Differences in Excitatory and Inhibitory Balance within the Paraventricular Nucleus Reflects Response Variability to Acute Stress
Authors: Knuepfer Mark M. , Zheng Hong , Hoffman‐Schepers Nicole B. , Sharma Neeru M. , Patel Kaushik P. 
Published: June 2021

The cardiovascular reactivity hypothesis states that humans have highly variable pressor responses to acute stress and that those susceptible to the development of hypertension have greater pressor responses to stress. Our studies have shown similar stress‐evoked pressor response variability in outbred Sprague‐Dawley rats (SDR). Several laboratories have reported that excessive excitatory (glutamate) and reduced inhibitory (nitric oxide) neurotransmission within the paraventricular nucleus of the hypothalamus (PVN) exists in animals with hypertension, heart failure or after chronic stress. Moreover, these changes have been linked to elevated sympathetic nerve activity. We hypothesize that those rats predisposed to develop hypertension as predicted by the cardiovascular reactivity hypothesis already have an imbalance of neurotransmission favoring excitation in the PVN. Therefore, we tested two different rat strains to determine whether rats with larger pressor responses to acute stress had greater excitatory and/or reduced inhibitory neurotransmission in the PVN. We tested male SDR and female borderline hypertensive rats (BHR). Rats were instrumented for recording arterial pressure (AP) and heart rate. After 5–7 days recovery, rats were tested for their pressor responsiveness to air jet (20 psi, 1–2 sec) and to cold water stress (1 cm deep for 1 min). Rats were separated into those with larger pressor responsiveness (LP) to startle with air jet or cold water and compared to those with smaller pressor responses (SP). In both rat strains, the initial pressor responses were averaged for each stressor. Those with responses above or below the mean were determined to be LP or SP, respectively. Expression of nNOS and NMDA‐NR1 were determined at transcriptional level by real‐time PCR and at protein level by Western blot, in PVN punches. Male SDR identified as SP or LP rats had cold stress‐induced increases in AP of 41.3 ± 0.9 and 58.6 ± 1.1 mmHg, respectively. In 12 rats tested, mRNA levels for nNOS were significantly lower in LP compared to SP and NMDA‐NR1 was significantly greater in LP compared to SP. There was a corresponding increase in protein expression for NMDA‐NR1 in LP rats. In response to cold water stress, female BHR had significantly greater pressor responses in SP or LP rats (47.2 ± 2.1 and 66.6 ± 2.8 mmHg, respectively) compared to SDR. As in SDR, female BHR (n=12) characterized as LP had significantly greater mRNA and protein expression of NMDA‐NR1 as well as reduced nNOS protein expression in the PVN compared to SP BHR. We propose that changes in nNOS and glutamatergic tone within the PVN reflect not only the existence of sympathetic overactivity but the predisposition towards sympathetic overactivity and development of hypertension. In addition, these changes can be seen in normotensive (SDR) and in stress‐sensitive BHR and in both sexes suggesting that they are universal traits contributing to elevated sympathetic nerve activity and predisposition to cardiovascular disease.Support or Funding InformationSupported by NIH P01 HL062222 and R01 DK114663 (KPP) and St. Louis Univ. (MMK)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.