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OBJECTIVE : The aim of the present study was to analyse the nitric oxide (NO)/cyclic GMP (cGMP) relaxing system in spontaneously hypertensive rats of the stroke-prone substrain (SHRSP). DESIGN : The study was performed in 20-week-old SHRSP rats. A group of normotensive Wistar-Kyoto (WKY) rats was used as control. RESULTS : The endothelium-dependent relaxation to acetylcholine was reduced in SHRSP rats (n = 15). No modifications in the expression of the endothelial nitric oxide synthase were found in the vascular wall of WKY rats (n = 15) and SHRSP rats. SHRSP rats demonstrated an impaired relaxing response to the NO-donor sodium nitroprusside that was accompanied by a reduction in the level of the main second messenger of NO, cyclic GMP. The expression of the soluble guanylate cyclase (sGC) beta1-subunit was markedly reduced in the vascular wall of SHRSP rats. In the experimental model of SHRSP, an increased concentration of catecholamines has been reported. Therefore, we evaluated the effect of an alpha1-receptor blocker, doxazosin, on the NO/cGMP system. Doxazosin [10 mg/kg body weight (bw) per day for 15 days, n = 15] reduced mean arterial pressure (MAP) in SHRSP rats. Treatment with doxazosin preserved the endothelium-independent relaxation response to sodium nitroprusside in aortic segments from SHRSP rats which was associated with an increased expression of the sGC beta1-subunit. A dose of doxazosin (1 mg/kg bw per day, n = 15) that did not modify MAP partially prevented sGC protein expression in the vascular wall. CONCLUSIONS : Independently of the endothelial NO-generating system, impaired vasorelaxation could also result from vascular smooth muscle cell layer dysfunction. Doxazosin treatment improved the endothelial-independent relaxation and preserved the cGMP generating system in the vascular wall of SHRSP rats.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11875314&dopt=Abstract
Life Sci. 2002 Feb 15;70(13):1491-500.
Interaction of digoxin with antihypertensive drugs via MDR1.
Takara K, Kakumoto M, Tanigawara Y, Funakoshi J, Sakaeda T, Okumura K.
Department of Hospital Pharmacy, School of Medicine, Kobe University, Japan.
The multidrug transporter MDR1 (P-glycoprotein)-mediated interaction between digoxin and 29 antihypertensive drugs of various types was examined by using the MDR1 overexpressing LLC-GA5-COL150 cells, which were established by transfecting MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells. These cells construct monolayers with tight junctions, and enable the evaluation of transcellular transport. The MDR1 was highly expressed on the apical membrane (urine side). The basal-to-apical and apical-to-basal transcellular transport of [3H]digoxin in LLC-GA5-COL150 cells was time- and temperature-dependent. The basal-to-apical transport of [3H]digoxin was markedly increased, whereas the apical-to-basal transport was decreased in LLC-GA5-COL150 cells, compared with the host LLC-PK1 cells, suggesting that [3H]digoxin was a substrate for MDR1. Most of the Ca2+ channel blockers used here markedly inhibited basal-to-apical transport and increased apical-to-basal transport. Exceptions were diltiazem, nifedipine and nitrendipine, which hardly showed inhibitory effects on transcellular transport of [3H]digoxin. Alpha-blocker doxazosin and beta-blocker carvedilol also inhibited transcellular transport of [3H]digoxin, but none of the angiotensin converting enzyme inhibitors and AT1 angiotensin II receptor antagonists used here were active. These observations will promote understanding of the digoxin-drug interactions resulting from their actions on MDR1, and which may aid in avoiding these unexpected effects of digoxin.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11895100&dopt=Abstract
Curr Med Res Opin. 2002;18(2):103-7.
The choice of antihypertensive drugs in patients with erectile dysfunction.
Khan MA, Morgan RJ, Mikhailidis DP.
Department of Urology, Royal Free University College Medical School (University College London), The Royal Free Hampstead NHS Trust, UK.
It is well established that hypertension and the more traditional anti-hypertensive drugs are associated with erectile dysfunction (ED). There is evidence showing that two antihypertensive drugs--doxazosin and losartan--have a positive effect on erectile function. Therefore these drugs may decrease the incidence of ED in patients who need treatment for hypertension. Doxazosin and/or losartan can also be beneficial in patients who develop ED after starting treatment with other antihypertensive drugs. These options could, in turn, ensure better compliance and blood pressure control. A fall in the overall cost of treatment will also be anticipated if there is a reduced need for drugs prescribed for ED in patients with hypertension.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12017207&dopt=Abstract
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