CAMP-increasing agents

The dopamine-stimulated formation of cAMP may initiate the dopamine-induced release of IR-PTH. A linear relationship exists between the dopamine-induced release of IR-PTH and the logarithm of the dopamine-induced accumulation of cAMP (17). Similarly, other agents increasing cAMP accumulation and IR-PTH release (e.g. beta-adrenergic agonists, secretin and phosphodiesterase inhibitors, also display such a log-linear relationship. Additional support for the possibility that intracellular cAMP might initiate PTH secretion comes from the observations that cholera toxin (JJ.), phosphodiesterase inhibitors (17) and dibutyryl cAMP (18), agents known to increase intracellular cAMP or mimic the biochemical effects of cAMP, increase the release of IR-PTH. 

Stimulation and inhibition of the enzyme by the GPCR-G-protein cycle occur by analogous mechanisms. Agonists induce hormone receptors to increase a Ga-GDP-GTP exchange and subsequent Ga 3y dissociation (GDP-a py + GTP GTP-ax + [3y + GDP) (Fig. 4). Consequently, agents that affect either the dissociation of either G or Gs, or the association of their respective as, a , or (3y subunits with adenylyl cyclase could affect rates of cAMP formation in enzyme preparations or in intact cells and tissues. There are several important examples. Gas is stably activated by poorly hydrolyzable analogs of GTP, e.g. GTPyS... 

Steroidogenic agents—including ACTH and cAMP in the adrenal cortex angiotensin 11, K", serotonin, ACTH, and cAMP in the zona glomerulosa of the adrenal LH in the ovary and LH and cAMP in the Ley dig cells of the testes—have been associated with increased amounts of phosphatidic acid, phosphatidylinositol, and polyphosphoinositides (see Chapter 14) in the respective target tissues. Several other examples could be cited. 

Other protein kinases may indirectly influence the activation of NF-kappap. For example, in contrast to the pro-inflammatory effects typically observed with activation of kinases, the elevation ofcAMP activates PKA and blocks transcription of iNOS mRNA [51,178, 229, 230]. Astrocytes contain a variety of NT receptors that are coupled to Gs-adenylate cyclase [231] and, either activation of P-adrenergic/dopamine receptors or employing agents that increase cAMP, such as forskolin (adenylate cyclase activator), PDE inhibitors [i.e. pentoxifylline], dibutyrl cAMP, or 8-bromo cAMP can attenuate lipopolysaccharide (LPS)/cytokine activated iNOS mRNA in microglia, astrocytes and a number of other cell types [51,176,177,178, 232-237]. In contrast, agents that suppress the intracellular concentration of cAM P such as H-89 and Rp-cAM P are pro-... 

Microtubules may function as a form of skeletal support for microfilaments. Agents that increase intracellular cGMP favour the assembly of microtubules, whereas those that increase intracellular Ca2+ and cAMP result in the dissolution of tubulin fibres. Furthermore, the oxidation state of the neutrophil may affect the integrity of the tubulin fibres. Oxidised glutathione (which is increased during oxidative metabolism) regulates tubulin disassembly, and oxidation may increase tubulin tyrosylation, which also promotes disassembly. 

Mechanism of Action Aglucose elevating agent that promotes hepatic glycogenoly-sis, gluconeogenesis. Stimulates production of cyclic adenosine monophosphate (cAMP), which results in increased plasma glucose concentration, smooth muscle relaxation, and an inotropic myocardial effect. Therapeutic Effect Increases plasma glucose level. 

Inamrinone, milrinone Phosphodiesterase type 3 inhibitors decrease cAMP breakdown Vasodilators lower peripheral vascular resistance also increase cardiac contractility Acute decompensated heart failure IV only duration 3-6 h Toxicity Arrhythmias Interactions Additive with other arrhythmogenic agents... 

Glucagon is sometimes useful for reversing the cardiac effects of an overdose of B-blocking agents because of its ability to increase cAMP production in the heart. However, it is not clinically useful in the treatment of cardiac failure. 

Evidence has been presented that the concentration of cAMP is transiently increased in PMNs stimulated to form O2 by FMLP or Csa . Paradoxically, agents which increase the intracellular concentration of cAMP caused a dose dependent fall in the formation of O by PMNs which was elicited by FMLP. A rise in the concentration of cAMP within PMNs was also observed by Smolen after stimulation with several agents. The increase in the concentration of cAMP preceded the release of lysosomal enzymes and the formation of O but did not occur before the change in membrane potential. The increase in the concentration of cAMP was judged not to be sufficient for the elaboration of O2 or the secretion of enzymes from lysosomes because three maneuvers produced changes in cAMP but no subsequent response. However, whether the concentration of cAMP must rise in the normal chain of events leading from stimulus to formation of O is not clear. 

The intracellular signal therefore persists only as long as the hormone receptor remains occupied by epinephrine. Methyl xanthines such as caffeine and theophylline (a component of tea) inhibit the phosphodiesterase, increasing the half-life of cAMP and thereby potentiating agents that act by stimulating adenylyl cyclase. 

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