critical aspect of the RAS in humans is the presence of its components in the tissues of many organs, including blood vessels. Renin and angiotensinogen may be taken up from the plasma or locally synthesized in blood vessels. Since angiotensin II is capable of releasing NE from nerve endings, it could effect smooth muscle contraction either by its own direct action or through NE. It is also known that angiotensin II is capable of inducing vascular smooth muscle cell hypertrophy, and thus its long-term effects could alter the vascular response to antihypertensive treatment. For example, angiotensin II could be responsible in part for the loss of compliance of the aorta and other large vessels. This would influence the development of systolic hypertension that would cause further vascular damage and stiffening. We have shown in an experimental model of hypertension (interrenal aortic coarctation) that the aorta above the constriction, which is exposed to hypertension and is distended, exhibits upregulation of the angiotensin II type 1 (AT1) receptor mRNA and the expression of the receptor protein [31]. Over-expression of AT1 receptors would lead “normal” levels of angiotensin II to bind in greater amounts and exert Fig. 3. Different responses to salt and water loading leading to hypertension in anephric and ESRD patients [19]. Martinez-Maldonado: Pathophysiology of hypertension in ESRD S-69 a greater pressor effect. It would also explain why exogenous infusion of angiotensin II does not increase vascular reactivity in ESRD patients [24]. A detailed analysis of these aspects in ESRD patients remains to be performed. ENDOTHELINS Endothelin-1 (ET-1) has been implicated in the genesis of hypertension in chronic renal failure. Patients with ESRD or reduced nephron mass, as induced by unilateral nephrectomy, have elevated circulating levels of the peptide [32, 33]. The levels of ET-1 have correlated with hypertension in some, but not all studies, but the use of various assays makes comparisons among these studies difficult [34]. Data exist supporting decreased renal clearance of ET-1 in hypertension and, since the kidney is a major site of ET-1 metabolism, reduced nephron mass might prolong its half-life. In fact, ET-1 clearance is reduced in patients with chronic renal failure since its urinary excretion is lower than in normal controls [34]. Since most ET-1 is nephrogenous, the reduced clearance in the presence of higher plasma levels suggests, but does not prove, that it is secreted into the blood in the presence of renal disease. A proposal as to how ET-1 may influence blood pressure in the presence of mild to moderate reductions in renal function is shown in Figure 4. NITRIC OXIDE Evidence for a role of nitric oxide (NO) in experimental one-kidney, one-clip hypertension is of interest since this model resembles one of the hemodynamic responses to salt loading in anephric or ESRD patients. The onset of hypertension in this model is mediated by an increase in cardiac output, but eventually total peripheral resistance is elevated (whole body autoregulation) [7]. Upon removal of the clip, blood pressure and cardiac output fall and a natriuresis and diuresis ensue. Saline infusion delays the hemodynamic recuperation, but does not prevent it, indicating a multifactorial mechanism in the genesis of the hypertension. A number of vasoactive substances have been considered mediators (including the RAS, kallikreinkinin system, prostaglandins, and platelet activating factor) of the response, but evidence in support of such a role has not been forthcoming. On the other hand, inhibition of NO synthesis prevents the reversal of hypertension upon clip removal, and a sulfhydryl group donor (N-acetyl-L-cysteine) that protects NO from free radical destruction potentiates the effect of unclipping [7]. Experimental inflammatory renal diseases, such as glomerulonephritis, have been shown to increase NO production while renal ablation or glomerulosclerosis reduce production of NO and excretion of urine nitrates [35]. Patients with mild, essential salt-sensitive hypertension, if salt loaded, will respond with an increased renal vascular resistance and impaired ability to produce NO by the renal circulation compared to salt-resistant patients [36]. Recently, it has been shown that vasodilation to acetylcholine is reduced in salt-sensitive hypertensive patients, even on a restricted salt diet [37] Moreover, salt-sensitive rats (DahlRapp and Dahl) have a genetic defect in nitrosovasodilation, emphasizing the importance of NO in extracellular volume regulation. Unfortunately, data are not available to shed light on the role of NO in the hypertension of ESRD or anephric patients [37]. OTHER VASODEPRESSORS Few studies have examined the role of prostaglandin and the kallikrein-kinin system in the genesis of hypertension in early- and late-stage renal disease, but the results are inconclusive. Theoretically, compounds that reduce vascular tone may help counteract the vasoconstrictive effects of constrictor agents, such as angiotensin II, norepinephrine and endothelin-1. Attempts to measure in urine and blood the concentration of these compounds have revealed ranges that run the gamut from low to high. Equally unclear is the role of atrial natriuretic peptide in the hypertension Fig. 4. Endothelin-1 (ET-1) can contribute to hypertension in several