β1 Receptors Protect the Renal Afferent Arteriole of Angiotensin-Infused Rabbits from Norepinephrine-Induced Oxidative Stress

Abstract

Renal afferent arterioles (Aff) from angiotensin II (AngII)-infused rabbits have enhanced contractions to AngII that are normalized by tempol (superoxide dismutase mimetic), whereas contractions to norepinephrine (NE) are normal and unaffected by tempol. Tested was the hypothesis that ␤-receptor stimulation with NE prevents enhanced reactivity and superoxide generation. Preconstricted Aff from AngII-or vehicle-infused rabbits were perfused at physiologic pressure. Aff from vehicle-infused rabbits had strong, endothelium-independent relaxations to dobutamine (␤ 1 -receptor agonist; 78 ؎ 6%; P < 0.0001; mean ؎ SD) but only weak relaxations to salbutamol (␤ 2 -receptor agonist; 13 ؎ 3%; P < 0.05) or BRL-37,344 (␤ 3 -receptor agonist; 14 ؎ 3%; P < 0.05). Contractions to NE were similar in Aff from vehicle-and AngII-infused rabbits (؊36 ؎ 5 versus ؊34 ؎ 3%; NS) and were unaffected by tempol (؊32 ؎ 4%; NS). In contrast, phenylephrine contractions (␣ 1 agonist) were enhanced in Aff from AngII-infused rabbits (؊59 ؎ 6 versus ؊46 ؎ 4%; P < 0.05) and normalized by tempol. NE contractions in Aff from AngII-infused rabbits (؊34 ؎ 4%) were enhanced (P < 0.01) by propranolol (nonselective ␤ antagonist; ؊53 ؎ 6%), CGP-20,712A (selective ␤ 1 -receptor antagonist; ؊61 ؎ 9%), or Rp-cAMP (competitive inhibitor of cAMP; ؊56 ؎ 4%); were normalized by tempol; but were unaffected by ICI-118,551 (selective ␤ 2 -receptor antagonist) or SR-59,230A (selective ␤ 3 -receptor antagonist). Superoxide generation in Aff from AngII-infused rabbits that were assessed from ethidium:dihydroethidium was enhanced by addition of CGP-20,712A to NE but was normalized by tempol. Aff have robust ␣ 1 -receptor contraction and ␤ 1 -receptor dilation. NE elicits ␤ 1 signaling via cAMP that moderates oxidative stress and contractions in Aff from AngII-infused rabbits.J Moreover, administration of permanent SOD reverses hypertension in the AngII-induced but not the NE-induced rat model (3). They concluded that AngII selectively induces vascular oxidative stress, which contributes to hypertension. Relatively low rates of infusion of AngII into mice (4), rats (1,5,6), rabbits (7), or humans (8) increase BP gradually ("slow pressor response"). This is considered a model of human hypertension because the plasma levels of AngII increase only within a physiologic range of 50 to 100% (9). The hypertension entails a renal mechanism because it depends on salt intake (10) and an enhanced vascular reactivity of the renal afferent arteriole (Aff) to AngII (11). Unlike AngII, infusion of NE leads to tachyphylaxis and a decreased BP response (8). The AngII slow pressor response has been related to ROS because it is prevented by co-infusion of the permeant SOD mimetic nitroxide tempol (4,6).Low rates of infusion of the thromboxane-prostanoid receptor (TP-R) mimetic U-46,619 (12) or endothelin-1 (ET-1) (13) also elicit slow pressor responses that are accompanied by oxidative stress. Moreover isolated, pressurized Aff that are dissected from the kidneys of rabbits that are und...

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