Nitric oxide pathway as new drug targets for refractory hypertension

Robert A. Augustyniak, Gail Thomas, Ronald G. Victor, Weiguo Zhang

Research output: Contribution to journalReview article

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3307-3315
Number of pages9
JournalCurrent Pharmaceutical Design
Volume11
Issue number25
DOIs
StatePublished - Sep 23 2005

Fingerprint

Nitric Oxide Synthase
Nitric Oxide
Hypertension
Pharmaceutical Preparations
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Gene Knockout Techniques
Nitric Oxide Synthase Type III
Vascular Smooth Muscle
Angiotensin-Converting Enzyme Inhibitors
Oxidants
Vasodilation
Superoxides
Antihypertensive Agents
Biological Availability
Brain Stem
Single Nucleotide Polymorphism
Norepinephrine
Protein Isoforms
Maintenance
Exercise

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery

Cite this

Augustyniak, Robert A. ; Thomas, Gail ; Victor, Ronald G. ; Zhang, Weiguo. / Nitric oxide pathway as new drug targets for refractory hypertension. In: Current Pharmaceutical Design. 2005 ; Vol. 11, No. 25. pp. 3307-3315.
@article{153f40d06f274e6c8653650d028d1d3f,
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.",
author = "Augustyniak, {Robert A.} and Gail Thomas and Victor, {Ronald G.} and Weiguo Zhang",
year = "2005",
month = "9",
day = "23",
doi = "10.2174/138161205774424672",
language = "English (US)",
volume = "11",
pages = "3307--3315",
journal = "Current Pharmaceutical Design",
issn = "1381-6128",
publisher = "Bentham Science Publishers B.V.",
number = "25",

}

Nitric oxide pathway as new drug targets for refractory hypertension. / Augustyniak, Robert A.; Thomas, Gail; Victor, Ronald G.; Zhang, Weiguo.

In: Current Pharmaceutical Design, Vol. 11, No. 25, 23.09.2005, p. 3307-3315.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Nitric oxide pathway as new drug targets for refractory hypertension

AU - Augustyniak, Robert A.

AU - Thomas, Gail

AU - Victor, Ronald G.

AU - Zhang, Weiguo

PY - 2005/9/23

Y1 - 2005/9/23

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=24944506507&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24944506507&partnerID=8YFLogxK

U2 - 10.2174/138161205774424672

DO - 10.2174/138161205774424672

M3 - Review article

VL - 11

SP - 3307

EP - 3315

JO - Current Pharmaceutical Design

JF - Current Pharmaceutical Design

SN - 1381-6128

IS - 25

ER -