Blockade of insulin receptor signaling in the medullary cardiovascular centers impairs open-loop arterial baroreflex function via attenuated neural arc in healthy male rats

Abstract

Evidence suggests that brain insulin availability acutely modulates arterial baroreflex function. However, little is known about the impact of blocking brain insulin receptor (IR) signaling on arterial baroreflex. We hypothesized that blockade of IR signaling in the brain acutely impairs arterial baroreflex function. Our hypothesis was tested using baroreflex open-loop analysis to evaluate the two subsystems of the arterial baroreflex: the carotid sinus pressure (CSP)–sympathetic nerve activity (SNA) relationship (the neural arc) and the SNA–arterial pressure (AP) relationship (the peripheral arc). In anesthetized healthy male rats, the bilateral carotid sinus baroreceptor regions were surgically isolated from the systemic circulation, and then CSP was changed stepwise from 60 to 180 mmHg before and over 120 min after lateral intracerebroventricular (ICV) administration of either artificial cerebrospinal fluid (control solution) or IR antagonist GSK1838705. ICV injection of GSK1838705 significantly decreased renal SNA (RSNA), AP, and heart rate during stepwise CSP input over a period of 120 min after administration (p < .05). The maximum gain of the neural arc was significantly reduced 120 min after ICV injection of GSK1838705 (p = .002). Furthermore, GSK1838705 significantly attenuated the operating-point RSNA (p = .025) and AP (p < .001) as estimated by the baroreflex equilibrium diagram. Moreover, 120-min baroreflex stimulation via stepwise CSP input significantly increased c-Fos expression in IR-positive neurons in medullary cardiovascular centers (p < .001). Our findings suggest that IR signaling in the brain can modulate AP regulation via alteration of the neural arc of the arterial baroreflex.