Sympathoexcitatory and pressor responses to increased brain sodium and ouabain are mediated via brain ANG II

Abstract

Intracerebroventricular administration of hypertonic saline, ouabain, brain ouabainlike activity (OLA), or angiotensin II (ANG II) causes sympathoexcitatory and pressor effects in rats. To clarify the possible interaction between increased brain sodium, brain OLA, and the brain renin-angiotensin system (RAS), increases in mean arterial pressure, heart rate (HR), and renal sympathetic nerve activity (RSNA) in response to intracerebroventricular 0.3 M NaCl, ouabain, and ANG II were recorded in conscious Wistar rats before and after intracerebroventricular pretreatment with the angiotensin-receptor (AT1) blocker losartan, antibody Fab fragments (Digibind), or, as control, gamma-globulins. These Fab fragments bind ouabain and brain OLA with high affinity. The arginine vasopressin (AVP) antagonist [d(CH2)5Tyr(Me)]AVP (30 micrograms/ kg) was injected intravenously before each intracerebroventricular injection. Intracerebroventricularly administered 0.3 M NaCl (3.8 mul/min for 10 min), ouabain (0.3 and 0.6 microgram), and ANG II (10 and 30 ng) caused similar pressor responses. However, the extent of HR and RSNA responses to ANG II was smaller than those to 0.3 M NaCl and ouabain. Intracerebroventricular losartan (10 and 20 micrograms) blocked responses to ANG II and 0.3 M NaCl and significantly attenuated the responses to ouabain (pressor response by 50-70%; RSNA and HR by 60-80%). In contrast, intracerebroventricular Fab fragments (66 micrograms) blocked only the responses to 0.3 M NaCl and ouabain and did not affect the responses to ANG II. These results suggest that an acute rise in brain sodium concentration increases brain OLA and the latter exerts its sympathoexcitatory and pressor effects at least partly via activation of the brain RAS.

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

“…37 The sympathoexcitatory and pressor responses to central infusion of aldosterone and Na + -rich aCSF can be prevented by central infusion of the sodium channel blocker benzamil or an ouabain blocker, 27,38 and the pressor responses elicited by central infusion of aldosterone or ouabain can be blocked by an AT 1 blocker. 27,39 In the RVLM, microinjection of an ouabain-like compound 40 or angiotensin II 21 elicits a pressor response and sympathoexcitation. Collectively, these data suggest that aldosterone in the RVLM might activate central mechanism(s) involving the MR-ENaC-ouabain pathway, thereby causing sympathetic hyperactivity and hypertension.…”

Mechanisms in the PVN mediating local and central sodium-induced hypertension in Wistar rats

“…Ouabain-binding Fab fragments (Digibind) (31) or vehicle were then infused at 2.9 g ⅐ 300 nl Ϫ1 ⅐ min Ϫ1 for 3.5 min before infusion of Na ϩ -rich aCSF (0.3 and 0.7 M Na ϩ ) at 300 nl/min for 15 min. The dose of Fab fragments was adapted from our previous study (13) showing the blockade of responses to intracerebroventricular ouabain or Na ϩ -rich aCSF.…”

“…These findings suggest that mineralocorticoid receptors (MRs) and benzamil-blockable Na ϩ channels or transporters in the CNS mediate the release of "ouabain" and hypertension caused by a chronic increase in CSF [Na ϩ ]. The sympathoexcitatory and hypertensive responses to intracerebroventricular infusion of Na ϩ -rich aCSF or ouabain can also be inhibited by intracerebroventricular losartan (13). Altogether, these results suggest that in response to a chronic increase in CSF [Na ϩ ], increased binding of an endogenous agonist (presumably aldosterone) (15) to MRs mediates the activation of benzamil-blockable Na ϩ influx, leading to "ouabain" release and ANG II type 1 (AT 1 ) receptor stimulation.…”

Endogenous Digitalislike Factor: An Update

“…Ouabain-induced hypertension may be caused by the action on the central nervous system rather than by the actions on the peripheral vessels and the heart. Furthermore, digoxin may be hypertensinogenic endogenous digitalis acting locally in the central nervous system by increasing both sympathetic outflow and pituitary hormone release, according to the finding demonstrated by Leenen et al (20,21). Long-term treatment with ouabain actually increases blood pressure in rats (17).…”

“…ICV injections of ouabain elevate blood pressure by acting on the hypothalamus (18). Yamada et al (19) report that Icy infusions of DigibindTM (Fab fragments of anti-digoxin antibody) lower blood pressure in reduced renal masssaline hypertension in rats, and Huang and Leenen (20) report the same result in ouabain-induced hypertensive rats, where sympathetic inhibition is involved mainly as the hypetensive mechanism. Ouabain-induced hypertension may be caused by the action on the central nervous system rather than by the actions on the peripheral vessels and the heart.…”