The present study demonstrates that: 1) diabetes blunted the aortic baroreflex sensitivity; 2) local microinjection of losartan (a selective AT1 receptor antagonist), apocynin (a NADPH oxidase inhibitor), and tempol (a SOD mimetic) into the nodose ganglion partially improved the aortic baroreflex sensitivity in STZ-induced diabetic rats; 3) losartan, apocynin, and tempol also fully normalized exogenous Ang II-attenuated aortic baroreflex sensitivity in sham rats; 4) Ang II concentration in plasma and nodose ganglia, NADPH oxidase activity, and superoxide production were increased in the diabetic rats. These results indicate that over-excited endogenous Ang II-NADPH oxidase-superoxide signaling in the nodose ganglia is involved in the attenuated aortic baroreflex sensitivity in the diabetic state.
Arterial baroreflex contributes to regulating the blood pressure and heart rate by acting on both sympathetic and parasympathetic efferent limbs of the cardiovascular autonomic nervous system and maintaining the enough blood flow into all organs. Previous studies have shown that the arterial baroreflex dysfunction occurs in type-1 diabetic patients and experimental animal models (1
). Diabetic patients with the impairment of the arterial baroreflex have a higher mortality rate than those without normal arterial baroreflex function (8
). However, the mechanisms for the attenuated arterial baroreflex are still unclear. Baroreceptors (the primary afferent limb of the arterial baroreflex arc) sense the systemic blood pressure by baroreceptor terminals innervating aortic arch and carotid sinus and then transmit the arterial baroreceptor afferent discharge into the dorsal medial nucleus tractus solitarii (NTS, the first site of baroreceptor contacting with central nervous system), in which the integrated input signal elicits parasympathetic activation and sympathetic inhibition with subsequent decreases in peripheral vascular resistance, heart rate, cardiac contractility, and arterial blood pressure (29
). In general, the process of translating changes in arterial wall tension into impulse traffic to the nucleus tractus solitarii involves two broad functional steps: 1) mechanotransduction which is governed by the properties of mechanosensitive ion channels in the nerve terminal and the mechanical properties of the coupling of the arterial wall to the sensory terminal; and 2) spike initiation which is governed by the excitability of membrane voltage sensitive ion channels that influence the electrical (cable) properties of the axonal projection and cell body. In the present study, the reflex decreases of blood pressure and heart rate to the electrical stimulation of the aortic depressor nerve are markedly attenuated in STZ-induced diabetic rats ( and ). In addition, local microinjection of Ang II into the nodose ganglion could mimic the diabetes to decrease the arterial baroreflex sensitivity (), and losartan (an AT1
receptor antagonist) significantly improved diabetes- and Ang II-induced the blunted arterial baroreflex sensitivity ( and ). These data provide the direct evidence that alteration of the baroreceptor function contributes to the attenuated arterial baroreflex sensitivity in STZ-induced diabetic rats.
Much evidence has indicated that Ang II-NADPH oxidase-superoxide signaling may be a potential candidate in the regulation of the arterial baroreflex in diabetes. Ang II binds with AT1
receptors to activate NADPH oxidase, and the latter is thought to be a main source of the intracellular superoxide in many tissues including nodose ganglia (18
). In the present study, Ang II concentration, NADPH oxidase activity and superoxide production in the nodose ganglia were enhanced in STZ-diabetic rats (). More importantly, losartan, apocynin, and tempol partially recovered the arterial baroreflex sensitivity in STZ-diabetic rats (). Additionally, exogenous Ang II, like the diabetes, decreased the arterial baroreflex sensitivity in sham rats through the AT1
receptor-NADPH oxidase-derived superoxide because losartan, apocynin, and tempol also normalized the effect of exogenous Ang II on the arterial baroreflex sensitivity in sham rats (). Our previous studies have shown that endogenous Ang II-NADPH oxidase-superoxide signaling is involved in diabetes-attenuated aortic baroreceptor neuron excitability (18
). Based on the above results, we believe that endogenous Ang II-NADPH oxidase-superoxide signaling contributes to the arterial baroreflex dysfunction in the type 1 diabetes mellitus via depressing the aortic baroreceptor neuron excitability.
Our present study also found that the plasma Ang II concentration was elevated in STZ-induced diabetic rats (). In addition, local microinjection of losartan, apocynin, and tempol into the nodose ganglion partially improved the diabetes-attenuated arterial baroreflex sensitivity (). It is possible that Ang II-NADPH oxidase-superoxide may also affect other site(s) of the arterial baroreflex arc to blunt the arterial baroreflex in the diabetic state (such as central neural areas because enhanced Ang II-NADPH oxidase-superoxide signal is found in the paraventricular nucleus from STZ-induced diabetic rats (17
)). It will be clarified in further study.
In conclusion, endogenous Ang II-NADPH oxidase-superoxide signaling is over-activated in the nodose ganglia, which contributes to the attenuated arterial baroreflex function in the diabetes. The present study provides new information on the mechanisms underlying the impaired arterial baroreflex in the type 1 diabetes and unveils important pharmacological targets for improving the arterial baroreflex function and reducing the mortality in the type 1 diabetes.