Endothelium-dependent contractions and endothelial dysfunction in human hypertension

Abstract

The endothelium is a crucial regulator of vascular physiology, producing in healthy conditions several substances with a potent antiatherosclerotic properties. Accordingly, the presence of endothelial dysfunction is associated with subclinical atherosclerosis and with an increased future risk of cardiovascular events. A large body of evidence supports the fundamental role of nitric oxide (NO) as the main endothelium-derived relaxing factor. However, in the presence of pathological conditions, such as hypertension, endothelial cells, in response to a number of agents and physical stimuli, become also a source of endothelium-derived contracting factors (EDCFs), including endothelins and angiotensin II and particularly cyclooxygenase-derived prostanoids and superoxide anions. These latter were at first identified as responsible for impaired endothelium-dependent vasodilation in patients with essential hypertension. However, cyclooxygenase-dependent EDCFs production is characteristic of the aging process, and essential hypertension seems to only anticipate the phenomenon. It is worth noting that both in aging and hypertension EDCF production is associated with a parallel decrease in NO availability, suggesting that this substance could be oxygen free radicals themselves. Accordingly, in hypertension both indomethacin, a cyclooxygenase inhibitor, and vitamin C, an antioxidant, increase the vasodilation to acetylcholine by restoring NO availability. In conclusion, hypertension is characterized by a decline in endothelial function, associated with a progressive decrease in NO bioavailability and increase in the production of EDCF. The mechanisms that regulate the balance between NO and EDCF, and the processes transforming the endothelium from a protective organ to a source of vasoconstrictor, proaggregatory and promitogenic mediators remain to be determined.

Figure 1

Schematic representation of the perfused forearm technique to evaluate endothelial function in human peripheral microcirculation. The brachial artery of the non-dominant forearm is cannulated for drug infusion at systemically ineffective rates, intra-arterial blood pressure (BP) and heart rate (HR) monitoring. Forearm blood flow is measured by strain-gauge venous plethysmography.

Figure 2

Schematic representation of the interplay between endothelium-derived relaxing (nitric oxide – NO) and contracting factors. Under endothelial stimulation nitric oxide synthase (eNOS) is stimulated to generate NO from L-arginine and NO, diffusing to the underlying smooth muscle cells, induces relaxation by increasing the production of cyclic-GMP. In pathologic conditions, such as hypertension, endothelial stimulation also leads to an increased production of superoxide anions (O₂^–) by NADPH-oxidase (NADPH-ox) and cyclooxygenase (COX). Released superoxide is able to scavenge NO, thus reducing its bioavailability and impairing endothelium-dependent vasodilation. Additionally, stimulated COX also produces endoperoxides and consequently thromboxane-A₂, prostaglandin-E₂, prostaglandin-F_2α prostaglandin-D₂ and prostacyclin, which binding to a specific receptor (TP) on smooth muscle cells, cause vasoconstriction.

Figure 3

Change in forearm blood flow (FBF%) in the forearm microcirculation in response to increasing doses of the endothelium-dependent vasodilator acetylcholine in healthy subjects and hypertensive patients. (A) Both essential and secondary hypertensive patients clearly show a reduced maximal vasodilation to acetylcholine. Moreover, only in healthy subjects this response is inhibited by the co-administration of the eNOS inhibitor L-NMMA, demonstrating the presence of endothelial dysfunction in hypertensive patients (role of NO). (B) The vasodilation to acetylcholine is not influenced by the co-administration of the COX-inhibitor indomethacin in healthy subjects and in secondary hypertension, while it is improved in essential hypertensives, demonstrating the significant role of COX-derived contracting factors in this patients. Reproduced using data from Taddei et al. (1997b). COX, cyclooxygenase; eNOS, nitric oxide synthase; L-NMMA, monomethyl-L-arginine.

Figure 4

Bars show the potentiating effect induced by indomethacin infusion (50 µg·100 mL^–1 forearm tissue per minute) on the vasodilating response to acetylcholine in normotensive subjects and patients with essential hypertension divided into subgroups according to age.