title: Advances in pharmacologic modulation of nitric oxide in hypertension.
abstract: A number of structural and functional mechanisms have been identified in the pathogenesis of hypertensive vascular disease, each of which requires effective therapy to reduce global cardiovascular risk. Hypertension, together with other cardiovascular risk factors, promotes endothelial dysfunction as evidenced by decreased nitric oxide (NO) release and reduced vascular responsiveness to normal vasodilatory stimuli. In addition, the mechanical forces inherent in hypertension activate neurohormonal mechanisms, including the renin-angiotensin system, which modulate vessel wall structure and function. Antihypertensive drugs may have class-specific hemodynamic and physiologic effects that attenuate these vascular disease processes. Pharmacologic approaches that enhance endothelial NO bioavailability have been shown to restore vasodilation while reducing clinical events. These agents improve NO bioavailability by increasing endogenous production through enzymatic mechanisms or by promoting the direct release of NO by its redox congeners in a spontaneous fashion. In this article, we review the basic mechanisms of endothelial dysfunction along with the use and comparative therapeutic benefits of various pharmacologic interventions, with particular emphasis on antihypertensive agents.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. ymizuno@elucidaresearch.com
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Robert F
authors.initials: RF
authors.lastname: Jacob
authors.forename: R Preston
authors.initials: RP
authors.lastname: Mason
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007333:Insulin Resistance; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012084:Renin-Angiotensin System / Q000187:drug effects; D012307:Risk Factors
chemical_list: D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D010726:Phosphodiesterase Inhibitors; D009569:Nitric Oxide
references.citation: Hypertension. 2004 Mar;43(3):661-6
references.pmid: 14744930
references.citation: Am J Hypertens. 1998 Sep;11(9):1134-7
references.pmid: 9752901
references.citation: J Mol Cell Cardiol. 2005 Jan;38(1):175-84
references.pmid: 15623434
references.citation: Hypertension. 2004 May;43(5):993-1002
references.pmid: 15007034
references.citation: Circulation. 2003 Nov 11;108(19):2400-6
references.pmid: 14557368
references.citation: Hypertension. 2006 Mar;47(3):312-8
references.pmid: 16432039
references.citation: J Clin Hypertens (Greenwich). 2006 Dec;8(12 Suppl 4):40-52
references.pmid: 17170605
references.citation: Basic Res Cardiol. 1990 Sep-Oct;85(5):461-6
references.pmid: 2275701
references.citation: J Clin Invest. 2003 Apr;111(8):1201-9
references.pmid: 12697739
references.citation: N Engl J Med. 2008 Dec 4;359(23):2417-28
references.pmid: 19052124
references.citation: Hypertension. 2005 Mar;45(3):380-4
references.pmid: 15699445
references.citation: Circ Res. 2002 Jan 11;90(1):21-8
references.pmid: 11786514
references.citation: Circulation. 2000 Feb 15;101(6):594-7
references.pmid: 10673249
references.citation: Hypertension. 2007 Feb;49(2):276-84
references.pmid: 17159081
references.citation: Hypertension. 2008 Mar;51(3):734-41
references.pmid: 18227404
references.citation: Hypertension. 2002 Oct;40(4):504-10
references.pmid: 12364354
references.citation: Circulation. 2006 Mar 7;113(9):1213-25
references.pmid: 16476843
references.citation: Hypertension. 2001 Mar;37(3):943-8
references.pmid: 11244022
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jun;25(6):1142-7
references.pmid: 15802620
references.citation: J Am Coll Cardiol. 2008 Feb 5;51(5):519-28
references.pmid: 18237679
references.citation: Eur J Pharmacol. 1988 Oct 26;156(1):95-103
references.pmid: 3208842
references.citation: Circulation. 1997 Feb 4;95(3):588-93
references.pmid: 9024144
references.citation: N Engl J Med. 1990 Jul 5;323(1):22-7
references.pmid: 2355955
references.citation: Am J Physiol. 1997 Aug;273(2 Pt 2):H718-24
references.pmid: 9277488
references.citation: J Clin Invest. 1997 Jan 15;99(2):278-87
references.pmid: 9005996
references.citation: Hypertension. 2004 Jun;43(6):1324-31
references.pmid: 15123571
references.citation: J Pharmacol Exp Ther. 2003 Dec;307(3):1171-8
references.pmid: 14560036
references.citation: Expert Opin Investig Drugs. 2006 Oct;15(10):1131-5
references.pmid: 16989589
references.citation: Circ Res. 2004 May 14;94(9):1211-8
references.pmid: 15044323
references.citation: Circulation. 2005 Aug 23;112(8):1198-205
references.pmid: 16116070
references.citation: N Engl J Med. 2004 Nov 11;351(20):2049-57
references.pmid: 15533851
references.citation: Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2009-23
references.pmid: 17586614
references.citation: Drugs. 1993 Feb;45(2):232-58
references.pmid: 7681374
references.citation: N Engl J Med. 1999 Sep 2;341(10):709-17
references.pmid: 10471456
references.citation: Circulation. 1998 Feb 17;97(6):576-80
references.pmid: 9494028
references.citation: Hypertension. 2007 Oct;50(4):750-5
references.pmid: 17646573
references.citation: J Clin Invest. 1998 Apr 15;101(8):1784-8
references.pmid: 9541510
references.citation: Circulation. 2005 Dec 13;112(24):3795-801
references.pmid: 16330685
references.citation: Clin Endocrinol (Oxf). 2009 Jul;71(1):1-6
references.pmid: 19138313
references.citation: J Clin Invest. 1997 Nov 1;100(9):2153-7
references.pmid: 9410891
references.citation: Hypertension. 2003 Feb;41(2):341-6
references.pmid: 12574105
references.citation: Hypertension. 2001 Jan;37(1):34-39
references.pmid: 11208753
references.citation: Hypertension. 2006 Jul;48(1):165-71
references.pmid: 16754797
references.citation: Arterioscler Thromb Vasc Biol. 2003 Apr 1;23(4):615-21
references.pmid: 12692005
references.citation: J Biol Chem. 2006 Nov 17;281(46):35137-46
references.pmid: 16982630
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2829-34
references.pmid: 19202069
references.citation: Hypertension. 2005 May;45(5):986-90
references.pmid: 15837835
references.citation: Circulation. 2003 Jan 21;107(2):234-7
references.pmid: 12538421
references.citation: Am J Hypertens. 2009 Nov;22(11):1160-6
references.pmid: 19730416
references.citation: Hypertension. 2002 Oct;40(4):511-5
references.pmid: 12364355
references.citation: Circulation. 2004 Jan 20;109(2):184-9
references.pmid: 14662706
references.citation: N Engl J Med. 1994 Nov 3;331(18):1188-93
references.pmid: 7935656
references.citation: J Pharmacol Exp Ther. 2006 Apr;317(1):188-95
references.pmid: 16330494
references.citation: Circulation. 2000 Apr 4;101(13):1539-45
references.pmid: 10747347
references.citation: Diabetes Care. 2003 Jan;26 Suppl 1:S5-20
references.pmid: 12502614
references.citation: Br J Clin Pharmacol. 2000 Oct;50(4):377-9
references.pmid: 11012562
references.citation: J Cardiovasc Pharmacol. 1999 Aug;34(2):173-81
references.pmid: 10445667
references.citation: J Am Coll Cardiol. 2002 Aug 21;40(4):754-60
references.pmid: 12204507
references.citation: Int J Impot Res. 2004 Feb;16(1):21-9
references.pmid: 14963467
references.citation: Circulation. 2003 Jan 28;107(3):422-8
references.pmid: 12551866
references.citation: Hypertension. 2003 May;41(5):1096-101
references.pmid: 12707286
references.citation: Br J Pharmacol. 2000 Apr;129(7):1530-5
references.pmid: 10742311
references.citation: Hypertension. 2007 Aug;50(2):384-91
references.pmid: 17533199
references.citation: Hypertension. 2008 Sep;52(3):563-72
references.pmid: 18645051
references.citation: Hypertension. 1997 Nov;30(5):1144-9
references.pmid: 9369268
references.citation: Physiol Rev. 2003 Jan;83(1):117-61
references.pmid: 12506128
references.citation: Circulation. 2003 Jun 3;107(21):2747-52
references.pmid: 12742996