Renal Denervation and Celiac Ganglionectomy Decrease Mean Arterial Pressure Similarly in Genetically Hypertensive Schlager (BPH/2J) Mice

Renal denervation (RDNX) lowers mean arterial pressure (MAP) in patients with resistant hypertension. Less well studied is the effect of celiac ganglionectomy (CGX), a procedure which involves the removal of the nerves innervating the splanchnic vascular bed. We hypothesized that RDNX and CGX would both lower MAP in genetically hypertensive Schlager (BPH/2J) mice through a reduction in sympathetic tone. Telemeters were implanted into the femoral artery in mice to monitor MAP before and after RDNX (n=5), CGX (n=6), or SHAM (n=6). MAP, systolic blood pressure, diastolic blood pressure, and heart rate were recorded for 14 days postoperatively. The MAP response to hexamethonium (10 mg/kg, IP) was measured on control day 3 and postoperative day 10 as a measure of global neurogenic pressor activity. The efficacy of denervation was assessed by measurement of tissue norepinephrine. Control MAP was similar among the 3 groups before surgical treatments (≈130 mm Hg). On postoperative day 14, MAP was significantly lower in RDNX (−11±2 mm Hg) and CGX (−11±1 mm Hg) groups compared with their predenervation values. This was not the case in SHAM mice (−5±3 mm Hg). The depressor response to hexamethonium in the RDNX group was significantly smaller on postoperative day 10 (−10±5 mm Hg) compared with baseline control (−25±10 mm Hg). This was not the case in mice in the SHAM (day 10; −28±5 mm Hg) or CGX (day 10; −34±7 mm Hg) group. In conclusion, both renal and splanchnic nerves contribute to hypertension in BPH/2J mice, but likely through different mechanisms.

Brain Prostaglandin D2 Increases Neurogenic Pressor Activity and Mean Arterial Pressure in Angiotensin II-Salt Hypertensive Rats

This study tested whether brain L-PGDS (lipocalin-type prostaglandin [PG] D synthase), through prostanoid signaling, might increase neurogenic pressor activity and thereby cause hypertension. Sprague Dawley rats on high-salt diet received either vehicle or Ang II (angiotensin II) infusion. On day 4, the developmental stage of hypertension, brains from different sets of control and Ang II–treated rats were collected for measuring L-PGDS expression, PGD2 levels, and DP1R (type 1 PGD2 receptor) expression. In a different set of 14-day Ang II-salt–treated rats, mini-osmotic pumps were used to infuse either a nonselective COX (cyclooxygenase) inhibitor ketorolac, L-PGDS inhibitor AT56, or DP1R inhibitor BWA868C to test the role of brain COX-PGD2-DP1R signaling in Ang II-salt hypertension. The acute depressor response to ganglion blockade with hexamethonium was used to quantify neurogenic pressor activity. During the developmental stage of Ang II-salt hypertension, L-PGDS expression was higher in cerebrospinal fluid, and PGD2 levels were increased in the choroid plexus, cerebrospinal fluid, and the cardioregulatory brain region rostral ventrolateral medulla. DP1R expression was decreased in rostral ventrolateral medulla. Both brain COX inhibition with ketorolac and L-PGDS inhibition with AT56 lowered mean arterial pressure by altering neurogenic pressor activity compared with vehicle controls. Blockade of DP1R with BWA868C, however, increased the magnitude of Ang II-salt hypertension and significantly increased neurogenic pressor activity. In summary, we establish that the development of Ang II-salt hypertension requires increased COX- and L-PGDS–derived PGD2 production in the brain, making L-PGDS a possible target for treating neurogenic hypertension.

Abstract 018: Afferent-targeted Renal Denervation Attenuates Established Deoxycorticosterone-salt Hypertension: A Central Role for Renal Afferent Nerves in Hypertension?

Cardiovascular disease (CVD) remains the most pervasive cause of death worldwide. High arterial pressure, or hypertension (HTN), is the highest risk factor for CVD morbidity and mortality. Increased peripheral and renal sympathetic nerve activity (SNA) is hypothesized to be a primary contributor to HTN etiology. Moreover, recent clinical and experimental studies show total renal denervation (T-RDNx), may reverse the HTN; however, the contribution of afferent and efferent renal nerves in this effect is unknown. We have recently reported T-RDNx and afferent-specific denervation (A-RDNx) identically attenuated the development of deoxycorticostereone acetate (DOCA)-salt hypertension. However, the efficacy of T-RDNx and A-RDNx to reverse the established phase of this model of HTN is unknown. Therefore, the present study tested the hypothesis that A-RDNx and T-RDNx would similarly decrease the mean arterial pressure (MAP) in DOCA-salt rats with established HTN. Twenty-four male Sprague Dawley rats (275-300g) instrumented with radiotelemeters were administered DOCA (100mg, s.c.) and 0.9% saline to drink ad libitum for 35 days. On day 21 of DOCA-salt, rats underwent T-RDNx (n=9), A-RDNx (n=9), or sham (n=6) treatments. MAP was monitored for an additional 14 days. Neurogenic pressor activity (NPA) was assessed 14 days after treatment by measuring the MAP response to acute ganglionic blockade (hexamethonium, 30mg/kg, i.p.). Data was analyzed with a one-way ANOVA with Bonferroni post-hoc test (α=0.05). Data presented as mean ± SEM. MAP was similar across all groups prior to treatment on Day 21 of DOCA-salt (Sham: 165±6; T-RDNx: 164±3; A-RDNx: 162±7mmHg). Whereas Sham had no effect (-2±3) on MAP 14 days after treatment, both RDNx treatments decreased MAP by approximately 20 mmHg (T-RDNx -18±8; A-RDNx -22±5). NPA 14 days after treatment in Sham rats was -97±12mmHg. This response was reduced by nearly half in both T-RDNx (-50±9mmHg) and A-RDNx (-48±4mmHg) groups. We conclude from these findings that: 1) RDNx is effective in treating the established phase of DOCA-salt hypertension, 2) the MAP response to RDNx is mediated by ablation of afferent renal nerves, and 3) the antihypertensive response to RDNx is mediated by a decrease global neurogenic pressor activity.

Possible role for brain prostanoid pathways in the development of angiotensin II-salt hypertension in rats

Prostanoids generated by the cyclooxygenase (COX) pathway appear to contribute to the neurogenic hypertension (HTN) in rats. The first goal of this study was to establish the time frame during which prostanoids participate in ANG II-salt HTN. We induced HTN using ANG II (150 ng·kg−1·min−1 sc) infusion for 14 days in rats on a high-salt (2% NaCl) diet. When ketoprofen pretreatment was combined with treatment during the first 7 days of ANG II infusion, development of HTN and increased neurogenic pressor activity (indexed by the depressor response to ganglion blockade) were significantly attenuated for the entire ANG II infusion period. This suggests that prostanoid generation caused by administration of ANG II and salt leads to an increase in neurogenic pressor activity and blood pressure (BP) via a mechanism that persists without the need for continuing prostanoid input. The second goal of this study was to determine whether prostanoid products specifically in the brain contribute to HTN development. Expression of prostanoid pathway genes was measured in brain regions known to affect neurogenic BP regulation. ANG II-treated rats exhibited changes in gene expression of phospholipase A2 (upregulated in organum vasculosum of the lamina terminalis, paraventricular nucleus, nucleus of the solitary tract, and middle cerebral artery) and lipocalin-type prostaglandin D synthase (upregulated in the organum vasculosum of the lamina terminalis). On the basis of our results, we propose that activation of the brain prostanoid synthesis pathway both upstream and downstream from COX at early stages plays an important role in the development of the neurogenic component of ANG II-salt HTN.

Cyclooxygenase-1 inhibition attenuates angiotensin II-salt hypertension and neurogenic pressor activity in the rat

Cyclooxygenase (COX)-derived prostanoids contribute to angiotensin II (ANG II) hypertension (HTN). However, the specific mechanisms by which prostanoids act are unclear. ANG II-induced HTN is caused partly by increased sympathetic nervous system activity, especially in a setting of high dietary salt intake. This study tested the hypothesis that COX-derived prostanoids cause ANG II-salt sympathoexcitation and HTN. Experiments were conducted in conscious rats. Infusion of ANG II (150 ng·kg−1·min−1 sc) caused a marked HTN in rats on 2% salt diet, but a much smaller increase in blood pressure in rats on 0.4% salt diet. The nonselective COX inhibitor ketoprofen (2 mg/kg sc) given throughout the ANG-II infusion period attenuated HTN development in rats on 2% NaCl diet, but not in rats on 0.4% NaCl diet. The acute depressor response to ganglion blockade was used to assess neurogenic pressor activity in rats on 2% NaCl diet. Ketoprofen-treated rats showed a smaller fall in arterial pressure in response to ganglion blockade during ANG-II infusion than did nontreated controls. In additional experiments, ketoprofen-treated rats exhibited smaller increases in plasma norepinephrine levels and whole body norepinephrine spillover than we previously reported in ANG II-salt HTN. Finally, the effects of the selective COX-1 inhibitor SC560 (10 mg·kg−1·day−1 ip) and the selective COX-2 inhibitor nimesulide (10 mg·kg−1·day−1 ip) were investigated. Treatment with SC560 but not nimesulide significantly reduced blood pressure and the depressor response to ganglion blockade in ANG II-salt HTN rats. The results suggest that COX-1 products are critical for sympathoexcitation and the full development of ANG II-salt HTN in rats.