| Baroreceptor reflex sensitivity (BRS) is blunted and sympathetic nerves activity is augmented in spontaneous hypertensive rats (SHR). It has been reported that injection of Ang II into the forth cerebral ventricle attenuated BRS in rabbits, which was mediated by AT1 receptor The rostral ventrolateral medulla (RVLM) is well established as a basic area in central cardiovascular regulation and a major source of sympathetic activation. AT1 receptor is rich in this area. Our recent data suggest that microinfusion of Ang II into the RVLM resulted in a significant inhibition of the BRS, which was almost completely abolished by pretreatment with microinjection of AT1 receptor antagonist losartan, indicating that AT1 receptors play an important role in modulating BRS in the normotensive rats. Therefore, whether the abnormal AT1 receptor is involved in the blunted BRS in hypertension is our focus. In the present study, we evaluated the role of AT1 receptor in the RVLM on the attenuation of the BRS in the SHR by administration of antisense oligodeoxynucleotides to AT1 receptor mRNA, AT1 receptor antagonist losartan and Ang II into the RVLM.Materials and MethodsTwenty six SHR and thirty two normotensive Wistar rats weighing between 300 and 400 g were used in the experiments. Each rat was anesthetized with intraperitoneal injection of urethane. According to the Paxinos and Watson rat atlas, a stereotaxic instrument was used and a cannula was positioned in the RVLM ( AP 12.7 mm, L and R 2.1 mm, H 10.1 mm) for microinjection (0.1) or microinfusion ( 0.5 l ?h) . Intravenous injections of graded doses of phenylephrine (1, 5, 10, 20 and 40 g/kg) increased the blood pressure to elicit the baroreceptor reflex. The BRS was estimated by fitting a least-squares regression line for the relationship between changes in heart rate (HR) in beats per minute (bpm) and changes in mean arterial pressure (MAP, mmHg). Antisense oligodeoxynucleotides (ASODN) targeted to AT1 receptor mRNA ( ASODN , 5'-TAACTGTGCCTGCCA-3' ) , scrambled oligodeoxynucleotides (ScrODN, 5'- CTTACTAGCCTAGGC -3') and Ang II were obtained from Sigma Chemical Co. Losartan was supplied by Merck Co. All data are presented as mean ?SE.Results1. MAP and BRS in SHR and normal rats The MAP of SHR (n=18) is 45.0% higher than normal rats (n=16) (135.0 ?4.5 vs 90.7 ?3.0 mmHg, P < 0.01). There was a 60.0% reduction in the BRS in SHR compared with normal rats (-1.4 ?0.1 vs -3.5 ?0.1 beats min mmHg, P<0.01 )(n=18).2. The effect of ASODN targeted to AT1 receptor mRNA on BRSAfter bilateral microinjection of ASODN to AT1 receptor mRNA into the RVLM, the blunted BRS was increased 57.1% in SHR at 210 min (-1.4 ?0.1 vs -2.2 ?0.2 beats min . mmHg, P < 0.01 ) (n=6) . However, no significant changes in the BRS were observed in normal rats. Microinjection of ScrODN (275 pmoL) into the RVLM did not significantly modify the BRS either in SHR or in normal rats.3. The effect of Ang n and losartan on BRS Bilateral microinfusion of AT1 receptor antagonist losartan ( 250 nmoL ?h) into the RVLM restored the blunted BRS 60% in SHR (-1.5 ?0.2 vs -2.4 ?0.4 beats minmmHg, P < 0.01 ) , but had no significant effect on the BRS in normal rats. Microinfusion of Ang II (1.5 nmol h) into the RVLM in normal rats significantly inhibited the BRS (-3.6 ?0.4 vs -2.3 ?0.2 beats min mmHg, P < 0.01), and this inhibitory effects of Ang II can be almost completely abolished by pretreatment with losartan. However, no significant changes in the BRS were observed during microinfusion of Ang II into the RVLM in SHR. DiscussionThe primary finding in the present study was that microinjection of ASODN targeted to AT receptor mRNA into the RVLM significantlyenhanced the blunted sensitivity of baroreceptor reflex in SHR and AT, receptor antagonist losartan also restored the blunted BRS. However, ASODN and losartan didn't show any significant effects on the BRS in normal rats. These results indicate that the enhanced AT receptor activity in the RVLM contributes to the blunted B... |
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