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OBJECTIVE: To evaluate the effect of the nonselective purinergic antagonist suramin and the alpha1-adrenergic antagonists, terazosin and BMY 7378, given intravenously or infused directly into the bladder during cystometry in conscious rats with bladder outlet obstruction induced by urethral ligation. MATERIALS AND METHODS: Cystometry was performed in conscious female rats recording bladder volume capacity (BVC), evaluated as the amount of saline infused between two voiding cycles, and micturition volume (MV). Changes in frequency and amplitude of spontaneous non-voiding bladder contractions (NVC) were also recorded. The effects of the intravenous administration of suramin (100 mg/kg), BMY 7378 (1 mg/kg), and terazosin (0.3 mg/kg) on NVC, BVC and MV were evaluated in obstructed rats with bladder infusion of saline. The effects of infravesical infusion of suramin (3-10 micromol/L), terazosin (1 micromol/L) and BMY 7378 (10 micromol/L) were also evaluated and compared with values observed in control rats during saline infusion into the bladder. RESULTS: Intravenous injection with suramin had no effects on NVC, BVC and MV, but suramin infused into the bladder induced a consistent reduction in the amplitude of NVC (significantly different from matched control animals) with a tendency to reduce their frequency. BVC and MV were slightly but significantly decreased by infravesical infusion of suramin. In contrast, BMY 7378 and terazosin, given intravenously, were extremely potent at inhibiting the frequency and amplitude of the NVC, but were inactive on NVC when infused into bladder. CONCLUSIONS: These findings confirm a role for alpha1-adrenergic receptors in bladder instability caused by bladder outlet obstruction. In addition, a purinergic neurotransmitter, presumably ATP, is shown to be involved.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12823397&dopt=Abstract
Naunyn Schmiedebergs Arch Pharmacol. 2003 Jul;368(1):49-56. Epub 2003 Jun 25.
Pharmacological characterization of unique prazosin-binding sites in human kidney.
Hiraoka Y, Taniguchi T, Tanaka T, Okada K, Kanamaru H, Muramatsu I.
Department of Pharmacology, School of Medicine, Fukui Medical University, 910-1193 Matsuoka, Fukui, Japan.
In human kidney, we found unique prazosin-binding sites that were insensitive to phentolamine and were thus unlikely to be alpha(1)-adrenoceptors.As the binding of [(3)H]prazosin to phentolamine-insensitive sites was prevented by 100 microM guanabenz, the insensitive sites were evaluated by subtracting [(3)H]prazosin binding in the presence of 100 microM guanabenz from that in the presence of 10 microM phentolamine. [(3)H]Prazosin bound to the phentolamine-insensitive sites monophasically with a high affinity (pK(d); 9.1+/-0.08, n=8), and the B(max) value (814+/-204 fmol mg(-1) protein, n=8) was more than ten times that of the phentolamine-sensitive alpha(1)-adrenoceptor (pK(d)=9.9+/-0.13, B(max)=66+/-23 fmol mg(-1) protein, n=7). The phentolamine-insensitive sites in human kidney were highly sensitive to other quinazoline derivatives such as terazosin and doxazosin. However, other alpha(1)-adrenoceptor antagonists (tamsulosin, WB4101 and corynanthine) did not inhibit the binding at a range of concentrations that generally exhibit alpha(1)-adrenoceptor antagonism, and noradrenaline, rauwolscine and propranolol were without effect on the [(3)H]prazosin binding. On the other hand, ligands for the renal Na(+)-transporter (amiloride and triamterene) and for imidazoline recognition sites (guanabenz, guanfacine and agmatine) displaced the binding of [(3)H]prazosin to phentolamine-insensitive sites at micromolar concentrations. Photoaffinity labeling with [(125)I]iodoarylazidoprazosin showed phentolamine-insensitive labeling at around 100 kDa, a molecular size larger than that of human alpha(1a)- and alpha(1b)-adrenoceptors expressed in 293 cells (50-60 and 70-80 kDa, respectively) on electrophoresis. In contrast, there was no detectable phentolamine-insensitive binding site but were phentolamine-sensitive alpha(1)-adrenoceptors in human liver (pK(d)=10.0+/-0.06, B(max)=44+/-6 fmol mg(-1) protein, n=3). Phentolamine-insensitive prazosin binding sites were also detected in rabbit kidney (approximately 50% of specific binding sites) but were minor in rat kidney (less than 20%).In conclusion, there are unique prazosin-binding sites in human kidney, the pharmacological profiles of which were distinct from those of known adrenoceptors.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12827214&dopt=Abstract [PubMed - in process]
Oncol Rep. 2003 Sep-Oct;10(5):1555-60.
The alpha1-adrenoceptor antagonist terazosin induces prostate cancer cell death through a p53 and Rb independent pathway.
Xu K, Wang X, Ling PM, Tsao SW, Wong YC.
Department of Urology, People's Hospital, Beijing, China.
Prostate cancer is the second leading cause of cancer-related death in men. Treatment failure in prostate cancer is usually due to the development of androgen independence and resistance to chemotherapeutic drugs at an advanced stage. Recently, it was reported that the alpha1-adrenoceptor antagonist terazosin was able to inhibit prostate cancer cell growth and indicated that it may have an implication in the treatment of prostate cancer. The aim of the present study was to investigate the mechanisms involved in terazosin-induced prostate cancer cell death using two androgen-independent cell lines, PC-3 and DU145. Our results showed that terazosin inhibited not only prostate cancer cell growth but also colony forming ability, which is the main target of chemotherapy. We also found that the sensitivity of these cells to terazosin was not affected by the presence of either functional p53 or Rb, suggesting that the terazosin-induced cell death was independent of p53 and Rb. However, the terazosin-induced cell death was associated with G1 phase cell cycle arrest and up-regulation of p27KIP1. In addition, up-regulation of Bax and down-regulation of Bcl-2 was also observed indicating that these two apoptotic regulators may play important roles in terazosin-mediated cell death pathway. Our results provide evidence for the first time that terazosin may have a therapeutic potential in the treatment of advanced prostate cancer.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12883741&dopt=Abstract [PubMed - in process]
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