Targeting nitric oxide with drug therapy.
Increasing knowledge of the role of nitric oxide (NO) in physiology and disease has stimulated efforts to target the NO pathway pharmacologically. These therapeutic strategies include NO donors that directly or indirectly release NO and agents that increase NO bioactivity. Traditional organic nitrates such as nitroglycerin, which indirectly release NO, were believed to have limited long-term efficacy and tolerability, chiefly because of nitrate tolerance. Recent studies, however, suggest more effective ways of using these agents and new applications for them. Nicorandil, a hybrid organic nitrate that also activates potassium channels, has demonstrated significant benefits in acute coronary syndromes. Other nitrates are being investigated for use in neurodegenerative diseases. Direct NO donors include NO gas, which is useful in respiratory disorders, and the more recent classes of diazeniumdiolates, sydnonimines, and S-nitrosothiols. Preliminary data suggest that these agents may be effective as antiatherosclerotic agents as well as in other disease states. In addition, hybrid agents that consist of an NO donor coupled with a parent anti-inflammatory drug, including nonsteroidal anti-inflammatory drugs, have demonstrated enhanced efficacy and tolerability compared with the anti-inflammatory parent drug alone in diverse experimental models. Established drugs that enhance NO bioactivity include antihypertensive agents, particularly angiotensin-converting enzyme inhibitors, calcium channel blockers, and newer vasodilating beta-blockers. In addition, 3-methylglutaryl coenzyme A reductase inhibitors (statins) promote NO bioactivity, both through and independent of lipid lowering. The NO-promoting actions of these established drugs provide some insight into their known benefits and suggest possible therapeutic potential.
Mason
R Preston
RP
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. rpmason@elucidaresearch.com
Cockcroft
John R
JR
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D002227:Carbazoles / Q000627:therapeutic use; D000077261:Carvedilol; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use; D006331:Heart Diseases / Q000188:drug therapy; D006801:Humans; D007548:Isosorbide Dinitrate / Q000627:therapeutic use; D000068577:Nebivolol; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D020108:Nicorandil / Q000627:therapeutic use; D009566:Nitrates / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use*; D011412:Propanolamines / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000627:therapeutic use
D000317:Adrenergic alpha-Antagonists; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001578:Benzopyrans; D002121:Calcium Channel Blockers; D002227:Carbazoles; D004983:Ethanolamines; D009566:Nitrates; D020030:Nitric Oxide Donors; D011412:Propanolamines; D014665:Vasodilator Agents; D000068577:Nebivolol; D000077261:Carvedilol; D020108:Nicorandil; D009569:Nitric Oxide; D007548:Isosorbide Dinitrate