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

Histamine activated adenylate cyclase in pig skin (epidermal) slices, resulting in the accumulation of cyclic AMP. This effect was highly potentiated by the addition of cyclic AMP-phosphodiesterase inhibitors (theophylline, papaverine). A specific H2 receptor inhibitor (metiamide) inhibited the effect of histamine completely, while other antihistamines (diphenhydramine, acetophenazine, perphenazine, fluphenazine, promethazine) inhibited the effect of histamine to various lesser degrees. It has been shown that both epinephrine and prostaglandin E stimulate epidermal adenylate cyclase. Our data using specific blocking agents indicate that histamine, epinephrine and prostaglandin E2 act independently on the epidermal adenylate cyclase system.
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PMID:Histamine (H2) receptor-adenylate cyclase system in pig skin (epidermis). 0 11

1. Dibutyryl cyclic AMP (Db cAMP, 75-500 microgram/kg), injected into the lateral ventricle of the brain of the cat increased blood pressure, heart rate and splanchnic discharge rate. 2. ATP, but not AMP, induced similar changes; GMP in small doses increased blood pressure. 3. A number of drugs are known to activate adenylate cyclase-induced hypertension, tachycardia and increase splanchnic discharge rate. This was shown for TRH, tetracosactide and a new beta2-adrenoceptor stimulant, NAB 365. 4. Injection into the lateral ventricle of theophylline or Ro 7/2956, both inhibitors of phosphodiesterase, similarly increased blood pressure. 5. Histamine administered by the same route induced similar reactions; it is not known if this action was exerted by activation of H1- or H2-receptors. 6. Somatostatin, known to reduce cAMP levels, induced a small but significant decrease in blood pressure. Melanocyte stimulating hormone release inhibiting factor (MIF) and TSH were ineffective. 7. These results provide evidence for the possibility of a role for cAMP in the central regulation of blood pressure at suprabulbar levels.
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PMID:Cyclic 3'5'-adenosine monophosphate and central circulatory control in cats and dogs. 2 Feb 56

Secretion of intrinsic factor (IF) has previously been demonstrated in isolated rabbit fundic mucosa maintained in organ culture. We have now investigated the possibility that cyclic nucleotides may play a role in IF secretion. A phosphodiesterase inhibitor, 3-isobutyl methylxanthine (IBMX), stimulated IF secretion nearly fourfold while increasing tissue levels of both cyclic AMP (cAMP) and cyclic GMP (cGMP). Peak IF secretion in response to IBMX was not reached until after tissue cAMP levels were maximal. Dibutyryl cAMP and 8-Br-cAMP increased secretion by the same order of magnitude as did IBMX, whereas corresponding analogues of cGMP had no such effect. Histamine increased secretion of IF. In the presence of 40 microM IBMX, histamine elevated tissue levels of cAMP, but not of cGMP, and the stimulating effect of 10 microM histamine on IF secretion was potentiated. An H2 receptor antagonist, cimetidine, blocked the increases in IF secretion and tissue cAMP levels due to histamine, and the increase in IF secretion due to IBMX. These observations are consistent with a role for cAMP in the secretion of IF by isolated gastric mucosa.
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PMID:Evidence for involvement of cyclic nucleotides in intrinsic factor secretion by isolated rabbit gastric mucosa. 9 56

The influence of oxyfedrine on the cardiostimulatory effects of aminophylline was studied in the isolated perfused guinea-pig heart. It was found that oxyfedrine potentiated the stimulatory effects of aminophylline on isometric contraction, dF/dt, coronary flow and heart rate. This potentation was abolished after pretreatment with propranolol. Histamine, though to a lesser extent, also potentiated the effects of aminophylline. When oxyfedrine and histamine were infused simultaneously in the presence of propranolol, the response of the heart to aminophylline was also potentiated; the magnitude of this potentiation was comparable to that obtained with histamine alone, indicating that propranolol abolished only the action of oxyfedrine but not that of histamine. The mechanical effects of aminophylline were accompanied by a slight (15 per cent) but significant inhibition of phosphodiesterase, which was not further augmented by oxyfedrine. The results suggest that the potentiating effects of oxyfedrine or histamine on the cardiostimulatory actions of aminophylline are elicited by their stimulatory actions on adenylate cyclase activity.
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PMID:Potentation of the cardiac response to aminophylline by oxyfedrine. 16 89

Imidazole (0.73-15.9mM) was found to increase both tension developed Td and the maximum rats of rise of tension, dT/dtmax, in the isolated hemidiaphragm of the rat during indirect stimulation. Similar effects were obtained during direct stimulation and in the presence of d-tubocurarine. Imidazole (0.73-22 mM) antagonized the action of d-tubocurarine. This effect was particularly pronounced in preparations pretreated with imidazole. Propranolol did not significantly change the action of imidazole on Td and dT/dtmax during direct stimulation. Similarly, propranolol did not affect the action of low concentrations of imidazole during indirect stimulation. When present in the bath for periods of time longer than 15 min, propranolol significantly depressed the effect of even high concentrations of imidazole on Td and dT/dtmax during indirect stimulation. Histamine (0.18-0.91 mM) did not affect either Td or dT/dtmax. In the experiments in vivo, imidazole (12.5-100 mg/kg) produced a small increase both in Td and dT/dtmax of the gastrocnemius muscle during sciatic nerve stimulation. The available evidence indicates that the action of imidazole on Td and dT/dtmax is not connected with its action on phosphodiesterase, but it is most probably due to a direct action on the muscle.
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PMID:The effect of imidazole on the isometric contractility of the isolated hemidiaphragm of the rat. 17 19

The response to combinations of gastric acid secretagogues was studied in isolated glands from the rabbit gastric mucosa in terms of changes in oxygen consumption and accumulation of the weak base aminopyrine (AP). The latter reflects the acid secreting status of the glands. The following secretagogues were investigated: histamine, carbachol, aminophylline and db-cAMP. The histamine respiratory dose-response curve was shifted to the left in the presence of the phosphodiesterase inhibitor aminophylline. Both ED-50 and maximum response were significantly increased. Histamine-induced AP accumulation was also strongly enhanced by aminophylline (5 X 10(-4) M). These results are consistent with the hypothesis that histamine stimulation of acid secretion is mediated by cyclic AMP. Carbachol-stimulated oxygen consumption could not be potentiated by aminophylline and the combined effect was only additive. The response to a combination of histamine and carbachol was a significant increase in oxygen consumption above what could be expected from an additive effect alone. Carbachol addition to glands prestimulated with histamine gave a rapid increase in the respiratory rate resulting in a new steady state level within 10-15 min, as compared with a time constant of about 40 min when both drugs were added simultaneously. Likewise AP accumulation increased more rapidly and reached a higher value after addition of histamine + carbachol as compared with histamine alone. The db-cAMP-stimulated oxygen consumption was in all respects equally affected by carbachol as was histamine stimulation. This indicates that the well known cholinergic potentiation of histamine stimulation is not due to an increased sensitivity of the histamine receptor but is of a more general nature. A mechanism involving intracellular availability of Ca2+ is proposed as one possible explanation of this potentiation.
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PMID:Potentiation by carbachol and aminophylline of histamine- and db-cAMP-induced parietal cell activity in isolated gastric glands. 19 Aug 65

1. The action of metiamide, a specific histamine H2-receptor antagonist, on the acid secretory response to various gastric stimuli in the perfused isolated whole mouse stomach is described. 2. Two kinds of stomach preparations, the non-distended stomach and distended stomach, were used. The distended stomach gave a marked and dose-related acid secretory response to histamine (10(-6) to 10(-3) M), pentagastrin (10(-8) to 10(-5) M), acetylcholine (5 X 10(-5) to 10(-5) M), eserine (10(-5) to 10(-3) M) to dibutyryl cyclic AMP (5 X 10(-5) to 10(-3) M). In the nondistended stomach, dibutyryl cyclic AMP regularly stimulated acid secretion in a dose-dependent manner; in contrast to dibutyryl cyclic AMP, histamine, pentagastrin or acetylcholine did not always stimulate acid secretion. 3. Histamine or pentagastrin but not acetylcholine always caused significant stimulation of acid secretion from the non-distended stomach in the presence of a phosphodiesterase inhibitor such as caffeine, theophylline or the I.C.I. compound, 63197. At the concentration of 10(-4) M, these phosphodiesterase inhibitors markedly potentiated the stimulatory effect of histamine or pentagastrin on acid secretion and the order of effectiveness was 63197 greater than theophylline greater than caffeine. 63197 also produced profound potentiation of histamine- or pentagastrin-stimulated acid secretion in the distended stomach. 4. Metiamide (5 X 10(-5) to 10(-4) M) did not antagonize stimulation of acid secretion by dibutyryl cyclic AMP in the non-distended or distended stomach. 5. In the distended stomach, metiamide (5 X 10(-4) M) produced significant inhibition of histamine-stimulated acid secretion with a linear and parallel displacement of the histamine dose--response curve to the right. Although at this concentration metiamide did not depress maximal acid secretory response to histamine, it caused marked reduction of the maximal acid secretory response attainable with pentagastrin. 6. In the distended stomach, metiamide (5 X 10(-5) M) did not cause significant inhibition of acetylcholine-induced acid secretion. Atropine (5 X 10(-6) M) abolished the stimulatory effect of acetylcholine; it also produced marked inhibition of pentagastrin-stimulated acid secretion but it had little effect on acid secretion induced by histamine. 7. The present results indicate that metiamide inhibited histamine-induced acid secretion by competitive antagonism of the histamine H2-receptor, but its inhibitory effect on pentagastrin-induced acid secretion seemed to be of non-competitive nature. The failure of metiamide to inhibit acid secretion induced by dibutyryl cyclic AMP suggests that cyclic AMP might regulate gastric acid secretion at a site beyond the histamine H2-receptor activation. It is also considered that the present results support the hypothesis that cyclic AMP may be involved in histamine- or pentagastrin-induced acid secretion in the isolated mouse stomach. 8...
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PMID:Metiamide and stimulated acid secretion from the isolated non-distended and distended mouse stomach. 19 84

The influence of adenosine 5'-triphosphate on gastric acid secretion stimulated by histamine, carbachol, dibutyryl-cAMP and the phosphodiesterase inhibitors 8-phenyl-theophylline and rolipram in isolated rabbit gastric glands was studied. Changes oi gastric acid secretion were measured by the aminopyrine accumulation method. Histamine-stimulated acid secretion was significantly inhibited by ATP 1 mM, whereas the secretory responses elicited by carbachol, dibutyryl-cAMP, 8-phenyl-theophylline or rolipram were not. Assays with indomethacin, a well known prostaglandin synthesis inhibitor, showed that this agent significantly reduced the inhibitory effect of ATP on histamine responses. The results indicate that the antisecretory effect of ATP was specific for histamine and that it was mediated, at least in part, via stimulation of endogenous prostaglandin production.
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PMID:[Specific inhibition by ATP of histamine-stimulated acid secretion in the gastric glands of the rabbit]. 132 61

LY 186655 (Tibenelast, Lilly) is a new phosphodiesterase inhibitor, not derived from the xanthine, possessing bronchodilating activity in animals. The aim of this work was to study the effect of LY 186655 and theophylline on histamine release from human leukocytes, skin and lung fragments. Histamine was measured using a spectrofluorometric method. Both drugs (3 x 10(-5)-3 x 10(-3) M) exhibited a dose-dependent inhibition on anti-IgE (1/2000)-induced histamine release from human leukocytes. At 3 x 10(-3) M, theophylline was significantly more effective than LY 186655 (mean inhibition 94 and 42%, respectively). On lung fragments, theophylline and LY 186655 (3 x 10(-5)-3 x 10(-3) M) caused strong and comparable inhibitory effects on anti-IgE (1/500)-induced histamine release with a mean inhibition reaching maximally 65%. Histamine release induced by compound 48/80 (1 mg/ml) on sliced human foreskin was reduced with both drugs (3 x 10(-3) M) by about 37%. We conclude that LY 186655 inhibits in vitro immunological histamine release from human lung and cutaneous mast cells as well as basophils with a similar pattern of activity to theophylline.
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PMID:LY 186655, a phosphodiesterase inhibitor, inhibits histamine release from human basophils, lung and skin fragments. 137 45

Rat gastric mucosal cells, containing 25-35% parietal cells, were obtained by a modified isolation procedure involving protease, ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, and mechanical treatments. Parietal cell responsiveness to secretagogues was assessed by the accumulation of the weak base [14C]aminopyrine in intracellular acidic compartments. Histamine, without phosphodiesterase inhibitors, dose dependently stimulated aminopyrine accumulation with an effective concentration producing 50% of maximal response of 13 microM and a maximal effective dose of 100 microM. Pentagastrin and rat gastrin-17 alone were ineffective but potentiated dose dependently the action of 100 microM histamine. The mean potentiating effect varied from 32 to 70% for 100 nM pentagastrin and from 36 to 95% for 100 nM rat gastrin-17. Pentagastrin (100 nM) also potentiated the effect of 1 mM dibutyryladenosine 3',5'-cyclic monophosphate (cAMP) by 44%, but it did not increase further the stimulation by carbachol. The potentiating effect of pentagastrin on histamine- and dibutyryl cAMP-stimulated aminopyrine accumulation was also observed after enrichment of parietal cells to 65-85%. The endogenous histamine was insufficient to stimulate acid production. Therefore gastrin appears to have a direct action also in rat parietal cells.
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PMID:Gastrin potentiates histamine-stimulated aminopyrine accumulation in isolated rat parietal cells. 165 74


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