Hypertension

As strange as it may seem, it has been difficult to establish a precise definition of hypertension. The problem was best stated by Sir George Pickering, who wrote that “there is no dividing line. The relationship between arterial blood pressure and mortality is quantitative; the higher the pressure the worse the prognosis” (Pickering and Pickering, 1995; Pickering et al, 1996). Indeed, cumulative data obtained from insurance companies have validated this point! Untreated blood pressure in excess of 140/90 mm Hg is associated with excess mortality, and diastolic pressures below 70 mm Hg are optimal (Lew, 1973). For operational purposes, the World Health Organization has defined hypertension in adults as a systolic pressure greater than 160 mm Hg or a diastolic pressure greater than 95 mm Hg or both. In addition, consistent elevation of blood pressure should be established with repeated readings before evaluation is instituted. In children, there is a rise in blood pressure with age; an upper normal limit of 130/80 mm Hg is reached by 12 to 15 years of age.

Renal Arterial Disease versus Renovascular Hypertension

The development of arteriography provided an accurate means of identifying renal arterial disease and heralded the advent of renal arterial vascular repair (Freeman et al, 1954), which renewed enthusiasm for surgical management of the disease. However, it soon became apparent that normotensive patients undergoing arteriography for other reasons often had renal arterial disease (Eyler et al, 1962), especially those with arteriosclerotic disease (Wilms et al, 1990), and autopsy figures supported the radiologic findings (Holley et al, 1964). Accordingly, the finding of renal arterial disease alone is not sufficient justification to warrant correction in a hypertensive patient. The lesion must be functionally significant (i.e., it must reduce blood flow by an amount sufficient to activate renin release, initiating RVH). Hence, a practical definition of RVH is hypertension resulting from a renal arterial lesion that is relieved by correction of the offending lesion or removal of the kidney.

Atherosclerosis

Approximately 70% of all renovascular lesions are caused by atherosclerosis (Novick et al, 1996). This disease may be limited to the renal artery but more commonly is a manifestation of generalized atherosclerosis, involving the abdominal aorta and coronary, cerebral, and lower extremity vessels. Atherosclerotic stenosis usually occurs in the proximal 2 cm of the renal artery, and distal arterial or branch involvement is distinctly uncommon. Owing to the proximal location of these lesions, oblique aortic views are often needed to adequately visualize the area of stenosis. The lesion involves the intima of the artery and, in two thirds of the cases, presents as an eccentric plaque (Fig. 39–1); in the remainder, the vessel is circumferentially involved, with narrowing of the lumen and destruction of the intima. Dissecting hematomas frequently complicate this disease, sometimes resulting in thrombosis of the entire vessel.

Figure 39–1 Histopathologic appearance of eccentric atherosclerotic plaque causing renal artery stenosis.

The natural history of atherosclerotic renal artery disease (RAD) has been studied by obtaining sequential abdominal aortography or duplex ultrasound scanning in patients with documented renal artery lesions who have been treated medically (Table 39–2). The largest of these studies have shown that progressive arterial obstruction occurs in 42% to 53% of patients with atherosclerotic renal artery disease, often within the first 2 years of radiographic follow-up. The incidence of progression to complete renal artery occlusion in these studies has ranged from 9% to 16%, and this has occurred more often in arteries that initially showed high degrees of stenosis.

Table 39–2 Natural History of Atherosclerotic Renal Artery Sclerosis

Schreiber and colleagues (1984) reviewed the natural history of atherosclerotic renal artery stenosis (ARAS) in 85 patients who were followed with sequential renal angiograms obtained 3 to 172 months after an initial diagnostic angiogram. Progressive obstruction of the renal artery due to atherosclerosis occurred in 37 patients (44%), including 14 (16%) in whom such progression eventuated in complete occlusion of the involved renal artery. In patients in whom progressive disease developed, it occurred primarily within the first 2 years of angiographic follow-up. The rate of progression of ARAS correlated directly with the degree of stenosis on the initial angiogram. The majority of renal arteries with mild (50%) or moderate (50% to 75%) stenosis on the initial angiogram were unchanged on follow-up angiograms. In contrast, 39% of renal arteries with more than 75% stenosis on the initial angiogram progressed to complete occlusion. Other studies have since validated this observation that progression to 100% occlusion occurs more often and more rapidly in renal arteries that are initially involved with a high degree (>75%) of stenosis (Tollefson and Ernst, 1991; Zierler et al, 1994).

Clinical follow-up of patients in the same study (Schreiber et al, 1984) also revealed that significantly more patients with progressive disease developed deterioration of overall renal function compared with patients with stable disease. Interestingly, serial blood pressure control was equivalent in these two groups, indicating that blood pressure is not a useful clinical marker for progressive ARAS.

These natural history data clearly show that atherosclerotic renal artery disease progresses in many patients, and that loss of functioning renal parenchyma is a common sequela of such progression. Such loss of renal function due to progressive atherosclerotic renal artery obstruction can result in end-stage renal disease (ESRD). In this setting, ESRD occurs in older patients with generalized atherosclerosis who are not suitable candidates for transplantation and whose prognosis on chronic dialysis is poor in terms of both the quality of life and longevity. An early study identified 25 patients in whom ESRD was clearly a consequence of advanced atherosclerotic renal artery disease (Novick, 1994b). Seventeen of these patients were maintained on chronic dialysis, and, of these, 13 died within 1 year (mean survival 8.7 months). The causes of death on dialysis were myocardial infarction (6), infection (2), gastrointestinal bleeding (1), ruptured aortic aneurysm (1), mesenteric infarct (1), cardiogenic shock (1), and cerebrovascular accident (1). In a subsequent study, Mailloux and colleagues (1988) analyzed the survival of patients started on dialysis from 1970 to 1985 according to the primary renal diagnosis. Patients with renovascular disease as the cause of ESRD had the poorest survival, with a 27-month median survival time and a 12% 5-year survival rate. In another study, in which 51 patients with bilateral ARAS were followed for 52 months, 12% of the patients progressed to ESRD, and an average rate of decline of GFR of 4 mL/min/yr was noted (Baboolal et al, 1998). A crude mortality rate of 45% was reported. These data further highlight that ESRD from atherosclerotic renal artery disease does not respond well to renal replacement therapy.

The exact incidence of ESRD caused by atherosclerotic renal artery disease in the United States is not known. Fatica and colleagues (2001) reported an increase in incidence of renal vascular disease (RVD) as a cause for ESRD in patients starting dialysis treatment. This increase was from 1.4% to 2.1%, with an annual increase of 12%. This information was derived from the recorded diagnosis of these patients in the U.S. Renal Data System database, and the disease was not specifically searched for. No increase in mortality on dialysis was found in these patients when compared with other etiologies of ESRD.

When investigating the use of CT angiography, van Ampting and coworkers (2003) reported a 27% incidence of significant renal artery stenosis (RAS) in 49 patients over 45 years of age starting dialysis.

Uzu and coworkers (2002) reported a higher (50%) incidence in 44 patients with ESRD who were studied by magnetic resonance angiography when additional vascular disease (cerebral, coronary, or peripheral) was also diagnosed.

In a report from England, Scoble and colleagues (1989) prospectively performed renal arteriography in all new patients with ESRD during an 18-month period. Atherosclerotic renal artery disease was the cause of ESRD in 6% of all patients, and in 14% of patients older than 50 years. Approximately 300,000 patients in the United States are currently being maintained on chronic dialysis. Their median age is older than 60 years, and a majority show evidence of generalized atherosclerosis obliterans. Although the exact number of patients with ESRD caused by atherosclerotic renal artery disease is not known, based on the data previously described, there appear to be several thousand patients in this category.

Fibrous (Fibromuscular) Dysplasia

Fibrous dysplasia (FD) is a nonatherosclerotic noninflammatory vascular disorder with multiple subtypes depending upon the portion of the vessel wall that is primarily involved. The vast majority of cases affect the media (medial fibroplasia); less common is perimedial fibroplasia, intimal fibroplasia, and fibromuscular hyperplasia.

Intimal Fibroplasia

Primary intimal fibroplasia occurs in children and in young adults and constitutes approximately 10% of the total number of fibrous lesions. This lesion is characterized by a circumferential accumulation of collagen inside the internal elastic lamina (Fig. 39–2). Disruption and duplication of the elastica interna occur more often in younger patients, with dissecting hematomas as a complication in many patients. The possibility of atherosclerosis as a cause of renal artery disease in this group can be excluded histologically by the absence of lipid demonstrable with special staining techniques. Intimal fibroplasia with complicating medial dissection is characterized pathologically by large dissecting channels in the outer half of the media. These lesions are thought to develop because of defects in the internal elastica with resultant medial dissection and aneurysmal dilatation.

Figure 39–2 A, Photomicrograph of a cross section demonstrates intimal fibroplasia with focal fragmentation and partial absence of the elastica interna. B, Photomicrograph of cross section demonstrates severe renal arterial intimal fibroplasia with a dense cuff of intimal collagen apposed to the luminal surface of a partially disrupted elastica interna. A small recannulized channel is noted in the lower left.

(From Novick AC. Renal vascular hypertension in children. In: Kelalis PP, King LR, Belman AB, editors. Clinical pediatric urology. Philadelphia: WB Saunders; 1984.)

Angiography in primary intimal fibroplasia reveals a smooth, fairly focal stenosis, usually involving the proximal or midportion of the vessel or its branches (Fig. 39–3). Dissecting hematomas may distort the area of the stenosis. With nonoperative management, progressive renal artery obstruction and ischemic atrophy of the involved kidney invariably occur. Severe intimal fibroplasia may subsequently develop de novo in the contralateral renal artery. Although primary intimal fibroplasia most commonly affects the renal arteries, it may also occur as a generalized disorder with concomitant involvement of carotid, upper and lower extremity, and mesenteric vessels.

Figure 39–3 Aortogram of a 6-year-old boy demonstrates proximal left renal artery stenosis (arrow) from intimal fibroplasia.

(From Novick AC. Renal vascular hypertension in children. In: Kelalis PP, King LR, Belman AB, editors. Clinical pediatric urology. Philadelphia: WB Saunders; 1984.)

Medial Fibroplasia

Medial fibroplasia is the most common of the fibrous lesions, constituting 75% to 80% of the total number. It tends to occur in women between the ages of 25 and 50 years and often involves both renal arteries. It may involve other vessels in the body, most notably the carotid, mesenteric, and iliac arteries. Microscopically, the internal elastic membrane is focally and variably thinned and lost. Within the alternating thickened areas, much of the muscle is replaced by collagen, hence the term medial fibroplasia. In other areas, thinning of the media occurs to the point of complete loss, and microaneurysms can be seen as saccules lined by only the external elastica. In extreme cases, giant aneurysms may be found in association with medial fibroplasia.

Angiographically, medial fibroplasia demonstrates a typical “string of beads” appearance involving the distal two thirds of the main renal artery and branches (Fig. 39–4). The areas of stenosis are often overshadowed by contrast medium in the microaneurysms, making the degree of actual stenosis difficult to assess. The aneurysms themselves are greater in diameter than the normal renal artery proximal to the disease, and extreme collateral circulation is absent. These are important features in differentiating the lesion from perimedial fibroplasia. Schreiber and colleagues (1984) studied the natural history of renal artery disease due to medial fibroplasia in 66 patients who were followed with serial angiography. Progressive renal artery stenosis (RAS) occurred in 22 patients (33%), and, contrary to an earlier report, this occurrence was no different whether patients were older or younger than 40 years. Significantly, there were no cases of progression to total arterial occlusion in this group. Also, clinical follow-up revealed that serial decreases in either overall renal function or the size of the involved kidney seldom occurred in patients with progressive medial fibroplasia, suggesting that the risk of losing renal function is relatively small in patients with this disease who are managed medically.

Figure 39–4 Selective right renal arteriogram reveals medial fibroplasia involving the main renal artery with typical “string of beads” appearance.

(From Novick AC. Renal vascular hypertension in children. In: Kelalis PP, King LR, Belman AB, editors. Clinical pediatric urology. Philadelphia: WB Saunders; 1984.)

Perimedial Fibroplasia

Perimedial fibroplasia occurs predominantly in young women between the ages of 15 and 30 years and has therefore been referred to, rather crudely, as girlie disease. It constitutes about 10% to 15% of the total number of fibrous lesions and occurs only in the renal artery. This is a tightly stenotic lesion that, pathologically, consists of a collar of dense collagen enveloping the renal artery for variable lengths and thicknesses. The collagen is deposited in the outer border of the media, usually replaces a considerable portion of the media, and may replace it completely in some areas (Fig. 39–5). Islands of smooth muscle are occasionally seen trapped within the collagenous ring. Special stains show that the lesion is confined within the external elastic lamina and contained in all cases by intact adventitial connective tissue. The arterial lumen may be further compromised by a process of secondary intimal fibroplasia. It has been suggested that this secondary thickening of the intima is related to slowing of blood flow through a narrowed arterial segment, with resultant platelet and fibrin deposition and subsequent fibrous organization.

Figure 39–5 Cross section of the main renal artery in a girl with perimedial fibroplasia demonstrates a dense collagenous collar (arrows) involving the outer media of the vessel, which causes a severe progressive stenosis.

(From Novick AC. Renal vascular hypertension in children. In: Kelalis PP, King LR, Belman AB, editors. Clinical pediatric urology. Philadelphia: WB Saunders; 1984.)

The arteriogram in perimedial fibroplasia may give the appearance of arterial beading, but careful observation shows that the caliber of the normal segment of the vessel is not exceeded by the “bead” (Fig. 39–6). This fact, along with the frequent occurrence of extensive collateral circulation, differentiates this lesion angiographically from that of medial fibroplasia. Perimedial fibroplasia produces severe stenosis, and, although complicating thrombosis or dissection is relatively uncommon, progressive obstruction with ischemic renal atrophy occurs in almost all patients managed nonoperatively.

Figure 39–6 Renal arteriogram in a patient with perimedial fibroplasia shows slightly irregular, yet severe, stenosis of the midrenal artery (arrows) associated with extensive collateral circulation to the kidney. The small size of the arterial irregularities and the presence of collateral circulation distinguishes this lesion radiographically from medial fibroplasia.

(From Novick AC. Renal vascular hypertension in children. In: Kelalis PP, King LR, Belman AB, editors. Clinical pediatric urology. Philadelphia: WB Saunders; 1984.)

Angiotensinogen

Angiotensinogen is a 452–amino acid protein and is the source of all angiotensins (Kageyama et al, 1984). It is formed as preangiotensinogen and loses the signal peptide as it becomes secreted from the cell as angiotensinogen. It functions as a serine protease inhibitor (serpin) similar to α₁-antitrypsin and antithrombin III, with which it shares some structural homology (Carrell et al, 1987). It is present in plasma in two forms, a smaller (52- to 60-kD) predominant molecule and a larger (450- to 500-kD) molecule that increases in pregnancy and after estrogen treatment (Tewksbury and Dart, 1982). The larger form is probably composed of the smaller molecule bound to other plasma proteins. Renin acts on the smaller form of angiotensinogen preferentially, cleaving AI off the larger molecule. Renin reacts with much less affinity with the larger form, also forming AI.

The liver is the primary site of synthesis of angiotensinogen, which is not stored but secreted directly after production. Angiotensinogen mRNA is widely present in several tissues that are regulated by local renin-angiotensin systems, including the central nervous system (CNS), kidney, adrenal, heart, and leukocytes (Dzau et al, 1987). Several hormones stimulate angiotensinogen synthesis by the liver, including estrogens and glucocorticoids. Stressful stimuli, such as infection or tissue injury, also increase plasma angiotensinogen levels (Hoj Nielsen and Knudsen, 1987). Feedback control through the RAAS is also present, with AII increasing and renin decreasing plasma levels of angiotensinogen.

Renin

Renin is a single–polypeptide chain aspartyl protease that is secreted from the juxtaglomerular cells of the afferent arteriole. The kidney is the major site of renin production, although renin mRNA is found in several other tissues where a local renin-angiotensin system functions. It is produced as pre-prorenin, and both active renin and prorenin are secreted (Atlas et al, 1980). The function of circulating prorenin is not clear, and it does not appear that prorenin is transformed to active renin in the circulation (Sealey et al, 1977). The action of renin is very specific, restricted to cleavage of a single bond, separating AI from angiotensinogen. Because renin controls the rate-limiting step of the RAAS, control of renin secretion regulates the activity of the RAAS. Several mechanisms affect the secretion of renin, as described in the following sections.

As the first and rate-limiting step for production of angiotensin II, targeting renin is an attractive option for inhibiting the RAAS. Recently a new class of orally effective medications targeting renin has been developed and approved for treatment of hypertension, direct renin inhibitors (DRI). The first of these medications is aliskiren, is a competitive analog and specific inhibitor of human renin, with therapeutic potential similar to other available antagonists of the RAAS (ACE inhibitors, angiotensin receptor blockers) (Nussberger et al, 2002).

Macula Densa Mechanism

The macula densa region of the thick ascending loop of Henle comes in close proximity to the juxtaglomerular cells and influences renin release. Reduction of distal tubule salt delivery stimulates renin secretion, and vice versa. Although sodium was initially thought to be responsible for this action, it now appears that the signal for macula densa–controlled renin release is the alteration of tubular chloride concentration (Lorenz et al, 1990).

Baroreceptor Mechanism

The juxtaglomerular cells of the afferent arteriole act as their own baroreceptors by responding directly to stretch of the afferent arteriole (Tobian et al, 1959). Diminished cell stretch, as a result of renal hypoperfusion, hyperpolarizes the juxtaglomerular cells, resulting in decreased intracellular calcium and increased renin release.

Neural Mechanism

The juxtaglomerular cells are richly innervated by β-adrenergic sympathetic nerve fibers. Stimulation of these β-adrenergic nerves leads to increased renin secretion (Keeton and Campbell, 1980). Dopamine is also stimulatory to renin release, although the limited number of dopaminergic nerve endings results in a much smaller role (Mizoguchi et al, 1983). Renal nerve stimulation is the mechanism through which renin release is increased as a result of exercise and tilting.

Endocrine and Paracrine Mechanisms

Several local and systemic hormones affect the rate of renin secretion. Foremost among these are prostaglandins. Prostaglandin E₂ and I₂ (prostacyclin), as well as exogenously administrated arachidonic acid, stimulate renin secretion (Franco-Saenz et al, 1980; Whorton et al, 1980). This prostaglandin effect is independent of the other mechanisms controlling renin release. AII inhibits renin release as a feedback mechanism. Other inhibitors of renin release include endothelin, vasopressin, and atrial natriuretic peptide.

Intracellular Mechanisms

Agents that increase adenylate cyclase activity increase the secretion of renin, including β-adrenergic agonists, prostaglandin E₂, prostaglandin I₂, dopamine, histamine, and parathyroid hormone. This is because cyclic adenosine monophosphate (cAMP) is an important second messenger in renin release. Intracellular calcium concentrations are also important in controlling renin release. AII, vasopressin, and adenosine increase intracellular calcium levels and inhibit renin secretion through their effect on intracellular calcium levels.

Angiotensin-Converting Enzyme

ACE is a zinc-containing single-chain glycoprotein enzyme. It is also known as kininase II and is a dipeptidyl carboxypeptidase (Ehlers and Riordan, 1989). It splits two amino acids off the carboxy terminus of AI to form AII and, at the same time, functions in the kallikrein-kinin system by inactivating bradykinin. ACE is found in a wide variety of organs, where it is primarily expressed on endothelial, epithelial, and neuroepithelial cells. A high concentration of ACE is found in the kidney, ileum, duodenum, and uterus (Lieberman and Sastre, 1983). Although pulmonary endothelial ACE was presumed to be the major site of ACE activity for the systemic RAAS, it is now believed that peripheral sites might play an equal role. The majority of circulating ACE originates from endothelial cells and macrophages.

ACE is expressed in several tissues where local renin-angiotensin systems function. Renal ACE is localized to the glomerular endothelial cells and the proximal tubule brush border, where it might play a role in cleaving filtered protein for reabsorption (Danilov et al, 1987). Within the CNS, ACE is found in several locations, where it functions in the local renin-angiotensin system. This local CNS renin-angiotensin system is thought to have dipsogenic and hypertensive effects as well as to stimulate vasopressin secretion (Strittmatter and Snyder, 1987). Adrenal ACE is found predominantly in the medulla, where it is thought to stimulate catecholamine secretion (Peach et al, 1971). ACE is found abundantly in the testes and prostate, in the Leydig cells, and also in cytoplasmic droplets in sperm (Pandey et al, 1984; Yotsumoto et al, 1984). In the female reproductive tract, ACE is found in follicular and fallopian tube oocytes (Brentjens et al, 1986). The precise role of ACE in the reproductive system has not been elucidated. Several hormones and disease states affect the level and activity of ACE. Corticosteroids, as well as thyroid hormones, stimulate ACE activity (Friedland et al, 1978; Smallridge et al, 1983). The serum ACE level is increased in silicosis, primary biliary cirrhosis, and sarcoidosis (Studdy et al, 1983). As mentioned previously, ACE is not the rate-limiting step in the RAAS cascade; so, changes in serum ACE levels do not directly affect the activity of the systemic RAAS (circulating AII levels).

In addition to ACE, several angiotensinases act in the RAAS to lesser degrees. The physiologic contribution of these enzymes to the function of the RAAS is not clear. Most of these enzymes are present in body tissues such as the kidney. Among these are aminopeptidase A and angiotensinase A, B, and C. Nonspecific angiotensinases hydrolyze AII and angiotensin III (AIII), inactivating them rapidly.

Angiotensin II

The role of the RAAS in the control of blood pressure and extracellular volume is carried out through the integration of a variety of actions performed by AII. Vasoconstriction and the release of aldosterone occur immediately and are of short duration, supporting the role of AII in maintaining tissue perfusion in hypovolemia. Other actions such as vascular growth and ventricular hypertrophy are slower in onset and longer in duration, lasting for several days or weeks.

Effect of Angiotensin II on Glomerular Circulation

One of the most important actions of AII is the autoregulation of the GFR in response to changes in renal perfusion. These are affected through changes in vascular resistance as well as mesangial cell tone. AII causes a marked increase in efferent arteriolar resistance in cases of renal hypoperfusion but does not affect afferent arteriolar resistance unless there is an increase in renal perfusion pressure. The result of this disproportionate increase in efferent over afferent resistance is an increase in capillary hydraulic pressure, and subsequently in filtration pressure, maintaining the GFR in the face of decreased renal perfusion (Hall et al, 1977). It is through inhibition of this action that ACE inhibitors result in a decrease in GFR in cases of renal artery stenosis. This effect of AII on the glomerular circulation is thought to be mediated through differential induction of vasodilatory prostaglandins from the afferent and efferent vessels (Hura and Kunau, 1988).

In addition to its effects on the glomerular vessels, AII directly results in mesangial cell contraction, leading to a decrease in the filtration coefficient of the glomerulus (Blantz et al, 1976).

Tubular Effects of Angiotensin II

AII-induced increases in the filtration fraction lead to an increase in the oncotic pressure in the postglomerular vessels. This leads to an increase in fluid reabsorption in the proximal tubules. AII receptors are also present on the proximal tubule brush border and basolateral sides, and AII is produced in large amounts locally within the proximal tubules. AII is present within the proximal renal tubule in much higher concentration than in the plasma (Seikaly et al, 1990). The effect of AII on sodium reabsorption is bimodal; physiologic concentrations of AII stimulate sodium reabsorption in the proximal tubule, whereas higher concentrations inhibit sodium transport (Harris and Young, 1977).

Medullary Effects

AII decreases medullary blood flow, leading to increased medullary hypertonicity and concentration of urine (Arendshorst and Finn, 1977).

Vascular Effects

AII raises blood pressure by increasing peripheral vascular resistance through a direct effect on vascular smooth muscle cells, causing them to contract. Medium-sized and small arteries are more responsive to AII than large vessels. Contraction occurs mainly in the vessels of the kidney, skin, mesentery, coronary arteries, and brain. Vessels of the lung and skeletal muscle are less responsive to AII. In addition to vasoconstriction, AII stimulates vascular smooth muscle cell growth, leading to a hypertrophic response (Geisterfer et al, 1988). Such smooth muscle proliferation results in left ventricular hypertrophy in cases of chronic stimulation of the RAS. AII is also involved in inflammatory processes including atherosclerosis. This cascade of cardiovascular events including hypertension, ventricular hypertophy, and atherosclerosis is felt to be central to the development of heart failure. With this mechanism in mind, interruption of the RAAS through multiple pharmacologic channels has become a major objective in lowering cardiac mortality associated with hypertension and heart failure.

Adrenal Effects

AII acts directly on the adrenal glomerulosa cells to stimulate aldosterone secretion. This is accomplished through increased desmolase activity and increased conversion of corticosterone to aldosterone (Aguilera, 1993). This augments the salt reabsorptive actions of AII to conserve sodium.

CNS Renin-Angiotensin-Aldosterone System

The CNS is affected mainly by the local renin-angiotensin system, but high circulating levels of AII may also affect CNS function. Central AII results in an increase in blood pressure as well as increased drinking and salt appetite (Sweet et al, 1971; Fitzsimons, 1980). Central AII also leads to increased secretion of corticotropin, prolactin, luteinizing hormone, oxytocin, and vasopressin (Unger et al, 1988).

Gonadal Renin-Angiotensin-Aldosterone System

Gonadal RAAS is present in both the testis and the ovary. The function of testicular RAAS is not clear; in the ovary, RAAS may play a role in oocyte maturation.

Angiotensin II Receptor Subtypes

Nonpeptide receptor antagonists have provided definite proof of at least two major angiotensin receptor subtypes, named AT1 and AT2. Both receptors are polypeptides containing 360 amino acids spanning the cell membrane several times. They are functionally distinct with a sequence homology of 30%. The gene for the AT1 receptor is located on chromosome 3, and the gene for the AT2 receptor is located on the X chromosome (Goodfriend et al, 1996). AT1 receptors are blocked by DuP 753 (losartan), and AT2 receptors are blocked by tetrahydroimidazopyridines such as PD 123177. AT1 receptors have a higher affinity for AII than AIII, but AT2 receptors bind both AII and AIII equally. AT1 receptors have been further subtyped into two isoforms, AT1A and AT1B, although the function of the subtypes is not clear.

The AT1A receptor is expressed in the liver, kidney, aorta, uterus, adrenals, ovary, spleen, and lung as well as in the hypothalamus. The AT1B receptor is expressed in the pituitary, adrenals, kidney, uterus, and liver and is absent in the heart, brain, and spleen. In fetal life, the AT2 receptor is widely present in the adrenals, kidney, liver, skin, tongue, and brain. In the adult, this distribution becomes restricted to the adrenals, uterus, ovary, heart, and some nuclei in the brain.

In the kidneys, AT1 receptors are located predominantly in the glomeruli and tubulointerstitium, whereas AT2 receptors are located in the large cortical blood vessels (Goldfarb et al, 1994).

Almost all the vascular effects of AII, including vasoconstriction, aldosterone release, and β-adrenergic stimulation, are mediated by the AT1 receptor (Timmermans et al, 1992). The development of AT1 receptor antagonists (e.g., losartan) has produced a new class of drugs, as well as an effective tool for blocking the RAAS in a variety of disease states, including hypertension. Further, these new drugs modulate cardiac and renal injury responses to disease.

The function of the AT2 receptor has not been fully defined; however, it may act in a manner antagonistic to the AT1 receptor, especially in the cardiovascular system, where it exerts antiproliferative, antihypertrophic, and proapoptotic functions (Horiuchi et al, 1999). AT2 receptors are thus thought to mediate protective actions that counterbalance the potentially harmful actions mediated through the AT1 receptors. AT2 receptors are also believed to play a crucial role during gestational growth and development, mainly due to the widespread distribution of these receptors in most body tissues during fetal life. Reexpression of these receptors in adult life occurs as a response to vascular injury or inflammation (Horiuchi et al, 1999).

The signal transduction mechanism initiated by binding of AII to the AT1 receptor has been well described; however, the signal transduction mechanism for the AT2 receptor is not yet known. Binding of AII to the AT1 receptor leads to the dissociation of subunits of a guanine nucleotide–binding protein, which activates phospholipase C to generate diacylglycerol and inositol triphosphate. Inositol triphosphate releases calcium from the endoplasmic reticulum, and AII also increases calcium entry through the cell membrane. The intracellular calcium, as well as diacylglycerol, activates protein kinase C and other enzymes that phosphorylate protein and ultimately regulates the specific cellular function induced by AII (Goodfriend et al, 1996).

Other Angiotensins

The parent peptide of the angiotensin family is the decapeptide AI. Several other peptides are formed within the RAAS, some of which have weak activity compared with AII, and some of which have undetermined activity. As previously mentioned, AII (also called angiotensin 1-8) is the major active peptide in the system; it is an octapeptide formed by the removal of terminal histidine and leucine from the carboxy terminus of AI. AIII (or angiotensin 2-8) is similar to AII but lacks the aspartyl amino acid at the amino terminus of the polypeptide chain. It can be formed from AII or directly from AI. Angiotensin 1-7 lacks the three amino acids at the carboxy terminus of AI and has undetermined receptor activity. AIV is a hexapeptide lacking the two terminal amino acids at both ends of the AI polypeptide chain (Goodfriend et al, 1996).

The actions of angiotensin 1-7 have been defined. It appears to be formed from AI directly by a different enzyme than ACE, called neprilysin. ACE inhibitors thus increase the levels of circulating angiotensin 1-7. It acts in an opposing fashion to AII, producing vasodilatation and natriuresis, and also has antiproliferative effects on vascular smooth muscle (Chappell and Ferrario, 1999).

Two-Kidney, One-Clip Model

In the two-kidney, one-clip model, the renal artery to one kidney is clipped, resulting in ischemia of the clipped kidney. The RAAS is activated as a result of renal hypoperfusion, resulting in generalized vasoconstriction and systemic hypertension. The adrenal cortex is also stimulated, resulting in secondary hyperaldosteronism and promoting sodium retention by the stenotic kidney. This is the early phase of RVH and is totally mediated by high circulating levels of AII. The normal contralateral kidney is subjected to higher-than-normal perfusion pressure and reacts by suppression of renin secretion as well as “pressure” natriuresis, excreting higher-than-normal levels of sodium and water. Renal vein renin (RVR) from the normal kidney is equal to the arterial value, indicating no secretion by the kidney. In this manner, both kidneys work against each other, with the normal kidney preventing the systemic blood pressure and sodium content from reaching levels high enough to suppress renin release from the stenotic kidney.

Briefly, the two-kidney, one-clip model is characterized by the unilateral release of renin from the ischemic kidney accompanied by contralateral suppression of renin release from the normal kidney, sodium retention by the stenotic kidney, and excretion by the contralateral kidney; euvolemia; and hypertension dependent on AII-induced vasoconstriction. Accordingly, unclipping of the ischemic kidney, ACE inhibitors, or AII antagonists result in a marked decrease in blood pressure.

One-Kidney, One-Clip Model

In the one-kidney, one-clip model, one renal artery is clipped and the contralateral kidney is removed. The solitary ischemic kidney secretes renin, activating the RAAS and resulting in systemic hypertension. Owing to the absence of the normal contralateral kidney, pressure natriuresis does not occur, and the stenotic kidney avidly conserves sodium and fluid, producing volume expansion. The elevation of blood pressure, sodium retention, and volume expansion gradually suppress renin release from the ischemic kidney. Accordingly, although the generating mechanism of hypertension is similar in both models, hypertension in the one-kidney, one-clip model is largely maintained by volume and sodium excess, in the face of normal circulating AII levels. ACE inhibitors or AII antagonists do not result in marked decrease of blood pressure. Under conditions of sodium depletion, hypertension once again becomes dependent on AII, with a marked response to ACE inhibition.

In addition, both models do not remain static but, rather, pass through an acute phase, a transitional phase, and then a final chronic phase (Table 39–3). In cases of two-kidney, one-clip hypertension, after several days or weeks a chronic phase is eventually reached in which unclipping of the stenotic kidney fails to normalize blood pressure. In this chronic phase, the elevated perfusion pressure, as well as high levels of AII, results in widespread arteriolar damage to the contralateral kidney. The excretory function (natriuresis) of the contralateral kidney declines, resulting in extracellular volume expansion, a decrease in circulating AII levels, and the gradual development of a “volume-dependent” type of hypertension. ACE inhibition or removal of the stenotic kidney fails to cure the hypertension in this phase of the disease unless sodium depletion is instituted. Systemic vasoconstriction continues to play a role in maintaining hypertension in the chronic phase, with increased sensitivity to AII, increased vasopressin secretion, and increased sympathetic nervous system activity.

Table 39–3 Phases of Experimental Renovascular Hypertension