Role of nitric oxide in the neural control of cardiovascular function

The discovery in 1990 that nitric oxide (NO) acts as a neuromodulator within the central and peripheral nervous system triggered intensive research which considerably extended our understanding how this factor regulates cardiovascular functions. In addition to its direct effects on blood vessels NO has additional targets at all levels of the neural control of circulation. When not scavenged by hemoglobin, NO is relatively stable and diffuses over large distances (> 500 microns) so that one NO-producing cell can influence several thousands of adjacent cells in vivo. In different brain regions, NO and its metabolites have excitatory as well as inhibitory effects. The modulation of autonomic functions by these factors is therefore highly complex and often variable between the different levels from the brain to postganglionic nerve endings. This review is focused on the available evidence derived from animal studies and will summarize the current discussion about (i) the modulation of the generation of sympathetic and parasympathetic activities within the brain stem by NO; (ii) the actions of NO on cardiovascular reflexes and (iii) the role of NO as a modulator of autonomic functions within the target organs. Finally, the available evidence from human studies and some pathophysiological implications of altered NO-mediated modulation of the neural control of circulation will be discussed.     

Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics

Mutations in the endothelial nitric oxide synthase (eNOS) gene may be associated with abnormal nitric oxide (NO) production and cardiovascular diseases. In this study, we investigated the prevalence of two eNOS polymorphisms, the Glu298Asp variant on exon 7, and the 4a/b variable number of tandem repeats (VNTR) on intron 4, and their association with blood pressure (BP), NO production, salt sensitivity and cardiovascular risk factors in healthy Venezuelans. The prevalence of both polymorphisms in Venezuelans was comparable to that described for Caucasians, but significantly different from that known for African-Americans and Japanese. The 4a/b genotype was associated with reduced levels of NO metabolites (25% decrease), larger BP lowering in response to salt restriction (9.0 vs 4.8 mmHg, P<0.05), greater prevalence of salt sensitivity (39% in 4a/b and 27% in 4b/b; P<0.05) and with higher LDL-cholesterol levels. The Glu298T polymorphism did not affect NO production, nor it was associated with salt sensitivity. Glu298Asp polymorphism was positively associated with higher weight, triglycerides and LDL-cholesterol. Neither polymorphism was associated with changes in fasting or postload serum glucose, BP, obesity and albuminuria. In conclusion, the prevalence of eNOS polymorphisms is strongly determined by ethnic factors. The 4a/b gene polymorphism could be a genetic susceptibility factor for the BP response to salt intake and for the genetic control of NO production. The reduced NO production in subjects with the 4a/b genotype may be responsible for the increased sensitivity of their BP to salt.     

Role of nitric oxide in the control of the hypothalamic-pituitary-adrenocortical axis

Zusammenfassung Ebenso wie in Endothelzellen und Makrophagen wird Stickoxid (NO) im Zentralnervensystem von Neuronen, die durch Glutamat über den ionotropen N-methyl-D-aspartate (NMDA)-Rezeptor erregt werden, in einer komplexen Reaktion von Stickoxidsynthase (NOS) aus L-Arginin synthetisiert. Nach Diffusion in den extraneuronalen Raum vermag NO in anderen Neuronen, die in der Regel keine NOS enthalten, die Guanylatzyklase zu stimulieren, wodurch je nach intrazellulärer Ausstattung mit Targetmolekülen des cGMP die neuronale Erregbarkeit verstärkt oder abgeschwächt wird. Eine weitere wichtige Eigenschaft des NO liegt in seiner Fähigkeit benachbarte Sulfhydryle (Thiole) zu Disulfiden zu oxidieren. Da die Öffnung des Ca²⁺-Ionen-Kanals des NMDA-Rezeptors neben anderen Rezeptoren über freie Thiolgruppen gesteuert wird, übt NO durch deren Oxidation zu Disulfiden eine hemmende Wirkung auf die glutamaterge Übertragung aus. Immunhistochemische Studien haben in nahezu allen Kerngebieten des Hypothalamus eine Koexistenz von NOS mit den entsprechenden Peptiden in zahlreichen Releasing-Hormon-produzierenden Neuronen nachgewiesen. Diese Ergebnisse lassen den Schluss zu, dass NO über den redoxsensitiven Mechanismus des NMDA-Rezeptors die Neurosekretion generell modulierend beeinflusst und über Corticotropin-Releasing-Hormon(CRH)-produzierende Neurone speziell die Steuerung der Hypothalamus-Hypophysen-Nebennierenrinden-Achse moduliert. Diese hemmende Wirkung von NO und CRH-Neurone ist um so mehr von Bedeutung, weil eine erhöhte Sekretion suprarenaler Glukokortikoide im Zentralnervensystem die glutamaterge Neurotransmission verstärkt, zum einen durch gesteigerte de novo Synthese von NMDA-Rezeptoren, und zum anderen durch die Blockade der präsynaptischen Wiederaufnahme von Glutamat. Summary The gaseous radical nitric oxide (NO) is catalyzed by conversion of L-arginine to L-citrulline by one cytokine inducible form (iNOS), which becomes active only within hours after the inducing event, and by two constitutively expressed forms, endothelial (eNOS) and neuronal (nNOS), which are regulated by the cytosolic concentration of free Ca²⁺. Brain nNOS is physiologically present in discrete populations of neurons, which are all excited by glutamate via the ionotropic N-methyl-D-aspartate (NMDA) receptor, which controls a Ca²⁺ channel. After its diffusion into the extraneuronal space, NO may activate in neurons, which as a rule do not stain for NOS, soluble guanylyl cyclase and formation of cGMP as an intracellular messenger. Beyond that, NO is important as a feedback regulator of glutamatergic excitation. NO as a nitrosylating agent enhances disulfide bonding of vicinal sulfhydryl (thiol) groups of the redox modulatory site of the NMDA receptor complex and thereby down-regulates its Ca²⁺ channel activity. Histochemically studies have revealed the presence of large number of NOS containing neurons in the magnocellular and parvocellular subdivisions of hypothalamic nuclei. Numerous studies conform to the view that NO participates in the control of many different neurosecretory processes, especially of the corticotropin-releasing hormone (CRH) neurosecretory system. The redox-modulatory site of the NMDA receptor appears, therefore, as a critical structure in the control of the hypothalamic-pituitary-adrenocortical (HPA) axis. Moreover, glucocorticoids augment neuronal excitotoxicity by increasing the expression of glutamate receptors and inhibition of glutamate reuptake. In attempting to explain the many conflicting results obtained in studies with NO, it may be worthwhile to consider that the actual redox-environment of distinct loci of the brain may determine the final function of NO, acting either as a transmitter or neuromodulator or, in the worst case, causing neurodestruction. It seems likely that any kind of stress by altering the ratio of reduced vs oxidized thiols within the central nervous system influences neuronal excitability, with NO working either as an amplifier or as a feedback regulator of neuronal excitation or inhibition, which may alter acutely or chronically, among others, the homeostasis of a given neurosecretory system.     

Nitric oxide and salt sensitivity

Studies in laboratory animals suggest that altered nitric oxide (NO) production may be associated with salt sensitivity. In this investigation we determined whether the endogenous NO production was altered in salt-sensitive human subjects when salt intake was changed. Salt sensitivity was assessed from the magnitude of the blood pressure (BP) lowering obtained when the salt intake was reduced from high to a low intake. The combined urinary excretion of nitrites and nitrates, the major metabolites of NO, was employed as an index of endogenous NO production. Salt-sensitive subjects (n = 23) were older, heavier, and had greater waist-to-hip ratios and higher baseline BP than salt-resistant individuals (n = 25). In salt-sensitive subjects, mean blood pressure (MBP) decreased 11.8+/-0.7 mm Hg, and NO metabolite excretion increased from 823+/-102 to 1530+/-148 mmol/24 h, when salt intake was reduced from 316 to 28 micromol/day. NO metabolite excretion was 45% lower during high salt (0.66+/-0.1 micromol/mg creatinine) than during low salt intake (1.12+/-0.1 micromol/mg creatinine) (P < .001). In contrast, when salt intake was reduced, salt-resistant subjects exhibited no significant mean changes in BP or NO metabolite excretion. During low salt intake, NO metabolite excretion (micromol/ day) was significantly higher in salt-sensitive individuals. The magnitude of decrease of systolic blood pressure, diastolic blood pressure, or MBP induced by reducing salt intake was not related to the increase in urinary excretion of NO metabolite levels (r2 = 0.009; P = .66). In summary, to the extent that urinary NO metabolite levels reflect the activity of the endogenous NO system, our results support the view that salt sensitivity may in part be determined by an inability to increase or to sustain NO production in response to high salt. Insufficient NO production during high salt may in turn lead to altered pressure-natriuresis relationships and to an increase in BP. The possibility that the increase in BP induced by high salt intake in salt-sensitive individuals could be the key factor in reducing NO metabolite levels can not be ruled out.     

Superoxide contributes to development of salt sensitivity and hypertension induced by nitric oxide deficiency

This study was performed to examine the role of superoxide (O2-) in the development of salt sensitivity and hypertension induced by inhibition of nitric oxide (NO) generation. Male Sprague-Dawley rats were fed with diet containing either normal salt (NS) (0.4% NaCl) or high salt (HS) (4% NaCl). These rats were treated with or without an NO synthase inhibitor, nitro-L-arginine methylester (L-NAME) (15 mg/kg/d) and O2- scavenger, tempol (30 mg/kg per day) in the drinking water for 4 weeks. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography and urine collection was performed during the course of experimental periods. At the end of 4 weeks, L-NAME treatment resulted in greater increases in SBP in HS rats (127+/-2 to 172+/-3 mm Hg; n=8) than in NS rats (130+/-2 to 156+/-2 mm Hg; n=9). Co-administration of tempol with L-NAME markedly attenuated these SBP responses to a similar level in both HS (128+/-3 to 147+/-2 mm Hg; n=8) and NS rats (126+/-2 to 142+/-3 mm Hg; n=8). Urinary 8-isoprostane excretion (UIsoV) increased in response to L-NAME treatment that was higher in HS (10.6+/-0.5 to 21.5+/-0.8 ng/d) than in NS rats (10.8+/-0.7 to 16.9+/-0.6 ng/d). Co-treatment with tempol completely abolished these UIsoV responses to L-NAME in both HS and NS rats but did not alter urinary H2O2 excretion rate. The decreases in urinary nitrate/nitrite excretion in response to L-NAME treatment were not altered by co-administration of tempol in both HS and NS rats. These data suggest that enhancement of O2- activity during NO inhibition contributes to the development of salt sensitivity that is associated with NO-deficient hypertension.     

一氧化氮和一氧化氮合酶与肿瘤放疗敏感性的关系

一氧化氮(nitricoxide,NO)的生物学作用具有复杂性和多样性,在基础条件下诱导型一氧化氮合酶(induciblenitricoxidesynthase,iNOS)活性很低,当机体遭受微生物内外毒素、炎症介质等刺激时iNOS可诱导合成大量的NO.肿瘤生物学上一般认为高水平的NO对肿瘤细胞具有直接的细胞毒作用,而较低水平的NO具有生长刺激作用.多种试验显示NO的供体能增加肿瘤的放疗敏感性.研究认为,NO的生物学作用可能是通过p53依赖途径介导的.调节NO杀灭肿瘤或促进肿瘤生长,p53起到关键性的作用.已有多种药品作为放射敏化剂,NO供体药物在体内给药可能导致系统低血压,增加肿瘤血液灌注和氧合作用,具有潜在的促进肿瘤生长的作用,限制了其临床使用.直接将iNOS基因转染入肿瘤细胞内,肿瘤内的乏氧环境,可降低iNOS的活性而影响NO的产量.携带iNOS基因的腺病毒(adenoviralvectorcarryingtheiNOScDNA,AdiNOS)转染靶细胞导致iNOS过表达,产生大量NO,有望成为一种增加肿瘤放疗敏感性有效可行的方法.     

一氧化氮在糖尿病性肾病中的变化及其临床意义

目的探讨一氧化氮（ＮＯ）在糖尿病性肾病（ＤＮ）中的变化规律及其与肾功能的关系。方法检测５４例糖尿病（ＤＭ）患者血清ＮＯ稳定代谢产物亚硝酸盐（ＮＯ２）与血浆内皮素（内皮缩血管肽，ＥＴ）的水平，并与２０例正常人进行比较。结果正常白蛋白尿和微量白蛋白尿糖尿病患者血清ＮＯ均显著高于正常人和大量白蛋白尿患者（Ｐ＜０．０１），ＮＯ与病程、血清尿素氮、血肌酐、血浆ＥＴ水平呈负相关，与肾小球滤过率呈正相关。结论提示ＤＭ早期高ＮＯ生成与肾小球高滤过有关，晚期低下的ＮＯ水平可能促进ＤＮ发展；ＮＯ与ＥＴ之间可能存在互相制约、动态平衡的关系，平衡紊乱与ＤＮ的发生、发展有关     

Role of nitric oxide in control of prolactin release by the adenohypophysis.

Nitric oxide synthase-containing cells were visualized in the anterior pituitary gland by immunocytochemistry. Consequently, we began an evaluation of the possible role of NO in the control of anterior pituitary function. Prolactin is normally under inhibitory hypothalamic control, and in vitro the gland secretes large quantities of the hormone. When hemipituitaries were incubated for 30 min in the presence of sodium nitroprusside, a releaser of NO, prolactin release was inhibited. This suppression was completely blocked by the scavenger of NO, hemoglobin. Analogs of arginine, such as NG-monomethyl-L-arginine (NMMA, where NG is the terminal guanidino nitrogen) and nitroarginine methyl ester, inhibit NO synthase. Incubation of hemipituitaries with either of these compounds significantly increased prolactin release. Since in other tissues most of the actions of NO are mediated by activation of soluble guanylate cyclase with the formation of cyclic GMP, we evaluated the effects of cyclic GMP on prolactin release. Cyclic GMP (10 mM) produced an approximately 40% reduction in prolactin release. Prolactin release in vivo and in vitro can be stimulated by several peptides, which include vasoactive intestinal polypeptide and substance P. Consequently, we evaluated the possible role of NO in these stimulations by incubating the glands in the presence of either of these peptides alone or in combination with NMMA. In the case of vasoactive intestinal polypeptide, the significant stimulation of prolactin release was augmented by NMMA to give an additive effect. In the case of substance P, there was a smaller but significant release of prolactin that was not significantly augmented by NMMA. We conclude that NO has little effect on the stimulatory action of these two peptides on prolactin release. Dopamine (0.1 microM), an inhibitor of prolactin release, reduced prolactin release, and this inhibitory action was significantly blocked by either hemoglobin (20 micrograms/ml) or NMMA and was completely blocked by 1 mM nitroarginine methyl ester. Atrial natriuretic factor at 1 microM also reduced prolactin release, and its action was completely blocked by NMMA. In contrast to these results with prolactin, luteinizing hormone (LH) was measured in the same medium in which the effect of nitroprusside was tested on prolactin release, there was no effect of nitroprusside, hemoglobin, or the combination of nitroprusside and hemoglobin on luteinizing hormone release. Therefore, in contrast to its inhibitory action on prolactin release NO had no effect on luteinizing hormone release. Immunocytochemical studies by others have shown that NO synthase is present in the folliculostellate cells and also the gonadotrophs of the pituitary gland. We conclude that NO produced by either of these cell types may diffuse to the lactotropes, where it can inhibit prolactin release. NO appears to play little role in the prolactin-releasing action of vasoactive intestinal polypeptide and substance P, but mediates the prolactin-inhibiting activity of dopamine and atrial natriuretic factor.     

Effects of lifestyle changes and metformin on salt sensitivity and nitric oxide metabolism in obese salt-sensitive Hispanics

Salt sensitivity is associated with obesity, and increased cardiovascular morbidity and mortality. We investigated whether treatment of obesity and its associated metabolic abnormalities corrects salt sensitivity and restores impaired nitric oxide (NO) metabolism characteristic of salt sensitivity. Twenty, otherwise, healthy obese salt-sensitive subjects completed a 12-month program of caloric restriction, aerobic exercise and metformin. Two salt sensitivity tests were performed, that is at baseline and end of program. Lifestyle-metformin treatment decreased weight (9.8+/-0.3 kg), body mass index (3.9+/-0.2 kg/m(2)), waist (11.5+/-0.5 cm), systolic blood pressure (SBP) (8.6+/-0.4 mm Hg), diastolic blood pressure (DBP) (5.5+/-0.4 mm Hg), triglyceride (40+/-5 mg/dl), fasting (8.3+/-1 microIU/ml) and post-load (20+/-4 microIU/ml) insulin levels, and salt sensitivity. Going from a high-sodium ( approximately 300 mmol) to a low-sodium diet ( approximately 30 mmol of sodium/day) lowered SBP/DBP by 14.7+/-1.7/7.4+/-0.9 mm Hg at baseline and by 8.6+/-1.9/3.2+/-1.2 mm Hg after treatment (P<0.001). More importantly, blood pressure (BP) sensitivity to customary levels of dietary salt ( approximately 150 mmol of sodium/day) was abolished by the lifestyle-metformin treatment. Differences in SBP/DBP between usual and low salt averaged 11+/-1/8+/-1 mm Hg before treatment, and 3+/-1/1+/-0.5 mm Hg after treatment (P<0.001). At baseline, NO-metabolite excretion was inhibited during high salt; this impairment was corrected by the lifestyle-metformin treatment. In conclusion, acquired correctable factors play an important role in the pathogenesis of salt sensitivity associated with obesity. Correction of salt sensitivity may account for the BP lowering induced by weight reduction. Restoration of the inability to increase or sustain NO production in response to high salt could account for the correction of salt sensitivity induced by the lifestyle-metformin treatment.     

Interaction between nitric oxide and endogenous vasoconstrictors in control of renal blood flow

The level of renal blood flow (RBF) is controlled by opposing vasoconstrictor and vasodilator influences. In a recent investigation in normotensive dogs, we found that combined blockade of endothelin type A (ET(A)) receptors and angiotensin II formation induces marked increases in RBF that were much larger than the effects of blocking either system alone. The aim of the present study was to determine the contribution of nitric oxide (NO) to this vasodilator response. Experiments were made in 6 conscious, chronically instrumented dogs subjected to 5 different experimental treatments on separate days. Blockade of ET(A) receptors alone by the selective antagonist LU 135252 had only minor effects on RBF compared with time-control experiments. Additional blockade of angiotensin II formation by angiotensin-converting enzyme inhibition with trandolaprilat caused a substantial increase of RBF by approximately 50%. This vasodilation was entirely suppressed when NO formation was prevented by inhibition of NO synthase with N(G)-nitro-L-arginine methyl ester HCl. However, when during NO synthase inhibition renal vascular NO concentrations were clamped at control levels by infusing the NO donor S-nitroso-N-acetyl-D, L-penicillamine, the vasodilator response to combined blockade of ET(A) receptors and angiotensin II formation was completely restored (DeltaRBF approximately 60%). These results indicate that the vasodilation after combined ET(A) receptor blockade and angiotensin-converting enzyme inhibition is not mediated by an increase in NO release but results from the unmasking of the tonic influence that is normally exerted by constitutively released NO. Accordingly, the tonic activity of endothelial NO synthase appears to be of major importance in the physiological regulation of renal vascular resistance by determining the vasomotor responses to endothelin and angiotensin II.     

Role of nitric oxide in modulating the chronic renal and arterial pressure responses to angiotensin II

The purpose of this study was to determine long-term role of nitric oxide in modulating the chronic renal and arterial pressure responses to angiotensin II (AII). In normal dogs, intrarenal AII infusion (1.0 ng/kg/min) decreased renal plasma flow (RPF) by 31% and glomerular filtration rate (GFR) by 17% and increased mean arterial pressure (MAP) by 22%. In dogs with chronic intrarenal NO synthesis blockade with N^ω-nitro-l-arginine methyl ester (3 μg/kg/min), AII decreased RPF by 25% and GFR by 19%, and increased MAP by 7%. These data indicate that chronic inhibition of NO synthesis within the kidney attenuated the long-term renal and arterial pressure responses to AII in dogs.     

Role of nitric oxide in the control of cerebral microcirculation under physiological and pathological conditions

Effect of nitric oxide (NO) on vasomotor tone of cerebral parenchymal arterioles was studied in rats. Then, the role of NO was clinically investigated in the pathogenesis of progressive cerebral vascular occlusive disease, moyamoya disease. In rat, the cerebral arterioles, about 30-60 microm in diameter, were dilated by L-arginine, a precursor of NO, at concentrations as low as 0.1 micromol with maximal dilation of 14% at 100 micromol. The arterioles were constricted by N(G)-monomethyl-L-arginine (L-NMMA), a NO synthesis inhibitor. Superoxide dismutase, which seems to protect NO from inactivation, increased sensitivity of L-arginine. Compared with control specimens of cerebral spinal fluid (CSF) obtained from 16 patients, concentrations NO metabolites in the CSF of 23 patients with moyamoya disease were significantly higher. NO metabolites concentrations obtained during initial surgery decreased during a second, contralateral procedure. NO plays an important role in the regulation of basal tone of cerebral parenchymal arterioles and contributes to the increase in collateral circulation in cerebral occlusive disease like moyamoya disease. Vascular bypass surgery can reduce NO metabolites together with abnormal collateral circulation.     

Role of angiotensin II in the neural control of renal function

The aim of the present study was to distinguish between the direct effects of the renal nerves on renal function and indirect effects via neurally mediated increased systemic angiotensin II. We applied low-level electrical stimulation (1 Hz) to the left renal nerves in pentobarbitone-anesthetized rabbits for 180 minutes and measured renal blood flow, sodium excretion, and urine flow rate from both the stimulated and the nonstimulated contralateral kidney in the presence and the absence of ACE inhibition (enalaprilat). Stimulation resulted in an angiotensin II-mediated rise in arterial pressure and decreases in renal blood flow, urine flow rate, and sodium excretion on the stimulated side. On the nonstimulated denervated side, we found no change in renal blood flow, but found a decrease in urine flow rate. With ACE inhibition, renal stimulation no longer caused an increase in arterial pressure, the antidiuretic responses of the stimulated kidney were attenuated, and, importantly, the decrease in urine flow rate on the nonstimulated kidney was completely abolished. We therefore propose that although a direct effect of the renal nerves on sodium excretion is clearly present, the antidiuresis and antinatriuresis observed during renal activation is further supported by a neurally mediated increase in systemic angiotensin II.     

Alpha-adducin polymorphism, salt sensitivity, nitric oxide excretion, and cardiovascular risk factors in normotensive Hispanics

BACKGROUND: Genetic and environmental factors determine the blood pressure (BP) response to changes in salt intake. Mutations in the alpha-adducin gene may be associated with hypertension and salt-sensitive hypertension. We investigated whether one alpha-adducin polymorphism, the Gly460Trp (G/T) variant, was associated with salt sensitivity, nitric oxide (NO) production; and cardiovascular risk factors in healthy adult normotensive Venezuelans. METHODS AND RESULTS: Subjects (n = 126) were screened for salt sensitivity. The alpha-Adducin polymorphism was tested in salt-sensitive (SS) and salt-resistant (SR) subjects. The G/T and G/G (wild gene) groups had similar BP levels. The G/T subjects had higher LDL-cholesterol (P =.01) and postload glucose AUC (P =.03) than G/G individuals. Genotype frequencies were not associated with BP or salt sensitivity (G/G, 38.1% SS and 61.9% SR vs G/T, 40.7% SS and 59.3% SR). Shifting from high salt to low salt diet produced comparable reductions in systolic BP and diastolic BP in G/T and G/G groups. The G/G and G/T groups excreted similar amounts of sodium on high and low salt diets. The SR subjects carrying the wild or the mutated gene showed no changes in NO metabolite excretion at different levels of salt intake. In SS subjects, the level of NO metabolite excretion was highly dependent on salt intake. A combination of SS and 460Trp mutation enhanced the sodium-dependent modulation of NO production. CONCLUSIONS: In normotensive Venezuelans, the alpha-adducin G/T polymorphism was not associated with BP, salt sensitivity, or with sodium excretion during sodium loading or restriction. G/T was associated with increased LDL-cholesterol and postload glucose levels. In SS, G/T was associated with greater salt-dependent modulation of NO excretion. However, this larger increase in NO excretion was not associated with a larger decrease in BP.     

Proximal tubular function and salt sensitivity

Blood pressure response to changes in dietary salt intake is highly variable among individuals. This heterogeneity results from the combined effects of genetic and environmental determinants. In recent years, considerable progress has been made in our understanding of the pathogenic mechanisms leading to the development of salt-sensitive hypertension. Much information has come from the investigation of rare monogenic forms of salt-sensitive hypertension, which has focused attention on alterations of renal sodium handling occurring essentially in the distal nephron. In this paper, we review the experimental, clinical, genetic, and epidemiologic evidence suggesting that proximal tubular function is also an important determinant of the blood pressure response to salt, which deserves greater attention.