Regulation of blood pressure and salt homeostasis by endothelin

Abstract

Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension.

Fig. 1

Biosynthetic and degradation pathways for endothelin (ET)-1. ET-1 mRNA encodes preproET-1. The short signal peptide is cleaved to yield proET-1 which, in turn, is cleaved by furin or PC7 convertases at dibasic amino acids to yield Big ET-1. Big ET-1 is cleaved by different ET converting enzymes (ECE) to mature ET-1. ET-1 is degraded by neutral endopeptidase and deamidase.

Fig. 2

Schema of ET in vasculature. Endothelial cells express ET_B exclusively and are the predominant vascular source of ET-1. ET-1 and nitric oxide synthase 3 (NOS3) can increase ET_B activity or amount, respectively, leading to nitric oxide (NO) and PGE₂ production with resulting vasorelaxation. Activation of vascular smooth muscle ET_A or ET_B leads to a signaling cascade involving G proteins, phospholipase C (PLC), and inositol trisphosphate (IP₃) that activate voltage-operated Ca²⁺ channel (VOC) and sarcoplasmic reticulum (SR)-mediated increases in [Ca²⁺]_i and calmodulin (CaM) activation. CaM, together with activation of protein kinase C (PKC) by diacylglycerol (DAG) and Ras/Raf/ERK1/2 activation, causes myosin light-chain kinase (MLCK) activation and cell contraction.

Fig. 3

Schema of functional ET receptors in the glomerulus and renal arterioles (A), nephron (B), and vasa recta (C). The amount of ET receptor shown in a given area is representative of the level of ET receptor activity in that region. Afferent arteriolar smooth muscle has more vasoconstrictive ET receptors than do efferent arterioles, while efferent arteriole endothelium has more vasodilatory ET_B than does afferent arteriole (A). Podocytes and mesangial cells contain primarily contractile ET_A (A). The inner medullary collecting duct (IMCD) has the greatest density of natriuretic ET receptors, although natriuretic ET receptors exist in the cortical collecting duct (CCD), thick ascending limb (TAL), and proximal tubule (PT) (B). Vasa recta express contractile ET_A on pericytes and vasodilatory ET_B on endothelial cells (C).

Fig. 4

Synthesis and actions of ET-1 in the proximal tubule. ET-1 production is enhanced during inflammation, hypoxia, glomerular injury, and acidemia. Most studies implicate ET_B in mediating ET effects on the proximal tubule, although ET_A activation may result in inhibition of Na reabsorption. ET_B effects appear to depend on the concentration of ET-1, with lower concentrations stimulating Na transport processes and higher concentrations having the opposite effect. It is likely that ET-1 exerts primarily a natriuretic effect on the proximal tubule under physiological conditions. See text for definitions.

Fig. 5

Synthesis and actions of ET-1 in the thick ascending limb. ET-1 production is stimulated by increased medullary osmolality which occurs during high Na intake. ET-1 can then act in an autocrine manner, via ET_B, to stimulate NOS3 activity and inhibit NKCC2. ET_B may also increase 20-HETE with possible inhibition of Na⁺-K⁺-ATPase activity. See text for definitions.

Fig. 6

Synthesis and actions of ET-1 in the collecting duct. ET-1 gene transcription is under complex control, involving transactivators binding to cis-elements in the ET-1 promoter, as well as histone methylation. The latter effect mediates aldosterone stimulation of collecting duct ET-1 production; this may serve as a negative-feedback regulator of aldosterone-stimulated Na transport in this nephron segment. ET_B mediates ET-1 inhibition of water transport, primarily through inhibition of AVP-stimulated adenylyl cyclase (AC) activity. ET_B also mediates ET-1 inhibition of ENaC activity; this involves both NO and MAPK. V2 and AT₁ receptors have been reported to inhibit ET_B expression in this nephron segment. The role of ET_A in regulating collecting duct Na and water transport is uncertain. See text for definitions.

Fig. 7

Synthesis and actions of ET-1 in adrenal cortical zona glomerulosa cells. These cells can synthesize ET-1. ET-1 increases aldosterone production via activation of both ET_A and ET_B, although there is uncertainty as to whether these effects are autocrine and/or paracrine mediated. ET_A activation also leads to zona glomerulosa cell growth and proliferation, increasing the potential to synthesize aldosterone. See text for definitions.

Fig. 8

Synthesis and actions of ET-1 in cardiomyocytes. Stretch, via angiotensin II (ANG II), stimulates ET-1 production. ET-1 can act in an autocrine manner to activate ET_A. This leads through several signaling pathways to increased Na⁺/H⁺ exchange activity which, in turn, activates Na⁺/Ca²⁺ exchange, thereby elevating [Ca²⁺]_i, leading to enhanced cell contraction. ET_B activation opposes this effect. Stretch, through as yet undefined mechanisms, stimulates ET-1 activation of ET_A which leads to increased ANP release. While components of the indicated pathways can regulate ANP production, there remains much uncertainty as to which signaling systems are predominantly involved in the ET-1 effect. See text for definitions.

Fig. 9

Schematic representation of ET-induced AVP secretion. Circulating ET-1 can stimulate neuronal activity in circumventricular organs via ET_A in the subfornical organ (SFO) or ET_B in the area anteroventral to the third ventricle (Av3V). These areas send projections to the supraoptic nucleus (SON) and paraventricular nucleus (PVN) which contain the vasopressinergic magnocellular neurons that release AVP from axon terminals in the posterior pituitary (PP). Stimulation of ET_A or ET_B within the SON leads to inhibition or stimulation, respectively, of AVP secretion. In addition, inputs to the PVN are further integrated; projections from the PVN to brain stem loci lead to increases in sympathetic efferent output and blood pressure. A−, inhibitory ET_A effect; A+, stimulatory ET_A effect; B+, stimulatory ET_B effect.

Fig. 10

Overall scheme of ET receptors in the baroreflex arc. Input from arterial baroreceptors enters the CNS via excitatory synapses with the nucleus tractus solitarius (NTS). NTS excitatory outputs project to the caudal ventrolateral medulla (CVLM), which sends inhibitory outputs to the rostral ventrolateral medulla (RVLM) from which emerge the preganglionic sympathetic neurons that synapse with the post-ganglionic sympathetic neurons within the paravertebral ganglia (G). The NTS and CVLM also send projections to the nucleus ambiguus (NA) and its vagal motor neurons from which emerge the parasympathetic outputs to the heart. Although not technically part of the baroreflex arc itself, the area postrema (AP) is a circumventricular organ outside the blood-brain barrier and receives input from substances within the plasma circulation. Inputs from the AP can modulate NTS neurons. The heart receives both postganglionic efferent sympathetic innervation (tachycardia) and parasympathetic innervation (bradycardia). ET influences the baroreflex arc via ET_A or ET_B receptors (see text for details). Within the central sites, most data support a role for ET_A receptors.

Fig. 11

Integrated systemic effects of ET_B. In general, ET_A activation leads to decreased arterial pressure and natriuresis through effects on the nervous system, heart, adrenal gland, kidney, and vasculature. ET_A-stimulated AVP and aldosterone release may mitigate its anti-hypertensive and natriuretic effects.

Fig. 12

Integrated systemic effects of ET_A. In general, ET_A activation leads to increased arterial pressure and Na retention through effects on the nervous system, heart, adrenal gland, kidney, and vasculature. ET_A-stimulated atrial natriuretic peptide (ANP) release and possibly Na excretion (at least in females) may mitigate its hypertensive and Na-retaining effects.