Health-related quality of life in diabetic patients and controls without diabetes in : a cross-sectional study

Ashraf Eljedi¹, Rafael T Mikolajczyk², Alexander Kraemer² and Ulrich Laaser³

Address:

¹Faculty of Nursing, The Islamic University of Gaza, Gaza strip, Palestinian Territories, ²Department of Public Health Medicine, School of Public Health, University of Bielefeld, Bielefeld, Germany and

³Department of Epidemiology and International Public Health, School of Public Health, University of Bielefeld, Bielefeld, Germany

Abstract

Background: Prevalence of diabetes mellitus is increasing in developed and developing countries. Diabetes is known to strongly affect the health-related quality of life (HRQOL). HRQOL is also influenced by living conditions. We analysed the effects of having diabetes on HRQOL under the living conditions in refugee camps in the Gaza strip.

Methods: We studied a sample of 197 diabetic patients who were recruited from three refugee camps in the Gaza strip and 197 age- and sex-matched controls living in the same camps. To assess HRQOL, we used the World Health Organization Quality of Life questionnaire (WHOQOL-BREF) including four domains (physical health, psychological, social relations and environment). Domain scores were compared for cases (diabetic patients) and controls (persons without diabetes) and the impact of socio-economic factors was evaluated in both groups.

Results: All domains were strongly reduced in diabetic patients as compared to controls, with stronger effects in physical health (36.7 vs. 75.9 points of the 0–100 score) and psychological domains (34.8 vs. 70.0) and weaker effects in social relationships (52.4 vs. 71.4) and environment domains (23.4 vs. 36.2). The impact of diabetes on HRQOL was especially severe among females and older subjects (above 50 years). Low socioeconomic status had a strong negative impact on HRQOL in the younger age group (<50 years).

Conclusion: HRQOL is strongly reduced in diabetic patients living in refugee camps in the Gaza strip. Women and older patients are especially affected.

Keywords :Health-related quality of life, diabetic patients, refugee camps in the Gaza strip, a cross-sectional study, HRQOL, WHOQOL-BREF, physical health, psychological, social relations and environment 

Sumber : Biomed Central

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Hepatoprotective Activity of Leucas lavandulaefolia Against Carbon tetrachloride-Induced Hepatic Damage In Rats

K.S. Chandrashekar¹*, K.S. Prasanna²

¹Department of Pharmacognosy, Nitte gulabhi Shetty Memorial Institute of Pharmaceutical Sciences, Deralakatte, Mangalore-574160, India

²Department of Community Medicine, FatherMuller Medical College, Mangalore-575002, India

Abstract

The aerial parts of Leucas lavandulaefolia Rees, family Labiatae was tested for hepatoprotective activity against CCl4 in rats. The ethyl acetate extract of Leucas lavandulaefolia has shown significant activity, lowering the serum enzymes like SGOT and SGPT in rats intoxicated with CCl4.

Keywords: Leucas lavandulaefolia, hepatoprotective, carbon tetrachloride

Sumber : (IJPSR) Vol.1 (2), 2010, 101-103

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Pioglitazone and Risk of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus A Meta-analysis of Randomized Trials

A. Michael Lincoff, Kathy Wolski, Stephen J. Nicholls and Steven E. Nissen

ABSTRACT

THIAZOLIDINEDIONES ARE AGOnists of the peroxisome proliferation–activated receptor _(PPAR-_), which regulate transcription of a variety of genes encoding proteins involved in glucose homeostasis and lipid metabolism.1,2 By virtue of their efficacy in achieving glycemic control, the thiazolidinediones pioglitazone and rosiglitazone are both widely used to treat patients with type 2 diabetes mellitus. Although these agents can cause peripheral edema and congestive heart failure,3,4 their beneficial effects on glucose metabolism and insulin sensitivity have stimulated interest that thiazolidinediones might reduce ischemic cardiovascular complications of diabetes mellitus.

However, a recent meta-analysis of 42 trials comparing rosiglitazone with placebo or active comparators in more than 27 000 patients with diabetes suggested that treatment with rosiglitazone was associated with an increased risk of myocardial infarction and cardiovascular death.5 Furthermore, a previous analysis had demonstrated that muraglitazar, an investigational dual agonist of both _- and _-isoforms of

Context Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence is mixed regarding the influence of medications of this class on cardiovascular outcomes.

Objective To systematically evaluate the effect of pioglitazone on ischemic cardiovascular events.

Data Sources and Study Selection A database containing individual patientlevel time-to-event data collected during pioglitazone clinical trials was transferred from the drug’s manufacturer for independent analysis. Trials were included if they were randomized, double-blinded, and controlled with placebo or active comparator.

Data Extraction The primary outcome was a composite of death, myocardial infarction, or stroke. Secondary outcome measures included the incidence of serious heart failure. A fixed-effects approach was used to combine the estimates across the duration strata and statistical heterogeneity across all the trials was tested with the I2 statistic.

Data Synthesis A total of 19 trials enrolling 16 390 patients were analyzed. Study drug treatment duration ranged from 4 months to 3.5 years. Death, myocardial infarction, or stroke occurred in 375 of 8554 patients (4.4%) receiving pioglitazone and 450 of 7836 patients (5.7%) receiving control therapy (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.72-0.94; P=.005). Progressive separation of time-to-event curves became apparent after approximately 1 year of therapy. Individual components of the primary end point were all reduced by a similar magnitude with pioglitazone treatment, with HRs ranging from 0.80 to 0.92. Serious heart failure was reported in 200 (2.3%) of the pioglitazone-treated patients and 139 (1.8%) of the control patients (HR, 1.41; 95% CI, 1.14-1.76; P=.002). The magnitude and direction of the favorable effect of pioglitazone on ischemic events and unfavorable effect on heart failure was homogeneous across trials of different durations, for different comparators, and for patients with or without established vascular disease. There was no evidence of heterogeneity across the trials for either end point (I2=0%; P=.87 for the composite end point and I2=0%; P=.97 for heart failure).

Conclusions Pioglitazone is associated with a significantly lower risk of death, myocardial infarction, or stroke among a diverse population of patients with diabetes. Serious heart failure is increased by pioglitazone, although without an associated increase in mortality.

Keywords : Pioglitazone, ower risk of death, myocardial infarction, stroke, patients with diabetes,  Risk of Cardiovascular Events, ischemic cardiovascular events, pioglitazone clinical trials, serious heart failure

Sumber : JAMA, September 12, 2007—Vol 298, No. 10

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Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy

David M. Nathan, MD,1 John B. Buse, MD, PhD,2 Mayer B. Davidson, MD,3 Ele Ferrannini, MD,4 Rury R. Holman, FRCP,5 Robert Sherwin, MD,6 and Bernard Zinman, MD7

ABSTRACT

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

Keywords : medical management, type 2 diabetes, 2006, principles used, development, the algoritm, january 2008, thiazolidinediones, new classes medication

Sumber : Clinical Diabetes, Volume 27, Number 1, 2009

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Primary Prevention of Cardiovascular Diseases in People With Diabetes Mellitus

Buse and Associates

ABSTRACT

The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: the ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.

Sumber : Diabetes Care 30:162–172, 2007

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Diabetes Atlas, Global estimates of the prevalence of diabetes for 2010 and 2030

J.E. Shaw *, R.A. Sicree, P.Z. Zimmet

ABSTRACT

Aim: We estimated the number of people worldwide with diabetes for the years 2010 and 2030.

Methods: Studies from 91 countries were used to calculate age- and sex-specific diabetes prevalences, which were applied to national population estimates, to determine national diabetes prevalences for all 216 countries for 2010 and 2030. Studies were identified using Medline, and contact with all national and regional International Diabetes Federation offices. Studies were included if diabetes prevalence was assessed using a population-based methodology, and was based on World Health Organization or American Diabetes Association diagnostic criteria for at least three separate age-groups within the 20–79 year range. Self-report or registry data were used if blood glucose assessment was not available.

Results: The world prevalence of diabetes among adults (aged 20–79 years) will be 6.4%, affecting 285 million adults, in 2010, and will increase to 7.7%, and 439 million adults by 2030. Between 2010 and 2030, there will be a 69% increase in numbers of adults with diabetes in developing countries and a 20% increase in developed countries.

Conclusion: These predictions, based on a larger number of studies than previous estimates, indicate a growing burden of diabetes, particularly in developing countries.

Keywords : Diabetes Prevalence, Ageing, Urbanization

Sumber : diabetes research and clinical practice, 87(2010) : 4 – 14

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Impact of Recent Increase in Incidence on Future Diabetes Burden, U.S., 2005–2050

VENKAT NARAYAN, JAMES P. BOYLE, LINDA S. GEISS, JINAN B. SAADDINE, THEODORE J. THOMPSON

ABSTRACT

In an earlier study, we had forecasted 39 million with diagnosed diabetes in 2050 in the U.S. (1,2). However, since then, national diabetes incidence increased (3) and the relative risk of death among people with diabetes declined (4,5). These changes will impact future forecasts. Incorporating these changes, we now project 48.3 million people with diagnosed diabetes in the U.S. in 2050. We also present age-, sex-, and race/ethnicityspecific forecasts, with Bayesian CIs, of the number of people with diagnosed diabetes through 2050.

Keywords : diabetes burden,diabetes burden in the world,diabetes burden of disease, inpact of recent increase, future diabetes in US, 2050

Sumber : DIABETES CARE, VOLUME 29, NUMBER 9, SEPTEMBER 2006

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K+-depolarization induces RhoA kinase translocation to caveolae and Ca2+-sensitization of arterial muscle

Nicole H. Urban, Krystina M. Berg, and Paul H. Ratz

Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23501

Abstract

KCl causes smooth muscle contraction by elevating intracellular free Ca²⁺, whereas receptor stimulation activates an additional mechanism, termed Ca²⁺-sensitization, that can involve activation of RhoA-associated kinase (ROK) and PKC. However, recent studies support the hypothesis that KCl may also increase Ca²⁺-sensitivity. Our data showed that the PKC inhibitor GF-109203X did not, whereas the ROK inhibitor Y-27632 did, inhibit KCl-induced tonic (5 min) force and myosin light chain (MLC) phosphorylation in rabbit artery. Y-27632 also inhibited BAY K 8644- and ionomycin-induced MLC phosphorylation and force but did not inhibit KClinduced Ca²⁺-entry or peak (_15 s) force. Moreover, KCl and BAY K 8644 nearly doubled the amount of ROK colocalized to caveolae at 30 s, a time that preceded inhibition of force by Y-27632. Colocalization was not inhibited by Y-27632 but was abolished by nifedipine and the calmodulin blocker trifluoperazine. These data support the hypothesis that KCl caused Ca²⁺-sensitization via ROK activation. We discuss a novel model for ROK activation involving translocation to caveolae that is dependent on Ca²⁺ entry and involves Ca²⁺-calmodulin activation.

Keywords: vascular smooth muscle; signal transduction; caveolin; Y-27632; confocal microscopy

Sumber : Am J Physiol Cell Physiol 285: C1377–C1385, 2003

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In vitro vascular effects of cicletanine in pregnancy-induced hypertension

A.B. Ebeigbe & *M. Cabanie

Department of Physiology, College of Medical Sciences, University of Benin, Benin City, Nigeria and *IHB Research Laboratories, 17 Avenue Descartes, F-92350 Le Plessis Robinson, France

Abstract

1.      The vascular effects of cicletanine have been studied in vitro on ring preparations of inferior epigastric arteries from normotensive human females and human females with pregnancy-induced hypertension (preeclampsia).

2.      Cicletanine (10^-3 M) elicited concentration-dependent relaxation of vessels precontracted with 10^-7 M noradrenaline (NA) or 60mm K⁺ but was more potent in the former. Relaxation was significantly greater in rings from preeclamptic patients and was uninfluenced by endothelium removal.

3.      The intracellular Ca-dependent contractile responses to 10^-5 M NA in Ca-free medium as well as the subsequent extracellular Ca-dependent contractions (on restoration of external Ca) were significantly attenuated dose-dependently by cicletanine (10^-5 M, 3 x 10^-4 M) in arterial rings from both normotensive and preeclamptic patients. Cicletanine also relaxed rings precontracted by 25 mm K⁺ but was ineffective against 80mm K⁺-induced contractions.

4.      The inhibition of intracellular Ca-dependent contractions was significantly greater in rings from preeclamptic than from normotensive patients whereas extracellular Ca-dependent contractions were comparably inhibited in both groups. Nifedipine, on the other hand, had little effect on the intracellular Ca-dependent contractions but significantly depressed extracellular Ca-dependent contractions.

5.      Cicletanine-induced relaxation was uninfluenced by pretreatment with propranolol, ouabain, tetraethylammonium, procaine, indomethacin, cimetidine or tetrodotoxin but was antagonized by glibenclamide.

6.      The results show that cicletanine inhibits contractile responses of human isolated inferior epigastric arteries by a mechanism unrelated to endothelial factors but associated with inhibition of calcium metabolism. An action of cicletanine on glibenclamide-sensitive K⁺ channels is also suggested. Cicletanineinduced inhibition was significantly greater in arteries from preclamptic patients.

Keywords: Cicletanine; pregnancy-induced hypertension; calcium; human epigastric arteries; vascular smooth muscle; endothelium

Sumber : Br. J. Pharmacol. (1991), 103, 1992-1996

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Chiral separation of thiazide diuretics by HPLC on Chiralcel OD-RHR, Chiralcel OJ-RR and Chirobiotic-TkR phases

Bala´zs Visegra´dy^a, Tu¨nde Konecsni ^a, Nina Grobuschek^b, Martin G. Schmid ^b, Ferenc Kila´r^a, Hassan Y. Aboul-Enein^c, Gerald Gu¨bitz^b,*

^aCentral Research Laboratory, Faculty of Medicine, University of Pe´cs, Szigeti u´ t 12, H-7643 Pe´cs, Hungary

^bInstitute of Pharmaceutical Chemistry and Pharmaceutical Technology, Karl-Franzens University Graz, Universita¨tsplatz 1, A-8010 Graz, Austria

^cBioanalytical and Drug Development Laboratory, Biological and Medical Research Department (MBC-03), King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia

Abstract

This contribution deals with comparative studies on the chiral separation of thiazide diuretics using cellulose tris(3,5-dimethylphenylcarbamate) (Chiralcel OD-RHR), cellulose tris(4-methylbenzoate) (Chiralcel OJ-RR) and teicoplanin (Chirobiotic TkR) phases. All columns showed good chiral recognition ability for this class of compounds. Out of seven compounds investigated, six were resolved with baseline resolution with at least one of the three columns.

Keywords: Enantiomer separation; Teicoplanin chiral stationary phase; Cellulose-based stationary phase;Diuretics

Sumber : J. Biochem. Biophys. Methods 53 (2002) 15–24

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Sedation and histamine H1-receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

A.N. Nicholson, Peta A. Pascoe, Claire Turner, C.R. Ganellin, P.M. Greengrass, A.F. Casy & Amanda D. Mercer

Royal Air Force Institute of Aviation Medicine, Farnborough, Hampshire GU14 6SZ;

Department of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ; **Pfizer Central Research, Sandwich, Kent CT13 9NJ and tSchool of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY

Abstract

1.      The effects of 10mg (+)- and (-)-chlorpheniramine and 5mg (+)- and (-)-dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well-being were studied in 6 healthy young adult humans. Each subject also took 5mg triprolidine hydrochloride as an active control and two placebos.

2.      Daytime sleep latencies were reduced with triprolidine, (+)-chlorpheniramine and (-)-dimethindene, and subjects also reported that they felt more sleepy after (+)-chlorpheniramine and (-)-dimethindene. Performance on digit symbol substitution was impaired with (+ )-chlorpheniramine.

3.      Changes in measures with (-)-chlorpheniramine and (+)-dimethindene were not different from changes with placebo.

4.      In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the histamine Hl-receptor. These findings strongly suggest that sedation can arise from H1-receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man.

Keywords: Antihistamines; H -receptor antagonists; chlorpheniramine; dimethindene; stereoselective effects; sedation in man

Sumber : Br. J. Pharmacol. (1991), 104, 270-276

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Paraoxon Attenuates Vascular SmoothMuscle Contraction through Inhibiting Ca2+ Influx in the Rabbit Thoracic Aorta

Shouhong Zhou^1,2, Liying Liu¹, Xuhong Yang¹, ShujinWu1, and Gengrong Chen¹

1Department of Pharmacology, Xiang-Ya Medical College, Central South University, Changsha, Hunan 410078, China

2Department of Physiology, School of Medicine, University of South China, Hengyang, Hunan 421001, China

Abstract

We investigated the effect of paraoxon on vascular contractility using organ baths in thoracic aortic rings of rabbits and examined the effect of paraoxon on calcium homeostasis using a whole-cell patch-clamp technique in isolated aortic smooth muscle cells of rabbits. The findings show that administration of paraoxon (30 μM) attenuated thoracic aorta contraction induced by phenylephrine (1 μM) and/or a high K⁺ environment (80mM) in both the presence and absence of thoracic aortic endothelium. This inhibitory effect of paraoxon on vasoconstrictor-induced contraction was abolished in the absence of extracellular Ca²⁺, or in the presence of the Ca²⁺ channel inhibitor, verapamil. But atropine had little effect on the inhibitory effect of paraoxon on phenylephrine-induced contraction. Paraoxon also attenuated vascular smooth muscle contraction induced by the cumulative addition of CaCl2 and attenuated an increase of intracellular Ca²⁺ concentration induced by K⁺ in vascular smooth muscle cells. Moreover, paraoxon (30 μM) inhibited significantly L-type calcium current in isolated aortic smooth muscle cells of rabbits. In conclusion, our results demonstrate that paraoxon attenuates vasoconstrictor-induced contraction through inhibiting Ca2+ influx in the rabbits thoracic aorta.

Key Word : Paraoxon, Vascular SmoothMuscle Contraction, Ca²⁺ Influx, Rabbit Thoracic Aorta, organ baths in thoracic aortic rings, phenylephrine, high K⁺ environment, thoracic aortic endothelium

Sumber : Journal of Biomedicine and Biotechnology, Vol. 2010

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Membrane depolarization-induced contraction of rat caudal arterial smooth muscle involves Rho-associated kinase

Mitsuo MITA*1, Hayato YANAGIHARA*, Shigeru HISHINUMA*, Masaki SAITO* and Michael P. WALSH.

*Department of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan, and .Canadian Institutes of Health Research Group in Regulation of Vascular Contractility and Smooth Muscle Research Group, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada

Abstract

Depolarization of the sarcolemma of smooth muscle cells activates voltage-gated Ca²⁺ channels, in¯ux of Ca²⁺ and activation of cross-bridge cycling by phosphorylation of myosin catalysed by Ca²⁺}calmodulin-dependent myosin light-chain kinase (MLCK). Agonist stimulation of smooth muscle contraction often involves other kinases in addition to MLCK. In the present study, we address the hypothesis that membrane depolarization-induced contraction of rat caudal arterial smooth muscle may involve activation of Rho-associated kinase (ROK). Addition of 60 mM K⁺ to de-endothelialized muscle strips in the presence of prazosin and propranolol induced a contraction that peaked rapidly and then declined to a steady level of force corresponding to approx. 30% of the peak contraction. This contractile response was abolished by the Ca²⁺-channel blocker nicardipine or the removal of extracellular Ca²⁺. An MLCK inhibitor (ML-9) inhibited both the phasic and tonic components of K⁺-induced contraction. On the other hand, the ROK inhibitors Y-27632 and HA-1077 abolished the tonic component of  K⁺-induced contraction,

Key words: HA-1077, ML-9, myosin phosphorylation, myosin light-chain kinase, Y-27632.

Sumber : Biochem. J. (2002) 364, 431±440

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Enantioseparation of Some Clinically Used Drugs by Capillary Electrophoresis Using Sulfated b-Cyclodextrin as a Chiral Selector

G. S. Yang¹, D. M. Chen², Y. Yang³, B. Tang², J. J. Gao², H. Y. Aboul-Enein⁴,&, B. Koppenhoefer⁵

1 Department of Chemistry, Shandong University, Jinan 250100, P. R. China

2 Shandong Key Laboratory of Chemical Function Materials, Shandong Normal University, Jinan 250014, P.R. China

3 Cell Biology Laboratory, School of Basic Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, P. R. China

4 Centre for Clinical Research (MBC 03-65), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354 Riyadh 11211, Saudi Arabia;

E-Mail: enein@kfshrc.edu.sa

5 Institute of Organic Chemistry, University of Tu¨bingen, Auf der Morgenstelle 18, D- 72076, Tu¨bingen, Germany

Abstract

The enantiomeric separation of 37 clinically used racemic basic drugs among 50 drugs was achieved using sulfated b-cyclodextrin (S-b-CD) as chiral selector at pH2.5 and in the reversed polarity mode. The results obtained in this study were different from the one obtained using neutral b-CD and its derivatives as chiral selectors. Using S-b-CD as chiral selector did not require the presence of the substructure 4H to achieve chiral separation as observed with b-Cyclodextrin (b-CD) and its derivatives since among the 37 separated drugs only 7 possess the 4H substructure. The chiral discrimination depends on the appropriate interaction between the analyte and the sulfated b-cyclodextrin.

Keywords : Capillary electrophoresis, Chiral separation, Sulfated b-cyclodextrin sodium salt, Racemic basic drugs, Reversed polarity model

Sumber : Chromatographia 2005, 62, October (No. 7/8)

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Calcium-independent phospholipase A2 participates in KCl-induced calcium sensitization of vascular smooth muscle

Paul H. Ratz^1,2 ,*, Amy S. Miner^1,2, and Suzanne E. Barbour¹

¹Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, USA

²Department of Pediatrics, Virginia Commonwealth University School of Medicine, USA

Abstract

In vascular smooth muscle, KCl elevates intracellular free Ca2+ ([Ca2+]i), myosin light chain kinase activity and tension (T), but also can inhibit myosin light chain phosphatase activity by activation of rhoA kinase (ROCK), resulting in Ca2+ sensitization (increased T/[Ca2+]i ratio). Precisely how KCl causes ROCK-dependent Ca2+ sensitization remains to be determined. Using fura-2-loaded isometric rings of rabbit artery, we found that the Ca2+-independent phospholipase A2 (iPLA2) inhibitor, bromoenol lactone (BEL), reduced the KCl-induced tonic but not early phasic phase of T and potentiated [Ca2+]i, reducing Ca2+ sensitization. The PKC inhibitor, GF-109203X (≥ 3μM) and the pseudosubstrate inhibitor of PKCζ produced a response similar to BEL. BEL reduced basal and KClstimulated myosin phosphatase phosphorylation. Whereas BEL and H-1152 produced strong inhibition of KCl-induced tonic T (~50%), H-1152 did not induce additional inhibition of tissues already inhibited by BEL, suggesting that iPLA2 links KCl stimulation with ROCK activation. The cPLA2 inhibitor, pyrrolidine-1, inhibited KCl-induced tonic increases in [Ca2+]i but not T, whereas the inhibitor of 20-HETE production, HET0016, acted like the ROCK inhibitor H-1152 by causing Ca2+ desensitization. These data support a model in which iPLA2 activity regulates Ca2+ sensitivity.

Keywords : vascular smooth muscle; rabbit artery; contraction; K+-depolarization; Ca2+ signaling; fura-2; signal transduction; Ca2+ sensitization; Rho-kinase; PLA2; BEL; ETYA; NDGA; HET0016; H-1152; HA-1077; Y-27632; 20-HETE; pyrrolidine-1; GF-109203X; PKC pseudosubstrate inhibitor.

Sumber : Cell Calcium. 2009 July ; 46(1): 65–72. doi:10.1016/j.ceca.2009.05.001.

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Characterization of histamine receptor sub-types regulating prostacyclin release from human endothelial cells

Characterization of histamine receptor sub-types regulating prostacyclin release from human endothelial cells

Helen A. Bull, P.F. Courtney, M.H.A. Rustin & 'Pauline M. Dowd

 Abstract

1.      The histamine receptor sub-types that are involved in the initiation and maintenance of prostacyclin (PGI2) release from human endothelial cells have been investigated.

2.      Endothelial cells cultured from umbilical vein (HUVEC) were incubated with either histamine, the selective HI-receptor agonists, 2-methyl histamine (2-MeHA) or thiazolylethylamine (ThEA), the H1- agonist/H3-antagonist, P-histine (,3-His), the selective H2-agonist, dimaprit, the H2-agonist/H3-antagonist, impromidine, the selective H3-agonist, (R)o-methylhistamine ((R)a-MeHA) and the H3-antagonist, thioperamide.

3.      The H1-agonists and the H3-agonist (R)a-MeHA induced a concentration (100 nM- mM) and time-dependent release of PGI2 as determined by radioimmunoassay for 6-keto-PGFj,, but were  less potent than histamine itself. The rank order of potency was the same following 30min and 24h incubation, i.e. histamine> ThEA> 2-MeHA> >1P-His> (R)a-MeHA.

4.      Histamine and 2-MeHA (1 gM-I mM), ThHEA (10O M-1 mM) and (R)x-MeHA (1 mM), but not 1-His, induced a significantly greater increase in PGI2 release after 24 h incubation than after 30 min incubation (P <0.05).

5.      Neither the selective H2-agonist, dimaprit, nor the H2-agonist/H3-antagonist, impromidine alone induced release of PGI2.

6.      The HI-antagonist, mepyramine (1O M), abolished release of PGI2 induced by histamine, the H1-agonists and (R)a-MeHA but the H2-antagonist cimetidine (10 jiM) and the H2/H3-antagonist, burimamide (10tiM) did not significantly modulate PGI2 release.

7.      Although the H3-agonist (R)ox-MeHA induced release of PGI2, it failed to modulate PGI2 release in the presence of histamine.

8.      Low concentrations of the H3-antagonist, thioperamide (100 nM) did not modulate histamine release of PGI2 at all but after 24 h incubation, thioperamide (10-4 M) partially reduced PGI2 release in the presence of histamine.

9.      These results indicate that PGI2 from HUVEC is initiated and maintained via histamine HI-receptor occupancy. There appears to be no involvement of either H2- or H3-receptors in this particular endothelial cell histaminergic response.

Keywords: Histamine receptors; endothelial cells; prostacyclin

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Sumber : Br. J. Pharmacol. (1992), 107, 276-281