Modulation of reflex function by endogenous angiotensins in older transgenic rats with low glial angiotensinogen

Abstract

Age-related impairments in baroreflex sensitivity in Sprague-Dawley rats are associated with low solitary tract nucleus content of angiotensin-(1-7). However, transgenic rats with low-brain angiotensinogen resulting from glial overexpression of an antisense oligonucleotide to angiotensinogen (ASrAOGEN) are spared age-related declines in cardiovascular function characteristic of Sprague-Dawley rats. We examine whether cardiovascular and reflex actions of angiotensin-(1-7) persist in the solitary tract nucleus of older (16 to 22 months) ASrAOGEN rats. Baroreflex sensitivity for control of heart rate and chemosensitive vagal afferent activation in response to phenylbiguanide were measured before and after bilateral microinjection of the angiotensin II type 1 receptor antagonist candesartan and angiotensin-(1-7) receptor antagonist (D-Ala(7))-angiotensin-(1-7) in urethane/chloralose-anesthetized rats. In older anesthetized ASrAOGEN rats, candesartan had no effect, whereas (D-Ala(7))-angiotensin-(1-7) significantly reduced baroreflex sensitivity (1.80+/-0.43 versus 0.50+/-0.17 ms/mm Hg). Phenylbiguanide responses were attenuated by injection of candesartan (-79+/-6 versus -55+/-12 mm Hg and -277+/-12 versus -156+/-27 bpm; P<0.05). In addition, resting blood pressure was reduced by injection of candesartan or (D-Ala(7))-angiotensin-(1-7). Within the solitary tract nucleus of older ASrAOGEN rats, it appears that glial angiotensinogen is the main source of angiotensin II attenuation of baroreflex sensitivity; endogenous angiotensin-(1-7) from nonglial sources enhances baroreflex sensitivity; nonglial sources of angiotensin II contribute to chemosensitive vagal afferent activation; and receptors for both peptides modulate resting arterial pressure under anesthesia. These results suggest a novel mechanism for the preservation of baroreflex sensitivity during aging.

Figure 1

Maximal transient changes in MAP and HR in response to NTS injection of CAN or D-Ala. A, All of the treatments, alone or in combination, significantly reduced MAP compared with baseline values. The reduction in pressure on CAN injection was significantly larger than when D-Ala was administered alone (#P<0.05). B, Injection of CAN alone, D-Ala in the presence of CAN, and D-Ala alone significantly reduced HR compared with baseline values. n=5 for each group; *P<0.05, **P<0.01, and ***P<0.001.

Figure 2

BRS for control of HR in response to intravenous phenylephrine before and after bilateral NTS injection of (A) CAN or (B) D-Ala. A, Administration of CAN alone (n=5) had no effect on BRS, whereas D-Ala in the presence of CAN (n=5) decreased BRS by 72%. B, Reversal of receptor antagonists revealed that administration of D-Ala alone (n=5) decreased BRS by 69%. CAN administered 60 minutes later in the presence of D-Ala (n=5) did not have any further effect on BRS compared with D-Ala alone. *P<0.05 vs baseline, &P<0.05 vs after CAN, #P<0.01 versus baseline.

Figure 3

Responses to CVA induced by intravenous phenylbiguanide before and after bilateral NTS injection of (A) CAN or (B) D-Ala. A, CAN alone (n=5) and D-Ala administered 60 minutes later in the presence of CAN (n=5) significantly reduced MAP and HR responses to CVA. B, On reversal of receptor antagonists, D-Ala alone (n=5) no longer reduced MAP but significantly reduced HR responses. CAN administered 60 minutes later in the presence of D-Ala (n=5) still reduced both MAP and HR responses to CVA. *P<0.05 vs baseline, &P<0.05 vs after CAN, #P<0.01 vs baseline, $P<0.001 vs baseline.