Comparative angiotensin II receptor blockade in healthy volunteers: The importance of dosing

Maillard, Marc; Würzner, Grégoire; Nussberger, Jürg; Centeno, Catherine; Burnier, Michel; Brunner, Hans R.

doi:10.1067/mcp.2002.121425

Cited by 83 publications

(47 citation statements)

References 17 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Various factors, including dose level, receptor binding and pharmacokinetic parameters, affect the capacity of ARBs to block the AT 1 receptor and ARBs have been shown to differ in these areas. 8,10,13 This is demonstrated by a recent study of the effects of several ARBs on the pressor response to exogenously administered angiotensin II. The increase in BP produced by angiotensin II administration was almost completely blocked by both OM 20 mg and irbesartan 300 mg, but only partially blocked by valsartan 160 mg and losartan 100 mg. 13 Importantly, the addition of HCTZ to either OM 20 mg or irbesartan 300 mg had no significant effect on their ability to antagonize the activity of the AT 1 receptor.…”

Section: Discussionmentioning

confidence: 96%

“…7 However, differences in angiotensin II (AT 1 ) receptor blockade observed with the various ARBs have been explained mainly by differences in dosing. 8 It can also be seen in the meta-analysis of Fabia et al that the ARB olmesartan medoxomil (OM) provides effective BP reductions over 24-h, which are maintained during the night-time and last few hours of the dosing interval. 7 Pharmacodynamic studies support this notion 9,10 and treating patients with the high (40 mg) dose of olmesartan should provide a high level of AT 1 -receptor blockade leading to increased BP reductions and control.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of high dose olmesartan medoxomil plus hydrochlorothiazide on blood pressure control in patients with grade 2 and grade 3 hypertension

et al. 2010

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Effects of high dose olmesartan medoxomil plus hydrochlorothiazide on blood pressure control in patients with grade 2 and grade 3 hypertension

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Plasma and urinary aldosterone concentrations more effective RAS inhibition than double the dose of the AT1 receptor antagonist (160 mg) or renin inhibitor (300 mg) alone. The question of the influence of dose selection and dosing interval remains critical for all RAS inhibitors and their effects on BP and end-organ protection (21)(22)(23). The additive or synergistic effects of such combinations are more evident at low doses (which are the usual dose) than at high doses (22).…”

Section: Combined Blockade Of the Ras By Aliskiren And Valsartanmentioning

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

View full text Add to dashboard Cite

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...

show abstract

“…Although the clinically used ARBs can differ with respect to pharmacokinetic characteristics such as half life, potency for AT 1 receptor blockade, degree of insurmountable antagonism, etc, one can usually minimize the practical impact of these differences on control of RAS activity and antihypertensive efficacy by making dose adjustments. 8 Thus, if one simply administers the appropriate doses required to control blood pressure and effectively inhibit the renin-angiotensin system, it is generally assumed that all ARBs will yield equally satisfactory protection against risk for cardiovascular disease.…”

Section: Angiotensin Receptor Blockers: Current Limitations and Unmetmentioning

confidence: 99%

Next generation multifunctional angiotensin receptor blockers

Kurtz

Klein

2009

Hypertens Res

View full text Add to dashboard Cite

Angiotensin receptor blockers (ARBs) are well-tolerated drugs that are known to be useful for inhibiting activity of the reninangiotensin (RAS) system, treating hypertension and reducing the risk for cardiovascular disease. However, inhibition of the RAS does not control all pathophysiological mechanisms of hypertension or cardiovascular risk and many patients continue to suffer from cardiovascular events and metabolic disturbances despite being treated with an ARB, an angiotensin-converting enzyme inhibitor or both, in addition to other standard therapies for cardiovascular disease. Recently, it has become apparent that bifunctional molecules can be designed that do more than just block AT 1 receptors and that can target additional mechanisms of hypertension, cardiovascular disease and diabetes besides just increased activity of the renin-angiotensin system. Specifically, next generation ARBs are becoming available that are intended to not only antagonize AT 1 receptors, but also block endothelin receptors, function as nitric oxide donors, inhibit neprilysin activity and increase natriuretic peptide levels, or stimulate the peroxisome proliferator-activated receptor c (PPARc). In this review, we: (1) discuss the potential importance of multifunctional ARBs that can reduce cardiovascular and metabolic risk through multiple mechanisms that go beyond just inhibition of the renin-angiotensin system and (2) describe specific examples of next generation ARBs in development that are intended to do more than simply block AT 1 receptors.

show abstract

Comparative angiotensin II receptor blockade in healthy volunteers: The importance of dosing

Cited by 83 publications

References 17 publications

Effects of high dose olmesartan medoxomil plus hydrochlorothiazide on blood pressure control in patients with grade 2 and grade 3 hypertension

Effects of high dose olmesartan medoxomil plus hydrochlorothiazide on blood pressure control in patients with grade 2 and grade 3 hypertension

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

Next generation multifunctional angiotensin receptor blockers

Contact Info

Product

Resources

About