Increased Respiratory‐Sympathetic Coupling Via C1 Neurons Contributes to the Development of Hypertension in the Spontaneously Hypertensive Rat

Abstract

An interaction between neurons in the central respiratory and sympathetic vasomotor networks leads to the generation of bursts of sympathetic nerve activity in phase with the respiratory cycle (RespSNA), which produce respiratory phase‐locked oscillations in blood pressure (BP) called Traube‐Hering waves (TH waves). RespSNA and TH waves are increased in Spontaneously Hypertensive (SH) rats at pre‐hypertensive ages and are proposed to contribute to the development of hypertension. In normotensive rats, pre‐sympathetic adrenergic C1 neurons are inspiratory modulated, and their inhibition decreases RespSNA. In SH rats, the inspiratory modulation of pre‐sympathetic neurons is exaggerated. To examine the involvement of C1 neurons in the increased RespSNA and TH waves in SH rats and the development of hypertension, we lesioned C1 neurons in pre‐hypertensive (21 days old, P21) SH and control Wistar Kyoto (WKY) rats with the immunotoxin anti‐dopamine beta‐hydroxylase‐saporin (anti‐DBH‐SAP). Using radiotelemetry we observed reduced BP in anti‐DBH‐SAP injected SH rats compared to control SH rats at 3 months (134 ± 3 vs. 116 ± 2 mmHg, P<0.001). These injections did not significantly alter BP in WKY rats. TH wave amplitude was significantly reduced, to WKY level, in anti‐DBH‐SAP injected SH rats. Power spectral analysis of systolic BP revealed a decrease, to WKY level, in low and high frequency power in anti‐DBH‐SAP injected SH rats, suggesting decreased basal SNA and RespSNA respectively. To gain mechanistic understanding about these decreases in BP and TH waves, we used a recombinant virus to induce expression of the inhibitory allatostatin receptor in C1 neurons of P21 SH and WKY rats. The cardiorespiratory effects of acute C1 neurons inhibition were assessed using the Working Heart‐Brainstem Preparation. Pharmacogenetic inhibition of C1 neurons markedly attenuated RespSNA and TH waves in SH rats down to WKY rats level, by selective diminution of the exaggerated inspiratory component of RespSNA. The SNA response to peripheral chemoreflex stimulation, which is exacerbated in SH rats, was also reduced down to WKY level during C1 inhibition. Therefore, this proof of concept study demonstrates that increased RespSNA and TH waves contribute to the development of hypertension in SH rats, and that this is mediated by C1 neurons. These results are of critical importance for understanding the mechanisms driving the development of human hypertension.