the two lower doses of DK-AH 269, but was significantly increased with the highest dose (C: 0.29 +/- 0.06, D1: 0.28 +/- 0.07, D2: 0.29 +/- 0.09, D3: 0.34 +/- 0.11 ml). The myocardial oxygen demand was dose-dependently decreased (C: 10.4 +/- 2.5, D1: 9.6 +/- 2.5, D2: 8.8 +/- 2.6, D3: 7.9 +/- 2.4 ml/min/100 g). The relation between subendocardial and subepicardial flow, assessed with colored microspheres, exhibited no changes in the presence of the highest dose of DK-AH 269 (C: 1.28 +/- 0.09, D3: 1.27 +/- 0.08). DK-AH 269 reduced heart rate in isolated rabbit hearts and increased the duration of diastole. Whereas systolic function was primarily left unchanged, coronary flow per beat and oxygen consumption were decreased. According to our results, this new bradycardic agent could be useful in treating coronary heart disease.

Unlabelled: After heart rate variability (HRV) had been established in the clinic, the question about the minimum interval length for analyzing electrocardiograms emerged. Respiration rate, heart rate and heart rate variability were analyzed in 25 sport divers during 6 min intervals at control, immersion, submersion and while SCUBA diving. Thereafter, the interval length was systematically shortened to 1 min., Results: Respiration rate was significantly reduced during submersion and diving. Heart rate, in turn, remained essentially unchanged during the four experimental steps. The HRV measures in the time domain (standard deviation, coefficient of variation, RMSSD and pNN50) exhibited significant changes during immersion, submersion and diving compared to control conditions. The spectral density in the low frequency range was increased compared to control, the increase being significant during diving. Immersion, submersion and diving, thus, present strong stimuli for the autonomic nervous system. The length of the HRV measures of the time domain could be shortened to 3 min without significant loss of information, except for pNN50. Reduction of the respiration rate during diving considerably shifted the respiratory arrhythmia from the high to the low frequency range. Such shifts deserve special attention interpreting HRV measures from the frequency domain. The interval length for the measures in the frequency domain could only be shortened to 5 min., Conclusion: Measures from the time domain, in particular standard deviation and co-efficient of variation, seem to be superior to measures from the frequency domain in analyzing short-term HRV.

The efficacy of a revascularization treatment after acute coronary artery occlusion can be evaluated by different diagnoses. The ECG and the time-course of, for example, the CK isoenzyme MB are widely used as quick, objective, and almost noninvasive tools. In addition, the assessment of functional recovery of the postischemic myocardium or the evaluation of the magnitude of irreversibly injured myocardium is essential for therapeutic strategies. In the present study, myoglobin that is not yet routinely established, is compared with CKMB to answer the following questions: do measurements of serum-CKMB and serum-myoglobin reliably demonstrate 1) the success of a revascularization treatment? 2) the functional recovery of the postischemic myocardium? 3) the magnitude of irreversibly injured myocardium? To answer these questions, the left anterior descending coronary arteries of 17 anesthetized pigs were occluded for 60 min and reperfused for 180 min after successful "revascularization". The major findings of this study on anesthetized pigs are: 1) The time-course of both the CKMB activity and the myoglobin concentration exhibit the successful revascularization. 2) The CKMB maximum does not exhibit the recovery of the ventricular function, whereas the myoglobin maximum moderately correlated with the contractile state (dP/dtmax) at the end of reperfusion and significantly with the recovery of dP/dtmax during reperfusion. Recovery of the regional function (= mean thickening velocity) within the 180 min reperfusion is predicted neither by CKMB nor myoglobin analysis. 3) Both investigated markers correlate closely with the magnitude of the irreversibly injured myocardium.

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.

Some homeothermic animals can survive adverse conditions by hibernation, i.e., by reducing their body temperature in accordance with ambient temperature, thus reducing metabolism and vital functions. Six years ago, the term hibernation was introduced to describe a particular state of the myocardium. Although the meaning is different from that used in zoology and, thus, is misleading, it is used increasingly to describe a condition induced by moderate reduction in coronary flow. Some evidence in the literature suggests that the myocardium can actively reduce its mechanical function as a consequence of reduced coronary flow in order to prevent ischemia-induced injury. It is conceivable that the hibernating myocardium is the result of such a down-regulation of function. The hibernating myocardium can be characterized by decreased function in the hypoperfused area, which still exhibits active metabolism and remains viable. This is in contrast to "stunned" myocardium, which represents dysfunction during postischemic reperfusion, i.e., with coronary blood flow being close to normal. In analogy to hibernation in its original meaning, down-regulation and hibernating myocardium are considered to represent a protective mechanism, because such myocardium can quickly regain its initial function after restoration of physiologic blood flow. Because hibernating myocardium is salvageable, it has to be distinguished from other dysfunctional tissue that has lost its function due to ischemic damage, so that appropriate clinical interventions can succeed in restoring normal coronary blood flow.

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)