Contribution of cyclooxygenase-2 overexpression to enhancement in tonically active glutamatergic inputs to the rostral ventrolateral medulla in hypertension.

OBJECTIVE: Cyclooxygenase (COX) is critical in regulating cardiovascular function, but its role involved in the central control of blood pressure (BP) is uncovered. The tonic glutamatergic inputs to the rostral ventrolateral medulla (RVLM) are enhanced in hypertension. Here, the present study was designed to investigate the effect and mechanism of central COX on tonic glutamatergic inputs to the RVLM and BP regulation. METHODS: Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) received RVLM microinjection of adeno-associated viral vectors to promote or inhibit the COX2 expression were subjected to subsequent experiments. Glutamate level and glutaminase expression were detected by ELISA and western blot, respectively. The function of tonic glutamatergic inputs was assessed by BP response to microinjection of the glutamate receptor antagonist into the RVLM. PC12 cells were used to detect the underlying signal pathway. RESULTS: The RVLM COX2 expression and prostaglandin E2 level were significant higher in SHRs than in WKY rats. Overexpression of COX2 in the RVLM produced an increase in basal BP, RVLM glutamate level, and glutaminase expression in WKY rats, while they were significantly reduced by interfering with COX2 expression in SHRs. Microinjections of the glutamate receptor antagonist into the RVLM produced a significant BP decrease in WKY rats with COX2 overexpression pretreatment. Furthermore, the increased levels of BP, glutamate content, and glutaminase activity in the RVLM evoked by central infusion of angiotensin II were attenuated in COX2 knockout mice. It was also found that prostaglandin E2 increased supernatant glutamate level and phosphorylation of signal transducer and activator of transcription 3 in PC12 cells. CONCLUSION: Our findings suggest that upregulated COX2 expression enhances the tonically active glutamatergic inputs to the RVLM, which is associated with cardiovascular regulation in hypertension.

The asymmetric dimethylarginine-mediated inhibition of nitric oxide in the rostral ventrolateral medulla contributes to regulation of blood pressure in hypertensive rats.

Nitric oxide (NO) contributes to the central control of cardiovascular activity. The rostral ventrolateral medulla (RVLM) has been recognized as a pivotal region for maintaining basal blood pressure (BP) and sympathetic tone. It is reported that asymmetric dimethylarginine (ADMA), characterized as a cardiovascular risk marker, is an endogenous inhibitor of nitric oxide synthesis. The present was designed to determine the role of ADMA in the RVLM in the central control of BP in hypertensive rats. In Sprague Dawley (SD) rats, microinjection of ADMA into the RVLM dose-dependently increased BP, heart rate (HR), and renal sympathetic never activity (RSNA), but also reduced total NO production in the RVLM. In central angiotensin II (Ang II)-induced hypertensive rats and spontaneously hypertensive rat (SHR), the level of ADMA in the RVLM was increased and total NO production was decreased significantly, compared with SD rats treated vehicle infusion and WKY rats, respectively. These hypertensive rats also showed an increased protein level of protein arginine methyltransferases1 (PRMT1, which generates ADMA) and a decreased expression level of dimethylarginine dimethylaminohydrolases 1 (DDAH1, which degrades ADMA) in the RVLM. Furthermore, increased AMDA content and PRMT1 expression, and decreased levels of total NO production and DDAH1 expression in the RVLM in SHR were blunted by intracisternal infusion of the angiotensin II type 1 receptor (AT1R) blocker losartan. The current data indicate that the ADMA-mediated NO inhibition in the RVLM plays a critical role in involving in the central regulation of BP in hypertension, which may be associated with increased Ang II.