Renal nerves and experimental hypertension: evidence and controversy

Noradrenergic fibers innervate various parts of the nephron and can contribute to sodium and water homeostasis by influencing hemodynamic variables, tubular reabsorptive mechanisms, and renin release. As renal function is considered to be a primary determinant of arterial pressure, efferent renal nerves may be an important link between the central nervous system and the kidney in the development and maintenance of hypertension. Little is known about the relative importance of renal nerves and their interactions with other factors in influencing renal function chronically. There is disagreement about the evidence for enhanced noradrenergic drive to the kidney in hypertensive rats, as the renal nerve firing rate, neurotransmitter release and metabolism, and receptor properties are generally not studied in association with measurements of renal function. However, chronic renal denervation has been shown to significantly affect arterial pressure in diverse forms of experimental hypertension in rats, including genetic models, as well as renovascular, mineralocorticoid, neurogenic, and angiotensin II hypertension. The actual mechanisms responsible for this effect of renal denervation are not clear, but presumably reflect changes in the arterial pressure-urinary sodium output relationship. On the whole, there is reasonable correlation between neurophysiological, biochemical, and renal denervation studies in the spontaneously hypertensive rat, suggesting that renal nerves do play a role in the onset of hypertension in these animals. The effect of renal denervation in other models of hypertension seems less clear, with recent reports showing that renal denervation does not alter the hypertensive process in renovascular, mineralocorticoid, and salt-related hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Morphological characteristics of the secretion of natriuretic factor by atrial cardiomyocytes in spontaneous hypertension in rats

The results of electron microscopic studies of the synthesis and secretion of atrial natriuretic factor (ANF) in right atrial cardiomyocytes of spontaneously hypertensive rats (SHR) and the corresponding normotensive controls are presented. Enhanced secretory activity in cardiomyocytes of SHR has been revealed. The role of enhanced ANF secretion in the origin of arterial hypertension is discussed. It is suggested that enhanced ANF secretion can be attributed to increased ANF demand in BP elevation, changes in the renal function in hypertensive subjects or genetic defect in the excretory renal function in SHR.     

Neuronal control of the kidney: contribution to hypertension.

The renal nerves contribute to hypertension in experimental models of the disease, and appear to play a role in human hypertension. Several lines of evidence indicate that both in spontaneously hypertensive rats and in deoxycorticosterone acetate--NaCl rats, the full development of hypertension is dependent on renal efferent nerves and their induction of excess sodium retention. Renal sensory (afferent nerve) feedback to the central nervous system does not contribute to either of these forms of hypertension. In contrast, renovascular hypertension in rats and aortic coarctation hypertension in dogs are mediated, at least in part, by overactivity of renal afferent nerves and a resultant increase in systemic sympathetic nervous system activity. These forms of hypertension are not associated with sodium retention, and selective sensory denervation of renal afferent nerves by dorsal rhizotomy and total renal denervation result in similar reductions in hypertension. Surprisingly, the renal nerves do not contribute to dietary NaCl exacerbated hypertension in the spontaneously hypertensive rat, dietary NaCl-induced hypertension in the Dahl NaCl-sensitive rat, or the chronic hypertensive and nephrotoxic effects of cyclosporine A therapy in the rat, despite the finding that in all three forms of hypertension, overactivity of the sympathetic nervous system is prominent. Clinical studies indicate that the renal afferent and efferent nerves contribute to hypertension of different etiologies. Together these data point to the complex role that the renal nerves likely play in human essential hypertension.     

The renal afferent nerves in the pathogenesis of hypertension

The renal nerves play a role in the pathogenesis of hypertension in a number of experimental models. In the deoxycorticosterone acetate - salt (DOCA-NaCl) hypertensive rat and the spontaneously hypertensive rat (SHR) of the Okamoto strain, total peripheral renal denervation delays the development and blunts the severity of hypertension and causes an increase in urinary sodium excretion, suggesting a renal efferent mechanism. Further, selective lesioning of the renal afferent nerves by dorsal rhizotomy reduces hypothalamic norepinephrine stores without altering the development of hypertension in the SHR, indicating that the renal afferent nerves do not play a major role in the development of hypertension in this genetic model. In contrast, the renal afferent nerves appear to be important in one-kidney, one-clip and two-kidney, one-clip Goldblatt hypertensive rats (1K, 1C and 2K, 1C, respectively) and in dogs with chronic coarctation hypertension. Total peripheral renal denervation attenuates the severity of hypertension in these models, mainly by interrupting renal afferent nerve activity, which by a direct feedback mechanism attenuates systemic sympathetic tone, thereby lowering blood pressure. Peripheral renal denervation has a peripheral sympatholytic effect and alters the level of activation of central noradrenergic pathways but does not alter sodium or water intake or excretion, plasma renin activity or creatinine clearance, suggesting that efferent renal nerve function does not play an important role in the maintenance of this form of hypertension. Selective lesioning of the renal afferent nerves attenuates the development of hypertension, thus giving direct evidence that the renal afferent nerves participate in the pathogenesis of renovascular hypertension.     

ETA receptor-mediated role of endothelin in the kidney of doca-salt hypertensive rats

Renal effects of FR139317, an endothelin ET_A receptor antagonist, were examined using anesthetized normotensive and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The intravenous bolus injection of FR139317 (10 mg/kg) produced a slight decrease in mean blood pressure (MAP; −13%) in the control rats and this hypotension was accompanied by a moderate renal vasodilation (renal vascular resistance: RVR; −12%). In the DOCA-salt hypertensive rat, FR139317 had a more pronounced hypotensive effect (MAP; −26%) accompanied by a potent renal vasodilation (RVR; −33%). FR 139317 significantly increased renal blood flow only in the DOCAsalt rats. In contrast, FR139317 produced a significant decrease in urine flow and urinary sodium excretion only in control rats. Northern blot analysis revealed that the renal prepro endothelin-1 (ET-1) mRNA level was significantly increased in DOCA-salt hypertensive rats. Thus, it seems likely that endogenous ET-1 is responsible for the maintenance of DOCA-salt-induced hypertension. We also suggest that at least in part, ET-1 and £ta receptors are involved in renal hemodynamic abnormalities in DOCA-salt-induced hypertension. The augmentation of renal ET-1 production may possibly have a function in the development and maintenance of DOCA-salt-induced hypertension.     

Abnormal response of urinary eicosanoid system to norepinephrine infusion in patients with essential hypertension.

To define the role of the renal eicosanoid system in sustaining renal homeostasis in hypertension, we investigated the alterations in urinary excretions of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), a stable metabolite of vasodepressor prostacyclin, and thromboxane B2 (TXB2), a stable metabolite of vasoconstrictor TXA2, when norepinephrine was continuously infused for 90 min in hypertensive (n = 13) and normotensive subjects (n = 14). There was no difference in plasma norepinephrine concentration after the infusion between the hypertensive and the normotensive subjects. Moreover, the percent changes in renal vascular resistance elicited by norepinephrine in the hypertensives were equal to those of the normotensive subjects. In the normotensive subjects, the norepinephrine infusion significantly increased urinary 6-keto-PGF1 alpha excretion and decreased urinary excretion of TX, both of which are beneficial for sustaining renal function. In fact, the greater the production of renal 6-keto-PGF1 alpha was, the less the reduction of renal blood flow and urinary sodium excretion was. In the hypertensive subjects, however, these normal responses of the renal eicosanoid system, seen in the normotensives, were abolished; urinary 6-keto-PGF1 alpha was unaltered and thromboxane generation was rather increased. Thus, the renal eicosanoid system dysfunctions in hypertensive subjects when the renal circulation is challenged by norepinephrine. These abnormal responses are likely to cause sodium retention and could contribute, in part, to the hypertensive mechanism in patients with essential hypertension.     

Semiquantitative histochemical investigation of lysosomal enzyme activities in the aortic endothelial cells of rats with renal hypertension

To obtain information about changes in lysosomal enzyme activities in the aortic endothelial cells in arterial hypertension, semi-quantitative histochemical investigations of acid phosphatase (Ac-Pase) and N-acetyl-beta-glucosaminidase (NAGase) activities in the aorta of rats with renal hypertension were performed on "H?utchen" monolayer preparations. The aortic endothelial cells in renal hypertensive animals showed increased Ac-Pase and NAGase activities compared with those in control normotensive rats and tended to increase with advancing age. These results, like our previous data from spontaneously hypertensive rats (SHR), indicated that degeneration of endothelial cells, expressed by increased lysosomal enzyme activity, was accelerated by hypertension, and the possible participation of genetic factors in the activation of these enzymes in SHR was ruled out. Increased lysosomal enzyme activity may be involved in the development of other hypertensive vascular changes.     

Increased reactive oxygen species contributes to kidney injury in mineralocorticoid hypertensive rats.

Hypertension is associated with increased reactive oxygen species (ROS). Renal ROS production and their effects on renal function have never been investigated in mineralocorticoid hypertensive rats. In this study we hypothesized that increased ROS production in kidneys from deoxycorticosterone (DOCA)-salt rats contributes to adverse renal morphological changes and impaired renal function in DOCA-salt hypertensive rats. We also determined whether ROS-induced renal injury was dependent on blood pressure. DOCA-salt hypertensive rats exhibited a marked increase in blood pressure, renal ROS production, glomerular and tubular lesions, and microalbuminuria compared to sham rats. Treatment of DOCA-salt hypertensive rats with apocynin for 28 days resulted in attenuation of systolic blood pressure and improvement of renal morphology. Renal superoxide level in DOCA-salt rats was 215% of sham-operated rats and it was significantly decreased to 140% with apocynin treatment. Urinary protein level was decreased from 27 +/- 3 mg/day in DOCA-salt hypertensive rats to 9 +/- 2 mg/day. 28 days of Vitamin E treatment also reduced renal injury in regard to urinary protein level and renal morphology but had no effect on blood pressure in DOCA-salt rats. Increased urinary 8-isoprostane, a marker for oxidative stress, in DOCA-salt hypertensive rats (55 +/- 8 ng/day) was diminished by vitamin E treatment (24 +/- 6 ng/day). These data suggest that renal injury characteristic of mineralocorticoid hypertension is associated with oxidative stress and is partly independent of blood pressure.     

Renin in hypertension: how important as a risk factor?

An analysis of the plasma renin levels in relation to the incidence of severe cardiovascular complications (coronary thrombosis, stroke, ruptured aortic aneurysm) was made in 325 patients with various types of hypertension. These patients had one to four measurements of plasma renin activity taken under standard conditions of sodium intake and posture in the period 1963-68. The follow-up was 5 to 10 years in the four groups of hypertensive patients (essential hypertension, malignant hypertension, hypertension secondary to renal parenchymatous disease and hypertension caused by, or associated with, renal artery obstruction). For all 325 patients, the incidence of such complications was 23.6, 20.4 and 44.7% in the low, normal and high renin groups. These findings are at variance with the claim that renin constitutes a serious risk factor in hypertensive patients, especially if it is isolated from other parameters such as the level of diastolic pressure, the adequacy of kidney function, the effectiveness of dietary and drug management of hypertension, and especially the presence or absence of atherosclerotic lesions of the large vessels at the time of the renin determination.     

Renal responses to acute reflex activation of renal sympathetic nerve activity and renal denervation in secondary hypertension

We tested whether the responsiveness of the kidney to basal renal sympathetic nerve activity (RSNA) or hypoxia-induced reflex increases in RSNA, is enhanced in angiotensin-dependent hypertension in rabbits. Mean arterial pressure, measured in conscious rabbits, was similarly increased (+16 +/- 3 mmHg) 4 wk after clipping the left (n = 6) or right (n = 5) renal artery or commencing a subcutaneous ANG II infusion (n = 9) but was not increased after sham surgery (n = 10). Under pentobarbital sodium anesthesia, reflex increases in RSNA (51 +/- 7%) and whole body norepinephrine spillover (90 +/- 17%), and the reductions in glomerular filtration rate (-27 +/- 5%), urine flow (-43 +/- 7%), sodium excretion (-40 +/- 7%), and renal cortical perfusion (-7 +/- 3%) produced by hypoxia were similar in normotensive and hypertensive groups. Hypoxia-induced increases in renal norepinephrine spillover tended to be less in hypertensive (1.1 +/- 0.5 ng/min) than normotensive (3.7 +/- 1.2 ng/min) rabbits, but basal overflow of endogenous and exogenous dihydroxyphenolglycol was greater. Renal plasma renin activity (PRA) overflow increased less in hypertensive (22 +/- 29 ng/min) than normotensive rabbits (253 +/- 88 ng/min) during hypoxia. Acute renal denervation did not alter renal hemodynamics or excretory function but reduced renal PRA overflow. Renal vascular and excretory responses to reflex increases in RSNA induced by hypoxia are relatively normal in angiotensin-dependent hypertension, possibly due to the combined effects of reduced neural norepinephrine release and increased postjunctional reactivity. In contrast, neurally mediated renin release is attenuated. These findings do not support the hypothesis that enhanced neural control of renal function contributes to maintenance of hypertension associated with activation of the renin-angiotensin system.     

Hyperleptinemia--non-haemodynamic risk factor for the left ventricular hypertrophy development in hypertensive overweight females

Obesity is directly and strongly associated with hypertension and left ventricular hypertrophy (LVH). Development of LVH is multifactorial, caused both by haemodynamic and non-haemodynamic factors. Hypertension is the main haemodynamic factor. Humoral mechanisms, as a non-haemodynamic factor for LVH development, have not been completely explained. The aim of this study is to determine whether hyperleptinemia can be one of humoral--non-haemodynamic factor inducing LVH together with haemodynamic factors in overweight females. The study was done on thirty six adult, overweight female patients, body mass index in range 25-30 kg/m2. Patients are nondiabetic with regular renal function. Twenty one female patients were hypertensive with left ventricular hypertrophy. Control group included fifteen hypertensive female patients without left ventricular hypertrophy. In all patients was determined glucose profile and creatinine clearance, cholesterol, triglycerides, LDL, HDL. Weight, high, circumference of the waist and hips was taken. Cardiovascular determination was done applying two-dimensional ultrasound. Serum leptin level was measured using radioimmunoassay method (RIA). Results showed that serum leptin level was significantly higher in hypertensive, overweight females with LVH. This suggests that non-haemodynamic factors, such as hyperleptinemia, participate in left ventricular hypertrophy development together with haemodynamic factors in adult hypertonic, overweight females.     

Minerals in renal and SHR hypertensive rats

References to individual trace minerals in hypertensive rats have been made; however, data on multiple minerals in SHR hypertensive rats is lacking. The purpose of this study was to investigate five trace minerals in normotensive, chronic renal and SHR hypertensive rats. Blood samples were drawn to measure serum levels of Ca, Fe, K, Mg, and Na. Serum K values were elevated in the chronic renal hypertensive animals. Iron levels were decreased in both the renal and SHR hypertensive animals. No difference was observed in levels of Ca, Mg, and Na between normotensive and chronic renal or SHR hypertensive rats. Further study of multiple trace minerals in experimental hypertension is recorded in order to extend these deviations.     

Renal concentrating capacity is linked to blood pressure in children with autosomal dominant polycystic kidney disease

Impaired glomerular filtration rate (GFR) is a risk factor for the development of hypertension in patients with autosomal dominant polycystic kidney disease (ADPKD). However, markers of tubular function were not tested whether they are linked to hypertension or blood pressure (BP) level. The aim of our study was to investigate the relationship between renal concentrating capacity and BP in children with ADPKD. Fifty-three children (mean age 11.8+/-4.4 years) were investigated. Standardized renal concentrating capacity test was performed after nasal drop application of desmopressin, BP was measured by ambulatory BP monitoring (ABPM). Renal concentrating capacity was decreased in 58 % of children. The prevalence of hypertension was significantly higher in children with decreased renal concentrating capacity (35 %) than in children with normal renal concentrating capacity (5 %) (p<0.05). Significant negative correlations were found between renal concentrating capacity, ambulatory BP and number of renal cysts (r = -0.29 to -0.39, p<0.05 to p<0.01). In conclusion, the concentrating capacity is decreased in about half of the patients and is linked to BP. Decreased renal concentrating capacity should be considered.     

Renal programming: cause for concern?

Development of the kidney can be altered in utero in response to a suboptimal environment. The intrarenal factors that have been most well characterized as being sensitive to programming events are kidney mass/nephron endowment, the renin-angiotensin system, tubular sodium handling, and the renal sympathetic nerves. Newborns that have been subjected to an adverse intrauterine environment may thus begin life at a distinct disadvantage, in terms of renal function, at a time when the kidney must take over the primary role for extracellular fluid homeostasis from the placenta. A poor beginning, causing renal programming, has been linked to increased risk of hypertension and renal disease in adulthood. However, although a cause for concern, increasingly, evidence demonstrates that renal programming is not a fait accompli in terms of future cardiovascular and renal disease. A greater understanding of postnatal renal maturation and the impact of secondary factors (genes, sex, diet, stress, and disease) on this process is required to predict which babies are at risk of increased cardiovascular and renal disease as adults and to be able to devise preventative measures.     

Prostaglandins,the kidney,and hypertension.

Prostaglandins are part of the family of oxygenated metabolites of arachidonic acid known collectively as eicosanoids. While they are formed, act, and are inactivated locally and rarely circulate in plasma, they can affect blood flow in some tissues and so might contribute to the control of peripheral vascular resistance. Few studies have shown any derangement of total body prostaglandin synthesis or metabolism in hypertension, but increased renal synthesis of one prostanoid, thromboxane A2, has been noted in spontaneously hypertensive rats and some hypertensive humans. This potent vasoconstrictor may account for the increased renal vascular resistance and suppressed plasma renin activity seen in many patients with hypertension. Increased renal vascular resistance could increase the blood pressure directly as a component of total peripheral resistance or indirectly by increasing glomerular filtration fraction and tubular sodium reabsorption. Specific thromboxane synthesis inhibitors not only decrease renal thromboxane production but also increase renal vasodilator prostaglandin synthesis when prostaglandin synthesis is stimulated. This redirection of renal prostaglandin synthesis toward prostacyclin might be of benefit in correcting a fundamental renal defect in patients with hypertension.     

Patterning of renal cGMP production by the natriuretic peptide receptor type A and blood pressure in spontaneously hypertensive rats

Although important advances have been made over past decades in studying the mechanisms of hypertension, the nature of cellular signaling patterns involved and their relationship remain unclear. High cGMP production rates in isolated renal glomeruli have been presented as a characteristic of spontaneously hypertensive rat (SHR) even before the development of hypertension, which suggests that this event might be a cause of the increase in blood pressure. Using cross-breeding between SHR and WKY parental strains to obtain F1 and F2 hybrids, we have investigated the patterning of high blood pressure and cGMP production rates. We have found that, in the F2 population, the mean blood pressure and both basal and ANP(1-28)-stimulated cGMP production are similar to the parental SHR. In addition, we have found a positive correlation between blood pressure and high cGMP production rates in the F2 population. The higher cGMP production was not a consequence of hypertension, since in DOCA-salt hypertensive rats cGMP production was similar to that observed in normotensive WKY rats. These observations suggest that high cGMP production is a characteristic linked to hypertension. Finally, reciprocal crosses between the SHR and WKY parental strains showed that in the F1 population blood pressure but not cGMP production are associated with the Y chromosome.     

UNILATERAL RENAL DISEASE AND HYPERTENSION

Cure is obtained in about 20 per cent of patients with unilateral renal disease and hypertension who have nephrectomy primarily for relief of hypertension. Carrying out urologic studies on a larger number of hypertensive patients might result in tracing the condition to renal disease in more cases. Renal angiography more accurately indicates renal origin of hypertension than any other diagnostic study. When it can reasonably be established that hypertension is of renal origin, nephrectomy should be performed unless there is some general contraindication to an operative procedure.     

Effect of valsartan on angiotensin II- and vasopressin-degrading activities in the kidney of normotensive and hypertensive rats.

Valsartan, a selective antagonist of angiotensin II at the AT(1) receptor subtype, is an efficacious, orally active, blood pressure-lowering agent used in hypertensive patients. Given that aminopeptidases (APs) play a major role in the metabolism of local peptides involved in blood pressure control, studying them helped us to understand cardiovascular control. We studied the effect of valsartan on angiotensin II- (GluAP) and vasopressin- (CysAP) degrading activities in the kidney in the rat model of renovascular hypertension, Goldblatt two-kidney one-clip. GluAP and CysAP in renal cortex and medulla exhibited different responses to hypertension and valsartan treatment. In the renal cortex, GluAP decreased in clipped and non-clipped kidneys of hypertensive animals. However, while hypertension did not affect GluAP in the clipped kidney medulla, the non-clipped kidney exhibited an increase in soluble and a decrease in membrane-bound activity. Valsartan decreased soluble GluAP in the medulla of normotensive and hypertensive animals. In the renal cortex, CysAP activity was mainly downregulated following hypertension. Valsartan decreased soluble CysAP activity in sham-operated, but not in hypertensive animals. The renal medulla showed a significant valsartan-related decreased activity in clipped and non-clipped kidneys of both sham-operated and hypertensive animals. These results suggest a functional relationship between the AT(1) receptor and vasopressin-degrading activity.