Decrease in peripheral sympathetic nervous system activity following renal denervation or unclipping in the one-kidney one-clip Goldblatt hypertensive rat.

Increased sympathetic nervous system activity has been demonstrated in established one-kidney one-clip hypertension in the rat. We have found that renal denervation in this model results in an attenuation of hypertension, unassociated with alterations in sodium or water balance or renin activity. To determine whether the depressor effect of renal denervation is associated with changes in peripheral sympathetic nervous system activity, sham operation (n = 12), renal denervation (n = 13), or unclipping (n = 13) was carried out 2 wk after the onset of one-kidney one-clip hypertension. Normotensive unine-phrectomized age- and sex-matched rats were used as controls (n = 14). Renal denervation resulted in a significant decrease in systolic blood pressure (201+/-7 to 151+/-6 mm Hg), while unclipping lowered systolic blood pressure to normotensive levels (130+/-6 mm Hg). 8 d after operation plasma norepinephrine and mean arterial pressure before and after ganglionic blockade with 30 mg/kg hexamethonium bromide were measured in conscious, unrestrained, resting animals, as indices of peripheral sympathetic nervous system activity. Plasma norepinephrine was significantly higher in hypertensive sham-operated rats (422+/-42 pg/ml) compared with normotensive controls (282+/-25 pg/ml) (P < 0.01). Both renal denervation and unclipping restored plasma norepinephrine to normal levels (273+/-22 and 294+/-24 pg/ml, respectively). Ganglionic blockade in hypertensive sham-operated animals resulted in a significantly greater decrease in mean arterial pressure than occurred in renal denervated, unclipped, or control rats. The data suggest that the depressor effect of renal denervation or unclipping in the one-kidney one-clip hypertensive rat is associated with a decrease in peripheral sympathetic nervous system activity.

Role of the renal sympathetic nerves in the development and maintenance of hypertension in the spontaneously hypertensive rat.

Neurogenic factors and, in particular, enhanced renal sympathetic tone, have been implicated in the pathogenesis of hypertension in the spontaneously hypertensive rat of the Okamoto strain. To examine the hypothesis that the renal sympathetic nerves contribute to the development and maintenance of hypertension by causing urinary sodium retention, 7-wk-old (early hypertensive) and 18-wk-old (established hypertensive) male spontaneously hypertensive rats were subjected to bilateral renal denervation and compared with sham-operated controls. In 7-wk-old animals renal denervation delayed the onset and slowed the rate of development of hypertension. These alterations were associated with a significantly greater fractional excretion of sodium (percentage of sodium intake excreted) during the first 3 wk after denervation. Blood pressure 2 wk after surgery was 169+/-3.5 (sham) vs. 150+/-2.4 mm Hg (denervated) (P < 0.001), corresponding to fractional sodium excretions of 65+/-1.3% (sham) vs. 80+/-2.3% (denervated) (P < 0.001). By the 5th wk after surgery, at which time an increase in renal norepinephrine content of denervated animals suggested reinnervation, blood pressures in the two groups converged (sham, 199+/-6.5 mm Hg vs. denervated 180+/-3.5 mm Hg, NS) and there was no difference in sodium excretion (sham, 77+/-2.5% vs. denervated 79+/-2.3%). Plasma and kidney renin activity of denervated animals did not differ significantly from that of sham-operated controls. In 18-wk-old rats renal denervation did not alter blood pressure or urinary sodium excretion. These data indicate that the renal sympathetic nerves contribute to the development of hypertension in the spontaneously hypertensive rat in part by causing enhanced sodium retention. Once hypertension is established the renal nerves do not play a significant role in the maintenance of increased blood pressure.

Importance of the renal nerves in the pathogenesis of experimental hypertension.

Anatomical studies have demonstrated sympathetic innervation of the renal arterioles, juxtaglomerular apparatus, and renal tubules. Physiologic studies of the effects of the renal efferent nerves on renin release and renal sodium handling indicate that they play an important role in body fluid homeostasis and cardiovascular regulation. In addition, evidence is accumulating that stimulation of intrarenal mechanoreceptors and chemoreceptors causes in increase in renal afferent nerve activity and that alterations in renal afferent nerve traffic are, in turn, associated with changes in blood pressure and in vasoconstrictor tone in the contralateral kidney. Further, recent studies have demonstrated functionally significant connections between renal afferent nerves and the central nervous system. Interruption of the renal sympathetic nerves has been shown to prevent or attenuate hypertension in a number of animal models, suggesting that the renal nerves have an important role in the pathogenesis of experimental hypertension. In the spontaneously hypertensive rate of the Okamoto strain (SHR) and the DOCA-NaCl rat, the delay in the development of hypertension produced by renal denervation is due in part to increased sodium excretion thought to be secondary to interruption of the renal efferent nerves. In contrast, in one-kidney, one clip and two-kidney, one clip Goldblatt hypertension in the rat and coarctation hypertension in the dog, the depressor effect of renal denervation is unrelated to changes in urinary sodium excretion or plasma renin activity. In these models the attenuation of hypertension following renal denervation appears to be secondary to a decrease in peripheral sympathetic activity. Evidence in the one-kidney model suggests that interruption of the renal afferent nerves lower blood pressure via an effect on central noradrenergic mechanisms.

Role of the renal nerves in the pathogenesis of one-kidney renal hypertension in the rat.

Increased sympathetic nervous system activity has been demonstrated in established one-kidney one clip hypertension in the rat. To determine the importance of the renal nerves in this model of hypertension, renal denervation or sham operation was carried out 2 weeks after clipping. Systolic blood pressure (BP) after clipping the renal artery in 27 uninephrectomized male Charles River rats increased significantly from 125 +/- 3 mm Hg to a stable level of 185 +/-7 mm Hg by 2 weeks, in association with a positive sodium balance. Renal denervation in 13 animals resulted in a significant decrease in BP to 137 +/- 7 mm Hg, while no change in BP was seen after sham operation in 14 animals. There was no difference in mean daily water intake, mean daily sodium intake, mean daily urine volume, or mean fractional urinary sodium excretion between sham-operation and renal-denervated animals during the 2 weeks after operation. Plasma renin activity (PRA) and creatinine clearance were not significantly different at sacrifice 2 weeks after operation. Six of the renal-denervated rats were followed for 11 weeks after surgery. The BP rose again to hypertensive levels (187 +/- 8 mm Hg) by 5 weeks after renal denervation. Repeat renal denervation resulted in a significant decrease to 142 +/- 8 mm Hg. Renal denervation in eight rats with established one-kidney Grollman hypertension (185 +/- 8 mm Hg) also resulted ina significant decrease in systolic BP (143 +/- 8 mm Hg). The data demonstrate the importance of intact renal nerves in the maintenance of hypertension in the one-kidney renal hypertensive rat. The depressor effect of renal denervation is not mediated by alterations in sodium intake or excretion, water intake or excretion, creatinine clearance or PRA.

Lofexidine and clonidine in moderate essential hypertension.

The efficacy, safety, and tolerability of lofexidine, a centrally acting imidazoline derivative, were compared to that of clonidine in a randomized double-blind trial in 28 patients with moderate essential hypertension. The study consisted of a washout phase, a placebo phase, a drug titration phase (0.2 to 1.6 mg/day, with hydrochlorothiazide added at 0.4 mg daily for supine and erect diastolic blood pressure above 90 mm Hg), and a maintenance phase lasting 3 mo. During the titration phase supine systolic and diastolic pressures fell in lofexidine patients from 143 +/- 4/98 +/- 3 to 122 +/- 3/81 +/- 2 mm Hg and in clonidine patients from 154 +/- 6/101 +/- 2 to 124 +/- 4/81 +/- 2 mm Hg (P less than 0.01), and erect systolic and diastolic pressures fell in lofexidine patients from 143 +/- 3/105 +/- 2 to 116 +/- 3/85 +/- 2 mm Hg and in clonidine patients from 156 +/- 6/104 +/- 2 to 117 +/- 4/82 +/- 2 mm Hg (P less than 0.01). Maximal doses of lofexidine and clonidine in combination with hydrochlorothiazide had equivalent antihypertensive effects, but when the effects of lofexidine and clonidine were compared at each dose level, larger doses of lofexidine patients in either the supine or erect position during the titration phase but heart rate fell in the clonidine patients (P less than 0.05) over the same period. Dry mouth and drowsiness were reported in both groups but were both less frequent and less severe in the lofexidine group than the clonidine group.

The role of the posterior hypothalamic area in the pathogenesis of hypertension in the spontaneously hypertensive rat.

To examine the hypothesis that abnormalities of noradrenergic innervation of hypothalamic pressor areas influence the pathogenesis of hypertension in the spontaneously hypertensive rat (SHR), the norepinephrine content of individual hypothalamic and brainstem nuclei was determined in SHR and control Wistar-Kyoto (WKY) rats at 5, 7, and 11 weeks of age. At 5 and 7 weeks of age, the norepinephrine content of the posterior hypothalamic area (PHA) of SHR was significantly greater than that of WKY controls. These changes occurred at a time when blood pressure was not significantly different between the two groups. The increase in the norepinephrine content of the PHA was accompanied by increases in the norepinephrine content of the A1 region and locus coeruleus in 5-week SHR. In seven week old animals, studies of norepinephrine turnover using alpha-methyl-p-tyrosine revealed no differences between SHR and WKY in turnover in the PHA. The increase in norepinephrine content of the PHA in the absence of changes in turnover is interpreted to indicate increased noradrenergic input to the PHA of SHR and supports the hypothesis that noradrenergic pathways to the PHA are important in the development of hypertension in this model.

Localization of renal sensory neurons using the fluorescent dye technique.

The location of cell bodies of renal sensory neurons was studied. Small injections of a fluorescent dye (True Blue or Fast Blue) were placed into either the right or left kidney of male or female rats. Whereas no differences were detected in the labeling patterns of males vs females, right kidney injections did label slightly higher dorsal root ganglia than left injections. In all cases the labeling was confined to the T6-L2 ganglia ipsilateral to the injection.

An analysis of the sensory innervation of the urinary system in the rat.

The neuronal cell bodies of the afferent fibers innervating the urinary system and the adrenal gland were identified utilizing the method of the retrograde transport of the fluorescent dyes, fast blue and nuclear yellow. Fast blue was injected into the bladder, left ureter, or left adrenal gland, and nuclear yellow was injected into the left kidney of the same animal. The results demonstrate that each organ receives a discrete sensory innervation and that none of the sensory neurons innervating the organs have collateral inputs to the kidney. The location of the DRG cell bodies indicates that more caudally placed organs are innervated by more caudally placed DRG. These findings confirm previous localization studies of the kidney afferents, and support the effectiveness of the use of the fluorescent dye method to localize peripheral afferent cell bodies.

Sodium-neural interactions in the development of spontaneous hypertension.

The influence of alterations in sodium intake on blood pressure and indices of peripheral sympathetic activity was studied during the development of hypertension in the SHR. Male SHRs were given a diet containing either low (0.05%), normal (0.29%) or high (3.4%) sodium content beginning at 7 weeks of age. Systolic blood pressure was measured weekly by the tail cuff method in conscious animals. Three weeks after initiation of the diets 24 hour urines were collected for analysis of catecholamines. Plasma catecholamines were measured and the blood pressure response to ganglionic blockade (hexamethonium bromide, 30 mgm/kg) determined. High sodium resulted in a marked increase in the severity of hypertension that was associated with an increase in plasma and urinary norepinephrine concentration and an exaggerated depressor response to ganglionic blockade. In addition, a highly significant positive correlation was seen between plasma norepinephrine concentration and systolic blood pressure. The results are compatible with the hypothesis that the increase in blood pressure in the SHR maintained on a high sodium intake is in part due to an increase in peripheral sympathetic activity.

Decrease in sympathetic nervous system activity and attenuation in response to stress following renal denervation in the one-kidney one-clip Goldblatt hypertensive rat.

We have found that renal denervation in the one-kidney one-clip Goldblatt hypertensive rat results in an attenuation of the hypertension associated with a decrease in sympathetic nervous system activity. To test further the hypothesis that the renal nerves (afferents) contribute to the maintenance of hypertension in this model by modulating sympathetic nervous system activity, plasma norepinephrine and epinephrine changes in response to stress were compared in hypertensive sham-operated (n = 6), renal denervated (n = 6) and control (n = 7) animals. Stress was produced in conscious resting unrestrained animals by administering two brief electrical stimulations to the hindlimb. Resting plasma norepinephrine was significantly higher (P less than 0.01) in hypertensive sham-operated (420 +/- 41 pg/ml) compared to renal denervated (289 +/- 23 pg/ml) or control (296 +/- 25 pg/ml) animals. There was no difference in resting plasma epinephrine among the groups. In response to stress there were significantly greater absolute increases in plasma norepinephrine and epinephrine in hypertensive sham-operated animals compared to renal denervated and control groups, suggesting that the one-kidney one-clip rat exhibits an enhanced sympathoadrenal response to stress. The response to stress in renal denervated rats was the same as that in the control group. Taken together, these data support the concept that the renal afferent nerves modulate sympathetic nervous system activity in the one-kidney one-clip hypertensive rat.

Central catecholamine depletion, vasopressin, and blood pressure in the DOCA/NaCl rat.

To determine whether impaired arginine vasopressin (AVP) release occurs when DOCA-NaCl hypertension is prevented following chemical sympathectomy with 6-hydroxydopamine (6-OHDA), male Sprague-Dawley rats treated with intraventricular injections of 6-OHDA (250 micrograms X 2) or Merlis solution received deoxycorticosterone acetate (DOCA) implants (100 mg/kg) and drank 0.5% saline. Systolic blood pressure in the 6-OHDA-treated DOCA/NaCl group (139 +/- 4 mmHg) was lower (P less than 0.001) than in the Merlis-DOCA/NaCl group (183 +/- 7 mmHg). 6-OHDA treatment produced widespread catecholamine depletion throughout the central nervous system, including the supraoptic and paraventricular nuclei, the cells of which are known to produce AVP, but hypothalamic, pituitary, and plasma AVP levels were similar in both experimental groups, the latter values averaging 1.5-2 times those of controls. Both groups of rats suppressed AVP secretion appropriately when water loaded. Such suppression, however, had no effect on blood pressure in the hypertensive animals and, furthermore, administration of the AVP antagonist d(CH2)5Tyr(Me)AVP produced small decrements in mean blood pressure of both groups that were not significantly different from responses seen in control normotensive rats. These data demonstrate that 6-OHDA does not prevent DOCA-NaCl hypertension by decreasing AVP levels and suggest that AVP is not necessary for the maintenance of hypertension in this model.

Hyperresponsiveness of monoaminergic mechanisms in DOCA/NaCl hypertensive rats.

To examine the role of the sympathetic nervous system in the development of deoxycorticosterone acetate (DOCA)/NaCl hypertension and to test the hypothesis that the responsiveness of the sympathetic nervous system to stress is enhanced during the developmental phase of hypertension in this model before resting sympathetic activity becomes increased, DOCA/NaCl-treated rats and uninephrectomized control animals were studied after 3, 7, 14, and 28 days of treatment. Basal plasma norepinephrine and epinephrine in conscious, unrestrained resting DOCA/NaCl-treated rats were the same as in controls at 3, 7, and 14 days but were significantly elevated at 28 days of treatment. Ganglionic blockade resulted in a significantly greater decrease in mean arterial pressure in DOCA/NaCl rats than in controls at 14 and 28 days of treatment. At 14 days, DOCA/NaCl rats exhibited significantly greater increments in plasma norepinephrine and epinephrine following cold stress than did H2O controls. Basal plasma prolactin levels were elevated and release of dopamine from isolated superfused mediobasal hypothalami reduced in 28-day DOCA/NaCl hypertensive rats. These results indicate that sympathetic nervous system activity increases progressively during the development of DOCA/NaCl hypertension and that the sympathoadrenal system is hyperresponsive to environmental stress even early in the course of DOCA/NaCl treatment and suggest that hypothalamo-hypophyseal function is altered in this model of hypertension.

Hyperoxia-induced converting enzyme insufficiency in conscious rat: cardiovascular effects.

The effects of exposing rats to hyperoxia (100 percent O2) at normal atmospheric pressure for periods of 24-48 hours on components of the renin-angiotensin system and on blood pressure control were examined. Intrapulmonary conversion of angiotensin I (AI) to angiotensin (AII) was assessed using an isolated lung preparation perfused at constant flow. Exposure of rats to hyperoxia for 44-48 hours reduced single pass conversion of AI to AII in the pulmonary circulation from control levels of 82 +/- 4 to 29 +/- 5 percent (p less than 0.001). AII levels in trunk blood of 44-48 hour O2 exposed animals were 5.2 +/- 1.9 pg/ml, compared to 37.9 +/- 10.0 pg/ml in controls (p less than 0.001). Mean arterial pressure decreased significantly from 117 +/- 4.3 to 103 +/- 6.7 mmHg (p less than 0.05) in the O2 exposed group despite a threefold increase in plasma renin activity. The pressor response to exogenous AI was significantly diminished by O2 exposure, while the pressor response to exogenous AII remained unchanged from control. Pulmonary angiotensin-converting enzyme activity fell to approximately 50 percent of control in O2 exposed animals, but circulating converting enzyme activity was not change in this group. None of these alterations was apparent following 24 hours of hyperoxic exposure. These data suggest that O2 induced impairment in activity of angiotensin-converting enzyme at the endothelial membrane level has functionally significant effects on cardiovascular homeostasis, probably via reduced generation of endogenous AII.