Relationship between endothelin and nitric oxide pathways in the onset and maintenance of hypertension in children and adolescents

Abstract

The mechanisms that regulate blood pressure are numerous and complex; one mechanism that plays an important role in this scenario is represented by the balance between the vasoconstrictor effect of endothelin-1 and the vasodilator effect of nitric oxide. While there is agreement on the fact that increased endothelin-1 activity and decreased nitric oxide bioavailability are present in hypertensive adults, the situation is less clear in children and adolescents. Not all studies agree on the finding of an increase in plasma endothelin-1 levels in hypertensive children and adolescents; in addition, the picture is often confused by the concomitant presence of obesity, a condition that stimulates the production of endothelin-1. Furthermore, there is recent evidence that, in younger obese and hypertensive subjects, there is an overproduction of nitric oxide, rather than a reduction. This condition may change over time, causing endothelial dysfunction due to a reduced availability of nitric oxide in hypertensive adolescents. The purpose of this review is to address the main biochemical and pathophysiological aspects of endothelin and nitric oxide involvement in hypertension and to summarize the available scientific evidence on their role in the onset and maintenance of high blood pressure in children and adolescents.

Keywords: Adolescents; Children; Endothelin-1; Hypertension; Nitric oxide; Obesity.

Fig. 1

Activation of endothelin and interaction with receptors. ANS, autonomic nervous system; CNS, central nervous system; ECE, endothelin-converting enzyme; ET, endothelin

Fig. 2

Balance between nitric oxide-mediated vasodilatory and ET-1-mediated vasoconstrictive activity. In larger arteries (conduit arteries), NO-dependent vasodilation is predominantly sGMP mediated, while EDH factors are more active in smaller arteries (resistance arteries). cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; ECE, endothelin-converting enzyme; EDHf, endothelium-dependent hyperpolarization factors; eNOS, endothelial NO synthases; ET_A/ET_B, endothelin receptors; ET, endothelin; KCa, calcium-dependent potassium channels; L-arg, L-arginine; NO, nitric oxide; PGs, prostaglandins; PLA2, phospholipase A2; sGC, soluble guanylate cyclase

Fig. 3

Hypotheses about NO and ET-1 changes in the onset and maintenance of hypertension from childhood to adulthood. NO, nitric oxide; ET-1, endothelin-1