Relaxation calcium-activated potassium

Andersson, D. A., Zygmunt, P. M., Movahed, P., Andersson, T. L., and Hogestatt, E. D. 2000. Effects of inhibitors of small- and intermediate-conductance calcium-activated potassium channels, inwardly-rectifying potassium channels and Na(+)/K(+) ATPase on EDHF relaxations in the rat hepatic artery. Br. J. Pharmacol. 129 1490-1496. 

Respiratory rhythmicity is an emergent property of the RCPG resulting from mutual inhibition of inspiratory and expiratory related neurons. A minimal model due to Duffin [1991] postulated the early-burst inspiratory (I) neurons and Botzinger complex expiratory (E) neurons to be the mutually inhibiting pair. Adaptation of the I neurons (e.g., by calcium-activated potassium conductance) results in sustained relaxation oscillation in the network under constant chemical excitation. Both neuron groups are assumed to have monosynaptic inhibitory projections to bulbospinal inspiratory (Ir) output neurons (Figure 11.3). The model equations are ... 

Fig. 76.2 Polyphenols and polyphenol-rich sources induce endothelial-dependent NO- and EDH-mediated relaxations. Polyphenols are potent inducers of the oidothelial formation of nitric oxide (NO) and endothelium-derived hyperpolarizatitm (EDH) via a redox-soisitive mechanism. SKca small conductance calcium-activated potassium channels, IKca intermediate conductance calcium-activated potassium channels, Src Src family kinase, PI3K phosphatidylinositol 3-kinase, eNOS endothelial NO synthase, L-Arg L-arginine, sGC soluble guanylyl cyclase, GTP guanosine triphosphate, cGMP cyclic guanosine monophosphate, AA arachidonic acid, COX cyclooxygenase, ATP adenosine triphosphate, cAMP cyclic adenosine monophosphate...

The resting membrane potential of most excitable cells is around —60 to —80 mV. This gradient is maintained by the activity of various ion channels. When the potassium channels of the cell open, potassium efflux occurs and hyperpolari2ation results. This decreases calcium channel openings, which ia turn preveats the influx of calcium iato the cell lea ding to a decrease ia iatraceUular calcium ia the smooth muscles of the vasculature. The vascular smooth muscles thea relax and the systemic blood pressure faUs. 

ATP is used not only to power muscle contraction, but also to re-establish the resting state of the cell. At the end of the contraction cycle, calcium must be transported back into the sarcoplasmic reticulum, a process which is ATP driven by an active pump mechanism. Additionally, an active sodium-potassium ATPase pump is required to reset the membrane potential by extruding sodium from the sarcoplasm after each wave of depolarization. When cytoplasmic Ca2- falls, tropomyosin takes up its original position on the actin and prevents myosin binding and the muscle relaxes. Once back in the sarcoplasmic reticulum, calcium binds with a protein called calsequestrin, where it remains until the muscle is again stimulated by a neural impulse leading to calcium release into the cytosol and the cycle repeats. 

The Di receptor is typically associated with the stimulation of adenylyl cyclase (Table 9-1) for example, Di-receptor-induced smooth muscle relaxation is presumably due to cAMP accumulation in the smooth muscle of those vascular beds in which dopamine is a vasodilator. D2 receptors have been found to inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx. 

Nicorandil is an effective vasodilator through two actions. It acts as a nitrate by activating cyclic GMP (see above) but also opens the ATP-dependent potassium channel to allow potassium efflux and h5rperpolarisation of the membrane which reduces calcium ion entry and induces muscular relaxation. It is indicated for use in angina, where it has similar efficacy to p-blockade, nitrates or calcium channel blockade. It is administered orally and is an alternative to nitrates when tolerance to these is a problem, or to the other classes when these are contraindicated by asthma or cardiac failure. Adverse effects to nicorandil are similar to those of nitrates, with headache reported in 35% of patients. It is the only antianginal drug for which at least one trial has demonstrated a beneficial influence upon outcome. ... 

At relevant inotropic and vasorelaxant concentrations, milrinone is a selective inhibitor of peak III cAMP phosphodiesterase isozyme in cardiac and vascular muscle. This inhibitory action is consistent with cAMP-mediated increases in intracellular ionized calcium and contractile protein phosphorylation and relaxation in vascular muscle. Additional experimental evidence also indicates that milrinone is not a beta-adrenergic agonist nor does it inhibit sodium-potassium adenosine triphosphatase activity as do the digitalis glycosides. 

The simple 2-indolecarboxylic acid (137) and 1-carbazolecarboxylic acid (138) inhibit parathyroid hormone stimulated bone resorption . A new class of calcium ion channel activators is FPL 64176 (139) <93JMC2739>, and nitropyrrole (140) is related to the potassium ion channel activator cromakalin and has smooth muscle relaxant properties <92BMC1595>. Pyrrole (141) is a reversible potassium ion competitive inhibitor of the gastric H /K -ATPase . Ali-... 

Interest in the use of ion-selective electrodes in the biomedical field is a natural consequence of the electrolyte composition of bulk body and cell fluids (Table 2.1), a proportion of which is in the ionised form. In extracellular fluids, sodium is the principal cation with chloride as the major anion. In intracellular fluids, potassium is the major cation and phosphate the principal anion — except in erythrocytes where chloride predominates. Of special interest is ionised calcium, because of its importance in various physiological and biochemical processes such as bone formation, nerve conduction, cerebral function, cardiac conduction and contraction, membrane phenomena, muscle contraction and relaxation, blood coagulation, and enzyme activation [2—4]. 

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