Contribution of endothelium-derived hyperpolarizing factor to exercise-induced vasodilation in health and hypercholesterolemia

Abstract

The role of endothelium-derived hyperpolarizing factor (EDHF) in either the healthy circulation or in those with hypercholesterolemia is unknown. In healthy and hypercholesterolemic subjects, we measured forearm blood flow (FBF) using strain-gauge plethysmography at rest, during graded handgrip exercise, and after sodium nitroprusside infusion. Measurements were repeated after l-NMMA, tetraethylammonium (TEA), and combined infusions. At rest, l-NMMA infusion reduced FBF in healthy but not hypercholesterolemic subjects. At peak exercise, vasodilation was lower in hypercholesterolemic compared to healthy subjects (274% vs 438% increase in FBF, p=0.017). TEA infusion reduced exercise-induced vasodilation in both healthy and hypercholesterolemic subjects (27%, p<0.0001 and -20%, p<0.0001, respectively). The addition of l-NMMA to TEA further reduced FBF in healthy (-14%, p=0.012) but not in hypercholesterolemic subjects, indicating a reduced nitric oxide and greater EDHF-mediated contribution to exercise-induced vasodilation in hypercholesterolemia. In conclusion, exercise-induced vasodilation is impaired and predominantly mediated by EDHF in hypercholesterolemic subjects. CLINICAL TRIAL REGISTRATION IDENTIFIER NCT00166166:

Keywords: endothelial function; endothelium-derived hyperpolarizing factor; exercise; hypercholesterolemia; nitric oxide; vasodilation.

Figure 1.

Study design. Aspirin (975 mg) was administered 1 hour prior to commencement of the study for cyclooxygenase inhibition. Forearm blood flow measurements were performed after handgrip exercise (15%, 30% and 45% of maximum grip strength) and after endothelium-independent vasodilation with intra-arterial sodium nitroprusside (SNP; 1.6, 3.2 μg/min). Measurements were repeated after l-NMMA (16 μmol/min) or TEA (1 μmol/min) and after combined blockade with l-NMMA and TEA.

Figure 2.

Contribution of NO and K⁺_Ca channel activation to resting vascular tone in healthy and hypercholesterolemic subjects. Resting forearm blood flow (FBF) (A and C) and forearm vascular resistance (FVR) (B and D) in response to l-NMMA, TEA, and combined l-NMMA and TEA infusions in 26 healthy (A and B) and 19 hypercholesterolemic subjects (C and D). Data are shown as mean ± 95% confidence intervals. *p-value <0.05 for comparison with baseline.

Figure 3.

Forearm vasodilator response to exercise-induced vasodilation in healthy and hypercholesterolemic subjects. (A) Forearm blood flow (FBF) and (B) forearm vascular resistance (FVR) responses to handgrip exercise in 26 healthy and 19 hyperlipidemic subjects. Data shown as mean ± SEM. *p<0.05, **p<0.005.

Figure 4.

Contribution of K⁺_Ca channel activation, in the presence and absence of nitric oxide, to exercise-induced forearm vasodilation in healthy and hypercholesterolemic subjects. Forearm blood flow (FBF) and forearm vascular resistance (FVR) changes in response to increasing handgrip exercise before and after TEA (1 μmol/min) and combined administration of TEA and l-NMMA (16 μmol/min) in (A) + (C) 10 healthy and (B) + (D) nine hypercholesterolemic subjects. Data shown as mean ± SEM. ⁺p<0.01, **p<0.001.

Figure 5.

Contribution of nitric oxide, in the presence and absence of K⁺_Ca channel activation, to exercise-induced forearm vasodilation in healthy and hypercholesterolemic subjects. Forearm blood flow (FBF) and forearm vascular resistance (FVR) changes in response to handgrip exercise before and after l-NMMA (16 μmol/min) and after combined administration of l-NMMA and TEA (1 μmol/min) in (A) + (C) 16 healthy and (B) + (D) 10 hypercholesterolemic subjects. Data shown as mean ± SEM. ⁺p<0.05, *p<0.01, **p<0.001.