Renal responses to stressful environmental stimuli

The effects of stressful environmental stimuli on urinary sodium excretion in conscious dogs, rats, and humans are reviewed. Environmental stress can increase sympathetic neural outflow and decrease sodium excretion. The antinatriuretic response to environmental stress is accompanied by an unchanged renal blood flow and glomerular filtration rate, which indicates mediation via an increased renal tubular sodium reabsorption. The antinatriuresis resulting from environmental stress is associated with increased renal sympathetic nerve activity, and is abolished by surgical renal denervation. In the central nervous system, but not in the kidney, beta adrenoceptors mediate the increased renal sympathetic nerve activity and antinatriuretic responses to environmental stress. The increased renal sympathetic nerve activity and antinatriuretic responses to environmental stress are greater in spontaneously hypertensive rats (SHR) than in normotensive Wistar-Kyoto (WKY) rats. In SHR, but not WKY rats, the increased renal sympathetic nerve activity and antinatriuretic responses are enhanced by a high-sodium diet. Similarly, stressful competition in human young adult males results in an antinatriuresis only if a positive family history of hypertension is present. Thus, environmental stress can increase renal tubular sodium reabsorption via a central beta-adrenoceptor mechanism with activation of the renal sympathetic nerves in both conscious dogs and SHR. The antinatriuretic response to environmental stress is greater in rats and humans with a genetic predisposition to develop hypertension.     

Interactions of agonists with peripheral alpha-adrenergic receptors

The alpha adrenoceptors may be subdivided based on their anatomical distribution within the synapse. Presynaptic alpha adrenoceptors are generally of the alpha 2 subtype and modulate neurotransmitter liberation via a negative feedback mechanism. Postsynaptic alpha adrenoceptors are usually of the alpha 1 subtype and mediate the response of the effector organ. Although this anatomical subclassification is generally applicable, many exceptions are now known. A more useful classification of alpha-adrenoceptor subtypes is based on a pharmacological characterization in which selective agonists and antagonists are used. Two major classes of alpha-adrenoceptor agonists are known: the phenethylamines, which are structurally related to norepinephrine, and the imidazolines, which are structurally related to clonidine. A number of important differences between these two classes of agonists have been observed and have led to the conclusion that the phenethylamines and imidazolines interact differently with alpha adrenoceptors. Many developments have recently been made in regard to peripheral alpha adrenoceptors in the cardiovascular system. Postsynaptic alpha adrenoceptors in the vasculature represent a mixed population of alpha 1 and alpha 2 adrenoceptors. Both alpha-adrenoceptor subtypes mediate vasoconstriction, but appear to do so through different mechanisms. alpha 1 adrenoceptors also exist in the heart and mediate a positive inotropic response. Renal alpha 1 and alpha 2 adrenoceptors have been identified and subserve a variety of functions such as regulation of renal blood flow, gluconeogenesis, renin release, and sodium and water reabsorption.     

Renal nerves and hypertension: an update

Increased efferent renal sympathetic nerve activity could facilitate the development of hypertension by shifting the arterial pressure-renal sodium excretion curve to the right. Accordingly, interruption of the renal nerves should prevent the development of hypertension in animal models in which increased sympathetic nervous system activity has been implicated. Renal denervation delays the development of hypertension and results in greater sodium excretion in the Okamoto and New Zealand spontaneously hypertensive rat and in the deoxycorticosterone acetate-salt-treated rat, which suggests that these responses result from, at least in part, loss of efferent renal nerve activity. Similar sympathetically mediated renal vasoconstriction has been implicated in the pathogenesis of early essential hypertension in humans. The efferent renal sympathetic nerves play a diminishing role once hypertension is established in these models. Renal denervation in established one-kidney, one-clip and two-kidney, one-clip Goldblatt hypertension in the rat and chronic coarctation in the dog results in an attenuation of the hypertension. The depressor effect of renal denervation in these models is not caused by changes in renin activity or sodium excretion but is associated with decreased sympathoadrenal activity. These findings suggest that the afferent renal nerves contribute to the pathogenesis of renovascular hypertension by enhancing the activity of the sympathetic nervous system. Interruption of afferent renal fibers also appears to be the mechanism by which renal denervation prevents or reverses the normal increase in arterial pressure seen after aortic baroreceptor deafferentation in the rat.     

Effect on renal function and renin secretion of noradrenaline infused into the renal artery.

Effect of noradrenaline on renal function and renin secretion was studied during infusion into the renal artery of anaesthetized dogs. Experiments were performed with or without alpha or beta receptor blockade. Noradrenaline infusion resulted in a significant elevation of renin secretion associated with marked vasoconstriction. Urine flow rate, the filtered and excreted amounts of sodium were diminished due to the decreased GFR. Alpha receptor blockade suppressed renin secretion in the presence of changes in renal haemodynamics. The simultaneous infusion of noradrenaline enhanced renin release without affecting renal haemodynamics or reducing Na-excretion. Following simultaneous inhibition of alpha and beta receptors renin secretion dropped markedly; there were no further changes in either renin secretion or renal haemodynamics upon the simultaneous administration of noradrenaline. Based on the present findings it is suggested that renin secretion is controlled by both alpha and beta receptors. Beta receptor simulation exerts a direct action, whereas alpha stimulation appears to be mediated in part by indirect mechanisms such as renal haemodynamics.     

Renal reflexes in the regulation of blood pressure and sodium excretion

The rich innervation of the kidney is distributed to all structures of renal parenchyma thus providing important anatomical support to the functional evidence that the renal nerves can control kidney functions and send signals on the kidney environment to the central nervous system. Efferent renal nerve fibres are known to influence renal haemodynamics by modifying arteriolar vascular tone, renin release by a direct action on juxtaglomerular cells, and the excretion of sodium and water by changing tubular reabsorption of sodium and water at the different tubular levels. Mechano- and chemo-receptors have been shown in the kidney. Afferent fibres connected with renal receptors convey signals to the central nervous system both at spinal and supraspinal levels. The central areas receiving inputs from the kidney are those involved in the control of cardiovascular homeostasis and fluid balance. Activation of renal receptors by the electrical stimulation of renal afferent fibres were found to elicit both excitatory and inhibitory sympathetic responses. Although the existence of excitatory renorenal reflexes has been suggested, electrophysiological and functional data demonstrate that neural renorenal reflexes exert a tonic inhibitory influence on the tubular sodium and water reabsorption and on the secretion of renin from the juxtaglomerular cells.     

脑室注射高低渗NaCl溶液对血浆肾素活性及肾交感神经活动的影响

第三脑室注射高渗NaCl溶液可引起肾交感神经活动(RSNA)减弱和血浆肾素活性(PRA)降低,低渗NaCl的作用则相反,引起KSNA及PRA升高。PRA和RSNA变化呈一定的正相关,切除肾神经后高、低渗NaCl对PRA的影响减弱或消失,表明脑室内Na~ 浓度改变后主要经肾交感神经的传出通路影响肾素释放。     

Differential sympathetic and angiotensinergic responses in rats submitted to low- or high-salt diet

The present study was designed to evaluate, in Wistar rats, the effect of high- or low-salt diet on the hemodynamic parameters and on the renal and lumbar sympathetic nerve activity. The renal gene expression of the renin angiotensin system components was also evaluated, aiming to find some correlation between salt intake, sodium homeostasis and blood pressure increase. Male Wistar rats received low (0.06% Na, TD 92141-Harlan Teklad), a normal (0.5% Na, TD 92140), or a high-salt diet (3.12% Na, TD 92142) from weaning to adulthood. Hemodynamic parameters such as cardiac output and total peripheral resistance, and the renal and lumbar sympathetic nerve activity were determined (n=45). Plasma renin activity, plasma and renal content of angiotensin (ANG) I and II, and the renal mRNA expression of angiotensinogen, renin, AT1 and AT2 receptors were also measured (n=24). Compared to normal- and low-salt diet-, high-salt-treated rats were hypertensive and developed an increase (P<0.05) in total peripheral resistance and lumbar sympathetic nerve activity. A decrease in renal renin and angiotensinogen-mRNAs and in plasma ANG II and plasma renin activity was also found in salt overloaded animals. The renal sympathetic nerve activity was higher (P<0.05) in low- compared to high-salt-treated rats, and was associated with an increase (P<0.05) in renal ANG I and II and with a decrease (P<0.05) in AT2 renal mRNA. Plasma ANG I and II and plasma renin activity were higher in low- than in normal-salt rats. Our results show that increased blood pressure is associated with increases in lumbar sympathetic nerve activity and total peripheral resistance in high-salt-treated rats. However, in low-salt-treated rats an increase in the renal sympathetic nerve was correlated with an increase in the renal content of ANG I and II and with a decrease in AT2 renal mRNA. These changes are probably in favor of the antinatriuretic response and the sodium homeostasis in the low-salt group.     

Postsynaptic alpha adrenoceptors on vascular smooth muscle

A heterogeneous population of alpha adrenoceptors mediates vasoconstriction in the canine saphenous vein (CSV). Studies with isolated strips of venous smooth muscle incubated with selective alpha-adrenoceptor agonists and antagonists revealed that both alpha 1 and alpha 2 adrenoceptors exist independently in this tissue and both subtypes mediate a contractile response. Measurement of contractile responses in reduced or zero external calcium conditions indicates that stimulation of alpha 1 adrenoceptors induces contractions by influx of extracellular calcium and release of calcium from internal stores. In contrast, 45Ca uptake studies suggest that activation of the postsynaptic alpha 2 adrenoceptor produces vasoconstriction dependent only on influx of extracellular calcium. The influx of calcium produced by the selective alpha 2-adrenoceptor agonist BHT-920 is inhibited by calcium entry blockers. Measurements of transmembrane potentials from smooth muscle cells of the CSV suggest that alpha 1-adrenoceptor activation produces depolarization and contraction (electromechanical coupling) whereas alpha 2-adrenoceptor stimulation does not result in concentration-dependent depolarization of the smooth muscle cells (pharmacomechanical coupling).     

Effects of temperature on alpha adrenoceptors in limb veins: role of receptor reserve

In cutaneous veins of the dog, cooling augments the response to sympathetic nerve stimulation and exogenous norepinephrine (NE). The postjunctional alpha adrenoceptors in this blood vessel belong to both the alpha 1 and alpha 2 subtypes. Cooling augments alpha 2-adrenergic responses (presumably because of an increased receptor affinity), but depresses alpha 1-adrenergic responses (presumably because of a direct inhibitory effect on the contractile process). When agonists of high efficacy such as NE or phenylephrine are used, an alpha 1-adrenoceptor reserve is present that buffers the response from the inhibitory effect of cooling. This allows the potentiating effect of cold on the alpha 2-adrenergic component of the response to catecholamines to predominate, and the contractile response to exogenous NE and sympathetic nerve stimulation is augmented. By contrast, in deep veins of the limb, cold reduces the contractions evoked by alpha 1- and alpha 2-adrenergic activation. This can be explained best by the absence of a receptor reserve for alpha 1-adrenergic agonists of high efficacy, combined with a reduced density of postjunctional alpha 2 adrenoceptors.     

Contribution of cardiopulmonary baroreceptors to the control of the kidney.

The role of cardiopulmonary receptors in the control of renal sympathetic nerve activity and of renin release is reviewed. The evidence indicates that cardiopulmonary receptors with vagal afferents exert a tonic inhibition on both renal nerve activity and on renin release. The magnitude of this inhibition appears directly related to changes in blood volume. Atrial as well as ventricular receptors can influence the secretion of renin. Cardiopulmonary receptors with vagal afferents may also reflexly modulate renal prostaglandin secretion. There is preliminary evidence to suggest that cardiopulmonary receptors with sympathetic afferents can influence renal nerve activity. The limitations of previous studies are outlined and a direction for future studies is suggested. It is concluded that alterations in cardiopulmonary vagal afferent input and the resulting changes in renal nerve activity and in renin release are appropriate for the maintenance of blood volume homeostasis.     

Renorenal reflexes: interaction between efferent and afferent renal nerve activity.

In rats, stimulation of renal mechanoreceptors by increasing ureteral pressure results in a contralateral inhibitory renorenal reflex response consisting of increases in ipsilateral afferent renal nerve activity, decreases in contralateral efferent renal nerve activity, and increases in contralateral urine flow rate and urinary sodium excretion. Mean arterial pressure is unchanged. To study possible functional central interaction among the afferent renal nerves and the aortic and carotid sinus nerves, the responses to renal mechanoreceptor stimulation were compared in sinoaortic denervated rats and sham-denervated rats before and after vagotomy. In contrast to sham-denervated rats, there was an increase in mean arterial pressure in response to renal mechanoreceptor stimulation in sinoaortic-denervated rats. However, there were no differences in the renorenal reflex responses among the groups. Thus, our data failed to support a functional central interaction among the renal, carotid sinus, and aortic afferent nerves in the renorenal reflex response to renal mechanoreceptor stimulation. Studies to examine peripheral interaction between efferent and afferent renal nerves showed that marked reduction in efferent renal nerve activity produced by spinal cord section at T6, ganglionic blockade, volume expansion, or stretch of the junction of superior vena cava and right atrium abolished the responses in afferent renal nerve activity and contralateral renal function to renal mechanoreceptor stimulation. Conversely, increases in efferent renal nerve activity caused by thermal cutaneous stimulation increased basal afferent renal nerve activity and its responses to renal mechanoreceptor stimulation. These data suggest a facilitatory role of efferent renal nerves on renal sensory receptors.     

Nitric oxide inhibition of renal vasoconstrictor responses to sympathetic cotransmitters in the pig in vivo.

The object of the present study was to investigate the involvement of nitric oxide (NO) in the regulation of renal vasoconstrictor responses to sympathetic nerve activation, and each of the known sympathetic cotransmitters separately, in the pig in vivo. Renal vasoconstrictor responses were elicited by sympathetic nerve stimulation, the alpha(1)-adrenoceptor agonist phenylephrine (10 nmol kg(-1), injected iv), neuropeptide Y (NPY, 120 pmol kg(-1), iv) acting on the NPY Y(1) receptor, and the stable ATP-analogue alpha,beta-methylene ATP (mATP, 10 nmol kg(-1)) presumably acting on the P2X(1) purinoceptor. Infusion of the NO-donor sodium nitroprusside, at a dose (0.1 mg kg(-1) h(-1), iv) that elevated renal blood flow (by 14 +/- 7%) and lowered mean arterial pressure (by 30 +/- 5%), inhibited renal vasoconstrictor responses to sympathetic nerve stimulation, phenylephrine, and NPY, but not to mATP. In contrast, injection of the NO synthase inhibitor Nomega-nitro-l-arginine methyl ester, at a dose (10 mg kg(-1), iv) that lowered renal blood flow (by 47 +/- 4%) and elevated mean arterial pressure (by 28 +/- 8%), potentiated the renal vasoconstriction evoked by sympathetic nerve stimulation, phenylephrine, and NPY, but not mATP. It is concluded that endogenous NO may function as an inhibitory modulator of vasoconstrictor responses to the sympathetic cotransmitters norepinephrine and NPY. In contrast, NO seems not to modify vasoconstrictor responses to the sympathetic cotransmitter ATP, a discrepancy that may be due to differences in the types of receptors and intracellular effector mechanisms.     

Effect of alpha-adrenergic stimulation on prostacyclin and renin release in the rat kidney

The relationship between renin secretion and PGI2 production, in response to intrarenal infusion of norepinephrine, was examined in the isolated perfused rat kidney. Infusion of norepinephrine in a dose which caused substantial vasoconstriction (100 ng/min), markedly increased urinary excretion of 6-keto PGF1 alpha, the stable derivative of PGI2, without significantly altering renin secretion measured in the effluent perfusate. No change in urinary 6-keto PGF1 alpha occurred when vasoconstriction was prevented by infusing the alpha-adrenoceptor blocking drug phenoxybenzamine (2 x 10(3) ng/min) alongside norepinephrine (100 ng/min). However, under these conditions there was marked stimulation of renin secretion which, as has been demonstrated previously, is mediated by a beta-adrenoceptor. There were significant increases in urine flow rates during both vasoconstrictor and non-vasoconstrictor infusions. These findings clearly indicate that in the rat kidney prostacyclin production and renin release in response to norepinephrine are dissociated.     

Neural mechanisms in body fluid homeostasis

Under steady-state conditions, urinary sodium excretion matches dietary sodium intake. Because extracellular fluid osmolality is tightly regulated, the quantity of sodium in the extracellular fluid determines the volume of this compartment. The left atrial volume receptor mechanism is an example of a neural mechanism of volume regulation. The left atrial mechanoreceptor, which functions as a sensor in the low-pressure vascular system, is located in the left atrial wall, which has a well-defined compliance relating intravascular volume to filling pressure. The left atrial mechanoreceptor responds to changes in wall left atrial tension by discharging into afferent vagal fibers. These fibers have suitable central nervous system representation whose related efferent neurohumoral mechanisms regulate thirst, renal excretion of water and sodium, and redistribution of the extracellular fluid volume. Efferent renal sympathetic nerve activity undergoes appropriate changes to facilitate renal sodium excretion during sodium surfeit and to facilitate renal sodium conservation during sodium deficit. By interacting with other important determinants of renal sodium excretion (e.g., renal arterial pressure), changes in efferent renal sympathetic nerve activity can significantly modulate the final renal sodium excretion response with important consequences in pathophysiological states (e.g., hypertension, edema-forming states).     

Adrenergic pharmacology of human and canine peripheral veins

A comparison has been made of the factors concerned with the response of canine and human saphenous veins to adrenergic stimulation. Both vessels have prejunctional muscarinic and beta-adrenergic receptors. When activated by appropriate agonists these receptors decrease and increase the output, respectively, of norepinephrine from the nerve endings. Both vessels have postjunctional alpha 1 and alpha 2 adrenoceptors and postjunctional beta adrenoceptors. Activation of the former two receptors leads to contraction of the smooth muscle, and of the latter to relaxation. There are, however, qualitative differences. In the human veins the responsiveness of the prejunctional beta adrenoceptors exceeds that of the postjunctional, whereas the reverse is true in the dog. As a consequence, in the human vein beta-adrenergic agonists augment, and in the canine veins they depress, the contractile response to sympathetic nerve stimulation.     

Cardiac, respiratory, and renal responses to stimulation of the external cuneate nucleus

The cardiac, respiratory, and renal responses of electrical stimulation and microinjection of excitatory amino acids into the external cuneate nucleus were investigated in 57 cats anesthetized with pentobarbital sodium, paralyzed, and artificially ventilated. Trains of rectangular cathodal pulses of 40-100 microA at 50 Hz and 0.1 ms duration were delivered through monopolar glass microelectrodes with a tip diameter of 10-20 micron, filled with indium-Woods metal alloy. Electrical stimulation at 232 histologically identified sites within the external cuneate nucleus could evoke changes in arterial blood pressure, heart rate, and efferent renal sympathetic nerve activity. In a further set of experiments, a change in respiration was observed at 74 identified sites. An increase or decrease in all parameters measured could be elicited at different stimulus sites within the external cuneate nucleus. Repositioning of the electrode (0.2-0.4 mm) in depth or laterally could result in a different response with stimulation. Microinjections of D,L-homocysteic acid or glutamate could mimic the evoked changes in blood pressure, heart rate, efferent renal sympathetic nerve activity, and respiration. This suggests that the external cuneate nucleus contains cell bodies that may modulate components of various cardiac, respiratory and renal reflexes. It is proposed that the external cuneate nucleus may be involved in the integration of somato-autonomic reflex responses.     

Morphological behavior of the renal corpuscle of the garden dormouse during hibernation

We studied 20 garden dormouses (Eliomys quercinus), 10 of which had hibernated. The renal tissue was fixed in Bouin's fluid, embedded in paraffin and sectioned at 7 microns; the sections were stained with azocarmin. These preparations were studied with an optical microscope (Leitz SM-Lux). Hibernation causes an increase in the corpuscular, glomerular and Bowman capsular areas. We thought that this statistically significant increase in the size of the corpuscular structures might be due to the glomerular blood stasis and larger flow of plasma ultrafiltrated towards the capsular space, because of an intense vasoconstriction of the efferent arteriole; this vasoconstriction is due to sympathetic stimulation and renin hypersecretion.     

Renal nerves and nNOS: roles in natriuresis of acute isovolumetric sodium loading in conscious rats

It was hypothesized that renal sympathetic nerve activity (RSNA) and neuronal nitric oxide synthase (nNOS) are involved in the acute inhibition of renin secretion and the natriuresis following slow NaCl loading (NaLoad) and that RSNA participates in the regulation of arterial blood pressure (MABP). This was tested by NaLoad after chronic renal denervation with and without inhibition of nNOS by S-methyl-thiocitrulline (SMTC). In addition, the acute effects of renal denervation on MABP and sodium balance were assessed. Rats were investigated in the conscious, catheterized state, in metabolic cages, and acutely during anesthesia. NaLoad was performed over 2 h by intravenous infusion of hypertonic solution (50 micromol.min(-1).kg body mass(-1)) at constant body volume conditions. SMTC was coinfused in amounts (20 microg.min(-1).kg(-1)) reported to selectively inhibit nNOS. Directly measured MABPs of acutely and chronically denervated rats were less than control (15% and 9%, respectively, P < 0.005). Plasma renin concentration (PRC) was reduced by renal denervation (14.5 +/- 0.2 vs. 19.3 +/- 1.3 mIU/l, P < 0.005) and by nNOS inhibition (12.4 +/- 2.3 vs. 19.6 +/- 1.6 mlU/l, P < 0.005). NaLoad reduced PRC (P < 0.05) and elevated MABP modestly (P < 0.05) and increased sodium excretion six-fold, irrespective of renal denervation and SMTC. The metabolic data demonstrated that renal denervation lowered sodium balance during the first days after denervation (P < 0.001). These data show that renal denervation decreases MABP and renin secretion. However, neither renal denervation nor nNOS inhibition affects either the renin down-regulation or the natriuretic response to acute sodium loading. Acute sodium-driven renin regulation seems independent of RSNA and nNOS under the present conditions.     

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.     

电刺激延髓最后区对血浆肾素活性及肾交感神经...

68 urethan-anesthetized rabbits were prepared for registration of changes of respiration, arterial blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) due to stimulation of area postrema (AP) by rectangular pulse trains each lasting for 4 s for every 30 s. During 40 min of such a stimulation paradigm the venous blood samples were collected for radioimmunoassay of plasma renin activity (PRA) (both pre- and post-stimulation), RSNA registered and processed by a computer. Animals were divided into three groups: (1) with AP stimulation only (n = 47); (2) AP stimulation after bilateral renal denervation (n = 13); (3) AP stimulation after propranolol injection (n = 8). In Group I, a 91% increase in PRA, an augmentation of RSNA, a rise of BP and a decrease of HR were observed, while respiration did not show obvious change. In Group II, hemodynamic and RSNA response was similar to that in Group I, but PRA was not changed significantly. In Group III, the effects on BP, HR, respiration and RSNA showed no remarkable changes compared with Group I, but significant inhibition of the response of PRA [from 0.65 +/- 0.07 ng/(ml.h-1) to 0.72 +/- 0.10 ng/(ml.h-1), P > 0.05] was observed. The results mentioned above suggested that electrical stimulation of AP may induce an increase in renin release and renal sympathetic nerve activity and hemodynamic changes in rabbits.