Intracellular concentration elevation

The second criterion to accept Ca2+ as a second messenger is its ability to stimulate LH release when intracellular concentrations are elevated by any means, even in the absence of GnRH. Incubation of gonadotropes with Ca2+ ionophores (A23187 or ionomycin) stimulates LH secretion in a dose- and time-dependent manner... 

The precise intracellular events that lead to acid secretion are not clear, but the second messengers in this process appear to be cAMP and Ca +. The H2 receptor is coupled to the adenylate cyclase system (Chapter 30), and its activation results in the intracellular elevation of cAMP concentration. Stimulation of cholinergic receptor systems is coupled to increased Ca + permeability. 

Wieland (1961) proposed a theory which attributes the defect in lipogenesis to an altered NADH NAD ratio in diabetes. The increased rate of fatty acid oxidation leads to a raised NADH NAD within the diabetic liver cell. This causes the NADH-dependent ox-aloacetate-malate equilibrium to shift in favor of malate and, therefore, a lowering of the limiting component of the citric acid cycle, viz. oxaloacetate. This would result in extreme intracellular deficiency of citrate. While this theory might have some pertinence for the liver, the same changes apparently do not take place in heart. The citrate concentration is elevated in hearts from diabetic or fasted rats (Parmeggiani and Bowman, 1963 Garland and Randle, 1964). 

FIGURE 2.17 Differential efficiency of receptor coupling for cardiac function, (a) Guinea pig left atrial force of contraction (inotropy, open circles) and rate of relaxation (lusitropy, filled circles) as a function (ordinates) of elevated intracellular cyclic AMP concentration (abscissae). Redrawn from [6]. 

Acute over-activation of NHE1 results in a marked elevation in intracellular sodium concentration with a subsequent increase in intracellular calcium, via the Na +/Ca++ exchanger. This in turn triggers a cascade of injurious events that can culminate in tissue dysfunction and ultimately apoptosis and necrosis. This is commonly seen in organs such as the heart, brain and kidneys as a consequence of ischemia-reperfusion. 

Sorafenib is a multikinase inhibitor that inhibits both intracellular and extracellular kinases to decrease renal cell cancer proliferation. The half-life of sorafenib is 25 to 48 hours, with a bioavailability of 38% to 49% and a time to peak concentration of 3 hours. Sorafenib is metabolized primarily by the liver by CYP450 3A4. Sorafenib is used for the treatment of renal cell cancer. The primary side effects of sorafenib include rash, hand-foot skin reaction, diarrhea, pruritus, and elevations in serum lipase. 

Of the above four factors, epinephrine is the most potent (EC50 = 5 nM), elevating the corneal Isc within 15 sec at a concentration as low as 1 nM [106], All three compounds probably elevate Cl secretion by increasing intracellular cAMP. Indeed, Klyce et al. [106] demonstrated that exposure of the mucosal side of the cornea to 1 mM dibutyryl cAMP elevated the 7SC by 144%, which correlated with a 200% change in the net CH secretion measured as 36C1 flux. This com-... 

H linked intracellular messengers. Activated H receptors are known to activate a pertussis-toxin-insensitive G protein, Gq, that stimulates phosphoinositide-specific phospholipase C (PI-PLC), with the subsequent generation of inositol 1,4,5-trisphosphate (IP3) and diacylglyc-erol (DAG). These two mediators are known to elevate intracellular Ca2+ concentrations and to activate PKC,... 

Adenosine and inosine can be transported across cell membranes in either direction, facilitated by a membrane-associated nucleoside transport protein. Concentrative transporters have also been identified. Messenger RNA for a pyrimidine-selective Na+-nucleoside cotransporter (rCNTl) and a purine-selective Na+-nucleoside cotransporter (rCNT2) are found throughout the rat brain. Most degradation of adenosine is intracellular, as evidenced by the fact that inhibitors of adenosine transport, such as dipyridamole, increase interstitial levels of adenosine. Dipyridamole is used clinically to elevate adenosine in coronary arteries and produce coronary vasodilation. In high doses, dipyridamole can accentuate adenosine-receptor-mediated actions in the CNS, resulting in sedation and sleep, anticonvulsant effects, decreased locomotor activity and decreased neuronal activity. 

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