Intracellular calcium signaling through the cADPR pathway is agonist specific in porcine airway smooth muscle. (49/251)

Cyclic ADP-ribose (cADPR) induces intracellular Ca2+ ([Ca2+]i) release in airway smooth muscle, and the cADPR antagonist, 8-amino-cADPR, abolishes [Ca2+]i oscillations elicited by acetylcholine (ACh), suggesting that cADPR is involved during muscarinic receptor activation. Whether the cADPR signaling pathway is common to agonists acting through different G protein-coupled receptors is not known. Using digital video imaging of Fura2-AM loaded porcine airway smooth muscle cells, we examined the effects of the membrane-permeant cADPR antagonist, 8-bromo-cADPR (8Br-cADPR), on the [Ca2+]i responses to ACh, histamine and endothelin-1 (ET-1). In cells preincubated with 100 microM 8Br-cADPR, the [Ca2+]i responses to ACh and ET-1 were significantly attenuated, whereas responses to histamine were not, suggesting agonist specificity of cADPR signaling. The effects of 8Br-cADPR were concentration dependent. We further examined whether muscarinic receptor subtypes specifically couple to this pathway, because in porcine airway smooth muscle cells, ACh activates both M2 and M3 muscarinic receptors coupled to Gai and Gaq, respectively. Methoctramine, an M2-selective antagonist, attenuated the [Ca2+]i responses to Ach, and there was no further attenuation by 8Br-cADPR. In airway smooth muscle, the CD38/cADPR signaling pathway is involved in [Ca2+]i responses to contractile agonists in an agonist-specific manner.  (+info)

H(1)-Receptor activation triggers the endogenous nitric oxide signalling system in the rat submandibular gland. (50/251)

BACKGROUND: Histamine is released from mast cells by immunologic and non-immunologic stimuli during salivary gland inflammation, regulating salivary secretion. The receptor-secretory mechanism has not been studied in detail. AIMS: The studies reported were directed toward elucidating signal transduction/second messenger pathways within the rat submandibular gland associated with 2-thiazolylethylamine (ThEA)-induced H(1)-receptor responses. MATERIALS AND METHODS: To assess the H(1) receptor subtype expression in the rat submandibular gland, a radioligand binding assay was performed. The study also included inositolphosphates and cyclic GMP accumulation, protein kinase C and nitric oxide synthase activities, and amylase release. RESULTS: The histamine H(1) receptor subtype is expressed on the rat submandibular gland with high-affinity binding sites. The ThEA effect was associated with activation of phosphoinositide-specific phospholipase C, translocation of protein kinase C, stimulation of nitric oxide synthase activity and increased production of cyclic GMP. ThEA stimulation of nitric oxide synthase and cyclic GMP was blunted by agents able to interfere with calcium movilization, while a protein kinase C inhibitor was able to stimulate ThEA action. On the other hand, ThEA stimulation evoked amylase release via the H1 receptor but was not followed by the L-arginine/nitric oxide pathway activation. CONCLUSIONS: These results suggest that, apart from the effect of ThEA on amylase release, it also appears to be a vasoactive chemical mediator that triggers vasodilatation, modulating the course of inflammation.  (+info)

Synthesis of (+/-)-trans- or cis-(5-aminomethyltetrahydrofuranyl)imidazole by Mitsunobu cyclization: synthetic studies toward novel histamine H3 or H4-ligands. (51/251)

The (+/-)-trans- or cis-4(5)-(5-aminomethyltetrahydrofuranyl)imidazole [1 and 2] were synthesized by the Mitsunobu cyclization, starting from L-glutamic acid.  (+info)

Multiple differences in agonist and antagonist pharmacology between human and guinea pig histamine H1-receptor. (52/251)

Species isoforms of histamine H2-, H3-, and H4-receptors differ in their pharmacological properties. The study aim was to dissect differences between the human H1R (hH1R) and guinea pig H1R (ghH1R). We coexpressed hH1R and gpH1R with regulators of G-protein signaling in Sf9 insect cells and analyzed the GTPase activity of Gq-proteins. Small H1R agonists showed similar effects at hH1R and gpH1R, whereas bulkier 2-phenylhistamines and histaprodifens were up to approximately 10-fold more potent at gpH1R than at hH1R. Most 2-phenylhistamines and histaprodifens were more efficacious at gpH1R than at hH1R. Several first-generation H1R antagonists were approximately 2-fold, and arpromidine-type H1R antagonists up to approximately 10-fold more potent at gpH1R than at hH1R. [3H]Mepyramine competition binding studies confirmed the potency differences of the GTPase studies. Phe-153-->Leu-153 or Ile-433-->Val-433 exchange in hH1R (hH1R-->gpH1R) resulted in poor receptor expression, low [3H]mepyramine affinity, and functional inactivity. The Phe-153-->Leu-153/Ile-433-->Val-433 double mutant expressed excellently but only partially changed the pharmacological properties of hH1R. Small H1R agonists and 2-phenylhistamines interacted differentially with human and guinea pig H2R in terms of potency and efficacy, respectively. Our data show the following: 1) there are differences in agonist- and antagonist-pharmacology of hH1R and gpH1R encompassing diverse classes of bulky ligands. These differences may be explained by higher conformational flexibility of gpH1R relative to hH1R; 2) Phe-153 and Ile-433 are critical for proper folding and expression of hH1R; and 3) H2R species isoforms distinguish between H1R agonists.  (+info)

Pharmacological characterization of the novel histamine H3-receptor antagonist N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). (53/251)

We present the pharmacological and pharmacokinetic profiles of a novel histamine H3 receptor antagonist, N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). The H3-receptor binding Ki values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively. The Ki values for SCH 79687 at histamine H1 and H2 receptors were greater than 1 microM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H3 receptor over alpha 2A-adrenoceptors and imidazoline I2, and >500-fold H3 selectivity compared with over 60 additional receptors. The pA2 value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 +/- 0.3. Similar H3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pKb = 9.4 +/- 0.3 and 10.1 +/- 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFS-induced contractions in HSV. SCH 79687 (ED50 = 0.3 mg/kg i.v.) attenuated (R)-alpha-methylhistamine inhibition of sympathetic hypertensive responses in the GP. At the time of activity evaluation, the GP plasma SCH 79687 concentration was 25 ng/ml at the dose of 0.3 mg/kg i.v. In feline nasal studies, combined administration of SCH 79687 (3 mg/kg i.v.) and the H1-antagonist loratadine (3 mg/kg i.v.), at individual doses that do not produce decongestion, inhibited the compound 48/80-induced congestion by 47%. The alpha-adrenergic agonist phenylpropanolamine (PPA; 1 mg/kg i.v.) also attenuated compound 48/80 nasal responses by 42%. Unlike the H3/H1 combination that did not affect blood pressure (BP), PPA (1 mg/kg i.v.) significantly increased BP compared with control animals by a maximum of 31 mm Hg. Orally, SCH 79687 (10 mg/kg) plus loratadine (10 mg/kg) also produced decongestion without effects on BP. In pharmacokinetic studies, oral dosing with SCH 79687 in the rat (10 mg/kg) and monkey (3 mg/kg) achieved plasma Cmax and area under the curve values greater than 1.5 and 12.1 microg. h/ml, respectively. SCH 79687 is an orally active H3 antagonist with a good pharmacokinetic profile that, in combination with an H1 antagonist, demonstrates decongestant efficacy comparable with oral sympathomimetic decongestants but without hypertensive liabilities.  (+info)

Regulation by prostaglandin E2 and histamine of angiogenesis in inflammatory granulation tissue. (54/251)

In an air pouch-type carrageenin-induced inflammation model in rats, the selective cyclooxygenase (COX)-2 inhibitor NS-398 dose dependently inhibited the granulation tissue formation, angiogenesis and the level of vascular endothelial growth factor (VEGF) in the granulation tissue. In culture of the minced granulation tissue, PGE2 induced VEGF production in a concentration-dependent manner. Histamine also induced VEGF production in the granulation tissue in vitro. The H2 receptor antagonist cimetidine, the cAMP antagonist Rp-cAMP and the protein kinase A inhibitor H-89 suppressed the histamine-induced VEGF production in the granulation tissue. However, the H1 receptor antagonist pyrilamine maleate, the H3 receptor antagonist thioperamide, the protein kinase C inhibitors Ro 31-8425 and calphostin C or the tyrosine kinase inhibitor genistein showed no effect. Subcutaneous implantation of a cotton thread in the dorsum of histidine decarboxylase-deficient (HDC-/-) mice, but not in mast cell-deficient (WBB6F1-W/Wv) mice, induced less angiogenesis with lower levels of VEGF in the granulation tissue than in their corresponding wild-type (HDC+/+ and WBB6F1(-)+/+) mice. In HDC-/- mice, the topical injection of histamine or the H2 receptor agonist dimaprit rescued the defective angiogenesis and granulation tissue formation. In addition, cimetidine but not pyrilamine maleate and thioperamide inhibited the histamine-induced angiogenesis in the granulation tissue in HDC-/- mice. These findings suggest that PGE2 and histamine augment angiogenesis in the inflammatory granulation tissue by inducing VEGF production, and histamine induces VEGF production possibly through the H2 receptor--cAMP--protein kinase A pathway.  (+info)

Hospital use of acid-suppressive medications and its fall-out on prescribing in general practice: a 1-month survey. (55/251)

BACKGROUND: Acid-suppressive medications are commonly used in hospitalized patients, but, to date, little is known about the overall use of these drugs in the hospital setting. AIM: To evaluate the appropriateness of acid-suppressive therapy in a large teaching hospital in northern Italy, and the fall-out of hospital prescription in general practice. METHODS: The use of antisecretory agents was monitored for 1 month in adult patients consecutively admitted to L. Sacco University Hospital by reviewing their clinical charts. The appropriateness of each prescription was reviewed jointly by two consultant gastroenterologists. RESULTS: A total of 46.8% of 799 hospitalized patients received acid-suppressive therapy. Ranitidine was the most frequently used drug (44.4%), followed by pantoprazole (31.8%) and omeprazole (23.0%). Stress ulcer prophylaxis and the prevention of non-steroidal anti-inflammatory drug-induced ulcer accounted for 60.4% of the indications for use. Overall, 68% of prescriptions were not appropriate as determined by consensus review; 56.4% of patients receiving unnecessary prophylactic treatment whilst in hospital were discharged on therapy, and 46% were still receiving the treatment 3 months later. CONCLUSIONS: Acid-suppressive agents are over-used in hospitalized patients. Most of the inappropriate hospital prescriptions are for ulcer prophylaxis in low-risk patients. This unnecessary use may also induce inappropriate drug consumption in general practice.  (+info)

The histamine H2-receptor antagonist, cimetidine, inhibits the articular osteopenia in rats with adjuvant-induced arthritis by suppressing the osteoclast differentiation induced by histamine. (56/251)

The effects of cimetidine on rat adjuvant arthritis (AA) and rat osteoclast differentiation were studied. For the in vivo experiments, AA was induced by injections of Mycobacterium tuberculosis H37RA either subcutaneously into the base of the tail or into the right hind paw. The osteoclast differentiation was assessed by estimating the number of tartrate-resistant acid phosphatase-positive multinuclear cells in the bone marrow culture. Cimetidine, at the dose of 25 mg/kg body weight, reduced the paw swelling by 70% (P<0.01). Cimetidine, at 10 microM concentration, inhibited 1,25-dihydroxyvitamin D(3) (1,25[OH](2)D(3)) and histamine mediated osteoclast differentiations by 40% (P<0.01) and 60% (P<0.001), respectively. Dimaprit, at 0.3 microM, stimulated the cell differentiation by 100% (P<0.01). Mepyramine reduced osteoclast differentiation, but the reduction was not statistically significant. Measurements of bone mineral density of the femur indicated that 5 mg/kg of cimetidine treated animals had 30% (P<0.01) higher mineral density in comparison with that of the AA control group that received no cimetidine. These results suggest that histamine is a potent inducer of osteoclast differentiation, at least in part, through the histamine H(2)-receptor, and cimetidine has a preventive effect on articular destruction and accompanying inflammation in arthritic rats. These observations may provide critical insights into the pathogenesis of the bone pathology seen in patients with RA.  (+info)