Relative effects of alpha 1-adrenoceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog. Alpha 1-adrenoceptor antagonists differentially control serotonin release in the hippocampus and striatum: a microdialysis study. Endothelin-1 in the human prostate: tissue levels, source of production and isometric tension studies. Rx drugs

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Circulation. 1994 Dec;90(6):3034-46.
Relative effects of alpha 1-adrenoceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog.

McDonald KM, Garr M, Carlyle PF, Francis GS, Hauer K, Hunter DW, Parish T, Stillman A, Cohn JN.

Department of Medicine, University of Minnesota Medical School, Minneapolis 55455.

BACKGROUND: Progressive ventricular remodeling after myocardial damage is associated with a poor prognosis. Optimal prevention of the histopathological processes involved in remodeling requires a more complete understanding of the mechanisms involved in initiating and maintaining these structural changes. Since the sympathetic nervous system and the renin-angiotensin system may be involved in the remodeling process, the structural effects of pharmacological inhibitors have been evaluated in a canine model of localized myocardial injury resulting from transmyocardial DC shock. METHODS AND RESULTS: The study is comprised of two protocols run in series. In protocol 1, zofenopril (Z), a converting enzyme inhibitor (CEI), prevented the increase in left ventricular mass (LVM) and end-diastolic volume (LVV) observed in the control group (C) at 16 weeks (Z: LVM, 69.8 +/- 3.4 to 65.4 +/- 2.6 g, P = NS; LVV, 45.4 +/- 2.7 to 51.6 +/- 2.7 mL, P = NS; C: LVM, 68.4 +/- 3.2 to 91.4 +/- 2.9 g, P = .0001; LVV, 56.6 +/- 3.0 to 71.9 +/- 2.4 mL, P = .0003). Terazosin, an alpha 1-adrenoceptor antagonist, failed to prevent remodeling at 16 weeks despite continued receptor blockade. In protocol 2, the antiremodeling effect of full-dose CEI therapy with ramipril was confirmed. Low-dose ramipril that exerted no hemodynamic effect failed to prevent remodeling (LVM, 89.7 +/- 4.6 to 105.7 +/- 3.4 g, P = .01; LVV, 61.8 +/- 3.8 to 76.8 +/- 3.3 mL, P = .002). An angiotensin II subtype 1 receptor blocker also failed to prevent the increase in LVM or LVV (LVM, 89.0 +/- 4.6 to 109.7 +/- 5.3 g, P = .0001; LVV, 66.0 +/- 1.9 to 78.4 +/- 3.6 mL, P = .007). CONCLUSIONS: High-dose CEI therapy can prevent progressive structural changes resulting from localized myocardial damage induced by DC shock. the failure of alpha 1-adrenoceptor blockade and angiotensin II subtype 1 blockade to attenuate remodeling argues against an important direct role for norepinephrine acting through alpha 1-receptors or angiotensin II acting through the type 1 receptor in the remodeling process in this model.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7994852&dopt=Abstract

Eur J Pharmacol. 1994 Aug 11;261(1-2):59-64.
Alpha 1-adrenoceptor antagonists differentially control serotonin release in the hippocampus and striatum: a microdialysis study.

Rouquier L, Claustre Y, Benavides J.

Synthelabo Recherche (L.E.R.S.), Biology Department, Bagneux, France.

Using the in vivo microdialysis technique, we have studied the effect of the systemic administration of several alpha 1-adrenoceptor antagonists on the extracellular levels of serotonin (5-HT) in the rat hippocampus. Prazosin, and to a lesser extent, terazosin, decreased these levels by 50-65% for 0.03-0.4 mg/kg, i.v. and by 30-40% for 0.1-0.4 mg/kg, i.v., respectively. In contrast, alfuzosin, an alpha 1-adrenoceptor antagonist with poor brain penetration, did not significantly affect these levels even at the high dose of 0.4 mg/kg, i.v. When perfused into the hippocampus through the dialysis probe, prazosin (1-10 microM) induced a more limited (20-30%) and delayed decrease in 5-HT outflow. These results support the existence of a central noradrenergic facilitatory influence, mediated by alpha 1-adrenoceptors, on serotonergic neurons projecting to the hippocampus. In the striatum prazosin (0.4 mg/kg, i.v.) decreased 5-HT levels to a smaller extent (-35%) than in the hippocampus (-65%), suggesting the existence of differences in the degree of noradrenergic influence on median and dorsal raphe nuclei, which preferentially project to the hippocampus and striatum, respectively.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8001654&dopt=Abstract

J Urol. 1993 Aug;150(2 Pt 1):495-9.
Endothelin-1 in the human prostate: tissue levels, source of production and isometric tension studies.

Langenstroer P, Tang R, Shapiro E, Divish B, Opgenorth T, Lepor H.

Department of Urology, Medical College of Wisconsin, Milwaukee.

Endothelins mediate contractile responses in many types of vascular and nonvascular smooth muscle. The present study represents the first detailed characterization of endothelins in the human prostate. The objectives of this study were to determine the tissue levels and source of endogenous endothelin-1 (ET1) in the human prostate. The contractile effects of ET1 were also investigated using in vitro isometric tension studies. The mean tissue level of ET1 was 0.58 +/- 0.08 pg./mg. tissue wet weight. Endothelin-like activity was markedly prominent in the glandular epithelium of the human prostate, whereas minimal endothelin-like activity was observed in the prostatic stroma. Strips of human prostatic tissue were suspended in isolated tissue chambers and challenged to a concentration response of ET1. The mean EC50 and Emax for ET1 was 3.2 x 10(-8) M. and 0.12 +/- 0.02 gm. force per mm.2 cross-sectional area (CSA), respectively. Preincubation with indomethacin, terazosin, or nifedipine did not alter the concentration-dependent response to ET1. A calcium-free buffer abolished the contractile response to ET1. Thus, ET1 mediates a potent contraction of human prostatic smooth muscle that is not mediated via alpha 1 adrenergic or dihydropyridine sensitive calcium channels or prostaglandin synthesis. The presence of marked endothelin-like immunoreactivity strongly suggests a biological significance for endogenous endothelins in the human prostate.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8100861&dopt=Abstract

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