Angiotensin-(1–7)–Induced Renal Vasodilation in Hypertensive Humans Is Attenuated by Low Sodium Intake and Angiotensin II Co-Infusion

Abstract

A ngiotensin-(1-7) (Ang-(1-7)) is a vasoactive peptide that plays an important role in the regulation of tissue blood flow.1 It is closely linked to the classical renin-angiotensin system (RAS) because the enzymes producing Ang-(1-7) use angiotensin I and angiotensin II (Ang II) as its substrate. Available data, limited to studies using animal models and human forearm vasculature, predominantly demonstrate a vasodilatory effect of Ang-(1-7).2,3 Human data on the effect of Ang-(1-7) in clinically important vascular beds, such as that of the kidney, are lacking. 4 As the kidney and RAS activation play a key role in blood pressure regulation and the development of hypertension, studying the intrarenal flow effects of Ang-(1-7) in hypertensive patients may lead to new insights in the pathophysiology of hypertension. We hypothesized that, in correspondence to the data currently available, Ang-(1-7) increases renal blood flow in hypertensive humans. For that reason we studied the effect of intrarenal Ang-(1-7) infusion on renal blood flow in hypertensive patients. To assess the influence of the RAS, various states of RAS stimulation were simulated by restriction of dietary sodium intake (inducing endogenous RAS activation) and co-infusion of Ang II (increasing Ang II availability). Methods Participants and ProtocolThis study was performed in 85 hypertensive outpatients (all whites) who were angiographically evaluated for the presence of renovascular abnormalities. Inclusion criteria were difficult-to-treat hypertension (mostly blood pressure remaining above goal in spite of the use of ≥3 full-dose antihypertensive drugs) or clinical suspicion on renovascular abnormalities based on clinical clues (eg, the presence of an abdominal bruit, peripheral vascular disease, or a rise in serum creatinine after treatment with a RAS inhibitor). Patients previously diagnosed with renovascular abnormalities or other secondary causes of hypertension were excluded. Three weeks before the angiography all antihypertensive medication was discontinued to avoid interference with the experiments. Patients in whom interruption of the medication was not possible because of a high risk for acute cardiovascular events (a recent cardiovascular event or [expected] blood pressure >180/110 mm Hg) were excluded from the study. Patients were randomly allocated to adhere to either a sodium-restricted diet (<55 mmol sodium/24 hours) or a sodium-rich diet (>200 mmol sodium/24 hours) during the week preceding the study. The day preceding the angiography study, patients underwent a noninvasive 24-hour ambulatory blood pressure measurement (using SpaceLabs ambulatory blood pressure monitor type 90207 or 90217-b) and collected a 24-hour urine specimen to measure urinary sodium excretion to monitor dietary compliance. All patients gave written Abstract-Current evidence suggests that angiotensin-(1-7) plays an important role in the regulation of tissue blood flow. This evidence, however, is restricted to studies in animals and human forearm. Therefore, we stu...

Acute eprosartan-induced intrarenal vasodilation in hypertensive humans is not influenced by dietary sodium intake or angiotensin II co-infusion

“…Our observation that eprosartan-induced vasodilation is not influenced by Ang II co-infusion or low sodium intake is in contrast to our hypothesis and in contrast to our previous findings with Ang-(1-7) [12]. These unexpected findings could be explained by various mechanisms.…”

“…Hence, Ang II co-infusion in the presence of eprosartan will lead to vasodilation to some extent, counteracting its vasoconstrictor effects. As we previously demonstrated, low sodium intake attenuates the effects of Ang-(1-7) [12], thus blunting the expected increase in effect of eprosartan during low sodium intake.…”

“…We chose to infuse a relatively high dose of Ang II (without systemic effects) to provide sufficient AT 1 R stimulation (1 ng/kg per min). Although not measured in this study because it would extend the duration of the measurements for the patients too much, infusion of Ang II alone results in substantial vasoconstriction in the kidneys of hypertensive humans: we previously demonstrated that low-dose Ang II (0.3 ng/kg per min) resulted in a decrease in renal blood flow of 92 AE 13 (high sodium diet) and 87 AE 5 (low sodium diet) ml/100 g kidney/min, respectively [12]. Despite infusion of a higher dose of Ang II (presumably inducing more vasoconstriction), eprosartan-induced vasodilation in a magnitude similar to the groups without Ang II coinfusion.…”

“…We chose the doses that resulted in an increase in renal blood flow without systemic effects on BP and/or heart rate. We infused a relatively high dose of Ang II (without inducing systemic effects) as compared with previous studies [12] to achieve maximal stimulation of the AT 1 R.…”

“…To improve our understanding of the renal AT 1 Rs in hypertensive patients, we infused the competitive AT 1 R antagonist eprosartan in the kidneys of essentially hypertensive patients (off-medication). As we previously demonstrated that the acute vasodilatory effects of angiotensin-(1-7) [Ang- (1)(2)(3)(4)(5)(6)(7)] are attenuated by RAS activation secondary to low sodium intake and/or angiotensin II (Ang II) co-infusion [12], we questioned whether low sodium intake and/or Ang II coinfusion would also influence the effect of intrarenal AT 1 R blockade. We hypothesized that the effect of eprosartan would be greater in patients receiving a low sodium diet, as the endogenous Ang II production is higher during RAS activation [13].…”