Cyclic nucleotide phosphodiesterase inhibitory

The role of cyclic AMP as modulator of prolactin secretion was first suggested by the finding of a stimulatory effect of cyclic AMP derivatives (17-22) and inhibitors of cyclic nucleotide phosphodiesterase activity such as theophylline and IBMX (22-26) on the secretion of this hormone. More convincing evidence supporting a role of cyclic AMP in the action of dopamine on prolactin secretion had to be obtained, however, by measurement of adenohypophysial adenylate cyclase activity or cyclic AMP accumulation under the influence of the catecholamine. As illustrated in Fig. 1, addition of 100 nM dopamine to male rat hemipituitaries led to a rapid inhibition of cyclic AMP accumulation, a maximal effect (30% inhibition) being already obtained 5 min after addition of the catecholamine. Thus, while dopamine is well known to stimulate adenylate cyclase activity in the striatum (27, 28), its effect at the adenohypophysial level in intact cells is inhibitory. Dopamine has also been found to exert parallel inhibitory effects on cyclic AMP levels and prolactin release in ovine adenohypophysial cells in culture (29) and purified rat mammotrophs (30). Using paired hemipituitaries obtained from female rats, Ray and Wallis (22) have found a rapid inhibitory effect of dopamine on cyclic AMP accumulation to approximately 75% of control. 

Some investigators have employed the enhancement of vascular tone in vivo after treatment with these drugs to inhibit amine reuptake where the flavonoids act as antagonists of plasma membrane amine transporters [104]. The vasodilatory mechanism of flavonoids seems to be mediated by the inhibition of protein kinase C [105]. Oilier recent studies on the potential vasorelaxant, antioxidant, and cyclic nucleotide phosphodiesterase (PDE) inhibitory effects of the citrus-fruit flavonoids nar-ingenin and hesperetin in intact rat aortic rings have shown that their vasorelaxant effects were mediated by the inhibition of different PDE isoenz5Tnes [106,107]. 

Figure 32.2 Inhibitory effects of XI on human thyroid signaling intracellular cascades. R, receptor ATP, adenosine triphosphate nucleotide PuR, purinergic receptor Gs, stimulatory G protein of adenylyl cyclase Gi, inhibitory G protein of adenylyl cyclase Gq, stimulatory G protein of phospholipase C AC, adenylyl cyclase PLC, phospholipase C IPS, inositol 1,4,5-trisphosphate DAG, diacylglycerol PKC, protein kinase C DUOX, dual oxidase PGE, prostaglandin E1 TSHR, TSH receptor cAMP, cyclic 3 -5 adenosine monophosphate PDE, cAMP phosphodiesterase 5 AMP, adenosine monophosphonucleotide cA PK, cAMP-dependent protein kinase FK, forskolin ------> Stimulation inhibition — generation.

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