The purpose of this study was to investigate total body norepinephrine (NE) kinetics as an index of global sympathetic nervous system (SNS) outflow in a rat model of chronic ANG II-salt hypertension. Male Sprague-Dawley rats fed a 0.4% (normal salt, NS) or 2% (HS) NaCl diet were instrumented with arterial and venous catheters. After 5 days of recovery and a 3-day control period, ANG II (150 ng·kg⁻¹·min⁻¹) was given subcutaneously by minipump for 14 days. Plasma NE levels and total body NE spillover and clearance were determined on control day 3 and ANG II infusion days 7 and 14 using radioisotope dilution principles. To perform this analysis, ³H-NE and NE were measured in arterial plasma after a 90-min infusion of tracer amounts of ³H-NE. Mean arterial pressure (MAP) was similar during the control period in NS and HS rats; however, MAP increased to a higher level in HS rats. During the control period, plasma NE tended to be lower in rats on HS, whereas NE clearance tended to be higher in HS rats. As a result NE spillover was similar in NS and HS rats during the control period. In NS rats, plasma NE, NE spillover, and NE clearance were unchanged by ANG II. In contrast, in rats on the HS diet, plasma NE and NE spillover increased during ANG II infusion, whereas NE clearance was unchanged. In conclusion, a HS diet alone or ANG II infusion in animals fed NS do not affect global sympathetic outflow. However, the additional hypertensive response to ANG II in animals fed HS is accompanied by SNS activation.

Excess sympathetic nervous system activity (SNA) is linked to human essential and experimental hypertension. To test whether sympathetic activation is associated with a model of deoxycorticosterone acetate (DOCA)-salt hypertension featuring two kidneys and a moderate elevation of blood pressure, we measured whole body norepinephrine (NE) spillover as an index of global SNA. Studies were conducted in chronically catheterized male Sprague-Dawley rats drinking water containing 1% NaCl and 0.2% KCl. After a 7-day surgical recovery and a 3-day control period, a DOCA pellet (50 mg/kg) was implanted subcutaneously in one group of rats (DOCA), while the other group underwent sham implantation (Sham). NE spillover was measured on control day 2 and days 7 and 14 after DOCA administration or sham implantation. During the control period, mean arterial pressure (MAP) was similar in Sham and DOCA rats. MAP was significantly increased in the DOCA group compared with the Sham group after DOCA administration (day 14: Sham = 109 ± 5.3, DOCA = 128 ± 3.6 mmHg). However, plasma NE concentration, clearance, and spillover were not different in the two groups at any time. To determine whether selective sympathetic activation to the kidneys contributes to hypertension development, additional studies were performed in renal denervated (RDX) and sham-denervated (Sham-DX) rats. MAP, measured by radiotelemetry, was similar in both groups during the control and DOCA treatment periods. In conclusion, global SNA is not increased during the development of mild DOCA-salt hypertension, and fully intact renal nerves are not essential for hypertension development in this model.

We previously reported that mild deoxycorticosterone acetate (DOCA)-salt hypertension develops in the absence of generalized sympathoexcitation. However, sympathetic nervous system activity (SNA) is regionally heterogeneous, so we began to investigate the role of sympathetic nerves to specific regions. Our first study on that possibility revealed no contribution of renal nerves to hypertension development. The splanchnic sympathetic nerves are implicated in blood pressure (BP) regulation because splanchnic denervation effectively lowers BP in human hypertension. Here we tested the hypothesis that splanchnic SNA contributes to the development of mild DOCA-salt hypertension. Splanchnic denervation was achieved by celiac ganglionectomy (CGX) in one group of rats while another group underwent sham surgery (SHAM-GX). After DOCA treatment (50 mg/kg) in rats with both kidneys intact, CGX rats exhibited a significantly attenuated increase in BP compared with SHAM-GX rats (15.6 ± 2.2 vs. 25.6 ± 2.2 mmHg, day 28 after DOCA treatment). In other rats, whole body norepinephrine (NE) spillover, measured to determine if CGX attenuated hypertension development by reducing global SNA, was not found to be different between SHAM-GX and CGX rats. In a third group, nonhepatic splanchnic NE spillover was measured as an index of splanchnic SNA, but this was not different between SHAM (non-DOCA-treated) and DOCA rats during hypertension development. In a final group, CGX effectively abolished nonhepatic splanchnic NE spillover. These data suggest that an intact splanchnic innervation is necessary for mild DOCA-salt hypertension development but not increased splanchnic SNA or NE release. Increased splanchnic vascular reactivity to NE during DOCA-salt treatment is one possible explanation.

Large-conductance Ca ²⁺ -activated potassium (BK) channels modulate vascular tone. Tempol, an O ₂ ⁻ dismutase mimetic, causes vasodilation via activation of vascular BK channels. In this study, we investigated the mechanisms underlying tempol-induced activation of BK channels in mesenteric arterial (MA) myocytes from sham and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In sham myocytes, whole-cell patch clamp studies showed that tempol enhanced peak outward currents ( I _o ). This effect was larger in DOCA-salt myocytes. Tempol caused a leftward shift in the activation curve for I _o in sham and DOCA-salt myocytes. In DOCA-salt myocytes, the peak I _o at +80 mV did not differ from sham myocytes, but iberiotoxin (BK channel blocker) caused a larger reduction of I _o in DOCA-salt compared with sham myocytes. Iberiotoxin but not 4-aminopyridine blocked the I _o activated by tempol. Tiron, another O ₂ ⁻ scavenger, had no effect on I _o . Using inside-out patches, we found that tempol caused a 4-fold increase in open probability (P _o ) of BK channels but did not change the mean channel open time in sham and DOCA-salt myocytes. Tempol did not change single channel conductance in sham or DOCA-salt myocytes. Western blot and immunocytochemical studies revealed that BK channel α-subunit expression was increased in DOCA-salt MA compared with sham MA. The data indicate that tempol directly activates BK channels by increasing channel P _o . We conclude that upregulation of the BK channel α-subunit protein and tempol-induced increases in BK channel P _o contribute to the enhanced depressor response caused by tempol in DOCA-salt hypertensive rats.

The objectives were to determine if ANG II-induced hypertension is maintained by activation of endothelin type A (ET_A) receptors by endogenous ET-1 and if this effect is influenced by salt intake. Male rats were maintained on high sodium intake (HS; 6 meq/day) or on normal sodium intake (NS; 2 meq/day). Hypertension was produced by intravenous infusion of ANG II (5 ng/min) for 15 days. Five-day oral dosing with the selective ET_A-receptor antagonist ABT-627 (∼2 mg · kg⁻¹ · day⁻¹) reduced mean arterial pressure (MAP) to baseline levels in rats on HS receiving ANG II infusion, but it did not affect MAP in normotensive HS controls. In rats on NS, ABT-627 only transiently decreased MAP in rats receiving ANG II and slightly reduced MAP in normotensive controls. ABT-627 produced mild retention of sodium and water in NS rats receiving ANG II, but not in any other group. These results indicate that ET-1 plays a role in ANG II-induced hypertension via activation of ET_Areceptors and that this role is more prominent in rats on HS.