Selective loss of microvascular endothelial function in human hypercholesterolemia.

Abstract

BACKGROUND Endothelial dysfunction is increasingly recognized as an early and important feature of vascular disease. Endothelium-dependent vasodilation is impaired in humans with hypercholesterolemia, although it is unknown whether this defect is selective for some pathways of nitric oxide production or indicates a more generalized abnormality of endothelial function. The aim of this study was to further elucidate the nature of endothelial dysfunction in human hypercholesterolemia by comparing vascular responses of agonists that use different signal transduction pathways to activate production of nitric oxide. METHODS AND RESULTS Forearm flow was measured in 12 hypercholesterolemic patients (total cholesterol, 286 +/- 35 mg/dL [mean +/- SD]) aged 50 +/- 11 years and in 12 healthy subjects (total cholesterol, 173 +/- 27 mg/dL) aged 48 +/- 7 years using strain-gauge plethysmography and brachial artery drug infusions. The endothelium-dependent vasodilators used were acetylcholine (7.5, 15, and 30 micrograms/min), which uses a pertussis toxin-sensitive signal transduction pathway, and bradykinin (100, 200, and 400 ng/min), which uses a pertussis toxin-insensitive signal transduction pathway to activate nitric oxide production. Sodium nitroprusside (0.8, 1.6, and 3.2 micrograms/min) was used to test endothelium-independent vasodilation. The maximum flow in response to acetylcholine was markedly impaired in patients compared with healthy subjects (8.0 +/- 5.1 versus 17.5 +/- 7.7 mL.min-1. 100 mL-1, P = .002). However, the maximum forearm flow in response to bradykinin was similar in the two groups (13.0 +/- 4.5 versus 16.2 +/- 5.5 mL.min-1 x 100 mL-, P = .14), as was the maximum flow in response to sodium nitroprusside (7.0 +/- 2.8 versus 8.4 +/- 2.2 mL.min-1 x 100 mL-1, P = .13). NG-Monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, reduced the maximum forearm vasodilation induced by bradykinin to the same extent in patients and in healthy subjects (-29 +/- 8% versus -32 +/- 6% reduction in peak flow, P = .80), with similar maximum flows in response to bradykinin (9.2 +/- 4.0 versus 10.4 +/- 2.6 mL.min-1 x 100 mL-1, P = .35). CONCLUSIONS Hypercholesterolemic patients are capable of normal nitric oxide bioavailability in response to bradykinin. Impairment of microvascular endothelial vasodilator function in human hypercholesterolemia is selective, and the defect occurs at the level of the acetylcholine receptor or its signal transduction pathway.

The Role of Nitric Oxide in Bradykinin-Induced Dilation of Coronary Resistance Vessels in Patients with Hypercholesterolemia.

“…Bradykinin uses a different signal transduction pathway than acetylcholine for this purpose (18,20). Bradykinin also induces dilation of human forearm vessels (18) and coronary resistance vessels (22)(23)(24).…”

“…Bradykinin uses a different signal transduction pathway than acetylcholine for this purpose (18,20). Bradykinin also induces dilation of human forearm vessels (18) and coronary resistance vessels (22)(23)(24). Gilligan et al (18) reported that bradykinin-induced dilation of humanforearm resistance vessels was preserved, whereas acetylcholine-induced dilation was impaired, in hypercholesterolemic patients and suggested that impaired endothelial vasodilator function of the forearm vessels in patients with hypercholesterolemia is related to an abnormality at the level of the muscarinic receptor or its signal transduction pathway.…”

“…Bradykinin also induces dilation of human forearm vessels (18) and coronary resistance vessels (22)(23)(24). Gilligan et al (18) reported that bradykinin-induced dilation of humanforearm resistance vessels was preserved, whereas acetylcholine-induced dilation was impaired, in hypercholesterolemic patients and suggested that impaired endothelial vasodilator function of the forearm vessels in patients with hypercholesterolemia is related to an abnormality at the level of the muscarinic receptor or its signal transduction pathway. In the present study, bradykinin-induced dilation of coronary resistance vessels was impaired, suggesting that impairment of endothelial vasodilator function of coronary resistance vessels dependson the location of the vascular bed.…”

“…Bradykinin, another endothelium-dependent vasoactive agent, is a potent vasodilator that acts through vascular endothelial B2 kinin receptors using a different signal transduction pathway than acetylcholine (18)(19)(20). Bradykinin has been shownto induce endothelium-dependent relaxation of large and small coronary vessels in humans (21)(22)(23)(24)(25).…”

LDL-cholesterol lowering and atherosclerosis - clinical benefit and possible mechanisms: an update

“…It has been shown in animal models that the release of protective, antiaggregating and vasodilating substances is dimin ished due to atherosclerosis of the vessels and also as a consequence of hypercholesterolaemia per se [118][119][120][121][122]. In humans, coronary atherosclerosis and hypercholesterolaemia have also been associated with dysfunction of endothelium-mediated vasomotion, which impairs coronary or myocardial blood flow and forearm blood flow [123][124][125][126]. Lipid-lowering therapy has shown to improve the endothelium medi ated vasomotion after relative short periods of time [127][128][129].…”