Interaction of amylin with calcitonin gene-related peptide receptors in the microvasculature of the hamster cheek pouch in vivo.
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1. This study used intravital microscopy to investigate the receptors stimulated by amylin which shares around 50% sequence homology with the vasodilator calcitonin gene-related peptide (CGRP) in the hamster cheek pouch microvasculature in vivo. 2. Receptor agonists dilated arterioles (diameters 20-40 microm). The -log of the concentrations (+/- s.e.mean; n = 8) causing 50% increase in arteriole diameter were: human betaCGRP (10.8 +/- 0.3), human alphaCGRP (10.8 +/- 0.4), rat alphaCGRP (10.4 +/- 0.3). Rat amylin and the CGRP2 receptor selective agonist [Cys(ACM2,7]-human alphaCGRP were 100 fold less potent (estimates were 8.5 +/- 0.4 and 8.2 +/- 0.3 respectively). 3. The GCRP1 receptor antagonist, CGRP8-37 (300 nmol kg(-1); i.v.) reversibly inhibited the increase in diameter evoked by human alphaCGRP (0.3 nM) from 178 +/- 22% to 59 +/- 12% (n = 8; P < 0.05) and by rat amylin (100 nM) from 138 +/- 23% to 68 +/- 24% (n = 6; P < 0.05). CGRP8-37 did not inhibit vasodilation evoked by substance P (10 nM; n = 4: P > 0.05). 4. The amylin receptor antagonist, amylin8-37 (300 nmol kg(-1); i.v.) did not significantly inhibit the increase in diameter evoked by human alphaCGRP (0.3 nM) which was 112 +/- 26% in the absence, and 90 +/- 29% in the presence of antagonist (n = 4; P < 0.05); nor that evoked by rat amylin (100 nM) which was 146 +/- 23% in the absence and 144 +/- 32% in the presence of antagonist (n = 4; P > 0.05). 5. The agonist profile for vasodilatation and the inhibition of this dilatation by CGRP8-37, although not the amylin8-37 indicates that amylin causes vasodilatation through interaction with CGRP1 receptors in the hamster cheek pouch. (+info)
Topical therapies for glaucoma: what family physicians need to know.
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Medication classes historically used in the management of glaucoma include beta blockers, miotics, sympathomimetics and carbonic anhydrase inhibitors. Because topically applied medications are more site specific, they are preferred in the treatment of glaucoma. Compared with oral medications, topical agents are associated with a decreased incidence of systemic side effects. With topical administration, conjunctival and localized skin allergic reactions are relatively common, whereas severe reactions, including death, are rare. Recently introduced topical agents for glaucoma therapy include dorzolamide and brinzolamide, the first topical carbonic anhydrase inhibitors; brimonidine and apraclonidine, more ocular-specific alpha agonists; and latanoprost, a prostaglandin analog, which is a new class of glaucoma medication. Latanoprost has the unique side effect of increasing iris pigmentation. Like their predecessors, the newer agents lower intraocular pressure by a statistically significant degree. Preservation of visual field, the more substantial patient-oriented end point, continues to be studied. (+info)
Pilocarpine induces an increase in the anterior chamber angular width in eyes with narrow angles.
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AIM: To determine the mechanical effects of pilocarpine on the trabecular-iris angle opening in eyes with narrow angles, compared with its effects on healthy control subjects with wide angles. METHODS: A narrow angle was defined as 25 degrees or less of trabecular-iris angle on ultrasound biomicroscopic examination. The change in anterior chamber depth (ACD), trabecular-iris angle (TIA), angle opening distance (AOD, distance between trabecular meshwork and iris) measured at 250 microm and 500 microm from the scleral spur (AOD250 and AOD500), and iris thickness was determined in 30 eyes of 30 patients (13 men and 17 women, between 63 and 82 years (mean 70.4 years)) with narrow angles and in 30 sex and age matched control subjects with wide angles before and 1 hour after the instillation of 2% pilocarpine hydrochloride by ultrasound biomicroscopy. RESULTS: In all eyes with narrow angles, pilocarpine increased the TIA, AOD250, and AOD500; these changes increased significantly and linearly as the corresponding pretreatment values decreased (r = 0.807, p = 0.0001; r = 0.787, p = 0.0001; r = 0.852, p = 0.0001). Of 30 eyes with wide angles, 23 eyes whose ACD was 2670 microm and more showed a decrease in the TIA, AOD250, and AOD500; the changes in TIA, AOD250, and AOD500 also significantly correlated with the corresponding pretreatment values (r = 0.913, p = 0.0001; r = 0.882, p = 0.0001; r = 0.895, p = 0.0001). Pilocarpine induced a smaller decrease in ACD in eyes with narrow angles than in those with wide angles (p = 0.0001). There was a linear correlation between the increase in ACD change and the decrease in pretreatment ACD in eyes with narrow angles and those with wide angles (r = 0.781, p = 0.0003; r = 0.798, p = 0.0001). CONCLUSIONS: The finding that pilocarpine increases angular width in patients with narrow angles indicates that this agent is useful for treating patients with narrow angles and angle closure glaucoma. The prediction of the pilocarpine induced change in the angle may assist ophthalmologists in treating such patients. (+info)
The effect of miotics on the intraocular pressure of conscious owl monkeys.
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The intraocular pressure of conscious, unsedated owl monkeys (Aotus trivirgatus) was measured with an applanation tonometer. Untreated eyes of the conscious animals were found to have higher values than those reported for owl monkeys anesthetized with pentobarbitone. Locally applied pilocarpine, carbachol, and oxotremorine gave concentration-related reduction in pressure, oxotremorine being the most potent and having longer duration of effect than the other compounds. Slight reductions were also observed with aceclidine and R. S. 86. These results are discussed in relation to the effects of miotics in man. (+info)
Adrenomedullin receptor antagonism by calcitonin gene-related peptide(8-37) inhibits carotid artery neointimal hyperplasia after balloon injury.
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Intimal injury by angioplasty results in a series of changes, including smooth muscle cell hyperplasia, that lead to vascular restenosis. Adrenomedullin, a potent vasodilator peptide, has natriuretic effects, and its plasma concentration is elevated in cardiovascular diseases. Adrenomedullin is secreted by endothelial and vascular smooth muscle cells, but its role in neointimal hyperplasia after balloon injury has not been previously described. We investigated the role of endogenous adrenomedullin in neointimal hyperplasia using an in vivo rat model of postinjury vascular restenosis. In the injured rats, bromodeoxyuridine-labeled nuclei in the media of untreated common carotid arteries were increased 2 days after injury, which were suppressed by in vivo treatment with the adrenomedullin receptor antagonist calcitonin gene-related peptide (CGRP)(8-37). Inhibition of neointimal hyperplasia by CGRP(8-37) was distinct at 7 and 14 days, whereas CGRP(1-37) had no effect. The expression of adrenomedullin in the media of both untreated and treated common carotid arteries was elevated at 2 days and further enhanced in hyperplastic intima of untreated common carotid arteries at 7 days. Our findings suggest a novel role for endogenous adrenomedullin in balloon injury-induced restenosis and indicate that CGRP(8-37) may be useful for the prevention of vascular restenosis. (+info)
An autocrine or a paracrine role of adrenomedullin in modulating cardiac fibroblast growth.
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OBJECTIVE: The aim of the present study was to determine the role of adrenomedullin (AM) in cardiac fibroblasts. METHODS: The production and secretion of AM were examined in cultured neonatal rat cardiac fibroblasts, and the effects of AM on proliferation and protein synthesis of these cells were assessed by [3H]thymidine and [3H]phenylalanine incorporation, respectively. RESULTS: Cultured cardiac fibroblasts secreted AM into the medium time-dependently at a rate of 20.3 +/- 3.0 fmol/5 x 10(4) cells/48 h, mean +/- S.D. Northern blot analysis showed expression of preproAM mRNA of 1.6 kb in these cells. In addition, 10(-6) mol/l of angiotensin II (Ang II) and endothelin-1 (ET-1) significantly increased the AM secretion by 55 and 48%, respectively. Synthetic AM significantly reduced 10(-6) mol/l Ang II- or 10(-7) mol/l ET-1-stimulated [3H]thymidine and [3H]phenylalanine incorporation in a dose-dependent manner, and these effects were attenuated by a calcitonin gene-related peptide (CGRP) type 1 receptor antagonist, CGRP(8-37). Synthetic AM also had a dose-dependent stimulatory effect on cAMP accumulation in these cells, which was significantly attenuated by CGRP(8-37). A cAMP analogue, 8-bromo-cAMP, mimicked the AM effects, inhibiting the Ang II-stimulated [3H]thymidine and [3H]phenylalanine incorporation. Blockage of the effect of endogenous AM by anti-AM monoclonal antibody not only significantly reduced the basal level of intracellular cAMP, but also enhanced the [3H]thymidine and [3H]phenylalanine incorporation into the cells. CONCLUSIONS: Cultured neonatal rat cardiac fibroblasts produce and secrete AM, and the secreted AM may inhibit proliferation and protein synthesis of these cells. AM may exert these inhibitory effects partly by elevating intracellular cAMP. It is suggested that AM has an important role in modulating the growth of cardiac fibroblasts in an autocrine or a paracrine manner. (+info)
Comparison of the intraocular pressure lowering effect of latanoprost and a fixed combination of timolol-pilocarpine eye drops in patients insufficiently controlled with beta adrenergic antagonists. French Latanoprost Study Group, and the Swedish Latanoprost Study Group.
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AIMS: To compare the effect on intraocular pressure (IOP) of latanoprost monotherapy and timolol-pilocarpine in patients with glaucoma or ocular hypertension with inadequately controlled IOP on topical beta adrenergic antagonists. METHODS: This was a multicentre, randomised, observer masked, 6 week study performed in France and Sweden. 23 centres enrolled 237 patients with glaucoma or ocular hypertension and an IOP of at least 22 mm Hg on treatment with topical beta adrenergic antagonists, alone or in combination. After a 21 day run in period on timolol 0.5% twice daily, patients were randomised either to latanoprost 0.005% once daily or to a fixed combination of timolol-pilocarpine twice daily. Changes in mean diurnal IOP from the baseline to the 6 week visit were determined with an analysis of covariance. RESULTS: Mean diurnal IOP was statistically significantly decreased from baseline in both groups (p<0.001). Switching to latanoprost treatment reduced mean diurnal IOP by 5.4 (SEM 0.3) mm Hg (ANCOVA -22%) and switching to timolol-pilocarpine treatment reduced mean diurnal IOP by 4.9 (0.4) mm Hg (-20%). Blurred vision, decreased visual acuity, decreased twilight vision, and headache were statistically significantly more frequent in the timolol-pilocarpine group. CONCLUSIONS: Latanoprost monotherapy was at least as effective as fixed combination timolol-pilocarpine twice daily treatment in reducing mean diurnal IOP in patients not adequately controlled on topical beta adrenergic antagonists. Latanoprost was better tolerated than timolol-pilocarpine regarding side effects. These results indicate that a switch to latanoprost monotherapy can be attempted before combination therapy is initiated. (+info)
Effect of cataract extraction and posterior chamber lens implantation on outflow facility and its response to pilocarpine in Korean subjects.
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AIM: To investigate the effect of the lens on outflow facility in Korean patients with cataracts. METHODS: Intraocular pressure was measured by Goldmann applanation tonometry in 42 patients with cataracts and outflow facility was determined by tonography preoperatively, before and after instillation of pilocarpine. All patients received clear corneal phacoemulsification and silicone foldable intraocular lens implantation within the capsular bag by one surgeon. Two months after surgery, slit lamp examination and gonioscopy were performed and intraocular pressure and outflow facility were again determined. Statistical analysis was carried out using the Student's paired t test. RESULTS: There were no anterior chamber reactions and no visible trabecular meshwork damage 2 months after surgery. Intraocular pressure 2 months after lens extraction decreased by a mean of 2.4 (SE 0.4) mm Hg (p<0.001) compared with the preoperative value; postoperative outflow facility with and without pilocarpine increased by 0.080 (0.019) microl/min/mm Hg (p<0.001) and 0.045 (0.014) microl/min/mm Hg (p<0.001), respectively, at 2 months compared with preoperative values. The facility response to pilocarpine after lens extraction, relative to the baseline value and preoperative response, increased by 10.7 (7.1)% which was not statistically significant (p>0.1). CONCLUSION: Lens extraction causes a reduction in intraocular pressure and an increase in outflow facility in Korean subjects. Pilocarpine causes an increase in outflow facility which persists after cataract extraction and posterior chamber lens implantation. (+info)