Intrarenal angiotensin II formation in humans: evidence from renin inhibition.

Fisher, N D; Allan,; Cl, Gaboury; Nk, Hollenberg

doi:10.1016/0895-7061(95)97932-h

Cited by 8 publications

(9 citation statements)

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“…Renal vascular responses to a renin inhibitor were sustained in healthy men and those with essential hy-pertension, in marked contrast to waning concentration and activity of the drug in the plasma compartment (Fisher et al, 1995). These results provided indirect but strong evidence for a biological influence of intrarenal Ang II formation in human subjects.…”

Section: B Clinical Studiesmentioning

confidence: 61%

The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease

et al. 2007

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Section: B Clinical Studiesmentioning

confidence: 61%

The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease

et al. 2007

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“…Such characteristics may have useful clinical consequences. Hollenberg et al (26) showed that renin inhibitors induce a greater renal vasodilator response than ACE inhibitors in sodiumrestricted healthy subjects, an observation also made with remikiren in guinea pigs (27). Under circumstances in which intrarenal activation of Ang II production occurs via ACE-or non-ACE-dependent pathways, such as in diabetic nephropathy or in black hypertensive individuals on a high-salt diet (28), specific renal benefits thus are expected from renin inhibition in renal tissue (29) by the administration of an orally active renin inhibitor.…”

Section: Potential Impact Of the Resultsmentioning

confidence: 99%

Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan on the Angiotensin II–Renin Feedback Interruption

Azizi¹,

Ménard²,

Bissery³

et al. 2004

Journal of the American Society of Nephrology

221

182

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Abstract. Interrupting the renin-angiotensin system (RAS) with a usual daily dose of a single-site RAS inhibitor does not achieve complete and long-lasting pharmacologic blockade. Hormonal and BP effects were compared for 48 h after administration of single oral doses of 300 mg (high dose) of the renin inhibitor aliskiren (A300) and 160 mg (standard antihypertensive dose) of the AT1 receptor antagonist valsartan (V160) and their combination each at half dose (A150ϩV80) in 12 mildly sodium-depleted normotensive individuals. In this doubleblind, placebo-controlled, randomized, four-period crossover study, A300 decreased plasma renin activity and angiotensin I and II levels for 48 h, stimulated immunoreactive active renin release more strongly than V160, and decreased urinary aldosterone excretion for a longer duration than V160. In contrast to V160, the A150ϩV80 combination did not increase plasma angiotensins. The renin and aldosterone effects of the A150ϩV80 combination were similar to those of A300 and greater than those of V160. When plasma drug concentrations were taken into account, the A150 ϩV80 combination had a synergistic effect on renin release. The A150ϩV80 combination lowered BP at least as effectively as either higher dose monotherapy. In conclusion, in mildly sodium-depleted normotensive individuals, the long-lasting effects of aliskiren alone or in combination with valsartan on plasma immunoreactive active renin and urinary aldosterone effects demonstrate strong and prolonged blockade of angiotensin II at the kidney and the adrenal level. Moreover, a renin inhibitor and AT1R antagonist combination may provide synergistic effects on RAS hormone levels.Numerous experimental and clinical studies have demonstrated that the combination of currently available angiotensin I-converting enzyme (ACE) inhibitors and AT1 receptor (AT1R) antagonists provides additive or synergistic effects on BP lowering (1) and on the prevention of cardiovascular (2) and renal lesions (3). These observations have previously been explained by AT1R blockers inhibiting the effects of non-ACE-dependent angiotensin II (Ang II) production (4,5) or by the bradykinin-NO-related effects of ACE inhibition (6). However, the additive effects of low doses of two different renin angiotensin system (RAS) inhibitors may be better explained by inhibition of the biologic effects of the reactive renin release that is triggered by single-site RAS blockade. The amount of compensatory renin release is proportional to the extent of decrease in the amount of Ang II generated or bound to the AT1R of the renal juxtaglomerular cells. This counterregulation may be overcome by using higher-than-usual or repeated doses of single-site RAS blockers (7,8) or by neutralizing the biologic effects of the counterbalancing rise in active renin by using a combined RAS blockade.Direct demonstration of the importance of renin in this counterregulatory mechanism has not previously been possible in humans because of the absence of convenient orally available renin inhi...

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“…The growthpromoting effects of Ang II on vascular smooth muscle cells is well established in vitro, 30,31 and Ang II is known to be elevated within the kidney in a number of forms of experimental and human hypertension. [32][33][34] We have infused Ang II at low doses directly into the renal artery for up to 1 month in both Sprague-Dawley rats 35 and greyhound dogs. 36,37 The doses used cause no immediate changes in arterial pressure and were doses at which little spillover into the systemic circulation would be expected (confirmed in rats).…”

Section: Ang Ii-mediated Renal Hypertensionmentioning

confidence: 99%

Renovascular Hypertension

et al. 2000

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Abstract-Experimental narrowing of the main renal artery to produce hypertension increases the aorta-glomerular capillary pressure difference and vascular resistance. This article examines the hypothesis that hypertension also may be caused by structural changes that narrow intrarenal blood vessels, similarly increasing preglomerular vascular resistance and the aortic-glomerular capillary pressure gradient. There is evidence of both wall hypertrophy and lumen narrowing of the preglomerular arteries in spontaneously hypertensive rats, with increased preglomerular resistance and aortic-glomerular capillary pressure difference. We have also attempted to induce structural changes in renal-preglomerular vessels experimentally by infusing angiotensin II at low doses (0.5 to 4.5 ng/kg per minute) into the renal artery of Sprague-Dawley rats and greyhound dogs for up to 4 weeks. This angiotensin II infusion produced apparent dose-related effects on preglomerular vessel structure and hypertension. The possibility that hypertension may be induced by structural changes in preglomerular resistance vessel walls, by simulation of the hemodynamic effects of main renal artery stenosis, deserves further investigation. Key Words: angiotensin II Ⅲ arterioles Ⅲ glomerular filtration rate Ⅲ rats, spontaneously hypertensive Ⅲ renal artery Ⅲ hypertrophy Ⅲ hypertension, renal M ore than 150 years ago, Richard Bright first linked the kidney to high blood pressure, but it was another 100 years before Goldblatt firmly established the potential of the kidney to cause hypertension. Goldblatt et al 1 produced the first reliable form of experimental hypertension with the remarkably simple intervention of narrowing the main renal artery to perturb renal hemodynamics. Since then, interest in the kidney in the development of essential hypertension has waxed and waned, with considerable debate on whether the kidney is the initiator, potentiator, and/or victim of essential hypertension. 2,3 Most investigators currently believe that the abnormalities and damage seen in the kidney in hypertension are entirely secondary. In particular, hypertrophy of the renal vessel walls is thought to be part of a response common to all systemic arterial vessels during sustained elevation of arterial pressure.The main argument in recent years for the importance of the kidney in hypertension has come from Hall et al, 4 Guyton, 5 and Cowley. 6 This work is widely accepted as showing the pivotal role of the arterial pressure/Na ϩ excretion rate relation in long-term blood pressure control. However, the mechanisms responsible for shifting this relation toward the right-that is, toward a prohypertensive situation in humans-remain unknown. In this article, we argue that primary changes in the structure of the preglomerular vessel walls may be one key mechanism responsible for a right shift of the pressure/Na ϩ excretion relation in hypertension. 4 -6 Using the simple situation of main renal artery stenosis as a background, we examined evidence for structurally based na...

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Intrarenal angiotensin II formation in humans: evidence from renin inhibition.

Cited by 8 publications

References 0 publications

The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease

The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease

Pharmacologic Demonstration of the Synergistic Effects of a Combination of the Renin Inhibitor Aliskiren and the AT1 Receptor Antagonist Valsartan on the Angiotensin II–Renin Feedback Interruption

Renovascular Hypertension

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