Type 2 diabetes, obesity, and the renal response to blocking the renin system with irbesartan.

AIM: Our recent studies revealed a striking but variable enhancement of renal vasodilator responses to blockers of the renin-angiotensin system in subjects with diabetes mellitus, possibly reflecting the level of intrarenal activation of the renin-angiotensin system, and thus a risk of nephropathy. As obesity is a common finding in diabetic individuals, and obesity has been linked to an increase in plasma angiotensinogen levels, we enrolled diabetic subjects with a wide range of body mass index (BMI) for this study. METHODS: Twelve Type 2 diabetic subjects in balance on a low sodium diet participated after baseline renal plasma flow and glomerular filtration measurements were made. Each subject then received 150 mg irbesartan, and renal function was measured every 45 min for 4 h. RESULTS: The average vasodilator response to irbesartan was 174 +/- 33 ml/min. No correlation was found between renal plasma flow response to irbesartan and duration of diabetes, baseline glucose, or HbA1c level. BMI, our measure of obesity, was highly correlated to the renal response to irbesartan (r = 0.7; P = 0.01). CONCLUSIONS: Our findings suggest an important role for obesity in activating the intrarenal renin system, perhaps via production of angiotensinogen. BMI may be an indicator of risk of nephropathy.

Adrenal response to angiotensin II in black hypertension: lack of sexual dimorphism.

Adrenal responsiveness to angiotensin (Ang) II is markedly blunted in black hypertensive patients compared with white hypertensive patients. One characteristic of this blunted adrenal response in whites is a powerful sexual dimorphism: premenopausal white women rarely show blunted responses. This abnormality, most evident when the system is activated by a low-salt diet, is a cardinal feature of the syndrome of nonmodulation, affecting a large percentage of white hypertensive patients. Nonmodulation is also marked by an increase in cardiovascular risk beyond that from hypertension itself. This study investigated whether young black women are likewise spared its expression or whether the adrenal unresponsiveness common among black hypertensive patients is unaccompanied by a gender bias. We compared the adrenal response to Ang II in 382 hypertensive patients (313 white, 69 black; 238 male, 144 female). Ang II was infused when subjects were in balance on a 10-mmol Na(+) intake. As anticipated, white hypertensive patients showed a very strong sexual dimorphism, with women having twice the aldosterone response of men (P=0.0001). Blacks, on the other hand, showed no gender difference (P=0.9). Increasing age had the dramatic effect of reducing responsiveness in white women but not in blacks. Young black women demonstrated the same blunting of adrenal responsiveness as older black women and black men of all ages. Mechanisms protecting against a blunted adrenal response to Ang II in young white women are absent in blacks. These differences may contribute to the markedly increased prevalence of hypertension in young black women.

Familial factors in the antihypertensive response to lisinopril.

BACKGROUND: Although it is widely recognized that there are familial elements in the pathogenesis of hypertension, remarkably little is known about the influence of family history on response to specific antihypertensive agents. METHODS: This study was designed to address that issue by comparing the depressor response to lisinopril in a dose range of 10 to 40 mg in 74 patients enrolled as sibling pairs. Because all patients were treated with lisinopril, ambulatory blood pressure monitoring (ABPM), an objective measure not influenced by the investigators, was used to assess the primary blood pressure (BP) outcome variable. RESULTS: Diastolic BP was highly correlated between sibling pairs at baseline (r = 0.476; P < .03) and on treatment (r = 0.524; P = .0021). Ethnicity/race had a striking influence on lisinopril dose and response rate. Among African American patients, 23 of 28 reached the top dose of 40 mg/day, whereas only 14 of 36 Caucasian patients reached that dose level. Among Caucasians, 92% responded, and only 48% of African Americans. Responders were characterized by being younger and heavier, having significantly lower microalbuminuria at baseline, higher baseline renal plasma flow (RPF), and higher urinary kallikrein. CONCLUSION: Among Caucasians, the presence of a hypertensive sibling predicts a striking therapeutic response to angiotensin converting enzyme inhibition.

Renal vascular responses to captopril and to candesartan in patients with type 1 diabetes mellitus.

BACKGROUND: Enhanced renal vasodilator responses to angiotensin-converting enzyme (ACE) inhibition in diabetes mellitus despite a normal or low plasma renin activity level have suggested intrarenal activation of the renin-angiotensin system in this disease. There is, however, a continuing debate as to the mediators of the renal hemodynamic response to ACE inhibition-reduced angiotensin II formation or pathways involving kinins, prostaglandins, and nitric oxide. METHODS: Twelve patients with type 1 diabetes mellitus of 18 +/- 3.2 (SEM) years of duration (7 females and 5 males, ages 17 to 50, 32 +/- 4.0 years) who were free of sustained microalbuminuria and on a high-salt diet were given the ACE inhibitor captopril (25 mg orally) on one day and the AT1 receptor blocker candesartan (16 mg orally) on another day. Renal plasma flow (RPF) and glomerular filtration rate were measured before and for four hours after administration. RESULTS: Both drugs caused a significant increase in RPF (captopril 574 +/- 26 to 625 +/- 37 mL/min/1.73 m2, P = 0.008; candesartan 577 +/- 26 to 643 +/- 37, P = 0.004). There was a highly significant correlation between the responses to captopril and to candesartan (r = 0.86, P < 0.001). Seven subjects had an RPF response to captopril that was accentuated (90 +/- 13 mL/min/1.73 m2), while five had a response that was normal (-4 +/- 9). There was no significant change in glomerular filtration rate on either drug. CONCLUSION: The remarkable rise in RPF in response to captopril and candesartan despite high-salt balance suggests the intrarenal activation of the renin-angiotensin system in diabetes that is not reflected in plasma renin levels. The high correlation between the renal hemodynamic response to captopril and to candesartan indicates that reduced angiotensin II formation is the main mechanism of action of the ACE inhibitor.

Renal perfusion and function in healthy African Americans.

BACKGROUND: Despite their increased risk of nephropathy, remarkably little is known about renal perfusion and function in healthy African Americans. METHODS: We enrolled 32 healthy African Americans and compared renal perfusion and function in 82 age-matched healthy Caucasians. Studies were performed on a diet containing 200 mmol of sodium and 100 mmol of potassium per day. In a separate study of 28 subjects, 10 African American and 18 Caucasians, the contribution of the renin-angiotensin system was assessed by measuring renal hemodynamic responses to angiotension II (Ang II) and captopril. RESULTS: Although glomerular filtration rate (GFR) was similar, renal plasma flow (RPF) was significantly less in age-matched African Americans (568 +/- 18) than Caucasians (620 +/- 13 mL/min/1.73 m(2), P = 0.0063). After captopril, African Americans had a sevenfold greater vasodilator response and a rise in RPF (35.3 +/- 4.9 vs. 4.9 +/- 12.4 mL/min/1.73 m(2) in African Americans and Caucasians, respectively, P < 0.028). Ang II administration caused a significantly smaller vasoconstrictor response in African Americans (Ang II-induced fall in RPF, -97 +/- 18 vs. -150 +/- 9 mL/min/1.73 m(2), P = 0.05), and angiotensin-converting enzyme (ACE) inhibition enhanced the response to Ang II in African Americans significantly. CONCLUSIONS: A reduction in RPF, blunting of the renal vascular response to Ang II, and an accentuated renal vasodilator response to captopril, which in turn corrects the blunting of responsiveness to Ang II, all suggest activation of the renin system in apparently healthy African Americans. As PRA was identical in Caucasians and African Americans, the findings suggest that it is the intrarenal-renin system that is activated in African Americans. This difference in normal control mechanisms could predispose to nephropathy.

Is there a future for renin inhibitors?

Pharmacological interruption of the renin-angiotensin system is possible at three major sites, the angiotensin-converting enzyme (ACE), the AT1 receptor and at the interaction of renin with its substrate, angiotensinogen. Skeggs and his associates in 1957 argued logically but without prognostic accuracy that 'since renin is the initial and rate-limiting substance in the renin-angiotensin system, it would seem that the renin inhibition approach would be the most likely to succeed'. In fact, the development of agents that act at all three levels has enjoyed substantial success, yet renin inhibition, which showed early progress in studies in humans, has languished. Our task in this essay is to review the reasons for the slow evolution of renin inhibition and to discuss the potential of such agents in modern pharmacotherapy. All of the structure-action relationships have involved variation on the original peptide structure. The possibility that alternative approaches based on x-ray crystallography and reconstruction of the structure of the active site would lead to novel agents, appears not to have been explored systematically. This opportunity is all the more attractive because renin is one of the few targets that is actually soluble and amenable to x-ray crystallographic studies. At the moment, it appears that all renin inhibitor development programs have been closed, although hints periodically reappear to indicate that one company or another is pursuing a novel agent. The decision to close programs seems to have reflected not the therapeutic potential of renin inhibitors, but rather the cost of their synthesis, continuing problems with bioavailability and the remarkable success of the competitor class--the AngII antagonists. We believe that the potential of renin inhibition in human therapy has been under estimated and still shows substantial promise.

Salt intake and non-ACE pathways for intrarenal angiotensin II generation in man.

Angiotensin-converting enzyme (ACE) plays a crucial role in the generation of angiotensin II (Ang II) via conversion from angiotensin I (Ang I). There has been substantial recent interest in non-ACE pathways of Ang II generation in the heart, large arteries, and the kidney. In the case of the human kidney, studied when in balance on a low-salt diet, the renal haemodynamic response to Ang II antagonists substantially exceeds the renal response to ACE inhibitors (ACE-I), suggesting that about 30-40% of Ang II-generation occurs via non-ACE pathways. In this study, we examined the relative contribution of non-ACE pathways, by comparing the response to candesartan and to captopril at the top of the dose-response in normal humans when in balance on a low-salt, as well as a high-salt, diet. As anticipated on a low-salt diet, the increase in renal plasma flow (RPF) in response to candesartan (165+/-14 mL/min/1.73 m2) significantly exceeded the response to captopril (118+/-12 mL/min/1.73 m2; p<0.01). In subjects studied on a high-salt diet, the response to candesartan (97+/-20 mL/min/1.73 m2) also significantly exceeded the response to captopril on the same diet(30+/-15 mL/min/1.73 m2; p<0.01). This remarkable response to candesartan in subjects on a high-salt diet,when compared with the response to captopril,suggests that non-ACE-dependent Ang II generation was influenced less than the classical renal pathway with an increase in salt intake, so that the percentage of Ang II generated via the non-ACE pathway rose to the 60-70% range.

Renal hemodynamic and hormonal responses to the angiotensin II antagonist candesartan.

The development of very specific blockers for the angiotensin II type 1 (AT(1)) receptor made it possible to examine the contribution of angiotensin II to normal control mechanisms and disease with a specificity beyond what ACE inhibitors could provide. In the present study, we explored the contribution of angiotensin II to 2 renal mechanisms: renal hemodynamics and the short feedback loop, in which angiotensin II acts as a determinant of renin release. To make that comparison, we studied healthy volunteers in balance on a 10-mmol sodium intake to activate the renin system. Our goal was to compare the relation between the dose of candesartan, an AT(1) receptor blocker, and the renal hemodynamic and hormonal responses. A second goal was to ascertain the relation between time after candesartan administration and the peak response. Twelve healthy subjects (mean age 33+/-2.3 years) in low-sodium balance were administered candesartan in 4-, 8-, 16-, and 32-mg doses. Candesartan produced a dose-related increase in renal plasma flow, with the maximum vasodilator response at 16 mg (142+/-13 mL. min(-1). 1.73 m(-2)) occurring during the first 4 hours after the dose. Likewise, candesartan caused a dose-related rise in plasma renin activity, with 32 mg as the dose producing the greatest response at 4 and 24 hours after administration. The peak plasma renin activity achieved in this study (15.3+/-1.6 ng. L(-1). s(-1); 55.0+/-5.6 ng angiotensin I. mL(-1). h(-1)) was found at the 4- to 8-hour interval after dosing in a subset of subjects (n=5) who received the 16-mg dose 4 hours earlier than the other subjects. On the basis of the difference in the relation between dose and response and the relationship between time after drug administration and response, the determinants of the renal hemodynamic and hormonal response can be said to differ. The remarkable rise in plasma renin activity after candesartan is substantially larger than that in earlier studies with ACE inhibition, providing additional evidence for non-ACE-dependent angiotensin II generation in the kidney.

Effect of ACE inhibition on pressor, renal vascular, and adrenal responses to infusion of angiotensin I in normal subjects eating a low-salt diet.

To examine the influence of angiotensin-converting enzyme (ACE) on pressor, renal vascular, and adrenal responses during angiotensin I (Ang I) infusion, we studied 10 normotensive, healthy men. Each was in balance with a 10-mEq sodium, 100-mEq potassium intake and was studied before and during ACE inhibition with enalapril. Ang I (3, 10, and 30 ng/kg/min) was infused in each subject. Then ACE inhibition was instituted with enalapril for 3 days, which induced the anticipated fall in blood pressure, plasma Ang II, and aldosterone concentration, and rise in renal plasma flow. During ACE inhibition only the 30-ng/kg/min Ang I dose raised plasma Ang II levels. There was a spectrum, however, in the end-organ response to Ang I during ACE inhibition. Responses of plasma aldosterone concentration and blood pressure were in excellent accord with the reduction in Ang II formation. On the other hand, responses of the renal blood supply were substantially less inhibited than anticipated. Under the conditions of this study, ACE inhibition led to nonuniform changes in the response to exogenous Ang I, suggesting intrarenal conversion of Ang I to Ang II.

Effects of gender and genotype on the phenotypic expression of nonmodulating essential hypertension.

Nonmodulation describes a subset of the normal/high renin essential hypertensive population. It is an inherited trait. This report reviews the genetic and gender data recently available that discuss the modification of the expression of the nonmodulating phenotype. Both the adrenal and the renal blood flow markers for nonmodulation are associated with a single nucleotide polymorphism (SNP) in the coding region of the angiotensinogen gene at codon 235. Even though the nonmodulating phenotype is associated with a somatic gene, gender modifies its expression. In women, the expression of the nonmodulating phenotype is approximately half of that in men. Additional analysis suggests that this gender difference is almost entirely explained by a difference in the frequency of nonmodulation in younger premenopausal women. In older, likely postmenopausal women, there is no gender difference. This suggests that the expression of the nonmodulating phenotype, presumably secondary to changes in the expression of the angiotensinogen gene, is modulated by female sex hormones.

Aldosterone stimulation by angiotensin II : influence of gender, plasma renin, and familial resemblance.

The aldosterone response to infused angiotensin II (Ang II) in patients receiving a low-salt diet has been described as an important phenotype for genetic studies on human hypertension. The objectives of the present study were to determine the parameters that influence this intermediate phenotype as a quantitative trait and to assess the importance of its familial resemblance in hypertensive sibling pairs. Two hundred one white hypertensive subjects (95 families: 84 pairs and 11 trios) were selected in 3 centers. The patients followed the same protocol, which included a 4-week withdrawal period of antihypertensive therapy, a 1-week period on a low-salt diet, and a 30-minute infusion of Ang II. The increase in the aldosterone level was greater in women than in men (29.1+/-16.2 versus 18.2+/-9.6 ng/dL, P<0.0001). A strong relationship was found with age (r=-0.54, P<10(-4)) and plasma renin activity (r=0.32, P<10(-4)) in women but not in men. Weak correlations of the aldosterone response to Ang II were observed for the whole set of sibling pairs (r=0.11, NS). Conversely, strong sibling correlations were found among brother-brother pairs (r=0.40, n=36) and among sister-sister pairs as soon as age or menopausal status was considered. Similar results were obtained when the Ang I-aldosterone response was analyzed as a qualitative trait (kappa=0. 35, P<0.008 in brother-brother pairs). We conclude that age, gender, and plasma renin are strong determinants of the aldosterone response to Ang II, with strong sibling correlations in men and postmenopausal women. These relationships will have to be considered in future linkage and association studies.

The paradox of the low-renin state in diabetic nephropathy.

Although diabetic nephropathy is often a low renin state, the renin system appears to be implicated in its pathogenesis. In this study, it was hypothesized that the low plasma renin activity (PRA) is misleading, masking and perhaps reflecting an activated intrarenal renin system. PRA and renal vascular responses (inulin and para-aminohippurate clearance) to graded doses of an angiotensin II (AngII) antagonist, irbesartan, were assessed in eight healthy volunteers and 12 patients with type 2 diabetes mellitus and nephropathy on a 10 mmol Na intake, to activate the renin system. Basal PRA was suppressed in type 2 diabetes mellitus compared with the healthy subjects (0.58 +/- 0.14 versus 1.58 +/- 0.28 ng/L per s, mean +/- SEM; P < 0.01). Despite the low PRA, renal perfusion rose more in response to irbesartan in type 2 diabetes mellitus (714 +/- 83 to 931 +/- 116 ml/min; P = 0.002) than normal (624 +/- 29 to 772 +/- 49 ml/min; P = 0.008). The youngest patients were hyperfiltrating and showed the largest rise in renal plasma flow in response to irbesartan, whereas renal plasma flow rose less and GFR fell in patients with low basal GFR. PRA rose in response to irbesartan more gradually in the patients with type 2 diabetes mellitus, but ultimately matched the normal response. To account for the apparent paradox of a heightened renal hemodynamic response to an AngII antagonist in the face of a low PRA in type 2 diabetes mellitus, and the rise in PRA following the AngII antagonist, it is proposed that there is increased intrarenal AngII production in type 2 diabetes mellitus. This increase could account for suppressed circulating renin, the exaggerated renal vasodilator response to irbesartan, and the therapeutic effectiveness of interrupting the renin system in diabetic nephropathy.

Altered adrenal sensitivity to angiotensin II in low-renin essential hypertension.

Low-renin essential hypertension (LREH) describes a widely recognized classification validated by clinical features, including salt-sensitive blood pressure and diuretic responsiveness. Classic physiological teaching has cited normal plasma aldosterone concentration despite suppressed renin as evidence for adrenal supersensitivity to angiotensin II (Ang II). We studied 94 patients with LREH, 242 normal-renin hypertensives, and 135 normal subjects as controls. Low-renin hypertensives did not differ significantly from the other groups in either basal or Ang II-stimulated aldosterone concentrations on a high-sodium diet. Stimulated with a low-sodium diet, LREH patients demonstrated the smallest rise in basal aldosterone secretion. Ang II responsiveness was also subnormal: the rise in aldosterone after Ang II infusion in LREH (613+/-39 pmol/L), although greater than in nonmodulators (180+/-17 pmol/L; P=0.001), was less than either the patients with intact modulation (940+/-53 pmol/L; P=0.001) or normotensives (804+/-50 pmol/L; P<0.05). Blacks with LREH demonstrated an even lower response than low-renin whites ((388+/-50 versus 610+/-47 pmol/L; P=0.0001). In contrast, the rise in systolic blood pressure with Ang II infusion on a low-salt diet was greatest among LREH patients (P=0. 001). Patients with LREH and nonmodulators were equally salt-sensitive. These results indicate that the adrenal response in LREH is normal on a high-salt diet but becomes progressively more abnormal as sodium control mechanisms are stressed. The factors that mediate enhanced adrenal response to Ang II with sodium restriction may be defective, suggesting the existence of alternative physiological mechanisms for sodium homeostasis in the low-renin state.

Renal response to captopril reflects state of local renin system in healthy humans.

BACKGROUND: Heightened activity of the renin-angiotensin system has been linked to the development of both essential hypertension and diabetic nephropathy. Blunting of the renal vasoconstrictor response to Ang II, specifically when it is corrected by angiotensin converting enzyme (ACE) inhibition, is a feature which we have employed as a marker for activation of the intrarenal RAS. In this study we tested the hypothesis that variation in the renal vasodilator response to ACE inhibition in healthy humans reflected the variation in angiotensin-mediated renal vasoconstriction provoked by a low-salt diet. METHODS: We studied 20 healthy people (ages 19 to 57; 15 males) who were in balance on a low sodium diet. Ang II was infused for 45 minutes (3 ng/kg/min), followed by 25 mg captopril and a repeat Ang II infusion; PAH clearance was measured at the end of each interval. RESULTS: All subjects responded to captopril with a rise in renal plasma flow (range 43 to 242, mean 118 + 12 ml/min/1.73 m2). Individual vasodilator response to captopril was a strong inverse predictor of the precaptopril vasoconstrictor response to Ang II (P = 0.006, r = -0.59). There was a stronger, positive correlation of the vasodilator response to captopril and enhancement of Ang II responsiveness after captopril (r = 0.57). Plasma renin activity was significantly correlated with captopril response among the large responders (P = 0.003; r = 0.83), but not at all among those with little response. CONCLUSION: These results suggest substantial variation in angiotensin-mediated control of the renal circulation in healthy individuals on a low sodium intake. Variation in the vasodilator response to captopril, correlated with responses to Ang II, provides a measure of that control.