Is carotid body input the only critical mechanism involved in hypertension in spontaneously hypertensive rat?

Spontaneously hypertensive rats (SHRs) have increased arterial pressure that reaches hypertensive levels when rats are around 10 weeks old. The increase in arterial pressure in SHRs is mainly due to increased sympathetic and angiotensinergic activities (Brody et al. 1978; Moreira et al. 2009). Central mechanisms are essential for the development and maintenance of hypertension in SHRs and peripheral mechanisms like signals from peripheral chemoreceptors may also play a role (Colombari et al. 1996; Sato et al. 2001; Moreira et al. 2009; Abdala et al. 2012). The rostralventrolateral medulla (RVLM) neurones are suggested to be more active in SHRs, because they either receive more excitatory inputs or less GABAergic inhibition (Ito et al. 2000). Acute inhibition of either the commissural portion of the nucleus of the solitary tract (cNTS) or the paraventricular nucleus (PVN) decreases sympathetic nerve activity (SNA) in SHRs, but not in normotensive control Wistar–Kyoto rats (Allen, 2002; Sato et al. 2002). Moreover, cNTS ablation reduces arterial pressure to normotensive levels in SHRs in the first 5 days after lesions with arterial pressure returning to hypertensive pre-lesion levels around 10 days after the ablations (Moreira et al. 2009). In contrast to the effects in SHRs, in normotensive rats inhibition of cNTS produces no change in arterial pressure, which suggests that cNTS pressor mechanisms are particularly active in SHRs, increasing SNA and arterial pressure (Moreira et al. 2009). Besides the reduction in arterial pressure in SHRs, cNTS ablations also abolish the pressor responses to arterial chemoreceptor activation without changing baroreflex control (Sato et al. 2001; Moreira et al. 2009). A relationship between increases in SNA and increases in chemoreflex activation in SHRs has been reported (Trzebski, 1992; Abdala et al. 2012), which suggests that the anti-hypertensive effects of cNTS lesions in SHRs might be related to the blockade of chemoreflex (Sato et al. 2002). In the same direction pointed by the results in SHRs with cNTS ablations, a recent study published in The Journal of Physiology (Abdala et al. 2012) showed that removal of the carotid chemoreceptor inputs by carotid sinus denervation (CSD) chronically reduces arterial pressure and sympathetic hyperactivity in SHRs, which suggests that the arterial chemoreceptors have a high activity in SHRs causing sympathetic hyperactivity and high arterial pressure in this strain. The only difference comparing the effects of cNTS lesions and those of CSD is the time course of the effects. Whereas cNTS lesions acutely (1–7 days) reduce arterial pressure in SHRs, the CSD takes at least 1 week to start reducing arterial pressure in SHRs. Also in opposite directions, arterial pressure is chronically reduced by CSD, whereas cNTS lesions reduce arterial pressure only acutely. It is not clear why disrupting peripheral chemoreceptor action by different methods results in different acute and chronic effects in the arterial pressure in SHRs. The CSD removes chemoreceptor and also part of baroreceptor signals, whereas cNTS ablations seem to remove exclusively chemoreceptor signals. In addition, it is possible that besides disrupting chemoreflex, cNTS lesions might affect other still unknown mechanisms involved in the control of arterial pressure in SHRs allowing cNTS hypertensive mechanisms to be replaced by another pressor mechanism that drives arterial pressure back to pre-cNTS lesion hypertensive levels 10 days after cNTS ablations in SHRs. One possibility is that forebrain mechanisms might replace the hindbrain hypertensive mechanisms impaired by cNTS lesions allowing the recovery of pre-lesion hypertensive levels in chronically cNTS lesioned SHRs (Moreira et al. 2009). In the forebrain, one area strongly involved in development and maintenance of different models of experimental hypertension is the tissue surrounding the anteroventral third ventricle (AV3V region) (Menani et al. 1990). Ablations of the AV3V region reduce pressor responses dependent on SNA and/or hormonal secretion, without changing baro- and arterial chemoreflexes (Vieira et al. 2004). AV3V ablations impair the development of neurogenic hypertension produced by sinoaortic denervation or by ablation of the medial NTS and the development of renal ANG II-dependent hypertension. Although AV3V lesions alone produce no effect in the hypertension in SHRs (Brody et al. 1978; Moreira et al. 2009), the combination of simultaneous AV3V and cNTS lesions chronically (for at least 40 days) reduces hypertension in SHRs, suggesting that multiple mechanisms are involved in the maintenance of hypertension in SHRs (Moreira et al. 2009). Therefore, without excluding a role of arterial chemoreceptor, hypertension in SHRs seems to be dependent on multiple mechanisms including the involvement of multiple central areas. One mechanism may compensate for the absence of the other, which increases the probability of hypertension in these animals. The results showing that acute or chronic ablations of the cNTS abolish the pressor responses to peripheral chemoreflex activation whereas only acute cNTS ablation reduces hypertension in SHRs suggest that signals from peripheral chemoreceptors are important to maintain hypertension in SHRs, but when absent might be replaced by other mechanisms, like those dependent on the AV3V region, that maintain hypertension in SHRs. On the other side, results with CSD suggest that only removing chemoreceptor action is enough to chronically reduces hypertension in SHRs. Future studies using different approaches are necessary to confirm the mechanisms involved in the maintenance of hypertension in SHRs and particularly the reasons for the differences comparing central and peripheral manipulation of the arterial chemoreflex or more specifically which are the additional mechanisms affected by cNTS lesions that allow a complete recovery of hypertensive levels in cNTS lesioned SHRs chronically, even if chemoreflex is not active anymore, whereas only the removal of the peripheral chemoreceptor action keeping cNTS intact has a chronic anti-hypertensive effect in SHRs.