Figure 131

Atrial natriuretic peptide (ANP). In response to increased intravascular volume, atrial distention stimulates the release of ANP from the atrial granules where the precursor is stored. Extracellular fluid volume expansion is associated with increased ANP levels, whereas reductions in vascular volume and dehydration elicit decreases in plasma ANP levels. ANP participates in arterial pressure regulation by sensing the degree of vascular volume expansion and exerting direct vasodilator actions and natriuretic effects. ANP has been shown to markedly increase the slope of the pressure natriuresis relationship (see Figs. 1-5 and 1-6). The vasorelaxant and transport actions are mediated by stimulation of membrane-bound guanylate cyclase, leading to increased cyclic GMP levels. ANP also inhibits renin release, which reduces circulating angiotensin II levels [33-35]. Related peptides, such as brain natriuretic peptides, have similar effects on sodium excretion and renin release [36].

Arachidonic acid metabolites. Several eicosanoids (arachidonic acid metabolites) are released locally and exert both vasoconstrictor and vasodilator effects as well as effects on tubular transport [16,37]. Phospholipase A2 catalyzes formation of arachidonic acid (an unsaturated 20-carbon fatty acid) from membrane phospholipids. The cyclooxygenase pathway and various prostaglandin synthetases are responsible for the formation of endoperoxides (PGH2), prostaglandins E2 (PGE2) and I2 (PGI2), and thromboxane (TXA2) [38,39].

States of volume depletion and hypoperfu-sion stimulate prostaglandin synthesis [16,17,38].

The vasodilator prostaglandins attenuate the influence of vasoconstrictor substances during activation of the renin-angiotensin system, sympathetic nervous system, or both [33]. These prostaglandins also have transport effects on renal tubules through activation of distinct prostaglandin receptors [40]. In some pathophysiologic conditions, enhanced production of TXA2 and other vasoconstrictor prostanoids may occur. The vasoconstriction induced by TXA2 appears to be mediated primarily by calcium influx [17,40].

Leukotrienes are hydroperoxy fatty acid products of 5-hydroperoxyeicosatetraenoic acid (HPETE) that are synthesized by way of the lipoxygenase pathway. Leukotrienes are released in inflammatory and immunologic reactions and have been shown to stimulate renin release. The cytochrome P450 mono-oxygenases produce several vasoactive agents [16,37,41,42] usually referred to as EETs and hydroxy-eicosatetraenoic acids (HETEs). These substances exert actions on vascular smooth muscle and epithelial tissues [16,41,42]. (Adapted from Navar [3].)

Kallikrein-kinin system Low molecular weight kininogen High molecular weight kininogen

Tissue kallikrein^^ ^^ Plasma kallikrein Bradykinin

Kininase I

Kininase II (ACE) NEP

Des Arg-bradykinin ^^ Kinin degradation products

B2-receptor

^^Endothelium-dependent

B1-receptor t Nitric oxide

Vasodilation natriuresis

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