Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated the hypothesis that thiazide-induced hypercalcemia reflects potentiation of the cAMP response to parathyroid hormone (PTH) consequent to inhibition of phosphodiesterase in bone and kidney. A panel of thiazide diuretics did inhibit low-Km phosphodiesterase activity from bone homogenates. However, furosemide, a nonthiazide diuretic that does not promote calcium retention, was more potent a phosphodiesterase inhibitor than either chloro- or hydrochlorothiazide (CTZ, HCTZ). Thiazides did not influence basal or PTH-stimulated cAMP levels in incubated calvaria or renal cortical slices. Administration of CTZ or HCTZ to rats for 4 days did not affect basal cAMP, nor did such treatment potentiate the cAMP response in Calvaria to infusion of parathyroid extract in vivo. CTZ, HCTZ, and furosemide increased basal adenylate cyclase from renal cortex but did not affect PTH-stimulated activity. Adenylate cyclase from bone was not affected by thiazides but was inhibited by furosemide. Thiazide treatment potentiated the calcemic response to parathyroid extract in vivo but did not affect the calcemic response to dibutyryl cAMP. We conclude that potentiation of the cAMP response to PTH does not underlie the unique effects of thiazides on calcium metabolism.
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PMID:Thiazide diuretics do not potentiate cAMP response to parathyroid hormone. 20

Alcoholic liver disease (ALD) is a worldwide health problem and hepatocyte apoptosis has been associated with the development/progression of ALD. However, no definite effective pharmacotherapy for ALD is currently available. Cilostazol, a selective type III phosphodiesterase inhibitor has been shown to protect hepatocytes from ethanol-induced apoptosis. In the present study, the underlying mechanisms for the protective effects of cilostazol were examined. Primary rat hepatocytes were treated with ethanol in the presence or absence of cilostazol. Cell viability and intracellular cAMP were measured. Apoptosis was detected by Hoechst staining, TUNEL assay, and caspase-3 activity assay. The roles of cAMP and AMP-activated protein kinase (AMPK) pathways in the action of CTZ were explored using pharmacological inhibitors and siRNAs. Liver from mice received ethanol (5 g/kg body weight) by oral gavage following cilostazol treatment intraperitoneally was obtained for measurement of apoptosis and activation of AMPK pathway. Cilostazol inhibited ethanol-induced hepatocyte apoptosis and potentiated the increases in cAMP level induced by forskolin. However, the anti-apoptotic effect of cilostazol was not reversed by an inhibitor of adenylyl cyclase. Interestingly, cilostazol activated AMPK and increased the level of LC3-II, a marker of autophagy. The inhibition of AMPK abolished the effects of cilostazol on LC3-II expression and apoptosis. Moreover, the inhibition of LKB1 and CaMKK2, upstream kinases of AMPK, dampened cilostazol-inhibited apoptosis as well as AMPK activation. In conclusion, cilostazol protected hepatocytes from apoptosis induced by ethanol mainly via AMPK pathway which is regulated by both LKB1 and CaMKK2. Our results suggest that cilostazol may have potential as a promising therapeutic drug for treatment of ALD.
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PMID:Cilostazol protects hepatocytes against alcohol-induced apoptosis via activation of AMPK pathway. 3069 51