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International audience

International audience

International audience

International audience

Mechanical studies of isolated muscle and analysis of molecular actomyosin interactions have improved our understanding of the pathophysiology of airway smooth muscle. Mechanical properties of airway smooth muscle are similar to those of other smooth muscles. Airway smooth muscle exhibits spontaneous intrinsic tone and its maximum shortening velocity (Vmax) is 10-30 fold lower than in striated muscle. Smooth muscle myosin generates step size and elementary force per crossbridge interaction approximately similar to those of skeletal muscle myosin. Special slow cycling crossbridges, termed latch-bridges, have been attributed to myosin light chain dephosphorylation. From a mechanical point of view, it has been shown that airway hyperresponsiveness is characterized by an increased Vmax and an increased shortening capacity, with no significant change in the force-generating capacity.

The aim of this study was to define the mechanical determinants of isotonic relaxation of isolated diaphragm muscle in the rat over a load range (n = 30). We tested several hypotheses to determine the effect of i) load conditions (preload, post-load), ii) sudden changes in load during contraction, iii) length of the muscle at peak shortening, iv) maximal amplitude of shortening (delta L) and v) stimulation conditions on peak rate of isotonic reelongation (+dL/dmax). At tetanus at 30 Hz, +dL/dmax was linearly correlated to delta L peak shortening and total load. Variations in preload, peak shortening or postload did not modify the +dL/dmax vs delta L relationship but such variations did affected the relationships +dL/dmax vs total load or +dL/dmax vs peak shortening. For a given value of L, +dL/dmax was weaker for twitch than for tetanus. In conclusion, four findings show that over a wide lad range the maximal amplitude of shortening the main mechanical determinant of the rate of isotonic reelongation of the isolated diaphragm muscle, independently of the length of the muscle at peak shortening, the initial length of the muscle and independently of the load during reelongation.

International audience

Antiarrhythmic drugs, especially the Class I family, exert a negative inotropic effect on the myocardium which is particularly undesirable in patients with depressed left ventricular function. Therefore, research has been directed to the development of new, more specific molecules of the Class III family. The authors studies the mechanical effects of RP 62719 on guinea pig left ventricular papillary muscle. This new molecule is a pure Class III antiarrhythmic, known to lengthen the duration of the cardiac action potential by selectively blocking the potassium current iK1 (inward rectifier K+ current). The mechanical parameters were determined during the phases of contraction and relaxation under isotonic and isometric conditions. At 0.2 and 2 microM concentrations, RP 62719 improved cardiac contraction under both isotonic and isometric conditions with an increase of about 30% of Vmax (p0.001), the maximum unloaded shortening velocity delta 1 (p0.001), the peak isometric active force normalized per cross-sectional area [AF/S (p0.001)]. At these two concentrations, a positive lusitropic effect (improved relaxation) was demonstrated by an increase in negative peak of derivative per mm2-dF/s and maximum lengthening velocity VR max (p0.01). At higher concentrations (20 microM), the inotropic and lusitropic effects were less marked with a bell-shaped form of the dose-effect curve. This study indicates that RP 62719 has moderate but significant positive inotropic and lusitropic effects. These actions could provide significant therapeutic advantages especially in patients cardiac failure.

Left ventricular dysfunction is rarely a prominent feature of septic shock. Initially, it is masked by circulatory changes and adaptive phenomena which increase the cardiac output. Evaluation of intrinsic myocardial function is therefore difficult in this pathology. The different experimental models used (cell culture, isolated muscle, isolated perfused heart and whole animal) and recent clinical studies using angiographic, catheter and echocardiographic data, have confirmed that this condition exists. Its physiopathology is not yet fully understood and involves several mediators. The direct effect of bacterial endotoxins has not been formally established. However, therapy with anti-endotoxin antibodies does give encouraging results. The cytokines, such as interleukin-1, tumour necrosis factor, and platelet activating factor play a key role between the infectious factors and cellular mediators. Their effects on the myocardium are subject of much on-going research. Current date, in particular with respect to the tumour necrosis factor, suggest that they may have a direct cardiodepressor factor. The presence of a circulating negative inotropic substance has been suspected for many years. Recent studies tend to confirm this hypothesis though the substance itself has not yet been isolated. The theory of reduced coronary flow causing myocardial dysfunction in septic shock has fallen out of favour. Some experimental evidence supports the clinical impression of reduced vascular and cardiac reactivity to catecholaminergic stimulation. The actions of different membrane structures involved have not been determined. At cellular level, changes in calcium metabolism, which regulates muscle contraction and relaxation, probably play an important role in septic shock. In addition to the symptomatic therapeutic advances that have been made in septic shock, specific myocardial treatment could be beneficial.