Sodium intake but not renal nerves attenuates renal venous pressure-induced changes in renal hemodynamics in rats.

Increased central venous pressure and renal venous pressure (RVP) are associated with worsening of renal function in acute exacerbation of congestive heart failure. We tested whether an acute isolated elevation of RVP in one kidney leads to ipsilateral renal vasoconstriction and decreased glomerular filtration rate (GFR) and whether this depends on dietary salt intake or activation of renal nerves. Male Lewis rats received a normal (1% NaCl, NS) or high-salt (6% NaCl) diet for ≥14 days before the acute experiment. Rats were then randomized into the following three groups: time control and RVP elevation to either 10 or 20 mmHg to assess heart rate, renal blood flow (RBF), and GFR. To increase RVP, the left renal vein was partially occluded for 120 min. To determine the role of renal nerves, surgical denervation was conducted in rats on both diets. Renal sympathetic nerve activity (RSNA) was additionally recorded in a separate group of rats. Increasing RVP to 20 mmHg decreased ipsilateral RBF (7.5 ± 0.4 to 4.1 ± 0.7 ml/min, P < 0.001), renal vascular conductance (0.082 ± 0.006 to 0.060 ± 0.011 ml·min-1·mmHg-1, P < 0.05), and GFR (1.28 ± 0.08 to 0.40 ± 0.13 ml/min, P < 0.05) in NS rats. The reduction was abolished by high-salt diet but not by renal denervation. Furthermore, a major increase of RVP (1.6 ± 0.8 to 24.7 ± 1.2 mmHg) immediately suppressed RSNA and decreased heart rate ( P < 0.05), which points to suppression of both local and systemic sympathetic activity. Taken together, acute elevated RVP induces renal vasoconstriction and decreased GFR, which is more likely to be mediated via the renin-angiotensin system than via renal nerves.

Renal perivascular adipose tissue: Form and function.

Renal sympathetic activity affects blood pressure in part by increasing renovascular resistance via release of norepinephrine (NE) from sympathetic nerves onto renal arteries. Here we test the idea that adipose tissue adjacent to renal blood vessels, i.e. renal perivascular adipose tissue (RPVAT), contains a pool of NE which can be released to alter renal vascular function. RPVAT was obtained from around the main renal artery/vein of the male Sprague Dawley rats. Thoracic aortic PVAT and mesenteric PVAT also were studied as brown-like and white fat comparators respectively. RPVAT was identified as a mix of white and brown adipocytes, because of expression of both brown-like (e.g. uncoupling protein 1) and white adipogenic genes. All PVATs contained NE (ng/g tissue, RPVAT:524 ±â€¯68, TAPVAT:740 ±â€¯16, MPVAT:96 ±â€¯24). NE was visualized specifically in RPVAT adipocytes by immunohistochemistry. The presence of RPVAT (+RPVAT) did not alter the response of isolated renal arteries to NE compared to responses of arteries without RPVAT (-RPVAT). By contrast, the maximum contraction to the sympathomimetic tyramine was ~2× greater in the renal artery +PVAT versus -PVAT. Tyramine-induced contraction in +RPVAT renal arteries was reduced by the α1-adrenoceptor antagonist prazosin and the NE transporter inhibitor nisoxetine. These results suggest that tyramine caused release of NE from RPVAT. Renal denervation significantly (>50%) reduced NE content of RPVAT but did not modify tyramine-induced contraction of +RPVAT renal arteries. Collectively, these data support the existence of a releasable pool of NE in RPVAT that is independent of renal sympathetic innervation and has the potential to change renal arterial function.

Blood Pressure Responses to Endovascular Stimulation: A Potential Therapy for Autonomic Disorders With Vasodilatation.

BACKGROUND: We have previously shown that sympathetic ganglia stimulation via the renal vein rapidly increases blood pressure. This study further investigated the optimal target sites and effective energy levels for stimulation of the renal vasculatures and nearby sympathetic ganglia for rapid increase in blood pressure. METHODS: The pre-study protocol for endovascular stimulations included 2 minutes of stimulation (1-150 V and 10 pulses per second) and at least 2 minutes of rest during poststimulation. If blood pressure and/or heart rate were changed during the stimulation, time to return to baseline was allowed prior to the next stimulation. RESULTS: In 11 acute canine studies, we performed 85 renal artery, 30 renal vein, and 8 hepatic vasculature stimulations. The mean arterial pressure (MAP) rapidly increased during stimulation of renal artery (95 ± 18 mmHg vs. 103 ± 15 mmHg; P < 0.0001), renal vein (90 ± 16 mmHg vs. 102 ± 20 mmHg; P = 0.001), and hepatic vasculatures (74 ± 8 mmHg vs. 82 ± 11 mmHg; P = 0.04). Predictors of a significant increase in MAP were energy >10 V focused on the left renal artery, bilateral renal arteries, and bilateral renal veins (especially the mid segment). Overall, heart rate was unchanged, but muscle fasciculation was observed in 22.0% with an output >10 V (range 15-150 V). Analysis after excluding the stimulations that resulted in fasciculation yielded similar results to the main findings. CONCLUSIONS: Stimulation of intra-abdominal vasculatures promptly increased the MAP and thus may be a potential treatment option for hypotension in autonomic disorders. Predictors of optimal stimulation include energy delivery and the site of stimulation (for the renal vasculatures), which informs the design of subsequent research.

Catecholamine-containing, dopamine-beta-hydroxylase-immunoreactive perivascular nerve specializations in the rat kidney.

Fluorescence histochemical visualization of catecholamines and immunolabeling of dopamine beta hydroxylase (DBH) were employed to study noradrenergic nerve terminals and perivascular nerve specializations in the rat kidney. Plexuses of catecholamine-containing and dopamine-beta-hydroxylase-immunoreactive nerves innervate the intrarenal arterial tree and larger intrarenal veins. Some perivascular nerve bundles have specialized segments composed of clusters of axonal enlargements that are immunoreactive for DBH and fluoresce intensely in ultraviolet light after fixation in a solution of formaldehyde and glutaraldehyde or treatment with glyoxylic acid. No fluorescent neural structures were found in denervated rat kidney sections treated with glyoxylic acid. Many such structures are associated with arteriolar branches of interlobar, arcuate, and interlobular arteries and are composed, in part, of axonal enlargements that contain mitochondria, microtubules, and one or more clusters of synaptic vesicles. These perivascular nerve specializations may be sites of axoaxonal interactions between noradrenergic axons or between these axons and other types of autonomic or sensory axons. The synaptic vesicles evidently store large amounts of catecholamine, but there is no evidence whether it is released into the surrounding tissue. These structures may be involved in changes in intrarenal innervation patterns which may occur as the rat ages. Regardless of the autonomic or sensory nature of intrarenal neural structures, close association of most such structures with arterioles suggests some neurovascular interaction.

Selective efferent chemical sympathectomy of rat kidneys.

Surgical denervation of kidneys results in interruption of both afferent and efferent renal nerves. We attempted selective efferent renal denervation in rats by slow infusions of 6-hydroxydopamine (6-OHDA) into the right renal artery. Integrity of efferent renal nerves was assessed by chemical and physiological methods and by measuring responses of mean arterial blood pressure (MAP) and heart rate (HR) to intrarenal (ir) infusion of bradykinin in conscious rats. Results were compared with those in surgically denervated and ir saline-infused rats. Surgical denervation of left kidney reduced renal norepinephrine (NE) to 58 and 14% of control levels at 1 and 7 days, respectively, after surgery. Increase in left renal resistance during posterior hypothalamus (PH) stimulation was only 70 +/- 28% (n = 5) compared with 289 +/- 69% (n = 6) in control animals. Response in opposite kidney was unchanged. Although 0.1 mg 6-OHDA ir caused considerable reduction of NE levels in both kidneys, responses to PH stimulation were unchanged. 6-OHDA (1 mg) reduced NE levels in infused and control kidney and atria. Functional evidence for denervation was only obtained in the kidney infused with 6-OHDA. Responses of MAP and HR to ir bradykinin were unchanged 7 days after 1 mg 6-OHDA. The data suggest that ir 6-OHDA results in functional efferent sympathectomy without affecting afferent renal nerves.

Substance P-immunoreactive nerves in the rat kidney.

Previously published data have indicated that in the rat, unlike other species examined, the kidney is not supplied by sensory nerves containing substance P (SP). As part of a study of reflex control of renal function in the rat, we have now reassessed this situation. Many fine, varicose, SP-immunoreactive nerve fibers were found in the wall of the proximal ureter and the renal pelvis, and around the larger renal blood vessels. Sparser populations of similar nerves were also seen running close to proximal and distal tubules in the renal cortex. Occasional fibers were seen at the margins of the glomeruli. Our findings suggest that sensory nerves containing SP may carry sensory information of several types from the rat kidney.

Vascular adrenergic neuroeffector function does not decline in aged rats.

To investigate adrenergic control of blood vessels during aging, rats aged 6, 12, 20, and 27 months were studied using in vitro techniques. Accumulation of [3H]norepinephrine, one index of adrenergic nerve density, did not alter with age in the femoral or renal arteries or renal vein. In the femoral vein [3H]norepinephrine accumulation was greater at 6 and 27 months of age. Norepinephrine sensitivity was determined in both an innervated vessel, the femoral artery, and a non-innervated vessel, the carotid artery. In both cases, sensitivity to norepinephrine did not alter with age. In the renal and femoral arteries and veins, no significant changes in maximum responses to norepinephrine (10(-5) M), potassium chloride, or transmural nerve stimulation were seen with advancing age. Furthermore, frequency response curves (2-16 Hz, 200 pulses) did not differ with age for any of the four vessels studied, with one exception. The response to stimulation at 4 Hz of the femoral vein from 6-month-old rats was significantly larger than responses at other ages. During nerve stimulation, the renal vein exhibited rapid contractions superimposed upon the maintained contractile response. This type of rapid contraction occurred only rarely (1 out of 5) in the renal vein from 27-month-old rats. In summary, neither adrenergic nerve density as reflected by [3H]norepinephrine accumulation nor norepinephrine sensitivity decline with age. As the net effect of various components, the ability of vascular smooth muscle to respond to adrenergic nerve stimulation is also maintained during advancing age.

Extrinsic innervation of the canine superior vena cava, pulmonary, portal and renal veins.

The responses of the superior vena cava, portal, pulmonary, and renal veins to electrical stimulation of sympathetic nerves were investigated in dog. The vascular response was measured by the method with an intravascular cuff. The contractile responses to neural stimuli were mediated mainly by adrenergic mechanism in the four veins and that of the portal vein was, in addition, mediated in part by cholinergic one. The latter mechanism was also found in some cases of the pulmonary vein. As for the superior vena cava and the left renal vein the right-side dominancy in innervation was observed. These observations suggest a possible correlation between the embryogenesis of vein and its innervation.

Effects of adrenoceptor agonists and antagonists on smooth muscle cells and neuromuscular transmission in the guinea-pig renal artery and vein.

In the guinea-pig renal artery and vein, the membrane potential was -66.8 mV and -46.8 mV, the length constant 0.54 mm and 0.43 mm, and the time constant 240 ms and 98 ms, respectively. The maximum slope of the depolarization produced by a 10 fold increase [K]o was 46 mV in the renal artery and 39 mV in the renal vein. Noradrenaline (NA over 5 X 10(-7)M in the artery and over 10(-7)M in the vein) depolarized the membrane and slightly reduced the membrane resistance, assessed from relative changes in the amplitude of electrotonic potential. The action of NA was suppressed by prazosin in the artery but by yohimbine in the vein, i.e. the alpha 1-adrenoceptor is present in the extrajunctional muscle membrane in the renal artery while the alpha 2-adrenoceptor is present in the renal vein. Dopamine and isoprenaline did not modify the membrane properties. In the renal artery, repetitive perivascular nerve stimulation (0.1 ms, 50 Hz, 5 shocks) evoked excitatory junction potential (e.j.p.). Applications of guanethidine (10(-6) M) or tetrodotoxin (3 X 10(-7) M) abolished the generation of the e.j.p.. Low concentrations of phentolamine (5 X 10(-7) M), prazosin (10(-7) M) and yohimbine (5 X 10(-7) M) enhanced the e.j.p. amplitude, while high concentrations of phentolamine (10(-5) M) and prazosin (greater than 10(-5) M) reduced the amplitude of e.j.p.s. NA, dopamine and clonidine consistently suppressed the amplitude of e.j.ps, at any given concentration over 10(-7) M. Spontaneous generated miniature e.j.ps (m.e.j.ps) were recorded on rare occasions. Phentolamine and yohimbine both at 5 x 10(-7) M and prazosin 10(-7) M increased the appearance of m.e.j.ps. 5 In the renal vein, repetitive nerve stimulation failed to generate the e.j.p. Sympathetic innervation to this tissue seems to be sparse. 6 Specificity of innervation and adrenoceptors present on smooth muscle cells in both the renal artery and vein are discussed, and the presynaptic regulation ofNA release is compared with findings in other vascular tissues.

Avian renal portal valve: a reexamination of its innervation.

The renal portal circulation of the avian kidney contains a unique smooth muscle valve that can direct blood flow from the posterior extremities to the central circulation or through the kidney. The neural control of the valve and adjacent venous tissue from Rhode Island Red roosters was characterized by measuring the isometric force developed following transmural nerve stimulation (TNS). During TNS, the valve relaxed while the iliac vein contracted. In the valve, a poststimulus contraction followed the relaxation. Propranolol and guanethidine abolished the TNS-induced relaxation of the valve, leaving a contraction that was increased by physostigmine and partially blocked by atropine or prazosin. In contrast, the TNS-induced contraction of the vein was blocked by guanethidine or prazosin. Measurement of choline acetyltransferase activity and norepinephrine content confirms that the valve is densely innervated with both cholinergic and adrenergic nerves. Thus the vein shows a predominantly adrenergic contractile response typical of most vascular smooth muscle, but the valve demonstrates a dual control, i.e., adrenergic nerves producing relaxation and cholinergic nerves causing contraction. Knowledge of the nature of neuronal control of the valve should aid in the design of experiments to determine its functional role.

Innervation of the renal vasculature of the toad (Bufo marinus).

The innervation of the dorsal aorta and renal vasculature in the toad (Bufo marinus) has been studied with both fluorescence and ultrastructural histochemistry. The innervation consists primarily of a dense plexus of adrenergic nerves associated with all levels of the preglomerular vasculature. Non-adrenergic nerves are occasionally found in the renal artery, and even more rarely near the afferent arterioles. Many of the adrenergic nerve profiles in the dorsal aorta and renal vasculature are distinguished by high proportions of chromaffin-negative, large, filled vesicles. Close neuromuscular contacts are common in both the renal arteries and afferent arterioles. Possibly every smooth muscle cell in the afferent arterioles is multiply innervated. The glomerular capillaries and peritubular vessels are not innervated, and only 3-5% of efferent arterioles are accompanied by single adrenergic nerve fibres. Thus, nervous control of glomerular blood flow must be exerted primarily by adrenergic nerves acting on the preglomerular vasculature. The adrenergic innervation of the renal portal veins and efferent renal veins may play a role in regulating peritubular blood flow. In addition, glomerular and postglomerular control of renal blood flow could be achieved by circulating agents acting via contractile elements in the glomerular mesangial cells, and in the endothelial cells and pericytes of the efferent arterioles. Some adrenergic nerve profiles near afferent arterioles are as close as 70 nm to distal tubule cells, indicating that tubular function may be directly controlled by adrenergic nerves.

Neurohistological observations on the kidney of Rattus rattus rufescens (Indian black rat) as revealed by cholinesterase technique.

The intrinsic innervation of the kidney in Rattus rattus rufescens (Indian black rat) has been studied by cholinesterase technique, under various temperatures, incubation periods and different pH values. The percentage of myelinated nerves was rather high in the medulla region, whereas the non-myelinated nerves dominated in association with the uriniferous tubules and their branches, glomerulus and renal vein in the cortex region. Periarterial AChE-positive ganglia were recorded in the medulla region. The perivenous and periglomerulus plexuses were formed by the non-myelinated nerves and their branches.

Adrenergic and nonadrenergic activation of isolated human renal veins of normotensive and hypertensive patients.

In human renal venous strips from normotensive and hypertensive patients, adrenergic- and nonadrenergic-induced contractions were elicited. The maximal amplitude of contractions remained unchanged whatever the mode of activation. However, in the hypertensive group the forces generated reached only about 20% of those in the normotensive group. Furthermore, preparations from hypertensive patients showed a reduced sensitivity for noradrenaline: the ED50 was shifted from 0.13 +/- 0.03 to 0.66 +/- 0.19 microgram/ml (p less than 0.01). This reduced sensitivity is discussed in connection with the pathogenesis of hypertension.

Sodium excretion and sympathetic activity in relation to severity of hypertension.

The relationship between the severity of hypertensive disease and sodium excretion and sympathetic activity has been studied in normotensive (n = 19) and hypertensive (n = 19) men of the same derived from screening a total population. Sympathetic activity was determined from noradrenaline excretion and the severity of hypertension was assessed by measuring resting diastolic BP, left ventricular hypertrophy on orthogonal ECG and the glomerular filtration rate. In the hypertensive group the resting BP correlated well both with signs of left ventricular hypertrophy, i.e. with the degree of severity of the hypertensive disease. Up to the level of 90 mm Hg resting diastolic BP, sodium excretion rose in agreement with theory of pressure diuresis. Above 90 mm Hg, however, both sodium and noradrenaline excretion fell with increasing BP. This indicated that in more advanced hypertension the sodium balance overrides the sympathetic activity in the long-term relation of BP. In another series of 49-year-old-men noradrenaline excretion fell with increasing renal vascular resistance indicating that the increase in the latter variable could not be explained by increased sympathetic tone. On the basis of the results a hypothesis on the sequence of events leading to development of hypertension, is presented.

Autonomic control of renal portal blood flow in the domestic fowl.

Electrical stimulation of the intrinsic nerves of the renal portal valve of the domestic fowl demonstrated the presence of noradrenergic inhibitory, and cholinergic excitatory fibres. They may be involved in the control of venous return.

Mechanism of the redistribution of renal cortical blood flow during hemorrhagic hypotension in the dog.

Studies were performed to define the mechanisms involved in the redistribution of renal cortical blood flow to inner cortical nephrons which occurs during hemorrhagic hypotension in the dog. The radioactive microsphere method was utilized to measure regional blood flow in the renal cortex. Renal nerve stimulation decreased renal blood flow 40% but had no effect on the fractional distribution of cortical blood flow. Pretreatment with phenoxybenzamine, phentolamine, propranolol, or atropine did not alter the redistribution of cortical flow during hemorrhage. A reduction in renal perfusion pressure by aortic constriction caused a qualitatively similar alteration in regional blood flow distribution as occurred during hemorrhage. When perfusion pressure was kept constant in one kidney by aortic constriction followed by hemorrhage, no redistribution occurred in the kidney with a constant perfusion pressure while the contralateral kidney with the normal perfusion pressure before hemorrhage had a marked increase in the fractional distribution of cortical flow to inner cortical nephrons. Additionally, retransfusion had no effect on the fractional distribution of flow in the kidney in which perfusion pressure was maintained at the same level as during hemorrhage while in the contralateral kidney in which pressure increased to normal there was a redistribution of flow to outer cortical nephrons. These studies indicate that the redistribution of renal cortical blood flow which occurs during hemorrhage is not related to changes in adrenergic activity but rather to the intrarenal alterations which attend a diminution in perfusion pressure.