title: Nitric oxide pathway as new drug targets for refractory hypertension.
abstract: Nitric oxide (NO) is thought to reduce blood pressure by evoking vasodilation either directly by causing relaxation of vascular smooth muscle or indirectly by acting in the rostral brainstem to reduce central sympathetic outflow, which decreases the release of norepinephrine from sympathetic nerve terminals. An increasingly large body of literature suggests that alterations in the NO system may play an important role in the development or maintenance of clinical hypertension. As proof of concept, pharmacological inhibition of nitric oxide synthase (NOS) in humans and animals causes moderate to severe hypertension. Certain forms of secondary hypertension are accompanied by the accumulation of endogenous NOS inhibitors, which may contribute to the development of hypertension. Furthermore, targeted disruption of the endothelial isoform of NOS in mice causes moderate hypertension, implying that hypertension may also develop from reductions in NOS expression. These gene knockout studies in animals have initiated the search for single nucleotide polymorphisms in human NOS genes, which could potentially lead to decreases in NOS protein expression. Conversely, increases in NOS expression or NO production have been linked with several commonly used cardiovascular therapies, including exercise training and the use of both statins and angiotensin-converting enzyme inhibitors. Finally, increases in the production of oxidants such as superoxide anion can lead to the inactivation of NO, thereby reducing NO bioavailability. Thus, alterations in the expression or activity of NOS or in the availability of NO have the potential to play a causal role in clinical hypertension. The purpose of this article is to show how emerging basic research on the NO pathway is elucidating novel antihypertensive drug targets that are on the cusp of clinical application.
authors.affiliation: The Donald W. Reynolds Cardiovascular Clinical Research Center and the Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Texas 75390-8586, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Augustyniak
authors.forename: Gail D
authors.initials: GD
authors.lastname: Thomas
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Victor
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D013481:Superoxides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester