Morphological evidence of celiac ganglion hyperfunction in spontaneous hypertension in rats

To elucidate the role of the autonomous nervous system in formation of a specific renal "resetting", typical for arterial hypertension, in 8-week-old spontaneously hypertensive rats, a study was made of the morphology of the celiac ganglion as one of the main sources of renal innervation. Light and fluorescent microscopy demonstrate the hypertrophy of the neurons and their nuclei, an increase in the whole ganglion volume and the volume density of the SIF cells. This evidence for hyperactivity of the celiac ganglion attests to the involvement of the renal nervous system in the structural and functional reorganization ("resetting") at the early stages of hypertension as well as a manifestation of hyperactivity of the nervous system in this disease.     

Contribution of renal innervation to hypertension in rat autosomal dominant polycystic kidney disease

The kidney has both afferent (sensory) and efferent (sympathetic) nerves that can influence renal function. Renal innervation has been shown to play a role in the pathogenesis of many forms of hypertension. Hypertension and flank pain are common clinical manifestations of autosomal dominant (AD) polycystic kidney disease (PKD). We hypothesize that renal innervation contributes to the hypertension and progression of cystic change in rodent PKD. In the present study, the contribution of renal innervation to hypertension and progression of renal histopathology and dysfunction was assessed in male Han:SPRD-Cy/+ rats with ADPKD. At 4 weeks of age, male offspring from crosses of heterozygotes (Cy/+) were randomized into either 1) bilateral surgical renal denervation, 2) surgical sham denervation control, or 3) nonoperated control groups. A midline laparotomy was performed to allow the renal denervation (i.e., physical stripping of the nerves and painting the artery with phenol/alcohol). Blood pressure (tail cuff method), renal function (BUN) and histology were assessed at 8 weeks of age. Bilateral renal denervation reduced the cystic kidney size, cyst volume density, systolic blood pressure, and improved renal function (BUN) as compared with nonoperated controls. Operated control cystic rats had kidney weights, cyst volume densities, systolic blood pressures, and plasma BUN levels that were intermediate between those in the denervated animals and the nonoperated controls. The denervated group had a reduced systolic blood pressure compared with the operated control animals, indicating that the renal innervations was a major contributor to the hypertension in this model of ADPKD. Renal denervation was efficacious in reducing some pathology, including hypertension, renal enlargement, and cystic pathology. However, sham operation also affected the cystic disease but to a lesser extent. We hypothesize that the amelioration of hypertension in Cy/+ rats was due to the effects of renal denervation on the renin angiotensin system.     

Sympathetic innervation of blood vessels in rats with aortic constriction hypertension

The adrenergic innervation of blood vessel wall was studied in various vascular beds of adult rats with experimental hypertension induced by the constriction of the aorta between the origins of both renal arteries. A moderate expansion of body fluids was demonstrated in this hypertensive model. The decrease of the density of adrenergic plexus in the vessel wall as well as the diminished catecholamine fluorescence were found only in renal vessels. These changes were pronounced in the left renal artery and vein even if the left kidney was not subjected to elevated blood pressure. Thus the alteration of vascular adrenergic innervation in hypertensive rats is not a consequence of high blood pressure but it seems to be a part of neurohumoral pathogenetic mechanisms.     

The adrenergic innervation of the renal artery and vein of the rat

Summary The adrenergic innervation of the extrarenal blood vessels of the rat left kidney was investigated by fluorescence histochemistry and by electron microscopy. The trunk of the renal artery proximal to the aorta is elastic and appears to be very sparsely innervated. In contrast, near the kidney the renal artery—which divides into 3 to 4 large branches of the muscular type possesses a dense adrenergic innervation. The adrenergic terminal axons are situated in the adventitia close to the external elastic lamella, but only rarely in close contact with smooth muscle cells. In most instances several terminal axons are grouped and enclosed by a Schwann cell, single axons being rare. All terminal axons are able to take up and to store 5-hydroxydopamine which strongly suggests that they are adrenergic. The innervation of the renal vein is more sparse than that of the muscular arteries but somewhat denser than that of the elastic artery. In addition, close to the origin of the renal artery the presence of small intensively fluorescent (SIF) cells as well as of some adrenergic ganglion cells is noted. The latter are situated in the adrenergic nonterminal axon bundles, which run parallel to the blood vessels.It is concluded that the uneven adrenergic innervation along the artery as well as individual variations in the branching of the artery are the main causes of the unusually high individual variations of the NA content of this organ such as used in pharmacological experiments.     

Role of adrenergic innervation in experimental renal hypertension

Renal hypertension was induced by ligation of the aorta between renal arteries in rats sympathectomized with 6-hydroxydopamine. In the early phase, equally severe hypertension developed in the denervated group as compared to innervated controls. Later, blood pressure was lower in the denervated rats. Initially, increases in plasma renin were seen in both groups; the levels, however, were markedly lower in the denervated rats. Later, the renin levels were similar and not different from baseline. It is concluded that adrenergic neural activity is not essential in the development of renal hypertension; the maintenance of the chronic state, however, depends in part on adrenergic innervation.     

Renal microvasculature in spontaneously hypertensive rats.

The renal microvasculature was studied in normotensive rats and in rats with spontaneous hypertension. The microvascular pattern was normal in both groups of animals, suggesting normal renin secretion. This may or may not indicate a role for renin in the cause of spontaneous hypertension.     

Protein concentration in the arterial and venous renal blood serum of the rabbit

In normal rabbits, under Nembutal anesthesia, the total protein and albumin content of the arterial blood serum are significantly higher than the same fractions of the renal venous blood serum. This condition is reversed in the rabbits after removal of more than 15 ml. blood/kg.Renal innervation plays a role in the regulation of the protein concentration in the renal venous blood, after hemorrhage.No significant difference of protein fractions in the arterial and renal venous blood sera has been observed in a series of rabbits with experimental renal hypertension.Parallel estimations of color intensity of previously injected Evans Blue, and of the protein fractions (by electrophoretic and turbidimetric methods) in the arterial and renal venous blood specimens of normal rabbits corroborate the possibility of a renal mechanism of albumin storage.     

Increased sensitivity of the fatty tissue of rats with spontaneous hypertension to the action of ACTH. The role of calcium]

The action of ACTH on the adipose tissue lypolysis was studied in rats with spontaneous and renal hypertension as well as in normotensive rats of the respective control groups. It was demonstrated that sensitivity of the adipose tissue SHR to ACTH was increased as compared to normotensive controls. The data presented indicate that the increased sensitivity is due to the state or content of intracellular calcium. The rats with renal hypertension did not show such an increased sensitivity of the adipose tissue to ACTH.     

Muscarinic cholinoceptors and choline acetyltransferase activity in the hypothalamus of spontaneously hypertensive rats

To study the role of central cholinergic mechanisms in hypertension, we have determined muscarinic receptors using [³H](-)quinuclidinyl benzilate (QNB) and choline acetyltransferase (ChAT) activity in the brain regions of spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP) and renal hypertensive rats. The number of muscarinic receptors was significantly (33–38%) elevated in the hypothalamus of SHR and SHRSP at the ages of 16 and 24 weeks compared to that of Wistar-Kyoto rats (WKY). An increased density of muscarinic receptors was consistently observed in the prehypertensive (5 weeks) and developmental (10 weeks) stages of hypertension. In contrast, in the hypothalamus of rats with renal hypertension there was no muscarinic receptor alteration. The receptor alteration in the SHRSP hypothalamus was not abolished by a chronic hypotensive treatment which prevented the development of hypertension, suggesting that an enhancement of the muscarinic receptors in spontaneous hypertension does not occur secondarily to the elevation of blood pressure. The hypothalamus of SHR and SHRSP at the ages of 5 and 24 weeks showed significantly less activity of ChAT. These data demonstrate that there is a specific increase in muscarinic receptors and a decrease in cholinergic activity in the hypothalamus of SHR and SHRSP. Thus, the present study suggests an important role for hypothalamic cholinergic receptors in the pathogenesis of spontaneous hypertension.     

Anatomy of the renal innervation: intrarenal aspects and ganglia of origin.

The intrinsic innervation of the kidney is described based on studies using ultrastructural, fluorescent, immunocytochemical, and autoradiographic techniques. The efferent sympathetic innervation reaches all the segments of the renal vasculature and to a much lesser extent the tubular nephron. The afferent renal nerves are localized predominantly in the pelvic region, the major vessels, and the corticomedullary connective tissue. The pathways of the renal innervation to the corresponding ganglia, as reported from observations resulting from the combination of axonal transport labeling and immunocytochemical methods, are presented. In the rat the ganglia of origin of the sympathetic efferent innervation include T13-L1 ipsilateral and contralateral paravertebral ganglia and the prevertebral superior mesenteric and celiac ganglia. The sensory afferent innervation presents a different segmental distribution of the dorsal root ganglia for the right and left kidney. For the left kidney, the corresponding ganglia extend from T8 to L2 with the greatest numbers in T12 and T13. For the right kidney, ganglia as high as T6 and as low as L2 harbor neurons innervating the kidney. Current knowledge of the anatomical bases of the function of the renal nerves is discussed.     

Sex differences in postnatal growth and renal development in offspring of rabbit mothers with chronic secondary hypertension

Previously, we demonstrated that adult blood pressure was increased in offspring of rabbit mothers with chronic secondary renal hypertension. Our study identified sex-specific differences in the programming of hypertension, with female, not male, offspring, having increased blood pressure at 30 wk of age. The aim of this study was to characterize the maternal hypertension during pregnancy to determine potential programming stimuli. Further, we examined the impact of chronic maternal hypertension on offspring birth weight, nephron number, and renal noradrenaline content (as an index of renal innervation density). Three groups of mothers and their offspring were studied: two-kidney, one-wrap (2K-1W, n = 9 mothers) hypertensive, two-kidney, two-wrap (2K-2W, n = 8) hypertensive, and a sham-operated group (n = 9). Mean arterial blood pressure was increased by approximately 20 mmHg throughout pregnancy in both hypertensive groups compared with sham mothers (P(G) < 0.001). Plasma renin activity (PRA; P(G) < 0.05) and aldosterone (P(G) < 0.05) levels were increased during gestation in the 2K-1W, but not the 2K-2W mothers. Birth weight was increased by approximately 20% in offspring of both groups of hypertensive mothers (P(T) < 0.001), though this was associated with a reduction in litter size. Renal noradrenaline content was increased ( approximately 40%, P < 0.05) at 5 wk of age in female 2K-1W offspring compared with sham offspring. Glomerular number was not reduced in female offspring of either group of hypertensive mothers; however, glomerular tuft volume was reduced in female 2K-2W offspring (P < 0.05), indicative of a reduction in glomerular filtration surface area. In conclusion, the two models of renal hypertension produced differential effects on the offspring. The impact of a stimulated maternal renin-angiotensin system in the 2K-1W model of hypertension may influence development of the renal sympathetic nerves and contribute to programming of adult hypertension.     

Spontaneous hypertension is primarily the result of sympathetic overactivity and immunologic dysfunction

Overactivity of the sympathetic nervous system and immunologic dysfunction have been shown to contribute to development and maintenance of hypertension in the Okamoto spontaneously hypertensive rat (SHR). In this study, the combined effects of reduction in sympathetic activity and immunologic manipulation on spontaneous hypertension have been determined. Neonatal SHRs received sham implants or implants of thymic tissue from Wistar donor rats. In addition, the thymus-implanted SHRs underwent bilateral renal denervation when they were 6 weeks old. At the same time, the sham-implanted SHRs underwent sham renal denervation. The denervations or sham operations were repeated when the SHRs were 9, 12, 15, and 18 weeks old. Wistar-Kyoto (WKY) rats also underwent serial sham renal denervations. Tail-cuff pressure measurements indicated that approximately 75% of the chronic hypertension in the SHRs was prevented by the combination of thymic implants and renal denervations. Direct arterial pressure measurements confirmed these results; when the rats were 21 weeks old, mean arterial pressure averaged 177 +/- 5.5 mm Hg in sham-operated SHRs, 134 +/- 2.7 mm Hg in implanted, denervated SHRs, and 121 +/- 2.1 mm Hg in sham-operated WKY rats. These data indicate that overactivity of the sympathetic nervous system and immunologic dysfunction account for the majority of the hypertension in the Okamoto SHR.     

Esophageal EMG activity in the pigeon (Columbia livia) in vivo

The pigeon esophageal smooth muscle shows "spontaneous" rhythmic bursts of spikes with increasing discharge frequency from pharynx to crop. There are no slow waves. The changes of the electric pattern induced by pharmacological administrations of atropine, prostigmine, hexamethonium and by asphyxia suggest that the electric activity is myogenic in origin. The innervation plays a role in the control of this activity and it is essential for the functional polarization.     

Decreased ANF atrial content and vascular reactivity to ANF in spontaneous and renal hypertensive rats

The relationship between ANF activity and hypertension was determined by measuring ANF atrial content and vascular reactivity in two different models: spontaneous hypertensive rats (SHR) and renal hypertensive rats (RHR). Atrial extracts and aortic strips were prepared from hypertensive and normotensive animals. Relaxant activities of extracts, synthetic ANF and nitroglycerin were assayed on superfused aortic strips previously contracted by norepinephrine. ANF atrial content was statistically significantly lower in both models of hypertension, presumably by increased ANF release into the circulation which results in depletion of tissue storage sites. Vascular subsensitivity to ANF and nitroglycerin was found in both models of hypertension. Diminished ANF vascular reactivity in hypertension could be due to receptor down-regulation and/or to a decrease in the ability of cGMP to induce relaxation.     

The relationship between altered blood vessel structure, hypertension, and the sympathetic nervous system

The relationship between sympathetic innervation and arterial medial development has been examined in normotensive, hypertensive, and diabetic rats. Using the jejunal artery as a model, the number of nerve fibres innervating the artery as determined from fluorescent preparations, and the medial thickness and lumen diameter as measured from resin embedded specimens were correlated from animals prepared in various ways. The rats used were normal Sprague-Dawley (SD), SD with induced hypertension, SD with diabetes induced with streptozotocin, SD sympathectomized with 6-hydroxydopamine, spontaneously hypertensive rats (SHR), SHR treated with capsaicin to prevent hypertension development, Wistar Kyoto rats (WKY), and WKY treated with capsaicin. Examination of the jejunal arteries from these rats at 12 weeks of age following normal development, or 8 weeks of hypertension development, or 8 and 12 weeks of diabetes, showed that increased innervation occurred in the SHR under all conditions, and in the diabetic rats after 8 weeks of diabetes. Medial hypertrophy occurred in the SHR and in the SD hypertensive only. It is concluded that the special relationship which exists between the sympathetic innervation and arterial media in the SHR does not occur during hypertension development in the SD rat, nor is it necessary for normal medial development in the SD rat. The sympathetic innervation does appear to have a trophic influence on vascular smooth muscle of diabetic rats, at least in the early stages of the disease.     

Innervation of the renal cortex.

Morphologic studies of renal innervation have utilized the methods of histochemistry and electron microscopy. Much information has been derived from examination of the renal cortex in monkey and rat. Fluorescence histochemistry shows a rich adrenergic innervation. Acetylcholinesterase can be demonstrated histochemically in the renal nerves by light and electron microscopy. Studies in the rat using 6-hydroxydopamine, a drug that selectively destroys adrenergic nerves, indicate that the glomerular arterioles and surrounding tubules are innervated by adrenergic nerves containing acetylcholinesterase. Distinct neurovascular and neurotubular junctions are observed the electron microscope. They are anatomically consistent with being the sites of synaptic transmission. Ultrastructural analysis of serial sections reveals that single individual axons contact multiple vascular cells and renal tubules. We now have a considerable body of information concerning the morphology of renal innervation are are beginning to appreciate the role of the renal nerves in kidney function.     

Transmembrane potential and electrogenicity of thrombocyte Na, K-ATPase in different forms of hypertension in rats

The fluorescent dye 3,3'-dipropylthiadicarbocyanine iodide, dis-C3-(5), was used to study the membrane potential of platelets in rats with renal, DOCA-induced and spontaneous hypertension. The magnitude of the transmembrane potential in platelets combines the activity of electrogenic Na, K-ATPase and the rate of ion diffusion across the plasma membrane. The basal potential is 12 = 14 mB as lowered only in spontaneously hypertensive rats. The decrease of the basal potential is made for electrogenicity of platelet Na, K-ATPase in spontaneously hypertensive rats.     

Innervation of the renal proximal convoluted tubule of the rat

Experimental data suggest the proximal tubule as a major site of neurogenic influence on tubular function. The functional and anatomical axial heterogeneity of the proximal tubule prompted this study of the distribution of innervation sites along the early, mid, and late proximal convoluted tubule (PCT) of the rat. Serial section autoradiograms, with tritiated norepinephrine serving as a marker for monoaminergic nerves, were used in this study. Freehand clay models and graphic reconstructions of proximal tubules permitted a rough estimation of the location of the innervation sites along the PCT. In the subcapsular nephrons, the early PCT (first third) was devoid of innervation sites with most of the innervation occurring in the mid (middle third) and in the late (last third) PCT. Innervation sites were found in the early PCT in nephrons located deeper in the cortex. In juxtamedullary nephrons, innervation sites could be observed on the PCT as it left the glomerulus. This gradient of PCT innervation can be explained by the different tubulovascular relationships of nephrons at different levels of the cortex. The absence of innervation sites in the early PCT of subcapsular nephrons suggests that any influence of the renal nerves on the early PCT might be due to an effect of neurotransmitter released from renal nerves reaching the early PCT via the interstitium and/or capillaries.     

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.     

High Prevalence and Associated Risk Factors for Impaired Renal Function and Urinary Abnormalities in a Rural Adult Population from Southern China

Background

The prevalence of chronic kidney disease (CKD) has increased and will continue to rise worldwide. However, data regarding the prevalence of CKD in a rural area of China are limited. We therefore investigated the prevalence and associated risk factors of impaired renal function and urinary abnormalities in an adult rural population in southern China.

Methods

Between December 2006 and January 2007, residents older than 20 years from four villages in Zhuhai city were randomly selected using a stratified, multistage sampling technique. All participants were interviewed and tested for hematuria, albuminuria and estimated glomerular filtration rate (eGFR). The associations between age, gender, diabetes mellitus, hypertension, hyperuricemia, education level and indicators of renal damage were examined.

Results

Overall, 1,214 subjects were enrolled in this study. After adjustment for age and gender, the prevalence of albuminuria was 7.1% (95% CI: 4.5, 8.1), reduced eGFR was 2.6% (95% CI: 1.7%, 3.3%), and hematuria was 4.6% (95% CI: 3.3%, 6.0%). Approximately 13.6% (95% CI: 12.0%, 15.1%) of the patients had at least one indicator of renal damage, but only 8.3% were previously aware. Age, diabetes, hyperlipidemia, hypertension, hyperuricemia, use of nephrotoxic medications, coronary heart disease and history of CKD were independently associated with impaired renal function and urinary abnormalities. Additionally, age, diabetes, and hypertension were independently associated with albuminuria. Age, hypertension, hyperuricemia, central obesity, and coronary heart disease were independently associated with reduced renal function.

Conclusions

The high prevalence and low awareness of impaired renal function and urinary abnormalities in this population illustrates the urgent need to implement a CKD prevention program in the rural areas of southern China.