CHARACTERIZING THE ROLE OF THE DORSOMEDIAL HYPOTHALAMIC NUCLEUS IN THE CARDIOGENIC SYMPATHETIC AFFERENT REFLEX IN RATS
Authors: Fraley Stephanie Kate , Lindsey Stacia Jayce , Hillard Kynlee Jo , Zahner Matthew Ralph 
Published: April 2020

Myocardial ischemia causes the production and release of metabolites such as bradykinin (BK), which stimulates cardiac spinal sensory afferents causing chest pain and an increase in sympathetic activity. This sympathetic reflex, which increases heart rate and blood pressure, is referred to as the cardiogenic sympathetic afferent reflex (CSAR). During myocardial ischemia, this sympathetic reflex activity is important for the maintenance of blood pressure and perfusion of vital organs. However, the increased sympathetic activity may also be detrimental because it further increases the oxygen demand of the ischemic myocardium. While the brain stem nuclei, such as the nucleus tractus solitarius and rostral ventrolateral medulla have been shown to play an important role in the CSAR, the role of other supramedullary nuclei and the sources that generate sympathetic activity in the CSAR are still not clear. We have previously characterized the role of the paraventricular nucleus (PVN) of the hypothalamus in the CSAR and shown that acute chemical inhibition of the PVN attenuates the CSAR. However, we also have shown that the CSAR recovers in rats after chronic ibotenic acid lesion of the PVN suggesting that other supramedullary sites are involved. The dorsomedial hypothalamic nucleus (DMH) is another important hypothalamic site that plays an important role in cardiovascular sympathetic regulation. However, little is known regarding the role of the DMH in the CSAR. In this study, we tested the hypothesis that “inhibition of the DMH attenuates the CSAR in rats”. Renal sympathetic nerve activity (RSNA) and blood pressure were recorded in anesthetized rats during epicardial application of BK (10 μg/ml). Bilateral microinjection of muscimol, a GABAA agonist (0.5 nmol in 50 nl), was used to inhibit the DMH. Vehicle injection into the DMH had no significant effect (n=6, P > 0.05) on blood pressure or RSNA. In vehicle‐injected rats, epicardial BK application significantly increased (P < 0.05) RSNA to 204.4 ±35.08% of baseline and mean arterial pressure from 103.4 ±2.02 mmHg to 118.1 ±4.73 mmHg. In a sperate group of rats (n=8) muscimol injection into the DMH significantly (P < 0.05) reduced basal blood pressure from 98.0 ±4.66 mmHg to 77.1 ±7.33 mmHg but had no significant effect (P > 0.05) on baseline RSNA. In this group of rats, epicardial BK application significantly increased (P < 0.05) RSNA to 193.9 ±28.00% of baseline and increased mean arterial pressure from 77.1 ±7.33 mmHg to 89.29 ±8.48 mmHg. Whereas muscimol injection into the DMH appears to attenuate the overall magnitude of the blood pressure response it had no effect on the RSNA response to epicardial bradykinin. These results suggest that in the presence of intact spinal and medullary circuits inhibition of DMH does not play an important role in the generation of sympathetic activity in the CSAR. Whereas inhibition of DMH does not appear to impair the CSAR there is good evidence to show that disinhibition of DMH increases basal vasomotor activity and augment reflex sympathetic responsiveness. Thus, our next objective is to determine if activation of DMH augments the CSAR and if so to determine the medullary connections of these DMH neurons.

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NHLBI R15HL145645‐01