Renal and vascular oxidative stress and salt‐sensitivity of arterial pressure

Oxidative stress occurs in a tissue or in the whole body when the total oxidant production exceeds the antioxidant capacity. Recent studies in human essential hypertension indicate that free radical production is increased and antioxidant levels are decreased, and more than one‐half of these hypertensives have a salt‐sensitive type of hypertension with progressive renal damage. Increased oxidative stress may also play a critical role in animal models of salt‐sensitive hypertension. The stroke‐prone spontaneously hypertensive rats (SHRSP) exhibits salt‐sensitivity, vascular release of superoxide is increased, and total plasma antioxidant capacity is decreased. The superoxide release in the SHRSP rats inactivates nitric oxide, and superoxide dismutase (SOD) administration returns the bioactive nitric oxide levels to normal. The deoxycorticosterone acetate (DOCA)‐salt hypertensive rat is salt‐sensitive, aortic superoxide production is increased, and renal inflammation is significant. Treatment of the DOCA‐salt rats with apocynin, an NADPH oxidase inhibitor, decreased aortic superoxide production and decreased arterial pressure. The Dahl salt‐sensitive (S) rat has increased mesenteric microvascular and renal superoxide production and increased plasma levels of H₂O₂. The renal protein expression of SOD is decreased in the kidney of Dahl S rats, and long‐term administration of Tempol, a superoxide mimetic, significantly decreased arterial pressure and renal damage. In conclusion, both human hypertension and experimental models of salt‐sensitive hypertension have increased superoxide release, decreased antioxidant capacity and elevated renal damage.     

Interactions between nitric oxide and superoxide on the neural regulation of proximal fluid reabsorption in hypertensive rats

This study investigated the role of nitric oxide (NO) and superoxide anions in modulating the renal nerve-dependent increases in proximal tubular fluid reabsorption (Jva). Renal nerve stimulation at 0.75 and 1.0 Hz (15 V, 0.2 ms) in anaesthetized Wistar rats had no effect on glomerular filtration rate but decreased urine flow and sodium excretion in a frequency-related manner, reaching 39 and 49% at 1.0 Hz, respectively (P < 0.01) and increased Jva by 11 and 31% (P < 0.01). In the stroke prone spontaneously hypertensive rats (SHRSP), basal mean blood pressure was higher (123 +/- 2 versus 99 +/- 2 mmHg, P < 0.001), glomerular filtration rate, urine flow, sodium excretion and proximal tubular fluid reabsorption (Jva) were lower (all P < 0.001) than in the Wistar rats. Renal nerve stimulation in the SHRSP did not change glomerular filtration rate but decreased urine flow, and sodium excretion by 18 and 34% (P < 0.05) at 1.0 Hz which was less (P < 0.05) than that in the Wistar rats. Under these conditions, Jva was increased at 0.75 Hz by 27%, and to a comparable extent at 1.0 Hz, which was a pattern very different from the frequency related rises reported in the Wistar rats. In the SHRSP, intratubular Nomega-nitro-L-arginine methyl ester (L-NAME) had no effect on baseline Jva or the pattern of response to renal nerve stimulation which contrasted with earlier reports in the Wistar rat. Intraluminal superoxide dismutase (SOD) had no effect on basal Jva in the Wistar rats but increased it in the SHRSP (P < 0.05) while the pattern of change in Jva during nerve stimulation was unaltered in both rat strains. By contrast, in the SHRSP, intraluminal sodium nitroprusside (SNP) resulted in a frequency related increase in Jva comparable to that obtained in the vehicle treated Wistar rats. These data suggest that in the hypertensive rats, superoxide anion production is raised which depresses Jva and interacts with NO preventing a normal Jva response to renal nerve stimulation.     

Dysfunction of paracellin-1 by dephosphorylation in Dahl salt-sensitive hypertensive rats

A high-salt diet reduced the levels of renal cAMP content and serine-phosphorylated paracellin-1 in Dahl salt-sensitive hypertensive rats. In MDCK cells expressing paracellin-1, protein kinase A inhibitor reduced the serine-phosphorylated paracellin-1 and transepithelial Mg(2+) transport, suggesting that a dephosphorylation of paracellin-1 induces the reduction of Mg(2+) reabsorption in salt-sensitive hypertension.     

Long-term blood pressure control prevents oxidative renal injury

Arterial hypertension is a leading contributor to the progression of chronic renal disease. Short-term studies had addressed the role of oxidative stress in hypertensive nephropathy. We have now studied oxidative stress and caspase activation in a long-term model of hypertensive renal injury. Nontreated spontaneously hypertensive rats with uninephrectomy displayed severe arterial hypertension over a 36-week follow-up. Uncontrolled high blood pressure in the context of modest renal mass reduction resulted in significant histological renal injury. Blood pressure control by the angiotensin-converting enzyme (ACE) inhibitor, quinapril, or the AT1 receptor antagonist, losartan, decreased the degree of renal injury. Hypertensive renal injury was associated with evidence of activation of the apoptotic pathway (increased activation of caspase-3) and local renal (increased staining for 4-hydroxy-2-nonenal) and systemic [increased serum levels of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha)] lipid oxidation when compared with normotensive control rats. In addition, severe hypertension decreased the renal antioxidant defenses, as exemplified by decreased expression of Cu/Zn superoxide dismutase. Treatment with quinapril or losartan decreased caspase-3 activation, 4-hydroxy-2-nonenal staining, and 8-iso-PGF2alpha levels and increased Cu/Zn superoxide dismutase expression. These results suggest that hypertension-associated oxidative stress and its consequences may be decreased by either ACE inhibition or AT1 receptor antagonist, emphasizing the role of angiotensin II in hypertensive renal damage.     

Gender differences in endothelial function and inflammatory markers along the occurrence of pathological events in stroke-prone rats

Spontaneously hypertensive stroke-prone rats (SHRSP) feature an established model for human cerebrovascular disease. SHRSP, kept on a high-salt permissive diet (JPD), develop hypertension, renal and brain damage. In this report we compared the behavior of female and male SHRSP regarding the main aspects of their pathological condition. Brain abnormalities, detected by magnetic resonance imaging, developed spontaneously in males after 42+/-3 days, in females after 114+/-14 days from the start of JPD. Survival was >3-fold longer for females than for males. The development of brain damage was preceded, in both genders, by an inflammatory condition characterized by the accumulation in serum and urine of acute-phase proteins. The increase in thiostatin level was significantly lower and delayed in female in comparison to male SHRSP. During JPD female and male SHRSP developed massive proteinuria, its worsening being significantly slower in females. The alterations of vasculature-bound barriers in kidney and brain were connected with endothelial dysfunction and relative deficiency in nitric oxide (NO). In thoracic aortic rings, basal release of NO was significantly higher in female than in male SHRSP, both if receiving and if not receiving JPD. The gender differences in SHRSP thus appear to be connected to a more efficient control in females of inflammation and of endothelial dysfunction.     

Superoxide dismutase reduces the impairment of endothelium-dependent relaxation in the spontaneously hypertensive rat aorta.

The involvement of the superoxide anion in endothelium-dependent relaxation (EDR) was examined in noradrenaline-contracted aortic smooth muscle preparations isolated from normotensive Wistar Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Acetylcholine (ACh, 10(-9)-10(-5) M) induced EDR in both WKY and SHRSP preparations in a concentration-dependent manner, but with a significantly smaller amplitude in those from SHRSP than in those from WKY. The ACh-induced EDR was inhibited by N(omega)-nitro-L-arginine (L-NOARG), in a concentration-dependent manner, both in WKY and SHRSP. The EDR produced in WKY in the presence of 3 x 10(-6) M L-NOARG was similar in magnitude to that produced in SHRSP in the absence of L-NOARG. Superoxide dismutase (SOD, 300 units/ml) increased the amplitude of EDR in SHRSP but not in WKY, with no alteration of the threshold or of the maximal amplitude. The maximal amplitude of EDR produced in SHRSP in the presence of SOD was still smaller than that in WKY. In WKY, a possible involvement of superoxide in the EDR was examined in aortae whose EDR was partially inhibited by treatment with a subthreshold concentration (3 x 10 (-6) M) of L-NOARG. In the L-NOARG-conditioned aorta, the reduced EDR was partially but significantly recovered by SOD. These results suggest that the impaired EDR in aortae of SHRSP may be causally related to a higher production of superoxide. The L-NOARG-induced inhibition of EDR in WKY may be produced, in part, by the reduction of effective NO due to its destruction by superoxide.     

Regulation of glomerular angiotensin II receptor densities in renovascular hypertension: response to reduced sympathetic and vasopressin influence.

The regulation of the density of angiotensin II receptors in renal glomeruli in response to changes in salt intake is altered in Sprague-Dawley rats with renovascular hypertension due to aortic constriction, and in hypertensive salt-sensitive Dahl rats (Sahlgren 1989, Sahlgren & Aperia 1989). This study examines the modulatory role of sympathetic activity and arginine-vasopressin on angiotensin II receptors in hypertensive Sprague-Dawley rats with aortic constriction as well as in normotensive control rats. Denervation of the left kidney caused a 50% increase in the glomerular angiotensin II receptor density in the denervated kidney in both hypertensive rats and normotensive controls. An even more marked increase in glomerular receptor density occurred in both hypertensive rats and controls after blocking the sympathetic nervous system with guanethidine. To block the effects of arginine-vasopressin we used a blocker of the V1-receptors (predominant in vessels) and found an approximately 100% increase in the glomerular receptor density of angiotensin II in rats with aortic constriction. There was no reduction in blood pressure. Thus, on the receptor level the renin-angiotensin system is markedly influenced by the activity of other major pressor systems.     

Regulation of glomerular angiotensin II receptor densities in renovascular hypertension: response to reduced sympathetic and vasopressin influence

The regulation of the density of angiotensin II receptors in renal glomeruli in response to changes in salt intake is altered in Sprague-Dawley rats with renovascular hypertension due to aortic constriction, and in hypertensive salt-sensitive Dahl rats (Sahlgren 1989, Sahlgren & Aperia 1989). This study examines the modulatory role of sympathetic activity and arginine-vasopressin on angiotensin II receptors in hypertensive Sprague-Dawley rats with aortic constriction as well as in normotensive control rats. Denervation of the left kidney caused a 50% increase in the glomerular angiotensin II receptor density in the denervated kidney in both hypertensive rats and normotensive controls. An even more marked increase in glomerular receptor density occurred in both hypertensive rats and controls after blocking the sympathetic nervous system with guanethidine. To block the effects of arginine-vasopressin we used a blocker of the V₁-receptors (predominant in vessels) and found an approximately 100% increase in the glomerular receptor density of angiotensin II in rats with aortic constriction. There was no reduction in blood pressure. Thus, on the receptor level the renin-angiotensin system is markedly influenced by the activity of other major pressor systems.     

Increase of urocortin-like immunoreactivity in the supraoptic nucleus of Dahl rats given a high salt diet

Urocortin-like immunoreactivity (Ucn-LI) in the supraoptic nucleus (SON) of Dahl rats was examined. Dahl salt-sensitive (S) rats fed with a high salt diet developed hypertension. Numbers of Ucn-LI neurons in the SON in Dahl S on a high salt diet were markedly increased, compared with those in Dahl salt-resistant (R) rats on the same. Sporadic Ucn-LI neurons were found in the SON of both Dahl S and R on a normal diet. Numbers of Ucn-LI neurons in the SON of spontaneously hypertensive rat (SHR) and stroke-prone SHR, genetic models of hypertension, and control rats (Sprague-Dawley and Wistar-Kyoto) were similar. These results suggest that Ucn in the SON is associated with salt loading-induced hypertension rather than spontaneous hypertension.     

Use of Interleukin- 2 in the Management of Haematological Malignancies

Somatic gene delivery approaches have received wide attention as a new technique for studying gene expression and as a potential therapeutic tool in treating both inherited and acquired diseases. Recent studies using nonviral and viral vectors have shown great promise for gene therapy in hypertensive diseases. Potential targets for prospective gene therapy in hypertension include vasopressor renin-angiotensin system components and a number of vasodilator polypeptides such as tissue kallikrein-kinin, atrial natriuretic peptide, adrenomedullin and nitric oxide synthase. Antisense inhibition with oligonucleotides or cDNAs encoding renin, angiotensinogen, angiotensin-converting enzyme and angiotensin receptors has been shown to cause a prolonged blood pressure reduction in spontaneously hypertensive rats. To evaluate the therapeutic potential of vasodilator proteins or peptides in high blood pressure, we delivered the genes encoding human tissue kallikrein, atrial natriuretic peptide, nitric oxide synthase, and adrenomedullin into hypertensive rat models and showed that a single injection resulted in a significant and sustained reduction of blood pressure for several weeks. The potency and duration of blood pressure reduction depends on the dose and the promoter of the gene administered, age and sex of the hypertensive animals as well as the vehicle used for gene delivery. Somatic gene transfer of human tissue kallikrein or atrial natriuretic peptide not only attenuated hypertension but also exerted a protective effect against salt-induced renal damage and cardiac hypertrophy in Dahl salt-sensitive rats after high salt loading. These results suggest that the application of antisense inhibition of vasopressors, or gene delivery of vasodepressors for gene therapy, may have potential in treating human hypertension, and cardiovascular and renal disorders.     

诱导型一氧化氮合酶与Dahl-盐敏感大鼠动脉血压的调节

目的和方法:为探讨诱导型一氧化氮合酶 (iNOS)在血液动力学调控中的作用,本研究通过慢性血液动力学实验观察了静脉输入诱导型一氧化氮合酶 (iNOS)抑制剂aminogunidine(AG)对大鼠平均动脉压的影响,并测定了一氧化氮 (NO)终产物NO₂及NO₃含量(UNOx)以及iNOS活性。结果:1.iNOS特异抑制剂AG能明显放大高钠引起的Dahl盐敏感大鼠(DS)的血压上升效应;2.高NaCl输入在导致的DS大鼠血压升高的同时,能引起iNOS活性及UNOx的明显升高。结论:iNOS对DS大鼠具有重要的血液动力学调节作用。     

芝麻素对肾性高血压伴高血脂大鼠肾脏的保护作用研究

目的： 观察芝麻素对肾性高血压伴高血脂大鼠肾脏的保护作用。方法：制备两肾一夹型肾性高血压伴高血脂大鼠模型(RHHR)，灌胃给予不同剂量的芝麻素7周后，测定各组血清肌酐（Scr）、血尿素氮（BUN）、24 h 尿蛋白含量（UPE）和肾组织匀浆中抗氧化酶的活性，包括总抗氧化能力（T-AOC）、超氧化物歧化酶（SOD）、总NOS（TNOS）、诱导型NOS（iNOS）、结构型NOS（cNOS）和抑制羟自由基能力及肾组织匀浆中丙二醛（MDA）、过氧化氢（H2O2）及一氧化氮（NO）含量。结果：高、中（100 mg/kg、33 mg/kg）剂量组芝麻素可抑制RHHR大鼠血清Scr、BUN和尿UPE水平升高（P<0.01）。与模型组比较可提高肾组织匀浆NO、cNOS、SOD、T-AOC和抑制羟自由基能力（P<0.01或P<0.05），降低MDA、iNOS 、H2O2（P<0.01或P<0.05）含量。结论：芝麻素对肾性高血压伴高血脂大鼠肾脏具有保护作用，其机制与抗氧化应激、清除自由基和抑制iNOS活性等有关。     

Salt-Sensitive Hypertension Resulting From Nitric Oxide Synthase Inhibition is Associated with Loss of Regulation of Angiotensin II in the Rat

In the Dahl salt-sensitive hypertensive rat, a diet containing L-arginine, the natural substrate for nitric oxide synthase, abrogates the hypertension. We postulated that nitric oxide synthase inhibition might induce a salt-sensitive form of hypertension and that this salt sensitivity might be linked to a loss of the regulatory effect of sodium ingestion on angiotensin II (Ang II) and angiotensinogen. Male Wistar-Kyoto rats were randomised to a diet containing 0.008 %, 2.2 % or 4.4 % sodium chloride and to treatment with the NO synthase inhibitor L-NAME (10 mg kg(-1) day(-1)) in the drinking water, or drinking water alone (Controls) for 4 weeks. Blood pressure was measured by tail cuff plethysmography twice weekly. After 4 weeks, the rats were anaesthetised and truncal blood collected for determination of angiotensinogen, renin, angiotensin I (Ang I), Ang II and aldosterone concentrations as well as angiotensin-converting enzyme (ACE) activity. Systolic blood pressure increased with increasing dietary sodium intake in the L-NAME-treated rats (P < 0.05). Plasma renin and aldosterone concentrations decreased with increasing dietary sodium intake in both Control and L-NAME-treated rats. Ang I and ACE activity were unchanged by increasing dietary sodium intake. In contrast, the plasma concentration of Ang II and angiotensinogen increased with increasing dietary sodium (P < 0.05 and P < 0.005, respectively). Treatment with the Ang II receptor blocker, losartan, reversed the blood pressure increase. We conclude that treatment with L-NAME induces an increase in blood pressure that is at least in part salt sensitive. Further, the salt-sensitive component appears to be Ang II-dependent, as it was associated with increasing plasma Ang II levels and could be reversed by treatment with an Ang II receptor antagonist.     

Estrogen therapy replenishes vascular tetrahydrobiopterin and reduces oxidative stress in ovariectomized rats

OBJECTIVE: We investigated whether the effect of estrogen therapy on vascular endothelial function is mediated through increasing the bioavailability of tetrahydrobiopterin (BH4) and associated antioxidant capacity in ovariectomized (Ovx) rats. DESIGN: Aortas of sham-operated, Ovx, and Ovx plus estrogen therapy (Ovx + ET) female Sprague-Dawley rats were used to measure vascular reactivity. Plasma levels of nitric oxide (NO) metabolites, total antioxidant capacity, aortic superoxide anion (O2.), and BH4 contents were determined. RESULTS: Vascular reactivity, assessed on isolated aortic segments, indicated that phenylephrine-induced contraction in the Ovx group was significantly greater than that in the sham and Ovx + ET groups. The vasodilator responses to acetylcholine (10 to 10 M) and L-arginine (L-Arg; 10 M) in the sham and Ovx + ET groups were significantly greater than those in the Ovx group. Pretreatment with BH4 (10 M) enhanced the vasodilator responses to L-Arg in the Ovx group compared with the untreated Ovx group. An inhibitor of BH4 synthesis, 2,4-diamino-6-hydroxypyrimidine (2 mM), significantly attenuated the vasodilator response to L-Arg in the sham and Ovx + ET groups. In addition, Ovx significantly increased O2. production in aortic tissues and decreased plasma NO metabolites levels, whereas ET significantly prevented these effects. Pretreatment with BH4 also significantly decreased aortic O2. production in the Ovx group; both plasma total antioxidant capacity and aortic BH4 contents in the Ovx group decreased significantly compared with those in the sham group, which were also improved by ET. There were no significant differences in the protein expression of endothelial NO synthase in aortas in these groups. CONCLUSIONS: ET increases the availability of vascular BH4 to attenuate O2. production and restores total antioxidant capacity, leading to improved NO-mediated vasodilation in Ovx rats.     

Prevention of salt-induced hypertension in the Dahl strain by 6-hydroxydopamine.

Salt-induced hypertension in Dahl's genetically hypertensive rat has been attributed to humoral or renal factors. However, a recent study from our laboratory suggested that neurogenic mechanisms contribute to salt-induced increased in hindquarters vascular resistance in Dahl salt-sensitive (S) rats. In the present study, we examined the hypothesis that "chemical sympathectomy" with 6-hydroxydopamine (6-OHDA) prevents salt-induced hypertension and increased vascular resistance in S rats. Hypertension did not develop during high-salt diet (8% NaCl) in S rats treated with 6-OHDA, (75--100 mg/kg ip), whereas in rats treated with vehicle, hypertension developed after 4 wk of high salt diet. Chow consumption, sodium excretion, and weight gain were not altered by 6-OHDA. Hindquarters vascular resistance and neurogenic vasoconstrictor tone were significantly lower in S rats treated with 6-OHDA than in S rats treated with vehicle. 6-OHDA also significantly reduced responses to direct sympathetic nerve stimulation and tyramine. These results suggest that an intact sympathetic nervous system plays an essential role in the development of salt-induced increase in blood pressure in Dahl S rats.     

Neuronal vulnerability of stroke-prone spontaneously hypertensive rats to ischemia and its prevention with antioxidants such as vitamin E

Stroke-prone spontaneously hypertensive rats (SHRSP/Izm) develop severe hypertension, and more than 95% of them die of cerebral stroke. Hypoxic stimulation followed by oxygen reperfusion induces neuronal damage in both normotensive Wistar Kyoto/Izm (WKY/Izm) and SHRSP/Izm rats, and the percentage of neurons that undergo apoptosis during hypoxia-reperfusion is markedly higher in SHRSP/Izm rats than in WKY/Izm rats. The biochemical characteristics of the SHRSP/Izm rats, unlike those of WKY/Izm rats, might act as a factor in the stroke proneness of SHRSP/Izm rats. In the hippocampus, the formation of hydroxyl radicals and the cerebral blood flow-independent formation of nitric oxide (NO) were strongly increased after reperfusion in SHRSP/Izm rats, and the neuronal expression of the thioredoxin and Bcl-2 genes was significantly decreased in the SHRSP/Izm rats compared with the WKY/Izm rats. On the other hand, the effects of antioxidants against neuronal death associated with cerebral ischemia-reperfusion were stronger in the SHRSP/Izm rats, in which the addition of vitamin E or ebselen almost completely inhibited neuronal death. Namely, the addition of 100 μg/ml of vitamin E under hypoxia/reoxygenation (H/R) conditions completely inhibited WKY and SHRSP/Izm neuronal death. Vitamin E exerts a marked inhibitory effect against neuronal damage via its incorporation into mitochondrial membranes, where it captures reactive oxygen and free radicals. The susceptibility of neurons to apoptosis in SHRSP/Izm rats is partly due to an insufficiency of mitochondrial redox regulation and apoptosis-inhibitory proteins. In this review, we describe the neuronal vulnerability of SHRSP/Izm rats induced by cerebral ischemia and the effects of antioxidants such as vitamin E.     

The morphology and antihypertensive effect of renomedullary interstitial cells derived from Dahl sensitive and resistant rats

The renomedullary interstitial cell (RIC) has been implicated in the antihypertensive action of the kidney. This cell has been isolated in tissue culture and shown to have an antihypertensive action in several models of experimental hypertension. Morphometric studies of RIC in vivo from Dahl rats sensitive and resistant to the hypertensive effects of high-salt diets indicate major differences between the RICs. These cells were therefore isolated from salt-sensitive and salt-resistant strains of rat, grown, and maintained in tissue culture. Major morphologic differences between the two cell lines were noted and persisted for multiple tissue culture passages. The cells from resistant animals were larger and had more lipid granules. These differences were similar to those seen in vivo. In short-term experiments these cells were compared for their antihypertensive effect. The two cell lines were injected subcutaneously into two groups of hypertensive recipient rats, one group of Dahl salt-sensitive rats on a high-salt diet and one group of Wistar rats subjected to the one-kidney, one-clip Goldblatt procedure. In both cases differences were noted between the cell lines. These data support the concept that differences between the Dahl salt-sensitive and salt-resistant rats may be related to variations in their RIC.     

TRPV1 activation prevents high-salt diet-induced nocturnal hypertension in mice

High dietary salt-caused hypertension is associated with increasing reactive oxygen species generation and reduced nitric oxide (NO) bioavailability. Transient receptor potential vanilloid type 1 (TRPV1), a specific receptor for capsaicin, is proposed to be involved in Dahl salt-sensitive hypertension, as determined in acute or short-term experiments. However, it remains unknown whether activation of TRPV1 by dietary capsaicin could prevent the vascular oxidative stress and hypertension induced by a high-salt diet. Here, we report that consumption of a high-salt diet blunted endothelium-dependent relaxation in mesenteric resistance arteries and elevated nocturnal blood pressure in mice. These effects were associated with increased superoxide anion generation and reduced NO levels in mesenteric vessels in mice on a high-salt diet. However, chronic administration of capsaicin reduced the high-salt diet-induced endothelial dysfunction and nocturnal hypertension in part by preventing the generation of superoxide anions and NO reduction of mesenteric arteries through vascular TRPV1 activation. Our findings provide new insights into the role of TRPV1 channels in the long-term regulation of blood pressure in response to high-salt intake. TRPV1 activation through chronic dietary capsaicin may represent a promising lifestyle intervention in populations with salt-sensitive hypertension.     

Mismatch between peripheral and central demands in salt-sensitive hypertensive Dahl rats

Sympathetic nerve activity in essential hypertension, which accounts for 90% of all hypertension cases, is in general thought to be elevated regardless of whether there is salt sensitivity or insensitivity. The cause is thought to be an abnormality in the sympathetic center. On the other hand, neuronal nitric oxide synthase-expressing neurons that function to inhibit the sympathetic center are clearly activated in the salt-sensitive hypertensive Dahl rat model. How is this related to sympathetic hyperactivity and hypertension? Also, how is hypertension associated with peripheral vessel contractility and renal function? Human life is supported by the body's various essential functions. The circulatory system links all these functions into one system that cannot be separated. Blood pressure is the driving force of this circulatory system, and both the central and peripheral demands determine the output. We examined the ‘mismatch’ between these two sides and its association with hypertension.