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1.
Sci Data ; 11(1): 282, 2024 Mar 09.
Article in English | MEDLINE | ID: mdl-38461156

ABSTRACT

Water temperature dynamics in large inland lakes are interrelated with internal lake physics, ecosystem function, and adjacent land surface meteorology and climatology. Models for simulating and forecasting lake temperatures often rely on remote sensing and in situ data for validation. In situ monitoring platforms have the benefit of providing relatively precise measurements at multiple lake depths, but are often sparser (temporally and spatially) than remote sensing data. Here, we address the challenge of synthesizing in situ lake temperature data by creating a standardized database of near-surface and subsurface measurements from 134 sites across 29 large North American lakes, with the primary goal of supporting an ongoing lake model validation study. We utilize data sources ranging from federal agency repositories to local monitoring group samples, with a collective historical record spanning January 1, 2000 through December 31, 2022. Our database has direct utility for validating simulations and forecasts from operational numerical weather prediction systems in large lakes whose extensive surface area may significantly influence nearby weather and climate patterns.

2.
Arch Environ Occup Health ; 69(2): 69-80, 2014.
Article in English | MEDLINE | ID: mdl-24205958

ABSTRACT

Hearing loss from occupational noise exposure is a significant occupational health problem, requiring effective health and safety strategies. Essential to this is an understanding of the noise exposure of workers and the use of hearing protection equipment (HPE). This study reports on data collected in New Zealand. Visits were made to companies in each economic sector. Personal dosimetry was used to assess individual noise exposure of 529 workers. Workers were also interviewed about their use of HPE. Overall, 40.4% of production workers had a daily noise exposure greater than 1 Pa(2)h, exceeding the New Zealand National Standard for occupational noise exposure without HPE. Of these, 88.5% reported to use HPE when working in noise; however, some observations suggested that workers do not consistently use the devices. These data add to the overall picture of noise exposure of workers in New Zealand and are especially useful in areas where data did not previously exist or were difficult to access.


Subject(s)
Ear Protective Devices/statistics & numerical data , Hearing Loss, Noise-Induced/prevention & control , Noise, Occupational/statistics & numerical data , Environmental Monitoring , Humans , Industry , New Zealand , Occupations
3.
Prim Dent Care ; 18(4): 145-9, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21968040

ABSTRACT

AIM: This study´s aim was to assess whether the use of Short Message Service (SMS) text reminders sent to patients prior to their dental appointments improved attendance rates for two dentists at a dental access centre in Kirkcaldy, Fife, Scotland. METHOD: Automated SMS text reminders were set up through practice management software at Kirkcaldy Dental Access Centre. Two audits, using a research methodology, were then performed. Failure to attend appointments with the two dentists at 150 consecutive appointments was assessed before and after implementing the SMS text reminders. The null hypothesis that SMS reminders do not improve attendance rates at the dental access centre was tested. The Yates´ corrected chi-square test was applied to the resulting data, with the level for statistical significance set at P<0.05. RESULTS: Patients readily accepted the text messages and found them to be non-intrusive. Failed attendance at appointments for the two dentists was reduced from 46/150 (31%) before the SMS text reminders were introduced to 21/150 (14%) after its introduction (P=0.00088). Thus the use of SMS text reminders resulted in a statistically significant reduction in the number of failed attendances at appointments for the two dentists. CONCLUSIONS: In this preliminary study, SMS appointment reminders reduced the number of failed appointments significantly. They can provide an automated, non-intrusive, and cost-effective method of improving patient attendance at dental appointments.


Subject(s)
Appointments and Schedules , Dental Health Services , Reminder Systems , State Dentistry , Cell Phone , Cost-Benefit Analysis , Dental Health Services/organization & administration , Humans , United Kingdom
4.
IEEE Trans Biomed Eng ; 56(2): 273-80, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19272917

ABSTRACT

This paper presents a validated model of calf compression with an external pressure cuff as used for deep vein thrombosis. Magnetic resonance (MR) images of calf geometry were used to generate subject-specific finite-element (FE) models of the calf cross section. Ultrasound images of deep vessel collapse obtained through a water-filled cuff were used to validate model behavior. Calf/cuff pressure interface measurements were applied to the FE model and the resulting tissue deformation was compared with MR image in normal volunteers (three females, four males, age range 20-55) using two distinct cuffs. MR observations and the model results showed good qualitative agreement. A similar reduction in cross-sectional area of the posterior tibial veins was obtained under both symmetric compression (89%) and asymmetric compression (81%), but greater compression of the anterior tibial veins was achieved with symmetric compression. The need to account for the effective compressibility of the calf tissue suggests that external measurements of the calf tissue deformation will not accurately predict deep vessel collapse. These results have implications for the modification of venous haemodynamics by such systems and could help to improve cuff design.


Subject(s)
Blood Vessels/physiology , Intermittent Pneumatic Compression Devices , Leg/blood supply , Models, Cardiovascular , Adult , Blood Vessels/anatomy & histology , Blood Vessels/diagnostic imaging , Female , Finite Element Analysis , Humans , Leg/anatomy & histology , Leg/diagnostic imaging , Magnetic Resonance Imaging , Male , Middle Aged , Pressure , Reproducibility of Results , Ultrasonography , Venous Thrombosis/prevention & control
5.
Clin Drug Investig ; 26(5): 287-96, 2006.
Article in English | MEDLINE | ID: mdl-17163262

ABSTRACT

BACKGROUND: Tanacetum parthenium (feverfew) has been used traditionally to treat migraine, and although its mechanism of action is not fully understood, serotonin 5-HT receptor blocking effects have been suggested. T. parthenium and Salix alba (white willow) either alone or in combination (Mig-RL) were recently shown to inhibit binding to 5-HT(2A/2C) receptors; T. parthenium failed to recognise 5-HT(1D) receptors, whereas S. alba or the combination did. It was hypothesised that S. alba in combination with T. parthenium may provide superior migraine prophylactic activity compared with T. parthenium alone. METHODS: A prospective, open-label study was performed in 12 patients diagnosed with migraine without aura. Twelve weeks' treatment with T. parthenium 300 mg plus S. alba 300 mg (Mig-RL) twice daily was administered to determine the effects of therapy on migraine attack frequency (primary efficacy criterion), intensity and duration (secondary efficacy criteria), and quality of life, together with tolerability for patients. RESULTS: Attack frequency was reduced by 57.2% at 6 weeks (p < 0.029) and by 61.7% at 12 weeks (p < 0.025) in nine of ten patients, with 70% patients having a reduction of at least 50%. Attack intensity was reduced by 38.7% at 6 weeks (p < 0.005) and by 62.6% at 12 weeks (p < 0.004) in ten of ten patients, with 70% of patients having a reduction of at least 50%. Attack duration decreased by 67.2% at 6 weeks (p < 0.001) and by 76.2% at 12 weeks (p < 0.001) in ten of ten patients. Two patients were excluded for reasons unrelated to treatment. Self-assessed general health, physical performance, memory and anxiety also improved by the end of the study. Mig-RL treatment was well tolerated and no adverse events occurred. CONCLUSION: The remarkable efficacy of Mig-RL in not only reducing the frequency of migraine attacks but also their pain intensity and duration in this trial warrants further investigation of this therapy in a double-blind, randomised, placebo-controlled investigation involving a larger patient population.


Subject(s)
Migraine Disorders/prevention & control , Plant Extracts/therapeutic use , Salix/chemistry , Tanacetum parthenium/chemistry , Adult , Capsules/administration & dosage , Drug Administration Schedule , Drug Combinations , Female , Humans , Male , Middle Aged , Migraine Disorders/drug therapy , Migraine Disorders/pathology , Nonprescription Drugs , Plant Extracts/administration & dosage , Plant Extracts/pharmacology , Prospective Studies , Quality of Life/psychology , Randomized Controlled Trials as Topic , Time Factors , Treatment Outcome
6.
Cephalalgia ; 22(1): 37-47, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11993612

ABSTRACT

We investigated the effects of donitriptan, which possesses a uniquely high affinity and efficacy at 5-HT1B/1D receptors, on carotid and systemic haemodynamics in anaes thetized pigs. Donitriptan (0.16-100 microg kg(-1), i.v.) dose-dependently decreased total carotid blood flow and vascular conductance (maximum response: -25 +/- 3%). This effect was entirely due to a selective reduction in the cephalic arteriovenous anastomotic fraction (maximum response: - 63 +/- 3%; ED50%: 92 +/- 31 nmol/kg); the nutrient vascular conductance increased. Donitriptan did not decrease vascular conductances in or blood flow to a number of organs, including the heart and kidneys; in fact, vascular conductances in the skin, brain and skeletal muscles increased. Cardiac output was slightly decreased by donitriptan, but this effect was confined to peripheral arteriovenous anastomoses. The haemodynamic effects of donitriptan were substantially reduced by the 5-HT1B/1D receptor antagonist GR127935. These results show that donitriptan selectively constricts arteriovenous anastomoses via 5-HT1B receptor activation. The drug should be able to abort migraine headaches and it is unlikely to compromize blood flow to vital organs.


Subject(s)
Blood Pressure/drug effects , Brain/blood supply , Cardiac Output/drug effects , Heart Rate/drug effects , Nitriles/pharmacology , Piperazines/pharmacology , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/pharmacology , Animals , Blood Flow Velocity/drug effects , Carotid Arteries/drug effects , Dose-Response Relationship, Drug , Oxadiazoles/pharmacology , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Regional Blood Flow/drug effects , Serotonin Antagonists/pharmacology , Swine , Tryptamines , Vascular Resistance/drug effects
7.
Naunyn Schmiedebergs Arch Pharmacol ; 363(4): 464-71, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11330341

ABSTRACT

The clinical anti-anginal effectiveness of ranolazine is currently being evaluated. However, the mechanism of its anti-ischaemic action is still unclear. The aim of this work was to establish whether ranolazine exerts functional beta-adrenoceptor antagonist activity in the rat cardiovascular system. Radioligand binding studies were performed in rat hearts and guinea-pig lungs for beta1- and beta2-adrenoceptor affinity, respectively. Ranolazine had micromolar affinity for both beta,- and beta2-adrenoceptors (pKi5.8 and 6.3, respectively). Developed tension was measured in isolated rat left atria (electrically driven at 4 Hz) and cumulative concentration/response curves to (+/-)isoprenaline (0.01-1,000 nM) constructed. Ranolazine (0.32-10 microM) surmountably but weakly antagonised isoprenaline-induced positive inotropic responses, with an apparent pA2 of 5.85 (5.69-6.00) and a slope of -0.74 (-0.70 to -0.77). In bivagotomised, atropinised pithed rats, ranolazine per se evoked marked bradycardia at doses above 10 mg/kg i.v. (maximum variation at 80 mg/kg -125+/-15 bpm, n=6, P<0.001) by a mechanism apparently unrelated to blockade of beta1- or beta2-adrenoceptors. Cumulative incremental doses of (+/-)isoprenaline (0.63 ng/kg to 0.16 mg/kg i.v.) administered to pithed rats induced concomitant depressor and chronotropic responses. Animals received either vehicle (saline 0.9% i.v., n=12), atenolol (0.04-2.5 mg/kg i.v., n=6 per dose), ICI 118551 (0.01-0.63 mg/kg i.v., n=6 or 7 per dose), (+/-)propranolol (0.01-0.63 mg/kg i.v., n=6 per dose) or ranolazine (2.5-80 mg/kg i.v., n=6 or 7 per dose) 10 min prior to isoprenaline. Ranolazine dose-dependently and competitively antagonised isoprenaline-induced decreases in diastolic arterial pressure (DAP, dose ratio 12.2 with 80 mg/kg ranolazine) and increases in heart rate (HR, dose ratio 20.3 with 80 mg/kg ranolazine). Collectively, these results demonstrate that ranolazine behaves as a weak beta1- and beta2-adrenoceptor antagonist in the rat cardiovascular system.


Subject(s)
Adrenergic beta-Antagonists/pharmacology , Cardiovascular System/drug effects , Enzyme Inhibitors/pharmacology , Myocardial Contraction/drug effects , Piperazines/pharmacology , Receptors, Adrenergic, beta/drug effects , Acetanilides , Animals , Enzyme Inhibitors/metabolism , Guinea Pigs , Hemodynamics/drug effects , Isoproterenol/antagonists & inhibitors , Male , Piperazines/metabolism , Ranolazine , Rats , Rats, Sprague-Dawley
8.
Eur J Pharmacol ; 397(2-3): 297-302, 2000 Jun 02.
Article in English | MEDLINE | ID: mdl-10844127

ABSTRACT

Stimulation of a Ca(2+)-dependent K(+) current by zolmitriptan, a 5-HT(1B/1D) receptor partial agonist, was investigated in C6 glioma cells stably expressing recombinant human 5-HT(1B) receptors. Outward K(+) currents (I(K)) were examined in non-transfected C6 glioma cells and in cells expressing cloned human 5-HT(1B) receptors using the patch-clamp technique in the whole-cell configuration. In C6 glioma cells expressing recombinant human 5-HT(1B) receptor, zolmitriptan increased I(K) in a concentration-dependent manner (maximum increase 16.3+/-7.8%, n=5, p<0.001) with a pD(2) value (geometric mean with 95% confidence intervals) of 7.03 (7.90-6.10). Zolmitriptan failed to elicit increases in I(K) in non-transfected C6 cells. In the presence of the mixed 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2(-methyl-4(5-methyl-1 ,2,4)-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide 2HCl (GR 127935, 0. 1 mcM), zolmitriptan (1 mcM) failed to significantly increase I(K) in C6 cells expressing human 5-HT(1B) receptors confirming that zolmitriptan-evoked responses were indeed mediated by human 5-HT(1B) receptors. In C6 cells expressing cloned human 5-HT(1B) receptors, zolmitriptan-induced increases in I(K) were prevented by the calcium chelator, EGTA (5 mM) when included in the patch pipette (maximum increase -3.3+/-4.2%, n=4, P=NS). The Ca(2+)-dependent K(+) channel blockers, iberiotoxin (0.1 mcM) and tetraethylammonium (TEA, 1 mM), abolished zolmitriptan-induced increases in I(K) (4.5+/-7.3%, n=4 and -0.8+/-1.7%, n=4, respectively, P=NS in each case) in C6 cells expressing human 5-HT(1B) receptors, confirming the involvement of Ca(2+)-dependent K(+) channels. In conclusion, the 5-HT(1B/1D) receptor partial agonist, zolmitriptan, stimulates I(K/Ca) in C6 glioma cells stably transfected with human 5-HT(1B) receptors suggesting an increase of hyperpolarizing current.


Subject(s)
Calcium/pharmacology , Membrane Potentials/drug effects , Oxazoles/pharmacology , Oxazolidinones , Potassium Channels/physiology , Serotonin Receptor Agonists/pharmacology , Animals , Dose-Response Relationship, Drug , Humans , Oxadiazoles/pharmacology , Peptides/pharmacology , Piperazines/pharmacology , Receptor, Serotonin, 5-HT1B , Receptors, Serotonin/drug effects , Receptors, Serotonin/genetics , Receptors, Serotonin/physiology , Recombinant Fusion Proteins/drug effects , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/physiology , Serotonin Antagonists/pharmacology , Tetraethylammonium/pharmacology , Tryptamines , Tumor Cells, Cultured
9.
Fundam Clin Pharmacol ; 14(2): 159-62, 2000.
Article in English | MEDLINE | ID: mdl-10796064

ABSTRACT

Lubeluzole, a novel neuroprotective compound, has been associated with cases of QT interval prolongation but its effects on the cardiac action potential have not been described to date. Thus, the electrophysiological effects of lubeluzole were studied in rabbit isolated Purkinje fibres. The results demonstrate that lubeluzole (0.001-1 microM) concentration-dependently lengthened action potential duration at 50% and 90% of repolarization (APD50 and APD90) without significantly modifying other parameters. Furthermore, APD lengthening induced by lubeluzole was not significantly decreased by reducing the basic cycle length (from 3,000 to 1,000 ms). The results demonstrate that lubeluzole potently and concentration-dependently increases APD from 0.01 microM, consistent with class III-type antiarrhythmic actions, which is likely to underlie QT interval prolongation induced by the drug.


Subject(s)
Action Potentials/drug effects , Cardiovascular Agents/pharmacology , Heart/drug effects , Piperidines/pharmacology , Purkinje Fibers/drug effects , Thiazoles/pharmacology , Animals , Dose-Response Relationship, Drug , Electric Stimulation , Heart/physiology , In Vitro Techniques , Male , Membrane Potentials/drug effects , Purkinje Fibers/physiology , Rabbits
10.
J Pharmacol Exp Ther ; 290(1): 83-95, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10381763

ABSTRACT

F 11356 (4-[4-[2-(2-aminoethyl)-1H-indol-5-yloxyl]acetyl]piperazinyl-1-yl] ben zonitrile) was designed to take advantage of the superior potency and efficacy characteristics of 5-hydroxytryptamine (5-HT) compared with tryptamine at 5-HT1B/1D receptors. F 11356 has subnanomolar affinity for cloned human and nonhuman 5-HT1B and 5-HT1D receptors, and its affinity for 5-HT1A and other 5-HT receptors, including the 5-ht1F subtype, is 50-fold lower and micromolar, respectively. In C6 cells expressing human 5-HT1B or human 5-HT1D receptors, F 11356 was the most potent compound in inhibiting forskolin-induced cyclic AMP formation (pD2 = 8.9 and 9.6), and in contrast to tryptamine and derivatives, it produced maximal enhancement of [35S]guanosine-5'-O-(3-thio)triphosphate-specific binding equivalent to 5-HT. F 11356 was equipotent to 5-HT (pD2 = 7.1 versus 7.2) and more potent than tryptamine derivatives in contracting rabbit isolated saphenous vein. In isolated guinea pig trigeminal ganglion neurons, F 11356 was more potent (pD2 = 7.3 versus 6.7) and induced greater increases in outward hyperpolarizing Ca2+-dependent K+ current than sumatriptan. In anesthetized pigs, F 11356 elicited highly cranioselective, more potent (from 0.16 microgram/kg i.v.) and greater carotid vasoconstriction than tryptamine derivatives. Decreases in carotid blood flow were observed in conscious dogs from 0.63 mg/kg oral F 11356 in the absence of changes in heart rate or behavior. Oral activity was confirmed when hypothermic responses were elicited in guinea pigs (ED50 = 1.6 mg/kg), suggesting that F 11356 also accesses the brain. F 11356 thus is a selective, high-potency agonist at 5-HT1B/1D receptors, which distinguishes itself from tryptamine and derivatives in exerting high intrinsic activity at these receptors in vascular and neuronal models relevant to migraine.


Subject(s)
Migraine Disorders/drug therapy , Nitriles/pharmacology , Piperazines/pharmacology , Receptors, Serotonin/drug effects , Animals , Carotid Arteries/drug effects , Carotid Arteries/physiology , Colforsin/pharmacology , Cyclic AMP/pharmacology , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology , Guinea Pigs , Heart/drug effects , Heart/physiology , Hemodynamics/drug effects , Humans , Hypothermia/chemically induced , In Vitro Techniques , Male , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Neurons/drug effects , Rabbits , Radioligand Assay , Rats , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Saphenous Vein/drug effects , Swine , Trigeminal Ganglion/cytology , Trigeminal Ganglion/drug effects , Tryptamines
11.
Clin Neuropharmacol ; 22(3): 123-36, 1999.
Article in English | MEDLINE | ID: mdl-10367177

ABSTRACT

Serotonin (5-hydroxytryptamine; 5-HT) is thought to play an important role in the pathogenesis of migraine. The discovery of the 5-HT1B/1D/1F agonist sumatriptan constitutes a substantial advance in the acute treatment of migraine, though it displays a number of nonnegligible shortcomings. Today, a number of second-generation drugs derived from tryptamine are under advanced clinical development or are about to be marketed worldwide for the acute treatment of migraine. These tryptamine derivatives display partial agonist properties at 5-HT1B/1D receptors. It is not yet clearly established whether these agents represent a major improvement over sumatriptan in therapeutic effectiveness. Most of them also show affinity for 5-ht1F binding sites and have better oral pharmacokinetics than sumatriptan. The acute antimigraine effects of this second-generation of triptans seem to be obtained in largely the same way as with sumatriptan: by cranial vasoconstriction and inhibition of trigeminovascular activation from both peripheral and central projections. Future directions in migraine therapy should focus on agents that exhibit high intrinsic activity at 5-HT1B/1D receptors, offer a good safety profile, and demonstrate long-lasting action which might also be considered in migraine prophylaxis.


Subject(s)
Migraine Disorders/drug therapy , Serotonin Receptor Agonists/therapeutic use , Sumatriptan/therapeutic use , Animals , Blood Pressure/drug effects , Forecasting , Humans , Migraine Disorders/physiopathology , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/pharmacology , Sumatriptan/analogs & derivatives , Vascular Resistance/drug effects , Receptor, Serotonin, 5-HT1F
12.
Curr Opin Drug Discov Devel ; 2(4): 304-10, 1999 Jul.
Article in English | MEDLINE | ID: mdl-19649958

ABSTRACT

The design of new generation drugs acting as 5-HT1 receptor agonists, in the field of acute treatment of migraine, is still very active. The reason is the need for safer medicines with improved response rates and a reduced rate of headache recurrence. This review focuses on the different classes of drugs, which have been classified based on the target upon which they act rather than upon structural characteristics. Short SAR studies are reported for each series with a detailed pharmacological profile for the most interesting compounds.

13.
J Cardiovasc Pharmacol ; 32(3): 435-42, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9733357

ABSTRACT

The effects of the 5-HT1B/D receptor agonist, sumatriptan, on coronary flow (CF) and left ventricular function in the isolated perfused guinea pig heart were investigated in the presence and absence of coronary endothelial dysfunction induced by nitric oxide (NO) synthase inhibition with Nomega-nitro-L-arginine methyl ester (L-NAME; 10 microM). Hearts were perfused under constant pressure (80 cm H2O) with oxygenated (95% O2/5% CO2) Krebs bicarbonate buffer (pH 7.4) and were driven at 4 Hz. In the absence of L-NAME (n=37), sumatriptan (0.1-32 microM) failed statistically significantly to affect left ventricular developed pressure (LVDP; maximal change, -8.1+/-1.8%; NS vs. vehicle), left ventricular end-diastolic pressure (LVEDP; +10.4+/-9.8%, NS), or CF (-12.2+/-1.4%; NS compared with vehicle). L-NAME per se significantly reduced coronary flow (CF; -26.3+/-2.9%; p < 0.001), thereby increasing coronary vascular tone, and decreased LVDP (-17.1+/-1.8%; p < 0.01). In hearts perfused with L-NAME (10 microM; n=61), sumatriptan (0.1-32 microM) still failed significantly to affect CF (maximal change, 0.2+/-5.7%, NS) but concentration-dependently increased LVEDP [maximal increase, 89.0+/-30.3%; p < 0.05; geometric mean EC50 3.6 (2.9-5.7) microM], which was not prevented by the 5-HT1B/D receptor antagonist, GR 127935 (0.1 microM; maximal increase, 51.8+/-11.1%; n=48, NS compared with sumatriptan alone). In conclusion, sumatriptan failed significantly to affect CF even in the presence of endothelial dysfunction. LV function similarly remained unaffected in normal hearts, but sumatriptan produced diastolic contracture in the presence of coronary endothelial dysfunction by a mechanism apparently not involving 5-HT1B/D receptors. Collectively the data indicate that 5-HT1B/D receptor expression or effector coupling or both are absent or low in the guinea pig heart, because no detectable functional responses were observed.


Subject(s)
Coronary Circulation/drug effects , Oxazolidinones , Serotonin Receptor Agonists/pharmacology , Sumatriptan/pharmacology , Ventricular Function, Left/drug effects , Animals , Diastole/drug effects , Dihydroergotamine/pharmacology , Endothelium, Vascular/physiology , Guinea Pigs , In Vitro Techniques , NG-Nitroarginine Methyl Ester/pharmacology , Oxadiazoles/pharmacology , Oxazoles/pharmacology , Perfusion , Piperazines/pharmacology , Rabbits , Receptor, Serotonin, 5-HT1B , Receptor, Serotonin, 5-HT1D , Receptors, Serotonin/drug effects , Receptors, Serotonin/physiology , Tryptamines
14.
J Cardiovasc Pharmacol ; 31(5): 800-4, 1998 May.
Article in English | MEDLINE | ID: mdl-9593082

ABSTRACT

R 56865, a cytoprotective agent, has been shown to prevent myocardial ischemia and reperfusion injury by blockade of the late sodium current (I(Nal)). The effect of R 56865 on I(Nal) in isolated human atrial myocytes was investigated by using the whole-cell patch-clamp technique. I(Nal) recorded at the end of a 350-ms test pulse evoked from -100 to +20 mV was significantly increased by the addition of veratrine (100 microg/ml: quantity of charge corresponding to total I(Nal): 6.1 +/- 1.2 at baseline vs. 86.9 +/- 15; p < 0.001). Tetrodotoxin (TTX; 1 microM) fully prevented veratrine-induced increases in I(Nal). R 56865 (0.1-10 microM, n = 14) significantly and reversibly decreased veratrine-induced I(Nal) (42.01 +/- 8.6%, n = 6; p < 0.001 at 10 microM). Moreover, R 56865 reduced I(Nal) without significantly affecting kinetic parameters of inactivation [tau1 = 1.04 +/- 0.1 ms and tau2 = 119.3 +/- 2.3 ms (baseline) vs. tau1 = 1.57 +/- 0.5 ms and tau2 = 134.4 +/- 14 ms in the presence of 10 microM R 56865; NS]. The data indicate that R 56865 is a potent blocker of the late inducible component of sodium current in human cardiomyocytes.


Subject(s)
Calcium Channel Blockers/pharmacology , Piperidines/pharmacology , Sodium Channels/drug effects , Thiazoles/pharmacology , Benzothiazoles , Dose-Response Relationship, Drug , Heart Atria/drug effects , Humans , Patch-Clamp Techniques , Sodium Channel Blockers , Sodium Channels/physiology
15.
Fundam Clin Pharmacol ; 12(2): 152-7, 1998.
Article in English | MEDLINE | ID: mdl-9565768

ABSTRACT

Contractile responses evoked by the 5-HT IB/D receptor agonists, dihydroergotamine, naratriptan and sumatriptan, were compared in canine isolated coronary artery rings before and after endothelial dysfunction as obtained by inhibition of nitric oxide synthase with Nw-nitro-L-arginine methyl ester (L-NAME; 10 microM). The three agonists contracted rings in the potency order of dihydroergotamine (geometric mean pD2 value with 95% confidence limits in parentheses: 6.9 [5.3-7.9] and 7.0 [5.4-7.3] in the absence and presence of nitric oxide synthase (NOS) inhibition [I], respectively) > or = naratriptan (6.8 [5.7-7.3] and 6.4 [5.7-6.6]) > sumatriptan (4.8 [3.6-5.6] and 5.0 [3.6-5.6]) independently of the presence or absence of L-NAME. In absence of L-NAME, efficacy, as assessed by the mean maximal contractile response (Emax), tended to be greater, although not significantly, for sumatriptan and naratriptan compared to dihydroergotamine. L-NAME per se markedly increased developed tension (43.0 +/- 4.6 mN; n = 50) and potentiated maximal responses (0.6 +/- 0.2 and 10.7 +/- 2.4 mN for dihydroergotamine in the absence and presence of L-NAME respectively; 1.7 +/- 0.6 and 18.7 +/- 3.7 mN for naratriptan; 2.5 +/- 0.6 and 21.3 +/- 3.8 mN for sumatriptan; P < 0.01 in each case). Emax values of sumatriptan and naratriptan were greater than those produced by dihydroergotamine in the presence of L-NAME but remained lower than the sub-maximal contractile responses evoked by the thromboxane A2 analogue, U-46619 (ie, 32.4 +/- 5.2 mN in the absence of L-NAME; n = 50), or L-NAME per se. In conclusion, 5-HT IB/D receptor agonist efficacies in contracting coronary arteries are relatively low under basal conditions and are potentiated in the presence of a dysfunctional endothelium, whereas agonist potencies remain unaffected.


Subject(s)
Coronary Vessels/drug effects , Dihydroergotamine/pharmacology , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Muscle, Smooth, Vascular/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Piperidines/pharmacology , Serotonin Receptor Agonists/pharmacology , Sumatriptan/pharmacology , Vasoconstrictor Agents/pharmacology , Animals , Dogs , Endothelium, Vascular/drug effects , In Vitro Techniques , Male , Muscle Contraction/drug effects , Tryptamines
16.
Br J Pharmacol ; 123(2): 205-14, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9489607

ABSTRACT

1 The receptors involved in mediating the haemodynamic effects of three 5-HT1B/D receptor agonists were investigated in pentobarbitone anaesthetized rats (n = 6-17 per group). 2 Cumulative intravenous (i.v.) infusions of rizatriptan and sumatriptan (from 0.63 to 2500 microg kg(-1); each dose over 5 min) induced dose-dependent and marked hypotension (-42+/-6 and -34+/-4 mmHg at the highest dose, respectively; both P<0.05 vs vehicle: +5+/-3 mmHg) and bradycardia (-85+/-16 and -44+/-12 beats min(-1) at the highest dose, respectively; both P<0.05 vs vehicle: +16+/-6 beats min(-1)). Zolmitriptan evoked only moderate hypotension at the highest dose (-19+/-9 mmHg; P<0.05 vs vehicle). 3 A high dose of the 5-HT1B/D receptor antagonist, GR 127935 (0.63 mg kg(-1), i.v.), failed to antagonize the hypotension and bradycardia evoked by sumatriptan (-35+/-6 mmHg and -52+/-19 beats min(-1), respectively; both not significant vs sumatriptan in untreated rats), but moderately reduced the hypotension and bradycardia evoked by rizatriptan (-20+/-5 mmHg and -30+/-17 beats min(-1), respectively; both P<0.05 vs vehicle and vs rizatriptan in untreated rats). 4 The selective 5-HT1A receptor antagonist, WAY 100635 (0.16 and 0.63 mg kg(-1), i.v.), dose-dependently attenuated the haemodynamic responses evoked by rizatriptan and sumatriptan, which were almost abolished by the higher dose of WAY 100635 (-4+/-3 mmHg and -15+/-8 beats min(-1); both not significant vs vehicle and P<0.05 vs rizatriptan in untreated rats). A slight but statistically significant reduction in mean arterial pressure (MAP) persisted at the highest dose of sumatriptan (-13+/-4 mmHg following the higher dose of WAY 100635; P<0.05 vs vehicle). 5 In pithed rats with MAP normalized by angiotensin II, rizatriptan failed to induce hypotension or bradycardia (+5+/-4 mmHg and -6+/-16 beats min(-1), respectively; both NS vs vehicle and P<0.05 vs rizatriptan in untreated rats). Similarly, sumatriptan failed to induce bradycardia in pithed rats (+5+/-6 beats min(-1); not significant vs vehicle and P<0.05 vs sumatriptan in untreated rats), whereas a slight but statistically significant reduction in MAP, compared to controls, occurred at the highest dose (-9+/-9 mmHg; P<0.05 vs both vehicle and sumatriptan in untreated rats). 6 In bilaterally vagotomized and atropine-treated (1 mg kg(-1), i.v.) rats, the reductions in MAP and heart rate evoked by rizatriptan (-31+/-4 mmHg and -64+/-9 beats min(-1), respectively; both P<0.05 vs vehicle and not significant vs rizatriptan in controls) and sumatriptan (-47+/-8 mmHg and -56+/-10 beats min(-1), respectively; both P<0.05 vs vehicle and not significant vs sumatriptan in controls) were not statistically significantly different from those observed in controls. 7 In conclusion, the 5-HT1B/D receptor agonists, rizatriptan and sumatriptan, elicit hypotension and bradycardia in the normotensive anaesthetized rat predominantly via activation of central 5-HT1A receptors, and a consequent reduction in sympathetic outflow.


Subject(s)
Blood Pressure/drug effects , Heart Rate/drug effects , Oxazolidinones , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/pharmacology , Animals , Autonomic Nervous System/physiology , Drug Interactions , Hemodynamics/drug effects , Male , Oxazoles/pharmacology , Parasympathetic Nervous System/physiology , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1B , Receptors, Serotonin/physiology , Sumatriptan/pharmacology , Triazoles/pharmacology , Tryptamines
17.
Naunyn Schmiedebergs Arch Pharmacol ; 358(6): 608-15, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9879718

ABSTRACT

The putative coupling between stably expressed recombinant h 5-HT1B or h 5-HT1D receptors and K+ channels which regulate excitability was investigated in C6 glioma cells. Outward K+ currents (IK) were examined in nontransfected C6 glioma cells and in cells expressing cloned h 5-HT1B or h 5-HT1D receptors using the patch-clamp technique in the whole-cell configuration. IK was elicited by a depolarizing step from a holding potential of -60 mV. In C6 glioma cells expressing either recombinant h 5-HT1B or h 5-HT1D receptors, sumatriptan similarly increased IK in a concentration-dependent manner (maximum increase 19.4+/-7.2%, n=8, P<0.05 and 25.1+/-3.9%, n=6, P<0.001, respectively) with EC50 values (geometric mean with 95% confidence intervals in parentheses) of 56.3 nM (7.9-140 nM) and 68.7 nM (16-120 nM), respectively. Sumatriptan failed to elicit increases in IK in non-transfected cells, confirming a specific involvement of the respective membrane h 5-HT1B and h 5-HT1D receptors in transfected C6 cells. In the presence of the mixed 5-HT1B/D receptor antagonist GR 127935 (0.1 microM), sumatriptan (1 microM) failed to significantly increase IK in C6 cells expressing h 5-HT1B receptors (-7.5+/-3.5%, P=NS, n=6), although a higher concentration of GR 127935 (1 microM) was required to significantly inhibit sumatriptan-evoked increases in IK in C6 cells expressing h 5-HT1D receptors (-1.8+/-3.5%, P=NS, n=6), confirming that sumatriptan-evoked responses were indeed mediated by h 5-HT1B and h 5-HT1D receptors, respectively. In C6 cells expressing either cloned h 5-HT1B or h 5-HT1D receptors, sumatriptan-induced increases in IK were prevented by the calcium chelator EGTA (5 mM) when included in the patch pipette (maximum increase 0.57+/-0.6%, n=3, P=NS and -2.8+/-1.6%, n=5, P=NS, respectively). In C6 cells expressing cloned h 5-HT1B receptors, sumatriptan (1 microM) similarly failed to significantly increase IK in the presence of dibutyryl cAMP (10 microM) or when a nominally Ca2+-free medium was included in the patch pipette (-19.4+/-5.1%, n=5 and -5.2+/-4.3%, n=5, respectively, P=NS in each case). In addition, the Ca2+-dependent K+ channel blockers iberiotoxin (0.1 microM) and tetraethylammonium (TEA, 1 mM) abolished sumatriptan-induced increases in IK (-0.5+/-1.0%, n=4 and -3.9+/-3.1%, n=4, respectively, P=NS in each case) in C6 cells expressing h 5-HT1B receptors, confirming the involvement of Ca2+-dependent K+ channels. In C6 cells expressing cloned h 5-HT1B receptors, sumatriptan (1 microM) similarly failed to significantly increase IK after 30-min incubation with thapsigargin (1 microM) or when heparin (2 mg/ml) was included in the patch pipette (1.1+/-0.4%, n=5 and 1.2+/-2.4%, n=5, respectively, P=NS). In conclusion, evidence is provided that both recombinant h 5-HT1B and h 5-HT1D receptors stably transfected in C6 glioma cells are positively coupled to Ca2+-dependent K+ channels, and the outward hyperpolarizing current mediated by these channels is dependent upon IP3 receptor-mediated intracellular Ca2+ release.


Subject(s)
Calcium/pharmacology , Glioma/genetics , Potassium Channels/physiology , Potassium/pharmacokinetics , Receptors, Serotonin/metabolism , Animals , Cyclic AMP/pharmacology , Dose-Response Relationship, Drug , Oxadiazoles/pharmacology , Piperazines/pharmacology , Rats , Recombinant Proteins , Serotonin Antagonists/pharmacology , Sumatriptan/pharmacology , Tumor Cells, Cultured
18.
Bioorg Med Chem Lett ; 8(6): 675-80, 1998 Mar 17.
Article in English | MEDLINE | ID: mdl-9871581

ABSTRACT

A new bivalent ligand of formula 3 which results from the covalent coupling of two sumatriptan molecules with a p-xylyl spacer at the level of the sulfonamide nitrogen has been prepared and evaluated as a 5-HT1B/1D receptors agonist. In vitro experiments at 5-HT1B human cloned receptors (Ki = 0.64 nM; EC50 = 0.58 nM) and at the level of the contraction of the New Zealand white rabbit saphenous vein (pD2 = 6.6) demonstrate the superior potency of dimer 3 as a 5-HT1B receptor agonist when compared to sumatriptan or zolmitriptan. Interestingly enough, the new bivalent agonist 3 was found to induce hypothermia in the guineapig upon oral administration suggesting good oral activity and access to the brain.


Subject(s)
Drug Design , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemical synthesis , Sumatriptan/chemical synthesis , Animals , Cell Line , Dimerization , Guinea Pigs , Humans , Models, Chemical , Rabbits , Receptor, Serotonin, 5-HT1B
19.
Am J Hypertens ; 10(9 Pt 1): 1058-63, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9324114

ABSTRACT

We explored the putative inhibitory effects of losartan, a potent nonpeptide, AT1 receptor antagonist, against thromboxane A2 (TxA2)/prostanoid (TP) receptor-mediated transcapillary shift of plasma fluid and proteins. The effects of the TP receptor agonist U-46619 (1.25 or 10 microg/kg intravenously) on hematocrit (Hct), albumin extravasation (AE), and mean arterial pressure (MAP) were evaluated in anesthetized Sprague-Dawley rats. U-46619 dose-dependently increased Hct (by 4.5% +/- 0.7% and 7.5% +/- 1.0% at the low and high dose, respectively; both P < .05 v vehicle-infused group) and decreased MAP (by 7.9% +/- 4.1% and 16.8% +/- 5.7% at the low and high dose, respectively; P = NS and P < .05 v vehicle-infused group, respectively). In these experiments, using a quantitative Evans blue technique, we showed that U-46619 dose-dependently increased AE in kidney, lung, spleen, and testis (by approximately 31%, 172%, 52%, and 57% at the highest dose) but not in adipose tissue, brain, liver, mesentery, and skeletal muscle. In the heart, AE was maximally increased by the low dose of U-46619. The U-46619 (10 microg/kg)-induced increases in Hct and AE and decreases in MAP were blocked by pretreatment with the TP receptor antagonist SQ 29,548 (2.5 mg/kg intravenously + 2.5 mg/kg/h) and the high dose of losartan (40 mg/kg intravenously). The low dose of losartan (10 mg/kg intravenously) did not significantly alter the responses to U-46619 except for the AE, which was reduced in some but not all tissues. Furthermore, the U-46619-induced changes in Hct (+6.3% +/- 1.7%), MAP (-13.9% +/- 8.4%) and AE were not affected in rats pretreated with the converting-enzyme inhibitor enalapril. Thus, selective activation of TP receptors by U-46619 induced plasma fluid and protein exudation; these responses were specifically attenuated by the relatively high dose of losartan, suggesting that this compound acts as a TP receptor antagonist in this experimental model.


Subject(s)
Capillary Permeability/drug effects , Capillary Permeability/physiology , Losartan/pharmacology , Prostaglandins/metabolism , Receptors, Cell Surface/physiology , Receptors, Thromboxane/physiology , 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Blood Pressure/drug effects , Bridged Bicyclo Compounds, Heterocyclic , Enalapril/pharmacology , Fatty Acids, Unsaturated , Hematocrit , Hydrazines/pharmacology , Male , Microcirculation/drug effects , Plasma Volume/drug effects , Rats , Rats, Sprague-Dawley , Serum Albumin/metabolism , Vasoconstrictor Agents/pharmacology
20.
J Pharmacol Exp Ther ; 280(2): 761-9, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9023289

ABSTRACT

Experiments performed in 226 pentobarbitone-anesthetized rabbits were designed to investigate the involvement of thromboxane/prostanoid and 5-hydroxytryptamine (5-HT)2A/C receptors during arterial thrombus formation in distinct low- and high-shear rate thrombosis models. Antithrombotic activities of the thromboxane/prostanoid receptor antagonist SQ 29,548 and two chemically distinct 5-HT2A/C receptor antagonists, ritanserin and ketanserin, were assessed first in low-shear rate (approximately 600 sec(-1)) arterial thrombosis, produced by insertion of a silk thread as thrombogenic substrate into the central section of an extracorporeal arteriovenous shunt established between the left carotid artery and the right jugular vein (n = 77), and second in high-shear rate (approximately 40,000 sec(-1)) arterial thrombosis, produced by critical stenosis and local endothelial injury of a carotid artery, characterized by cyclic flow reductions (CFRs) due to recurrent platelet aggregation and subsequent dislodgement of the thrombus (n = 149). Under low shear rate, SQ 29,548 (10-2500 microg/kg plus 10-2500 microg/kg/hr i.v.), but not ritanserin or ketanserin (both at 2500 microg/kg i.v.), dose-dependently inhibited thrombus formation. In contrast, under high shear rate, SQ 29,548 (10-160 microg/kg plus 10-160 microg/kg/hr i.v.) and both ritanserin and ketanserin (both at 10-2500 microg/kg i.v.) dose-dependently reduced CFR frequency, with ID50 values of 35 microg/kg (95% confidence limits, 24-58 microg/kg), 77 microg/kg (95% confidence limits, 40-132 microg/kg) and 89 microg/kg (95% confidence limits, 36-285 microg/kg) i.v., respectively. Furthermore, local infusion of the stable thromboxane A2 analog U-46619 (0.63 microg/kg/min) or 5-HT (20.8 microg/kg/min) proximal to the site of injury and stenosis in rabbits pretreated with either SQ 29,548 (40 microg/kg plus 40 microg/kg/hr i.v.) or ritanserin (160 microg/kg i.v.), respectively, restored CFR frequency to vehicle group levels in animals whose CFR frequency was previously reduced. The inhibitory activity of ketanserin and ritanserin on CFRs could not be attributed to 5-HT1B/D or alpha-1 adrenoceptor antagonist properties or to any hypotensive activity. These results provide firm evidence that thromboxane/prostanoid receptors are involved in arterial thrombosis in rabbits independently of the shear rate, whereas 5-HT2A/C receptors play a major role only in high-shear rate thrombus formation.


Subject(s)
Carotid Stenosis/physiopathology , Hemodynamics/drug effects , Hydrazines/pharmacology , Receptors, Prostaglandin/physiology , Receptors, Serotonin/physiology , Receptors, Thromboxane/physiology , Animals , Arteriovenous Shunt, Surgical , Aspirin/pharmacology , Blood Pressure/drug effects , Bridged Bicyclo Compounds, Heterocyclic , Carotid Arteries/pathology , Carotid Arteries/physiopathology , Carotid Arteries/surgery , Carotid Stenosis/pathology , Endothelium, Vascular/drug effects , Endothelium, Vascular/pathology , Endothelium, Vascular/physiopathology , Fatty Acids, Unsaturated , Heart Rate/drug effects , Jugular Veins/surgery , Ketanserin/pharmacology , Male , Oxadiazoles/pharmacology , Piperazines/pharmacology , Platelet Aggregation , Prazosin/pharmacology , Rabbits , Receptor, Serotonin, 5-HT2A , Receptor, Serotonin, 5-HT2C , Ritanserin/pharmacology , Serotonin Antagonists/pharmacology , Stress, Mechanical
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