Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isolated canine parietal cells were used to study the ability of misoprostol to inhibit acid secretion in the presence of a number of acid secretagogues. Misoprostol inhibited histamine-stimulated acid secretion in a dose-dependent and noncompetitive manner. A concentration of 2-3 X 10(-9) M misoprostol inhibited maximal histamine-stimulated acid secretion by one half. Misoprostol had little to no effect on acid secretion stimulated by carbachol and dibutyryl cAMP, had no effect on the acid secretion directly stimulated by pentagastrin, and only modestly inhibited acid secretion stimulated by forskolin. Misoprostol noncompetitively inhibited cAMP formation in response to histamine, with an IC50 value similar to that for the inhibition of histamine-stimulated acid secretion. These results indicate that: (1) misoprostol specifically inhibits histamine-stimulated acid secretion in parietal cells, and (2) the antisecretory action of misoprostol is closely related to the reduction of histamine-stimulated cAMP formation with the site of major action most likely in the coupling process between histamine H2 receptor sites and histamine-sensitive adenylate cyclase.
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PMID:Effect of misoprostol on histamine-stimulated acid secretion and cyclic AMP formation in isolated canine parietal cells. 304 Mar 57

In isolated leukocytes, elevation of cAMP can inhibit various proinflammatory and immune functions. The prostaglandins E (PGEs) are known to stimulate leukocyte cAMP production, and for years they have been viewed as potential immunosuppressive and/or anti-inflammatory agents. However, their clinical use is severely limited by extreme metabolic instability and by poor oral absorption, which necessitates administration by infusion or injection. Misoprostol is a synthetic analog of PGE(1) that is relatively stable and orally absorbable. We examined the effects of misoprostol on cAMP production in leukocytes, in view of the possibility that it mimics PGE(1) and, thus, might represent a clinically useful immunosuppresive or anti-inflammatory drug. Our results indicate the following: (1) Misoprostol increases leukocyte cAMP production in a dose-dependent manner (similar20 nM to >100 &mgr;M) and acts by stimulating adenylate cyclase. (2) Its potency and maximal effect are somewhat less than those of PGE(1) (3) cAMP generation in response to either misoprostol or PGE(1) is transient (in the presence of isobutylmethylxanthine to inhibit endogenous phosphodiesterases). (4) Misoprostol's stimulation of adenylate cyclase is synergistically increased by pretreatment of cells with colchicine, a microtubule-disrupting agent that is currently used for prophylaxis and treatment of gout. (5) Colchicine acts by increasing the initial rate of cAMP production and not by prolonging the response to misoprostol. (6) A clinically relevant dose of colchicine (0.25 &mgr;M) is effective given sufficient pretreatment time. (7) Whereas a clinically relevant dose of misoprostol (3 nM) is ineffective alone, preexposure of cells to colchicine enables such a dose to stimulate cAMP generation significantly. The combination of misoprostol with colchicine might eventually prove useful in the therapy of immune or inflammatory disease.
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PMID:Misoprostol Stimulates cAMP Generation in Human Leukocytes: Synergy with Colchicine Suggests a New Potential for Established Drugs. 1185 51