Under physiological conditions, the endothelium generates vasodilator signals [prostacyclin, nitric oxide NO and endothelium-dependent hyperpolarization (EDH)], for the regulation of vascular tone. The relative importance of these two signals depends on the diameter of the blood vessels: as the diameter of the arteries decreases, the contribution of EDH to the regulation of vascular tone increases. The mechanism involved in EDH varies with species and blood vessel types; nevertheless, activation of endothelial intermediate-and small-conductance calcium-activated potassium channels (IKCa and SKCa, respectively) is characteristic of the EDH pathway. IKCa-and SKCa-mediated EDH are reduced with endothelial dysfunction, which develops with ageing and hypertension, and is less pronounced in female than in age-matched male until after menopause. Impaired EDH-mediated relaxation is related to a reduced involvement of SKCa, so that the response becomes more dependent on IKCa. The latter depends on the activation of adenosine monophosphate-activated protein kinase (AMPK) and silent information regulator T1 (SIRT1), proteins associated with the process of cellular senescence and vascular signalling in response to the female hormone. An understanding of the role of AMPK and/or SIRT1 in EDH-like responses may help identifying effective pharmacological strategies to prevent the development of vascular complications of different aetiologies.