Revealing the role of the autonomic nervous system in the development and maintenance of Goldblatt hypertension in rats

Abstract

Despite extensive use of the renovascular/Goldblatt model of hypertension—2K-1C, and the use of renal denervation to treat drug resistant hypertensive patients, autonomic mechanisms that underpin the maintenance of this hypertension are important yet remain unclear. Our aim was to analyse cardiovascular autonomic function by power spectral density analysis of both arterial pressure and pulse interval measured continuously by radio telemetry for 6 weeks after renal artery clipping. Mean arterial pressure increased from 106 ± 5 to 185 ± 2 mm Hg during 5 weeks post clipping when it stabilized. A tachycardia developed during the 4th week, which plateaued between weeks 5 and 6. The gain of the cardiac vagal baroreflex decreased immediately after clipping and continued to do so until the 5th week when it plateaued (from − 2.4 ± 0.09 to − 0.8 ± 0.04 bpm/mm Hg; P < 0.05). A similar time course of changes in the high frequency power spectral density of the pulse interval was observed (decrease from 13.4 ± 0.6 to 8.3 ± 0.01 ms2; P < 0.05). There was an increase in both the very low frequency and low frequency components of systolic blood pressure that occurred 3 and 4 weeks after clipping, respectively. Thus, we show for the first time the temporal profile of autonomic mechanisms underpinning the initiation, development and maintenance of renovascular hypertension including: an immediate depression of cardiac baroreflex gain followed by a delayed cardiac sympathetic predominance; elevated sympathetic vasomotor drive occurring after the initiation of the hypertension but coinciding during its mid-development and maintenance.

Increased Expression of Angiotensin II Type 2 Receptors in the Solitary–Vagal Complex Blunts Renovascular Hypertension

“…For example, circulating ANG II levels are high, especially during phase I (first 4 weeks) of 2K1C renovascular hypertension, 9,10 and ANG II acting at AT1R within the NTS has been reported to attenuate baroreflex function. 12,14 Similar to the findings in the present study, Oliveira-Sales 7 demonstrated that during phase I of 2K1C hypertension there is an impairment of the baroreflex, and this may be related to the high levels of ANG II.…”

“…In phase II, both SNA and MAP are increased by volume retention, decreased sodium excretion, and an increase in ANG II sensitivity. 7,9,10 all of which might be not directly affected by the AT2R overexpression in the solitary-vagal complex.…”

“…7,8 It has been reported that NTS inhibition reduces arterial pressure and SNA in SHR. 15 Although we have not directly measured SNA, we observed that in 2K1C-eGFP there was in increase in LF of SBP.…”

“…It is well established that the baroreflex is attenuated in 2K1C rats and impairment of the baroreflex seems to be critical to the development and maintenance of 2K1C hypertension 5–7 since a reduction in the baroreflex gain might also contribute to the increase in sympathetic outflow and high blood pressure. 34 Evidence suggests that in 2K1C rats ANG II acting via its AT1R in the NTS is responsible for dampening the baroreflexes in renovascular hypertension.…”

“…2,3 Animal models of renovascular hypertension were demonstrated ~80 years ago using the Goldblatt two kidney 1 clip (2K1C). 4 These animals also display impaired baroreflexes 5–7 , an increase in sympathetic nerve activity (SNA), 7,8 and an overactivity of the RAS. 9,10 Considering the impairment of the baroreflex and overactivity of the sympathetic nervous system seen in renovascular hypertension, the role of the central nervous system (CNS) in the development and maintenance of renovascular hypertension has also been demonstrated.…”