Contraction modulation

Neuromodulator - peripheral Schistocerca Extensor -tibiae muscle Inhibits myogenic contractions Modulates neuromuscular transmission DUMETi 2 41,42... 

In vitro, eicosanoids are produced by all layers of the arterial wall (see above). Endogenous production of prostaglandins by smooth muscle is related partly to tone, for example gut, umbilical artery, ductus arteriosus and coronary artery (Eckenfels and Vane 1972, Tuvemo and Wide 1973, Coceani et al. 1975, Kalsner 1975). Clinically this has led to the successful use of indomethacin for the treatment of patent ductus arteriosus. To what extent do changes in smooth muscle contraction modulate endogenous production of eicosanoids by the smooth muscle cells Does generation of eicosanoids within the arterial wall either mediate or modulate the actions of other vasoactive agents on arterial smooth muscle Clearly these questions are interlinked. 

Long-lasting vasoconstriction is produced by the ETs in almost all arteries and veins and several studies have shown that ET-1 causes a reduction in renal blood flow and urinary sodium excretion. ET-1 has been reported to be a potent mitogen in fibroblasts and aortic smooth muscle cells and to cause contraction of rat stomach strips, rat colon and guinea pig ileum. In the central nervous system, ETs have been shown to modulate neurotransmitter release. 

FIGURE 2.19 Potentiation and modulation of response through control of cellular processes, (a) Potentiation of inotropic response to isoproterenol in guinea pig papillary muscle by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). Ordinates percent of maximal response to isoproterenol. Abscissa percent receptor occupancy by isoproterenol (log scale). Responses shown in absence (open circles) and presence (filled circles) of IBMX. Data redrawn from [7], (b) Effect of reduction in calcium ion concentration on carbachol contraction of guinea pig ileum. Responses in the presence of 2.5 mM (filled circles) and l.5mM (open circles) calcium ion in physiological media bathing the tissue. Data redrawn from [8],... 

Although blood pressure control follows Ohm s law and seems to be simple, it underlies a complex circuit of interrelated systems. Hence, numerous physiologic systems that have pleiotropic effects and interact in complex fashion have been found to modulate blood pressure. Because of their number and complexity it is beyond the scope of the current account to cover all mechanisms and feedback circuits involved in blood pressure control. Rather, an overview of the clinically most relevant ones is presented. These systems include the heart, the blood vessels, the extracellular volume, the kidneys, the nervous system, a variety of humoral factors, and molecular events at the cellular level. They are intertwined to maintain adequate tissue perfusion and nutrition. Normal blood pressure control can be related to cardiac output and the total peripheral resistance. The stroke volume and the heart rate determine cardiac output. Each cycle of cardiac contraction propels a bolus of about 70 ml blood into the systemic arterial system. As one example of the interaction of these multiple systems, the stroke volume is dependent in part on intravascular volume regulated by the kidneys as well as on myocardial contractility. The latter is, in turn, a complex function involving sympathetic and parasympathetic control of heart rate intrinsic activity of the cardiac conduction system complex membrane transport and cellular events requiring influx of calcium, which lead to myocardial fibre shortening and relaxation and affects the humoral substances (e.g., catecholamines) in stimulation heart rate and myocardial fibre tension. 

Purinergic System. Figure 2 Schematic of sympathetic cotransmission. ATP and NA released from small granular vesicles (SGV) act on P2X and a-i receptors on smooth muscle, respectively. ATP acting on inotropic P2X receptors evokes excitatory junction potentials (EJPs), increase in intracellular calcium ([Ca2+]j) and fast contraction while occupation of metabotropic ar-adrenoceptors leads to production of inositol triphosphate (IP3), increase in [Ca2+]j and slow contraction. Neuropeptide Y (NPY) stored in large granular vesicles (LGV) acts after release both as a prejunctional inhibitory modulator of release of ATP and NA and as a postjunctional modulatory potentiator of the actions of ATP and NA. Soluble nucleotidases are released from nerve varicosities, and are also present as ectonucleotidases. (Reproduced from Burnstock G (2007) Neurotransmission, neuromodulation cotransmission. In Squire LR (ed) New encyclopaedia of neuroscience. Elsevier, The Netherlands (In Press), with permission from Elsevier). 

Although in in vivo circumstances an intracellular free calcium increase apparently acts as the primary modulator of contraction, it can be bypassed in highly permeabilized smooth muscle preparations where the active subunit of MLCK can be introduced to phosphorylate myosin and induce contraction. The MLCK catalyzed phosphorylation of serine-19 is seen as the necessary event in the activation of smooth muscle myosin to form crossbridges. Thus, the rising phase of force during an isometric smooth muscle contraction follows an increase in the degree of phosphorylation of myosin, and that in turn follows the transient rise of (a) cytosolic free Ca, (b) Ca-calmodulin complexes, and (c) the active form of MLCK. The regulation of the intracellular calcium is discussed below. The dynam-... 

There is nothing in Equations 1-8 which is an all-or-none situation. There are no positive feedback loops which might cause some kind of flip-flop of states of operation of the system. There are some possibilities for saturation phenomena but all relationships are graded. Overall, transient or steady-state, the changes of concentration of P-myosin are continuous, monotonic functions of the intracellular Ca ion concentration. On this basis it is more appropriate to say that smooth muscle contraction is modulated rather than triggered by Ca ion. 

The general picture of muscle contraction in the heart resembles that of skeletal muscle. Cardiac muscle, like skeletal muscle, is striated and uses the actin-myosin-tropomyosin-troponin system described above. Unlike skeletal muscle, cardiac muscle exhibits intrinsic rhyth-micity, and individual myocytes communicate with each other because of its syncytial nature. The T tubular system is more developed in cardiac muscle, whereas the sarcoplasmic reticulum is less extensive and consequently the intracellular supply of Ca for contraction is less. Cardiac muscle thus relies on extracellular Ca for contraction if isolated cardiac muscle is deprived of Ca, it ceases to beat within approximately 1 minute, whereas skeletal muscle can continue to contract without an extraceUular source of Ca +. Cyclic AMP plays a more prominent role in cardiac than in skeletal muscle. It modulates intracellular levels of Ca through the activation of protein kinases these enzymes phosphorylate various transport proteins in the sarcolemma and sarcoplasmic reticulum and also in the troponin-tropomyosin regulatory complex, affecting intracellular levels of Ca or responses to it. There is a rough correlation between the phosphorylation of Tpl and the increased contraction of cardiac muscle induced by catecholamines. This may account for the inotropic effects (increased contractility) of P-adrenergic compounds on the heart. Some differences among skeletal, cardiac, and smooth muscle are summarized in... 

Although research has been suggestive of caffeine modulated increases in muscular contractions leading to hand tremor, it is more likely that the hand tremor response is the result of caffeine s effects on the central nervous system.32 There is even evidence that moderate doses of caffeine may actually diminish muscle tone.32... 

Turner WH, Brading AF 1997 Smooth muscle of the bladder in the normal and the diseased state pathophysiology, diagnosis and treatment. Pharmacol Ther 75 77—110 van Breemen C, Chen Q, Laher I 1995 Superficial buffer barrier function of smooth muscle sarcoplasmic reticulum. Trends Pharmacol Sci 16 98-105 Wray S 1993 Uterine contraction and physiological mechanisms of modulation. Am J Physiol 264 C1-C18... 

FIG. 2. The effect of modulating CICR on uterine contraction. Spontaneous Ca2+ transients (Indo-1 ratio) and contractions in term pregnant, non-labouring human myometrium, before and after 50 juM ryanodine application. (Taken from Kupittayanant et al 2002.)... 

Wray S 1993 Uterine contraction and physiological mechanisms of modulation. Am J Physiol 264 0-08... 

Hellstrand You have shown the coding of the response to PE in terms of frequency of oscillations, but not amplitude modulation. Have you come across any example where the modulation of amplitude also changes the force of contraction, or do you think the amplitude is constant in this system ... 

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