Drugs online research references
Circulation. 2003 Jan 7;107(1):127-31.
Doxazosin induces apoptosis in cardiomyocytes cultured in vitro by a mechanism that is independent of alpha1-adrenergic blockade.
Gonzalez-Juanatey JR, Iglesias MJ, Alcaide C, Pineiro R, Lago F.
Cardiology Research Unit, University Clinical Hospital, Santiago de Compostela, Spain.
BACKGROUND: The alpha1-adrenoceptor-blocking antihypertensive doxazosin has been associated with increased risk of heart failure and is known to induce prostate cell apoptosis. We hypothesized that it might also induce apoptosis in cardiomyocytes. METHODS AND RESULTS: Hoechst dye vital staining and flow cytometry provided evidence that doxazosin induced apoptosis time- and dose-dependently in cardiomyocytes of the HL-1 cell line. TUNEL assays and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) viability test confirmed that doxazosin induced DNA damage and cell death in these cells. MTT tests showed that doxazosin treatment decreased cell viability in primary cultures of neonatal rat cardiomyocytes, and Hoechst dye vital staining demonstrated doxazosin-induced apoptosis in primary cultures of human adult cardiomyocytes. The proapoptotic effect of doxazosin on cardiomyocytes seems not to depend on alpha1 blockade, because it was not modified by cotreatment with alpha- or beta-adrenergic agonists or with the irreversible alpha1-blocker phenoxybenzamine and because doxazosin also decreased the viability of NIH 3T3 cells, which lack alpha1-adrenoceptors. It also does not involve calcineurin, being unaffected by the presence of the calcineurin inhibitors cyclosporin A and FK506. Three other alpha1-blockers were also investigated; prazosin was proapoptotic, like doxazosin, but 5-methylurapidil and terazosin were not. CONCLUSIONS: The alpha1-blockers doxazosin and prazosin induce the apoptosis of cardiomyocytes cultured in vitro by a mechanism that is independent of alpha1 blockade and calcineurin.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12515754&dopt=Abstract
Am J Hypertens. 1999 Jul;12(7):673-81.
Effect of hypertension and its treatment on lipid, lipoprotein(a), fibrinogen, and bilirubin levels in patients referred for dyslipidemia.
Papadakis JA, Ganotakis ES, Jagroop IA, Mikhailidis DP, Winder AF.
Department of Chemical Pathology and Human Metabolism, Royal Free Hospital & School of Medicine, University of London, England.
We measured the serum lipid profile, together with plasma fibrinogen and serum lipoprotein(a) (Lp[a]), glucose, bilirubin, and albumin levels in 491 patients (310 men) who were referred for the management of primary dyslipidemia. All these variables have been shown to predict vascular events. The patients were not taking lipid-lowering drugs; hypertension was present in 156 (31.7%) of them. Of the hypertensive patients, 52 (33%) were not receiving any treatment to control their blood pressure. This omission was not due to a lower prevalence of established vascular disease. The treated hypertensives were divided into three groups according to their treatment: 62 were taking lipid-hostile antihypertensives (beta-blockers, thiazides), 37 were taking lipid-neutral antihypertensives (angiotensin converting enzyme inhibitors, Ca-channel blockers, angiotensin II receptor blockers, indapamide sustained release), and five were taking lipid-friendly antihypertensives (doxazosin). Lipid-hostile antihypertensive drugs were associated with a significantly higher fibrinogen concentration when compared with untreated hypertensives or those taking lipid-neutral/lipid-friendly drugs (median values: 383, 353, and 336 mg/dL, respectively; P < .01). Lipid-neutral/lipid-friendly antihypertensive drugs were associated with lower Lp(a) levels when compared with untreated hypertensives (median values: 22 and 45 mg/dL, respectively; P < .05). The serum bilirubin level was significantly lower in the untreated hypertensives when compared with normotensives or the treated hypertensives. There were no significant differences in lipids, glucose, or albumin among the groups of hypertensives or normotensives. The influence of antihypertensive drugs on additional cardiovascular risk factors should be considered when selecting medication to reduce blood pressure.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10411364&dopt=Abstract
J Urol. 2003 Mar;169(3):1150-6.
Anoikis induction by quinazoline based alpha 1-adrenoceptor antagonists in prostate cancer cells: antagonistic effect of bcl-2.
Keledjian K, Kyprianou N.
Divisionof Urology, University of Maryland, Baltimore, USA.
PURPOSE: The ability of the quinazoline derived alpha1-adrenoceptor antagonists doxazosin and terazosin to induce apoptosis in benign and malignant prostate cells has been established. In this study we investigated the effect of the 2 piperazidinyl quinazoline based alpha1-adrenoceptor antagonists and the methoxybenzene sulfonamide alpha1-antagonist tamsulosin on human prostate cancer cell adhesion. MATERIALS AND METHODS: Androgen independent PC-3 prostate cancer cells and PC-3 transfectant clones over expressing the apoptosis suppressor bcl-2 were used as an in vitro model. Cells were treated with pharmacologically relevant doses of 1 of the 3 alpha1-adrenoceptor antagonists and the effect on cell viability/cell adhesion on various substrates was examined. Analysis of expression of key attachment factors, such as vascular endothelial growth factor (VEGF) and hypoxia inducible factor-alpha, was performed. RESULTS: Our results indicate a significant decrease in prostate cancer cell adhesion to gelatin and collagen but not to fibronectin in prostate cancer cells treated with doxazosin or terazosin (25 microM.) compared with untreated control cultures (p <0.05). In contrast, tamsulosin had no effect on prostate cancer cell adhesion. The 2 quinazolines doxazosin and terazosin but not tamsulosin had a significant inhibitory effect on prostate tumor cell invasion. In bcl-2 over expressing prostate cancer cells there was significant suppression of doxazosin induced anoikis and cell invasion compared with neocontrol transfectants (p <0.05). Doxazosin resulted in transient down-regulation (2-fold decrease) of VEGF at the mRNA and protein levels, as detected by reverse transcriptase-polymerase chain reaction and Western blotting, respectively. No significant changes in the expression profile of hypoxia inducible factor-1 alpha were observed after treatment with quinazolines. Furthermore, bcl-2 resulted in partial reversion of the doxazosin induced VEGF decrease. CONCLUSIONS: These findings demonstrate that the quinazoline derived alpha1-antagonists doxazosin and terazosin but not sulfonamide based tamsulosin induce anoikis and inhibit prostate cancer cell invasion, an effect that is antagonized by bcl-2. This molecular basis of an alpha1-adrenoceptor independent action against prostate cancer cells by the quinazolines may have potential therapeutic significance in prostate cancer.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12576871&dopt=Abstract
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