Baroreflex control of heart rate (HR) is impaired in diabetes mellitus. We hypothesized that diabetes mellitus induced functional changes of neural components at multiple sites within the baroreflex arc. Type 1 diabetic mice (OVE26) and FVB control mice were anesthetized. Baroreflex-mediated HR responses to sodium nitroprusside- (SNP) and phenylephrine- (PE) induced mean arterial blood pressure (MAP) changes were measured. Baroreceptor function was characterized by measuring the percent (%) change of baseline integrated aortic depressor nerve activity (Int ADNA) in response to SNP- and PE-induced MAP changes. The HR responses to electrical stimulation of the left aortic depressor nerve (ADN) and the right vagus nerve were assessed. Compared with FVB control mice, we found in OVE26 mice that (1) baroreflex-mediated bradycardia and tachycardia were significantly reduced. (2) The baroreceptor afferent function in response to MAP increase did not differ, as assessed by the parameters of the logistic function curve. But, the inhibition of Int ADNA in response to MAP decrease was significantly attenuated. (3) The maximum amplitude of bradycardic responses to right vagal efferent stimulation was augmented. (4) In contrast, the maximum amplitude of bradycardic responses to left ADN stimulation was decreased. Since Int ADNA was preserved in response to MAP increase and HR responses to vagal efferent stimulation were augmented, we conclude that a deficit of the central mediation of baroreflex HR contributes to the overall attenuation of baroreflex sensitivity in OVE26 mice. The successful conduction of physiological experiments on the ADN in OVE26 mice may provide a foundation for the understanding of cellular and molecular mechanisms of diabetes-induced cardiac neuropathy.

Baroreflex control of heart rate (HR) is impaired in human type 1 diabetes mellitus. The goal of this study is to use a transgenic mouse model of type 1 diabetes (OVE26) to assess the diabetes-induced baroreflex impairment in the conscious state. OVE26 transgenic mice (which develop hyperglycemia within the first three weeks after birth due to the specific damage of beta cells) and normal control mice (FVB) 5-6 months of age were anesthetized, and the left femoral artery and both veins were catheterized. On the second day after surgery, baroreflex-mediated HR responses to arterial blood pressure (ABP) changes that were induced by separate microinfusion of phenylephrine (PE) and sodium nitroprusside (SNP) at different doses (0.03-0.4 μg/min) were measured in the conscious state. Compared with FVB control, we found that in OVE26 diabetic mice 1) mean ABP (MABP) and HR were decreased (p < 0.05). 2) PE-induced MABP increases were comparable to those in FVB mice (p > 0.05). 3) Baroreflex-mediated bradycardia was attenuated (p < 0.05). 4) SNP-induced MABP decreases was reduced (p < 0.05). 5) Baroreflex-mediated tachycardia was attenuated (p < 0.05). Since baroreflex control of HR in conscious OVE26 mice is impaired in a similar fashion to human diabetes mellitus, we suggest that OVE26 mice may provide a useful model to study the neural mechanisms of diabetes-induced baroreflex impairment.

Baroreflex sensitivity is impaired by diabetes mellitus. Previously, we found that diabetes induces a deficit of central mediation of baroreflex-mediated bradycardia. In this study, we assessed whether diabetes induces degeneration of the nucleus ambiguus (NA) and reduces heart rate (HR) responses to l-Glutamate (L-Glu) microinjection into the NA. FVB control and OVE26 diabetic mice (5-6 months) were anesthetized. Different doses of L-Glu (0.1-5 mM/l, 20 nl) were delivered into the left NA using a multi-channel injector. In other animals, the left vagus was electrically stimulated at 1-40 Hz (1 ms, 0.5 mA, 20 s). HR and mean arterial blood pressure (MAP) responses to L-Glu microinjections into the NA and to the electrical stimulation of the vagus were measured. The NA region was defined by tracer TMR-D injection into the ipsilateral nodose ganglion to retrogradely label vagal motoneurons in the NA. Brainstem slices at - 600, - 300, 0, + 300, and + 600 μm relative to the obex were processed using Nissl staining and the number of NA motoneurons was counted. Compared with FVB control, we found in OVE26 mice that: 1) HR responses to L-Glu injection into the NA at doses of 0.2-0.4 (mM/l, 20 nl) were attenuated (p < 0.05), but MAP responses were unchanged (p > 0.05). 2) HR responses to vagal stimulation were increased (p < 0.05). 3) The total number of NA (left and right) motoneurons was reduced (p < 0.05). Taken together, we concluded that diabetes reduces NA control of HR and induces degeneration of NA motoneurons. Degeneration of NA cardiac motoneurons may contribute to impairment of reflex-bradycardia in OVE26 diabetic mice.