Serum from patients with severe CHF downregulates eNOS expression and increases apoptosis. High levels of TNF-alpha likely play a role, but they cannot be the only factor responsible.

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In the heart mitochondria exert two roles essential for cell survival: ATP synthesis and maintainance of Ca2+ homeostasis. These two processes are driven by the same energy source: the H+ electrochemical gradient (delta microH) which is generated by electron transport along the inner mitochondrial membrane. Under aerobic physiological condition mitochondria do not contribute to the beat to beat regulation of cytosolic Ca2+, although Ca2+ transient in mitochondrial matrix has been described. Increases in mitochondrial Ca2+ of mumolars concentration stimulate the Krebs cycle and NADH redox potential and, therefore, ATP synthesis. Under pathological conditions, however, mitochondrial Ca2+ transport and overload might cause a series of vicious cycles leading to irreversible cell damage. Mitochondrial Ca2+ accumulation causes profound alterations in permeability of the inner membrane to solutes, leading to severe mitochondrial swelling. In addition Ca2+ transport takes precedence over ATP synthesis and inhibits utilization of delta microH for energy production. These processes are important to understand the sequence of the molecular events occurring during myocardial reperfusion after prolonged ischaemia which lead to irreversible cell damage. During ischaemia an alteration of intracellular Ca2+ homeostasis occurs and mitochondria are able to buffer cytosolic Ca2+, suggesting that they retain the Ca2+ transporting capacity. Accordingly, once isolated, even after prolonged ischaemia, the majority of the mitochondria is able to use oxygen for ATP phosphorylation. When isolated after reperfusion, mitochondria are structurally altered, contain large quantities of Ca2+, produce excess of oxygen free radicals, their membrane pores are stimulated and the oxidative phosphorylation capacity is irreversibly disrupted. Most likely, reperfusion provides oxygen to reactivate mitochondrial respiration but also causes large influx of Ca2+ in the cytosol as result of sarcolemmal damage. Mitochondrial Ca2+ transport is therefore stimulated at maximal rates and, as consequence, the equilibrium between ATP synthesis and Ca2+ influx is shifted towards Ca2+ influx with loss of the ability of ATP synthesis.

No abstract

Inducible nitric oxide synthase is expressed in circulating monocytes of patients with severe congestive heart failure. This phenomenon is linked to the activation of the tumour necrosis factor-alpha system.

We determined the temperature-induced synthesis of the 72-kD heat-shock protein (hsp72) in hearts of normotensive and spontaneously hypertensive rats (SHR) subjected to whole-body hyperthermia (42.0±0.5°C for 15 minutes). The animals were studied at three diiferent ages: young (2 months), adult (6 months), and old (18 months). The hsp72 was determined by Western blot analysis using a monoclonal antibody. The results were calculated densito-metrically as a percentage of a commercial standard. Young SHR responded to hyperthermic stress with increased synthesis of hsp72 compared with age-matched normotensive rats (298.8 ±70.0% versus 88.3±25.5%). This trend was maintained in adult rats (118.1±31.0% A common feature of genetically hypertensive animals is a greater sensitivity to environmental temperature with respect to that of their normotensive control counterparts. 1-2 The increased thermosensitivity is genetically linked with hypertension 3 and at the molecular level is characterized by an over-expression of heat-shock proteins, 46 a group of highly conserved proteins synthesized during stress and involved in cellular protection. 712 Increased synthesis of the 72-kD heat-shock protein (hsp72) is a specific marker of the stress response in the heart as hsp72 is induced in the myocardium after heat treatment, ischemia, hemodynamic overload, or hypox-j a i3-i6 T n e synthesis of hsp72 in the myocardium of heat-shocked hypertensive animals has never been fully studied. This is particularly relevant because recently the induction of hsp72 synthesis has been shown to protect the myocardium against ischemia, 9 " 11 a pathological condition often associated with hypertension. During aging, the heart undergoes progressive functional alterations and becomes more vulnerable to isch-emic insult. 17 This is true of the hypertrophic heart of the spontaneously hypertensive rat (SHR). 18-19 Several studies show an age-dependent decrease in the expression of heat-shock protein in response to environmental stress in both isolated cell systems 20-21 and tissues. 22-23 The first aim of this study was to determine the synthesis of hsp72 in the heart of normotensive Wistar-Kyoto (WKY) rats and SHR subjected to whole-body hyperthermia. The second aim was to investigate the effects of aging on the synthesis of hsp72. versus 54.8±21.3%) but not in old rats (65.3±29.4% versus 43.6±15.1%). Aging caused a reduction of hsp72 expression in response to hyperthermic stress in both SHR (4.6-fold) and normo-tensive rats (twofold). These data show that hearts of young and adult SHR respond to heat shock with enhanced synthesis of hsp72. This abnormal response, attenuated by aging, is independent of the presence and degree of hypertension or hypertrophy and is potentially linked to the genetic determination of the disease. (Hypertension. 1994^4:620-624.) Key Words • heat-shock proteins • hypertension, essential • aging • heart Methods Animals The experiments were carried out in compliance with the Guide for the Care and Use of Laboratory Animals o...

The present study demonstrates that CHF, but not compensatory hypertrophy, is a specific stimulus for chronic HSP72 induction in the heart and liver. On the contrary, CHF does not affect HSP in lungs and peripheral muscles. HSP 72 induction represents an intracellular marker of stress reaction which can persist chronically.

The majority of calcium antagonists used clinically belong to three distinct chemical classes: the phenylalkylamines, the dihydropyridines, and the benzothiazepines. In recent years their mode of action has been unravelled, their limitations recognized, and their efficacy and use in the management of patients with a broad spectrum of cardiovascular and other disorders defined. It is clear, however, that these drugs are not all alike, providing an explanation for their differing effects. The final therapeutic effect in humans depends on the mechanisms of action at the molecular level, the tissue selectivity, and the hemodynamic changes of each agent. All these aspects are examined in detail in this article. Concepts that are highlighted are as follows: (a) Molecular biology has allowed recognition of the polypeptide components of the alpha 1 subunit of the L-type Ca2+ channel and the finding of peptide segments covalently labelled by all three classes of drugs. (b) The location of these segments within the peptides is different: Binding sites for dihydropyridines are located externally, whereas those for verapamil and diltiazem are located internally, in the cytosolic part of the membrane. (c) Dihydropyridine binding is voltage dependent. This explains the selectivity of this class of drugs for vascular smooth muscle, which is more depolarized than cardiac muscle. (d) Phenylalkylamines and benzothiazepines reach their receptors at the internal surface of the sarcolemma through the channel lumen. Their binding is facilitated by the repetitive depolarization of atrioventricular and cardiac tissue, a phenomenon described as use dependence. This explains why these drugs are not highly selective, but equipotent for the myocardium, the atrioventricular conducting tissue, and the vasculature. (e) Dihydropyridines act through selective vasodilatation and may increase heart rate and contractility via a reflex mechanism. On the contrary, phenylalkylamines and diltiazem act through a combination of effects, including reduction of afterload, heart rate, and contractility. When taken together, all these differences distinguish the preferential clinical utilization of one of these compounds for a given cardiovascular pathology.