A rationale for combination therapy in risk factor management: a mechanistic perspective.
Endothelial dysfunction contributes to mechanisms of atherogenesis and its clinical manifestations, including coronary heart disease. Cardiovascular risk factors have been linked directly to a loss of endothelial function, such as endothelium-dependent nitric oxide (NO) release, resulting in abnormal vasodilation in response to various stimuli. There is evidence that multiple risk factors, including hypertension and hyperlipidemia, lead to a synergistic effect on endothelial dysfunction, likely through oxidative stress mechanisms. Damage to the endothelium leads to reduced NO bioavailability and facilitates vessel wall permeability to low-density lipoprotein. Certain agents, including the antihypertensive drug amlodipine and the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) atorvastatin, are known to influence endothelial function and NO bioavailability directly; these properties may contribute to clinical benefits. Recent experimental evidence at the cellular level indicates that these agents stimulate NO release from human endothelial cells in a highly synergistic fashion. The clinical implications of these observations are discussed in this article in the context of cardiovascular risk factor management strategies.
Mason
R Preston
RP
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. rpmason@elucidaresearch.com
D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use; D000069059:Atorvastatin; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000378:metabolism*; D019468:Disease Management; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D012307:Risk Factors
D006538:Heptanoic Acids; D011758:Pyrroles; D017311:Amlodipine; D009569:Nitric Oxide; D000069059:Atorvastatin