Central Gαi₂proteins, sympathetic nervous system and blood pressure regulation

Carmichael et al. (2015) demonstrated that the inactivation of brain Gαi2 proteins prolonged the duration of blood pressure response elicited by intravenous administration of hypertonic saline. Some of their findings indicated that brain Gαi2 protein inactivation altered the central mechanisms responsible for the suppression of sympathetic outflow which occurs in intact rats challenged by hypertonic saline. These mechanisms involve sodium-evoked activation of parvocellular neurones in paraventricular nucleus. This study on the role of central Gαi2-protein-mediated signal transduction in the response of Sprague–Dawley rats to acute salt loading is an exciting paper, especially if we consider its results in the context of previous studies by Kapusta and Wainford. Brain Gαi2-subunit proteins participate in central sympathoinhibition in animals subjected to acute salt loading in which the inactivation of brain Gαi2 proteins causes sodium retention, sympathoexcitation and blood pressure elevation (Kapusta et al. 2012). Highly important are also the findings that brain Gαi2 proteins are responsible for salt resistance in the rat. Recently, Wainford et al. (2015) reported that chronic intracerebroventricular infusion of targeted Gαi2 oligonucleotides enabled the development of salt hypertension even in salt-resistant Dahl rats and the same phenomenon was also observed in Sprague–Dawley rats (Kapusta et al. 2013). Indeed, blood pressure effects resulting from the sympathoexcitation in animals subjected to the inactivation of brain Gαi2 proteins were confirmed by enhanced blood pressure response to ganglionic blockade (Kapusta et al. 2013, Carmichael et al. 2015, Wainford et al. 2015). Another highly interesting part of the paper by Carmichael et al. concerns the impact of Gαi2 ODN pre-treatment on the baroreflex function. Central Gαi2 downregulation, which is associated with facilitation of salt hypertension development, caused a moderate attenuation of baroreflex efficiency. There was a less steep slope of baroreflex curve (heart rate to mean arterial pressure relationship) in Gαi2 ODN-pre-treated rats, indicating decreased baroreflex sensitivity in Gαi2 ODN-pre-treated rats. This is clearly evident in high-pressure part of the analysed baroreflex curve. It is generally accepted that baroreflex function is altered in hypertensive subjects and animals. These alterations appearing during hypertension development consist of the resetting of baroreflex set point to high blood pressure values and the decrease in baroreflex sensitivity. Nevertheless, this study shows that the inactivation of brain Gαi2 proteins caused the changes in baroreflex sensitivity without previous blood pressure changes. It would therefore be desirable to analyse the changes of baroreflex sensitivity prior to high blood pressure appearance in salt-sensitive Dahl rats developing salt hypertension as well as in salt-resistant Dahl rats in which salt hypertension development was enabled by Gαi2 ODN pre-treatment (Wainford et al. 2015). Thus, the altered function of central α2-adrenergic mechanism causing sympathoinhibition through the activation of Gαi2-protein-gated signal transduction pathways might be the key to better understanding of pathophysiology of salt hypertension in Dahl rats which are characterized by enhanced sympathetic nerve activity and its augmented contribution to high blood pressure maintenance (Takeshita & Mark 1978, Takeshita et al. 1979, Zicha et al. 2001) (for reviews, see also Mark 1991 and Zicha et al. 2012). Further studies should be focused on possible alterations of Gαi2-dependent sympathoinhibitory mechanisms in other models of salt hypertension as well as on the participation of these mechanisms in other forms of experimental hypertension. It is of interest that Gi proteins participate not only in central but also in peripheral mechanisms of blood pressure control, but blood pressure effects of their brain or peripheral inactivation are quite opposite. Blood pressure of spontaneously hypertensive rats (SHR), which is highly dependent on sympathetic vasoconstriction (for recent review, see e.g. Pintérová et al. 2011), can be considerably lowered by peripheral Gi protein inactivation following intravenous pertussis toxin administration (Tabrizchi & Triggle 1991, Pintérová et al. 2010). Chronic treatment of immature SHR with pertussis toxin retarded effectively the onset of genetic hypertension development (Li & Anand-Srivastava 2002). The contribution of peripheral mechanisms to blood pressure reduction elicited by Gi protein inactivation was studied by Pintérová et al. (2010) who reported the attenuation of sympathetic vasoconstriction in pertussis toxin-treated rats, the effects being substantially greater in hypertensive animals than in their normotensive controls. Using conscious rats subjected to acute ganglionic blockade, we demonstrated a rightward shift of blood pressure response to noradrenaline in pertussis toxin-treated rats, indicating diminished vascular responsiveness to noradrenaline in animals with peripheral Gi protein inactivation. This shift of noradrenaline dose–response curve to the right was caused by the disappearance of nifedipine-sensitive component of vascular contraction in pertussis toxin-treated SHR, suggesting an important role of peripheral α2-adrenergic mechanisms in the pathogenesis of genetic hypertension (Pintérová et al. 2009, 2010). There is no conflict of interest from my side.