Critique of a biologic mechanism linking calcium antagonists to increased risk for cardiovascular events in diabetes.
Calcium antagonists represent a chemically and pharmacologically diverse group of agents that function by modulating the transmembrane influx of Ca2+ into contractile cells. These compounds, widely used for the treatment of hypertension and angina, bind in a highly specific and reversible fashion to voltage-sensitive Ca2+ channels in vascular smooth muscle cells. A recent study raised concerns about the safety of certain calcium antagonists for treatment of hypertension in diabetic patients. The safety issue has not been resolved and is the subject of other articles in this supplement. However, a biologic mechanism has been proposed to rationalize the potentially deleterious effects of calcium antagonists in this group of patients. This mechanism is based on an assumption that the biochemical composition of cellular membranes in patients with diabetes is fundamentally different, leading to an abnormal increase in the membrane concentration of calcium antagonists and, hence, adverse pharmacologic effects. In support of this model, original research on the lipid composition of membranes from patients with diabetes was cited, along with our own published findings, showing that accumulation of calcium antagonists in membranes is influenced by the molar ratio of cholesterol to phospholipid (C:P). A careful review of these and other related scientific reports, however, yields no evidence for reproducible changes in the membrane C:P molar ratio of diabetic patients that would lead to adverse pharmacologic effects of calcium antagonists.
Mason
R P
RP
Cardiovascular and Pulmonary Research Institute, Department of Biochemistry, MCP-Hahnemann School of Medicine, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212-4772, USA.
Mason
P E
PE
D001792:Blood Platelets / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000097:blood / Q000139:chemically induced* / Q000150:complications*; D002784:Cholesterol / Q000097:blood; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000097:blood; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D010743:Phospholipids / Q000097:blood; D015203:Reproducibility of Results; D012306:Risk
D002121:Calcium Channel Blockers; D010743:Phospholipids; D002784:Cholesterol