Prevention of Hypertension by Irbesartan in Dahl S Rats Relates to Central Angiotensin II Type 1 Receptor Blockade

Abstract

Abstract-Hypertension in Dahl S rats on high-salt intake is in general considered a model of "low-renin hypertension," unresponsive to treatment with blockers of the renin-angiotensin system. However, direct central administration of an angiotensin II type 1 (AT 1 ) receptor blocker prevents both the sympathoexcitation and hypertension caused by high-salt intake in Dahl S rats. In the present study, we tested the hypothesis that chronic peripheral administration of an AT 1 receptor blocker inhibits the salt-induced hypertension relative to the extent of central AT 1 receptor blockade that is induced. Dahl S rats received a high-salt (1370 mol Na ϩ /g) or regular (101 mol Na ϩ /g) diet from 4 to 8 weeks of age. In 3 different sets of experiments, Dahl S on high salt were randomized to intracerebroventricular (ICV) treatment with control infusion versus irbesartan at 50 or 250 g ⅐ kg Ϫ1 ⅐ d Ϫ1 , oral treatment with control versus irbesartan at 125 or 500 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 once daily by gavage, or subcutaneous treatment with control versus irbesartan at 50 or 150 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 by once daily injection. At 8 weeks of age, MAP was measured in conscious rats at rest and in response to angiotensin II ICV or IV. On high-salt intake, Dahl S developed the anticipated marked increase in MAP to Ϸ160 mm Hg. Irbesartan ICV did not affect pressor responses to angiotensin II IV, but irbesartan administered subcutaneously or by gavage markedly inhibited these responses. Irbesartan ICV or by gavage partially inhibited pressor responses to angiotensin II ICV and the development of hypertension. Irbesartan subcutaneously at the higher dose more completely inhibited pressor responses to angiotensin II ICV and fully prevented the salt-induced hypertension. The degree of central but not peripheral AT 1 receptor blockade parallels the antihypertensive effect of irbesartan, indicating that inhibition of the brain renin-angiotensin system can contribute to a significant extent to the therapeutic effectiveness of AT 1 receptor blockers such as irbesartan when administered in sufficiently high doses to cause central AT 1 receptor blockade. Key Words: Rats, Dahl Ⅲ hypertension, sodium-dependent Ⅲ brain Ⅲ renin-angiotensin system Ⅲ receptors, angiotensin II Ⅲ irbesartan R ecent studies have demonstrated that the brain renin-angiotensin system (RAS) plays a pivotal role in the sympathoexcitation and hypertension caused by high-salt intake in animal models of salt-sensitive hypertension. Although it is not yet known whether (and where) angiotensin (Ang) II or III increases, Ang II type 1 (AT 1 ) receptor stimulation appears to be essential, because chronic intracerebroventricular (ICV) infusion of AT 1 receptor blockers prevents the sympathoexcitation and hypertension by highsalt intake in both spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (Dahl S) rats. [1][2][3] In contrast, the circulatory RAS is suppressed during the development of hypertension in Dahl S on high-salt intake, 4 -6 and this model of "low-renin hypertension...

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…ANG, chronic peripherally given irbesartan attenuated those to centrally administered ANG (Leenen and Yuan, 2001). Possible brain penetration by orally administered irbesartan and losartan was also explored by a different approach, i.e., by testing inhibition of the dipsogenic response to ANG injected intracerebroventricularly in normotensive and spontaneously hypertensive rats (Polidori et al, 1998).…”

Oxidative stress in the cardiovascular center has a pivotal role in the sympathetic activation in hypertension

“…76 Recent studies suggest that the systemic administration of the AT1 receptor blockers also act on the AT1 receptors within the brain, thereby reducing blood pressure in hypertensive rats. [80][81][82] The extent of the actions of the AT1 receptor blockers within the brain depends partly on the lipophilicity and pharmacokinetics. 77,78 However, even the hydrophilic AT1 receptor blockers are able to block the AT1 receptors within the blood-brain barrier.…”

Oxidative Stress Mediates Angiotensin II–Dependent Stimulation of Sympathetic Nerve Activity

“…Key Words: angiotensin II Ⅲ sympathetic nerve activity Ⅲ nitric oxide Ⅲ interleukins S ubstantial evidence indicates that angiotensin II (Ang II) enhances sympathetic nerve (SNS) activity centrally and peripherally. 1-3 Intracerebroventricular administration of Ang II causes a dose-dependent increase in blood pressure (BP), 4 probably through activation of Ang II type 1 (AT 1 ) receptors localized in the median preoptic nucleus, juxtaventricular neurons of the subfornical organ, organum vasculosum laminae terminalis, 5,6 brain stem, or in preganglionic neurons in the rostral ventrolateral medulla and the intermediolateral column. 7 In a previous study, we showed that intracerebroventricular infusion of Ang II raises BP, renal sympathetic nervous system activity (RSNA), and norepinephrine (NE) secretion from the posterior hypothalamic nuclei (PH).…”