Relation between energy metabolism, glycolysis, noradrenaline release and duration of ischemia

We studied the effect of 12-36 min of global ischemia followed by 36 min of reperfusion in Langendorff perfused rabbit hearts (n = 26). Metabolism was determined in terms of peak and total release of purines (adenosine, inosine, hypoxanthine), lactate and noradrenaline during reperfusion; and myocardial content of nucleotides (ATP, ADP, AMP), glycogen and noradrenaline at the end of reperfusion. An inverse relationship (r = -0.79) existed between duration of ischemia and developed pressure post-ischemia. Early during reperfusion, after 12 min of ischemia, the purine concentration (peak release) increased 100x (p < 0.01), that of lactate and noradrenaline 10x (p < 0.05). Total purine release rose with progression of the ischemic period (30x after 36 min of ischemia; p < 0.01), concomitant with a reduction in nucleotide content. Lactate release was independent from the duration of ischemia, although glycogen had declined by 30\% (p < 0.01) after 36 min of ischemia. The acid insoluble glycogen fraction, which presumably contains proglycogen, increased substantially during short-term ischemia. Peak noradrenaline increased 100x, and 200x, (p < 0.05) after 24 and 36 min of ischemia, respectively. Total noradrenaline release due to various periods of ischemia mirrored its peak release. Function recovery was inversely related to total purine and noradrenaline efflux (both r = -0.81); it correlated with tissue nucleotide content (r = 0.84). In conclusion, larger amounts of noradrenaline are released only after a substantial drop in myocardial ATP. During severe ischemia ATP consumption more than limited ATP production by anaerobic glycolysis, is a key factor affecting recovery on subsequent reperfusion. In contrast to lactate efflux, purine and noradrenaline release are useful markers of ischemic and reperfusion damage

Catecholamines: the cardiovascular and neuroendocrine system.

The development of profound autonomic dysfunction and of neuroendocrine activation characterizes and possibly contributes to the progression of heart disease to congestive heart failure. Sympathetic activation is a generalized process and the proposed mechanisms for neurohumoral activation include decreased input from excitatory afferences and increased input from excitatory chemoceptors and metabaroceptor. These phenomena vary to a great extent in different subjects: in the more impaired patients, renal and cardiac overflow of catecholamines can increase three- and ten-fold, respectively, accounting for about 60\% of the increase of noradrenaline in congestive heart failure. Efficient methods to quantify sympathetic cardiovascular influences and neuroendocrine indices have been developed and it has been recognized that sympathoneural activation independently predicts the survival of patients. The pathophysiological role and the clinical relevance of neuroadrenergic abnormalities also constitute the grounds for the understanding of the therapeutic benefit obtained with interventions aimed at mitigating the harmful consequences of adrenergic hyperactivity

Recognized molecular mechanisms of heart failure: approaches to treatment.

Abnormalities of cytosolic calcium handling and myocyte energetics appear to play an important role in mediating contractile dysfunction in heart failure. Systolic and diastolic dysfunction in the failing heart are related to abnormalities of the excitation-contraction mechanism as well as myofilament calcium sensitivity. These abnormalities can be viewed as a compensatory mechanism as the myocytes by down regulating its function and metabolic activity preserve energy consumption and allow better maintenance of basal cellular homeostasis. The end point of myocyte dysfunction, however, is a reduced contraction, which, in turn, might cause a reduced cardiac output and a threatening of arterial pressure. This causes a second level of adaptation, which implies a neuroendocrine response of the whole organism. Consequently, the syndrome of congestive heart failure is characterized not only by impaired ventricular function, but also by an increase in some endogenous substances leading to vasoconstriction and water and salt retention. Although activation of the systems that release these substances is presumed to be compensatory, the sympathetic nervous system and renin-angiotensin-aldosterone system as well as the endothelins may contribute to the pathogenesis of the syndrome. Opposite to the effects of these systems are those evoked by the release of atrial natriuretic peptides. The peptides exert a potent direct vasodilatation and natriuresis. In addition, atrial natriuretic peptides inhibit the release of norepinephrine from nerve terminals and suppress the formation of renin. However, the natriuretic and vasodilator effects of these peptides in patients with congestive heart failure are outweighed by the sodium retention and vasoconstriction caused by sympathetic stimulation and activation of the renin-angiotensin-aldosterone system. The reasons for this are not entirely known. The atrial stretch receptors that are responsible for the release of the atrial peptides become impaired, and it has been suggested that patient with heart failure may adapt to the physiologic effects of atrial natriuretic peptides. The possibility that congestive heart failure is in part a humoral disease is reviewed here and consequently pharmacologic treatment aimed at reducing the effects of the neuroendocrine response as to be advantageous for patients with heart failure

The neuroendocrine and sympathetic nervous system in congestive heart failure.

A review of recent randomized clinical trials has shown that neurohormonal activation starts early in the natural history of left ventricular dysfunction and levels of the circulating hormones increase in proportion to the severity of heart failure. Most studies suggest that high levels of neurohormones predict a poor prognosis. Among the several neurohormones, the sympathetic system is the one which is activated earlier, it increases in proportion to the severity of the disease and has a negative prognostic implication. These concepts have been also proven in untreated patients. Augmented sympathetic activity in the syndrome of heart failure is initially beneficial, appears to be adaptive and helps support blood pressure and cardiac output. Prolonged and excessive sympathetic activation has deleterious effects with adverse consequences at both cardiac and vascular levels which aggravates the clinical status of the syndrome and negatively affects its prognosis. Evidence is accumulating that, contrary to popular belief, beta-blockers may be beneficial in heart failure by inhibiting sympathetic activation. In addition to neuroendocrine activation, another class of biologically active molecules, termed cytokines, are excessively secreted by cells in heart failure. Important among these cytokines are tumour necrosis factor-alpha and interleukin-6. They appear to exert deleterious effects on the heart and circulation which may be also involved in the progression of heart failure

[Comparative protective effect of gallopamil in myocardial ischemia and reperfusion]

[Comparative protective effect of gallopamil in myocardial ischemia and reperfusion

New findings on calcium antagonism

The family of calcium antagonist substances is continuously increasing. Often it is difficult, if not impossible, to have clear, objective criteria to differentiate between the available molecules. We have considered some molecular aspects of calcium channels and of the effects of calcium antagonists which may be relevant for the clinical utilization of these drugs. In particular, differences between L and T type of calcium channels in the myocytes and between VOC and ROC calcium channels in the smooth muscle are described. Then we have considered the main differences in the mechanism of action and clinical use of the three prototypes of calcium antagonists: phenilalkilamines, dihydropyridines and benzothiazepines. Finally, we have synthetically depicted the characteristic of the second generation agents such as nisoldipine, amlodipine, felodipine, isradipine, lacidipine and gallopamil

Oxidative stress during myocardial ischaemia and reperfusion: Experimental and clinical evidence.

Oathopysiology of oxidative stress during myocardial ischaemia and reperfusion in ex vivo experimental model and in humans during open heart surger

Myocardial damage during ischaemia and reperfusion.

Reperfusion, without doubt, is the most effective way to treat the ischaemic myocardium. Late reperfusion may, however, cause further damage. We attempted to identify the nature and time-course of metabolic changes occurring during ischaemia followed by reperfusion either in isolated and perfused rabbit hearts or in coronary artery disease (CAD) patients undergoing intracoronary thrombolysis or aortocoronary bypass grafting. In isolated hearts, reperfusion after prolonged ischaemia causes exacerbation of cell damage, leading to a breakdown of the permeability barrier of ions as well as of larger molecules, such as creatine phosphokinase. As consequence, reperfusion results in a large increase in intracellular calcium, leading to mitochondrial calcium overload with subsequent damage to the mitochondrial structure and loss of the ability to produce adenosine triphosphate (ATP). The ultimate mediator of the membrane damage is not known. It has been suggested that myocardial production of oxygen free radicals above the neutralizing capacity of the myocytes is an important cause of reperfusion damage. There is evidence that prolonged ischaemia reduces the naturally occurring defence mechanisms of the heart against oxygen free radicals, particularly mitochondrial manganese superoxide dismutase, and the intracellular pool of reduced glutathione. Consequently, reperfusion results in severe oxidative damage, as evidenced by tissue accumulation and release of oxidized glutathione. An oxygen free radical-mediated impairment of mechanical function also occurs during reperfusion of the human heart. During surgical reperfusion of CAD patients, we observed a prolonged and sustained release of oxidized glutathione; the degree of oxidative stress can inversely correlated with recovery of mechanical and haemodynamic function.(ABSTRACT TRUNCATED AT 250 WORDS