Maria Maliszewska-Scislo

Neuronal nitric oxide synthase within paraventricular nucleus: blood pressure and baroreflex in two-kidney, one-clip hypertensive rats.

The renin–angiotensin system is activated in the early phase of two‐kidney, one‐clip (2K‐1C) hypertension. The paraventricular nucleus (PVN) integrates inputs regulating sympathetic outflow. The PVN receives inputs from plasma angiotensin II via projections from circumventricular organs and from renal afferent nerves transmitted via the nucleus tractus solitarii. Nitric oxide within the PVN may exert a sympathoinhibitory effect. These studies tested whether decreasing endogenous nitric oxide by introducing dominant negative (DN) constructs for neuronal nitric oxide synthase (nNOS) into PVN chronically augments hypertension and/or modulates baroreflex function. Male 6‐week‐old Sprague–Dawley rats underwent sham surgery or right renal artery clipping and placement of radiotelemetry transmitters. One week later, the PVN was injected bilaterally with 250 nl artificial cerebrospinal fluid containing 250 ng μl−1 of RSV β‐galactosidase (β‐Gal), cytomegalovirus (CMV) wild‐type (WT nNOS), or respiratory syncytial virus (RSV) haeme domain or RSV haemeRedF (DN nNOS). Haemodynamics were monitored for 5 weeks. Then left renal nerve electrodes were placed, and 2 days later the rats underwent baroreflex testing in the conscious state. The rise in mean arterial pressure (MAP) was significantly potentiated in the DN nNOS 2K‐1C group beyond 15 days after PVN injection. By day 35, MAP in the 2K‐1C groups was 152 ± 6.3 (β‐Gal), 155.1 ± 6.6 (WT nNOS) and 179 ± 5.4 mmHg (DN nNOS; P < 0.01 versus all other groups). Sham‐clipped rats remained normotensive. All groups displayed progressive bradycardia over time that was attenuated in the DN nNOS 2K‐1C group. Baroreflex curves shifted to higher pressures, and baroreflex sensitivity of heart rate was diminished to a similar extent in all groups of 2K‐1C rats. The baroreflex response of renal sympathetic nerve activity was preserved. The PVN tissue from DN nNOS rats had decreased dimerization of nNOS and generation of total nitric oxide. These findings indicate that chronic interference of nNOS dimerization required for generation of nitric oxide within the PVN potentiates the increase of blood pressure by modulating the sympathoexcitation that accompanies renovascular hypertension.

Subfornical organ differentially modulates baroreflex function in normotensive and two-kidney, one-clip hypertensive rats

During activation of the renin-angiotensin system, hindbrain circumventricular organs such as the area postrema have been implicated in modulating the arterial baroreflex. This study was undertaken to test the hypothesis that the subfornical organ (SFO), a forebrain circumventricular structure, may also modulate the baroreflex. Studies were performed in rats with two-kidney, one-clip (2K,1C) hypertension as a model of endogenously activated renin-angiotensin system. Baroreflex function was ascertained during ramp infusions of phenylephrine and nitroprusside in conscious sham-clipped and 5-wk 2K,1C rats with either a sham or electrolytically lesioned SFO. Lesioning significantly decreased mean arterial pressure in 2K,1C rats from 158 +/- 7 to 131 +/- 4 mmHg but not in sham-clipped rats. SFO-lesioned, sham-clipped rats had a significantly higher upper plateau and range of the renal sympathetic nerve activity-mean arterial pressure relationship compared with sham-clipped rats with SFO ablation. In contrast, lesioning the SFO in 2K,1C rats significantly decreased both the upper plateau and range of the baroreflex control of renal sympathetic nerve activity, but only the range of the baroreflex response of heart rate decreased. Thus, during unloading of the baroreceptors, the SFO differentially modulates the baroreflex responses in sham-clipped vs. 2K,1C rats. Since lesioning the SFO did not influence plasma angiotensin II (ANG II), the effects of the SFO lesion are not caused by changes in circulating levels of ANG II. These findings support a pivotal role for the SFO in the sympathoexcitation observed in renovascular hypertension and in baroreflex regulation of sympathetic activity in both normal and hypertensive states.

Paraventricular nucleus control of blood pressure in two-kidney, one-clip rats: effects of exercise training and resting blood pressure.

Exercise-induced changes in γ-aminobutyric acid (GABA) or nitric oxide signaling within the paraventricular nucleus (PVN) have not been studied in renovascular hypertension. We tested whether exercise training decreases mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in two-kidney, one-clip (2K-1C) hypertensive rats due to enhanced nitric oxide or GABA signaling within PVN. Conscious, unrestrained male Sprague-Dawley rats with either sham (Sham) or right renal artery clipping (2K-1C) were assigned to sedentary (SED) or voluntary wheel running (ExT) for 6 or 12 wk. MAP and angiotensin II (ANG II) were elevated in 2K-1C SED rats. The 2K-1C ExT rats displayed lower MAP at 6 wk that did not decline further by 12 wk. Plasma ANG II was lower in 2K-1C ExT rats. Increases in MAP, heart rate, and RSNA to blockade of PVN nitric oxide in 2K-1C SED rats were attenuated compared with either Sham group. Exercise training restored the responses in 2K-1C ExT rats. The increase in MAP in response to bicuculline was inversely correlated with baseline MAP. The rise in MAP was lower in 2K-1C SED vs. either Sham group and was normalized in the 2K-1C ExT rats. Paradoxically, heart rate and RSNA responses were not diminished in 2K-1C SED rats but were significantly lower in the 2K-1C ExT rats. Thus the decrease in arterial pressure in 2K-1C hypertension associated with exercise training is likely due to diminished excitatory inputs to PVN because of lower ANG II and higher nitritergic tone rather than enhanced GABA inhibition of sympathetic output.

Hemodynamic and neural responses to renal denervation of the nerve to the clipped kidney by cryoablation in two-kidney, one-clip hypertensive rats

Renal artery stenosis is increasing in prevalence. Angioplasty plus stenting has not proven to be better than medical management. There has been a reluctance to use available denervation methodologies in this condition. We studied conscious, chronically instrumented, two-kidney, one-clip (2K-1C) Goldblatt rats, a model of renovascular hypertension, to test the hypothesis that renal denervation by cryoablation (cryo-DNX) of the renal nerve to the clipped kidney decreases mean arterial pressure (MAP), plasma and tissue ANG II, and contralateral renal sympathetic nerve activity (RSNA). Five-week-old male Sprague-Dawley rats underwent sham (ShC) or right renal artery clipping (2K-1C), placement of telemetry transmitters, and pair-feeding with a 0.4% NaCl diet. After 6 wk, rats were randomly assigned to cryo-DNX or sham cryotreatment (sham DNX) of the renal nerve to the clipped kidney. MAP was elevated in 2K-1C and decreased significantly in both ShC cryo-DNX and 2K-1C cryo-DNX. Tissue norepinephrine was ∼85% lower in cryo-DNX kidneys. Plasma ANG II was higher in 2K-1C sham DNX but not in 2K-1C cryo-DNX vs ShC. Renal tissue ANG II in the clipped kidney decreased after cryo-DNX. Baseline integrated RSNA of the unclipped kidney was threefold higher in 2K-1C versus ShC and decreased in 2K-1C cryo-DNX to values similar to ShC. Maximum reflex response of RSNA to baroreceptor unloading in 2K-1C was lower after cryo-DNX. Thus, denervation by cryoablation of the renal nerve to the clipped kidney decreases not only MAP but also plasma and renal tissue ANG II levels and RSNA to the contralateral kidney in conscious, freely moving 2K-1C rats.

Haemodynamic and renal sympathetic responses to V1b vasopressin receptor activation within the paraventricular nucleus

What is the central question of this study? Does antagonism of V1b receptors prevent the haemodynamic and renal sympathetic nerve responses that occur with application of exogenous vasopressin into the paraventricular nucleus (PVN) of conscious, chronically instrumented rats? What is the main finding and its importance? Microinjection of vasopressin into the PVN increased mean arterial pressure, heart rate and renal sympathetic nerve activity, all of which were inhibited by pre‐injection of the PVN with the V1b antagonist, nelivaptan. The administered vasopressin did not enter the peripheral circulation or increase plasma vasopressin. Ganglionic blockade prevented each of the responses, consistent with mediation by enhanced sympathetic output rather than an increase in circulating vasopressin.