Is there a link between salt-intake and atrial natriuretic peptide system during hypertension induced by nitric oxide blockade?

Long-term nitric oxide (NO) blockade is known to induce a severe and progressive hypertension. The influence of the salt-intake on atrial natriuretic peptide (ANP) system in this hypertension model is unknown. The aim of this study was to evaluate ANP plasma levels, content and mRNA in atria of male Wistar rats chronically treated with oral Nomega-nitro-L-arginine methyl ester (L-NAME) after 4 weeks of high-salt diet. The high-salt diet induced an increase (P < 0.05) in ANP plasma levels in normotensive rats and no significant changes in hypertensive animals. We observed a significant increase in the ANP content in the left and right atria of hypertensive rats (P < 0.001) when compared to normotensive ones. However, no significant changes were observed during high-salt diet in normotensive and hypertensive animals. Northern blot analysis revealed that ANP gene expression is higher in the right and left atria of hypertensive rats when compared to normotensive rats. However, we found no significant changes in ANP mRNA of rats treated with high-salt diet in normotensive and hypertensive rats when compared to low-salt diet. The present observations indicate no interaction between salt-intake and activation of the ANP system during chronic nitric oxide synthase (NOS) inhibition.     

Respective contribution of age, mean arterial pressure, and body weight on central arterial distensibility in SHR

In spontaneously hypertensive rats (SHR), carotid and aortic distensibilities measured at operational blood pressure (BP) are reduced. Increased body weight and mean arterial pressure (MAP) are both known to reduce distensibility independently. However, whether, after adjustment to body weight and mean BP, distensibility remains reduced in SHR has never been investigated. Carotid and abdominal aorta distensibilities were measured under anesthesia in SHR at 5, 12, 52, and 78 wk of age, and measurements were compared with age-matched normotensive Wistar rats. Each age group was composed of 9 or 10 animals. We determined distensibility using echo-tracking techniques of high resolution. Compared with Wistar rats, carotid and aortic distensibilities measured at operational MAP are reduced in SHR. This reduction is accentuated with age, particularly for the carotid artery. After adjustment to body weight and MAP, carotid and aortic distensibilities become identical in Wistar and SHR (or even slightly increased in SHR) but continue to be reduced with age, mainly for the carotid artery. In conclusion, in SHR, age and high BP do not have a parallel and similar influence on the reduction of arterial distensibility. Aging constantly reduces arterial distensibility, whereas MAP levels contribute to maintenance of arterial function.     

Interaction between mild hypercholesterolemia, HDL-cholesterol levels, and angiotensin II in intimal hyperplasia in mice

Two month old C57BL/6 mice were placed on three different diets: 1) normal diet (NC; 0.025% cholesterol), 2) hypercholesterolemic Western-type diet (HC-W; 0.2% cholesterol), and 3) hypercholesterolemic Paigen-type diet (HC-P; 1.25% cholesterol plus 0.5% cholic acid). At 6 months of age, the animals underwent ligation of the left carotid artery and were randomly assigned to vehicle (PBS, subcutaneous) or angiotensin II (Ang II; 1.4 mg/kg/day, subcutaneous) treatment for 4 weeks. Low density lipoprotein-cholesterol levels were similarly increased in both HC diets (NC, 4 +/- 3 mg/dl; HC-W, 123 +/- 17 mg/dl; HC-P, 160 +/- 14 mg/dl). However, the levels of high density lipoprotein-cholesterol (HDL-C) were reduced only in animals fed the HC-P diet (NC, 82 +/- 6 mg/dl; HC-W, 79 +/- 7 mg/dl; HC-P, 58 +/- 7 mg/dl). In Ang II-treated mice, carotid artery ligation induced intimal smooth muscle cell proliferation to a similar extent in NC- and HP-W-fed animals. However, a significantly larger intimal area developed in ligated vessels from Ang II-treated mice fed the HC-P diet (3.6-fold higher than in Ang II-treated NC mice). Together, these results show the accelerating effect of mild hypercholesterolemia, reduced HDL-C levels, and Ang II on intimal hyperplasia after carotid artery ligation in mice.     

The borderline hypertensive rat (BHR): a new model for the study of environmental factors in the development of hypertension

While many studies have attempted to produce hypertension through the use of various environmental stressors, few have succeeded in producing chronic elevations in blood pressure beyond levels considered to be borderline hypertensive (140-160 mm Hg systolic). The problem with most studies stems from the use of genetically normotensive animals and the selection of stressors to which animals readily adapt. A new approach is suggested, which recognizes the role of genetics in human essential hypertension. Animals with one hypertensive parent do not develop spontaneous hypertension but show a more sensitive cardiovascular response to environmental stressors than animals with normotensive parents. Preliminary studies revealed that animals with a mixed genetic history of hypertension develop spontaneous borderline hypertension. When subjected to shock-shock conflict, these borderline hypertensive rats (BHR) developed permanent hypertension that failed to abate even after a ten-week, shock-free recovery period. The hypertension was accompanied by elevated heart weight to body weight ratios and by significant cardiac pathology. Subsequent work has demonstrated that these animals also become hypertensive when fed a high-sodium diet. Finally, in a series of exercise studies, we found that BHRs subjected to a shock stressor were protected against stress-induced hypertension if they exercised daily. The potential of this model for studies of the mechanisms by which environmental variables produce permanent hypertension is discussed.     

Biomechanical response of arterial wall to DOCA-salt hypertension in growing and middle-aged rats

To study arterial remodeling in response to hypertension, Deoxycortico-sterone acetate (DOCA)-salt hypertension was induced in immature (aged 16 weeks) and middle-aged (48 weeks) rats, and biomechanical properties and wall dimensions of common carotid arteries were determined. Arterial segments were excised at 10 or 16 weeks postoperatively from the immature rats and at 16 weeks from the middle-aged ones. In vitro pressure-diameter tests were performed under normal (in Krebs-Ringer solution), active (norepinephrine), and passive (papaverine) conditions. Non-treated, age-matched rats (26, 32, and 64 weeks) were used to obtain control data. Wall thickness at in vivo blood pressure level was increased by hypertension at all ages; however, there were no significant changes in inner diameter. In hypertensive rats, arterial outer diameter was smaller under normal condition than under passive condition, indicating the increase of smooth muscle tone by hypertension. Diameter reduction developed by norepinephrine was increased by hypertension, which was significant above 100 mmHg; however, there were no significant differences between hypertensive and normotensive arteries, if compared at respective in vivo blood pressures. No significant differences were observed in wall stiffness at in vivo pressure. Wall hoop stress at in vivo blood pressure had a significant positive correlation with the pressure in 26-week old arteries. However, there were no differences in the stress between hypertension and normotension in 32- and 64-week old arteries. These results were essentially similar to previous ones observed in Goldblatt hypertension and in younger animals. Age-related differences in arterial wall remodeling were not clearly observed.     

Atherosclerotic lesion-specific copper delivery suppresses atherosclerosis in high-cholesterol-fed rabbits

Dietary cholesterol supplements cause hypercholesterolemia and atherosclerosis along with a reduction of copper concentrations in the atherosclerotic wall in animal models. This study was to determine if target-specific copper delivery to the copper-deficient atherosclerotic wall can block the pathogenesis of atherosclerosis. Male New Zealand white rabbits, 10-weeks-old and averaged 2.0 kg, were fed a diet containing 1% (w/w) cholesterol or the same diet without cholesterol as control. Twelve weeks after the feeding, the animals were injected with copper-albumin microbubbles and subjected to ultrasound sonication specifically directed at the atherosclerotic lesions (Cu-MB-US) for target-specific copper delivery, twice a week for four weeks. This regiment was repeated 3 times with a gap of two weeks in between. Two weeks after the last treatment, the animals were harvested for analyses of serum and aortic pathological changes. Compared to controls, rabbits fed cholesterol-rich diet developed atherosclerotic lesion with a reduction in copper concentrations in the lesion tissue. Cu-MB-US treatment significantly increased copper concentrations in the lesion, and reduced the size of the lesion. Furthermore, copper repletion reduced the number of apoptotic cells as well as the content of cholesterol and phospholipids in the atherosclerotic lesion without a disturbance of the stability of the lesion. The results thus demonstrate that target-specific copper supplementation suppresses the progression of atherosclerosis at least in part through preventing endothelial cell death, thus reducing lipid infiltration in the atherosclerotic lesion.     

Low ethanol intake prevents salt-induced hypertension in WKY rats

Low alcohol intake in humans lowers the risk of coronary heart disease and may lower blood pressure. In hypertension, insulin resistance with altered glucose metabolism leads to increased formation of aldehydes. We have shown that chronic low alcohol intake decreased systolic blood pressure (SBP) and tissue aldehyde conjugates in spontaneously hypertensive rats and demonstrated a strong link between elevated tissue aldehyde conjugates and hypertension in salt-induced hypertensive Wistar-Kyoto (WKY) rats. This study investigated the antihypertensive effect of chronic low alcohol consumption in high salt-treated WKY rats and its effect on tissue aldehyde conjugates, platelet cytosolic free calcium ([Ca^{2 +}] _i )_,and renal vascular changes. Animals, aged 7 weeks, were divided into three groups of six animals each. The control group was given normal salt diet (0.7% NaCl) and regular drinking water; the high salt group was given a high salt diet (8% NaCl) and regular drinking water; the high salt + ethanol group was given a high salt diet and 0.25% ethanol in drinking water. After 10 weeks, SBP, platelet [Ca^{2 +}] _i , and tissue aldehyde conjugates were significantly higher in rats in the high salt group as compared with controls. Animals on high salt diets also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidney. Ethanol supplementation prevented the increase in SBP and platelet [Ca^{2 +}] _i and aldehyde conjugates in liver and aorta. Kidney aldehyde conjugates and renal vascular changes were attenuated. These results suggest that chronic low ethanol intake prevents salt-induced hypertension and attenuates renal vascular changes in WKY rats by preventing an increase in tissue aldehyde conjugates and cytosolic [Ca^{2 +}] _i .     

Heart rate,arterial distensibility,and optimal performance of the arterial tree

In this study we explore the ability of a previously developed model of pulsatile flow for explaining the observed reduction of arterial distensibility with heart rate. The parameters relevant for the analysis are arterial wall distensibility together with permeability and reflection coefficients of the end capillaries. A non-specific artery and the ensemble of tissues supplied by that artery were considered in the model. The blood current within that artery was equalized to the sum of all micro currents in the tissues supplied by that artery. A formula emerged that relates changes in arterial distensibility with heart rate, and also with some particular aspects of microcirculation. Then, that formula was tested with data of distensibilities of the radial and carotid arteries observed at the heart rates of 63, 90, and 110 b.p.m. The formula correctly predicted the trend of decreased distensibility with heart rate for both arteries. Moreover, due to the fact that the carotid artery supplies the brain, and because the Blood–Brain barrier is highly restrictive to colloids in the blood, for the carotid artery the formula predicted a less marked decrease in distensibility than in the case of the radial artery feeding muscle tissue, which has a greater permeability to colloids, a trend that was confirmed by data. It was found that reduction of arterial distensibility with heart rate was greater in arteries that supply end capillaries with high permeability and low reflection coefficients.     

Carotid distensibility, baroreflex sensitivity, and orthostatic stress.

In this study, we tested the hypothesis that carotid arteries undergo rapid changes in distensibility on moving from the supine to head-up tilt (HUT) postures and, subsequently, that this change in carotid distensibility (cDa) might be associated with concurrent reductions in cardiovagal baroreflex sensitivity (BRS). Thus the effect of posture on carotid vascular mechanics and cardiovagal BRS with consideration for altered central hemodynamics (i.e., stroke volume; Doppler ultrasound) was examined. Carotid pulse pressure (cPP; Millar transducer) and contralateral B-mode ultrasound images were assessed at the carotid artery during supine and 60 degrees HUT postures. From these measures, cDa was calculated at 5-mmHg pressure increments experienced during the cardiac cycle (n = 6). cPP (n = 9) was not different in the two postures. A smaller stroke volume being ejected into a smaller carotid artery in HUT explained the maintenance of cPP in HUT. Also, compared with supine, cDa was reset to a lower level in HUT (main effect of posture; P < 0.05). Cardiovagal BRS (sequence method) was diminished in HUT vs. supine (P < 0.05). A positive correlation was observed between the tilt-induced changes in maximal cDa (in early systole) and cardiovagal BRS (r2 = 0.75; P < 0.05), but there was little predictive relationship between changes in cPP, systolic vessel dimensions, or average cDa and the corresponding change in BRS. The present results indicate that HUT elicits rapid changes in carotid artery mechanics and further suggest that reductions in the maximal cDa measured in early systole contribute to reduced cardiovagal BRS with HUT.     

Strain differences of hypertension induced by dietary NG-nitro-L-arginine in normotensive rats.

When the potent inhibitor of nitric oxide (NO) synthesis NG-nitro-L-arginine (L-NNA) was incorporated into the diet, hypertension was induced and sustained due to the effects of the long-term inhibition of endothelium-dependent relaxing factor (EDRF)/NO. The effects of L-NNA on normotensive rats of four strains (Donryu, Sprague-Dawley (SD), Wistar, and Wistar-Kyoto (WKY)) were compared relative to control rats. L-NNA administration caused a sharp initial increase in systolic blood pressure (SBP) at 2 weeks in all animals, and this was followed by a gradual and steady increase until 4 weeks. At the end of the experiments (5 weeks), the mean SBP of Donryu and SD rats was decreased. The maximum blood pressure of Donryu and Wistar rats during the experiments exceeded 200 mmHg, but that of SD and WKY rats was below 200 mmHg. Body weight loss and death were observed only in L-NNA-fed Donryu rats. Pathological changes in the kidneys and the morbidity rates for the lesions were determined, and indicated that the Donryu L-NNA group was 100% positive. These results suggest that the Donryu strain is more sensitive to L-NNA than the other strains. That dietary L-NNA-induced hypertension in normotensive rats of the four strains provides a new artificially-induced hypertensive model in which vasoconstriction occurs mainly due to EDRF deficiency.     

Compliance characteristics of the hind-limb arterial system of normal and hypertensive rabbits

Pressure transients resulting from square-wave changes in abdominal aortic blood flow rate were used to derive effective arterial compliance and peripheral resistance of the hind-limb circulation of anaesthetized rabbits. The model for deriving these parameters proved applicable if step changes in flow were kept less than 35% of mean flow. Under resting conditions, the effective hind-limb arterial compliance of normal rabbits averaged 3.46 X 10(-3) mL/mmHg (1 mmHg = 133.322 Pa). Hind-limb arterial compliance decreased with increasing pressure at low arterial pressures, but unlike compliance of isolated arterial segments, compliance did not vary at and above normal resting pressures. Baroreflex destimulation (bilateral carotid artery occlusion) caused an increase in effective hind-limb vascular resistance at 48.4% and a decrease of arterial compliance of 50.7%, so that the constant for flow-induced arterial pressure changes (resistance times compliance) was largely unchanged. Similarly, the arterial time constant for rabbits with chronic hypertension was similar to that for controls because threefold increases in hind-limb vascular resistance were offset by decreases in compliance. Reflex-induced decreases in arterial compliance are probably mediated by sympathetic nerves, whereas decreases associated with hypertension are related to wall hypertrophy in conjunction with increased vasomotor tone. Arterial compliance decreased with increasing pressure in hypertensive animals, but this effect was less pronounced than in normotensive rabbits.     

Chronic changes in plasma triglyceride levels do modify platelet membrane microviscosity in rats

Lipid metabolism disorders were proposed to mediate numerous cell membrane alterations in various forms of hypertension. Elevated plasma triglycerides were found to be associated with changes in membrane structure and function related to altered microviscosity in particular domains of the cell membrane. The aim of our study was to determine if an abnormal triglyceride metabolism might play a causal role in these alterations of membrane dynamics. Using genetically hypertensive rats of the Prague hereditary hypertriglyceridemic (HTG) strain we investigated whether the elevation of circulating triglycerides induced by high fructose intake and/or their lowering by chronic gemfibrozil treatment (for 10 weeks starting at the age of 6 weeks) are followed by reciprocal changes in membrane microviscosity. Two different fluorescent probes exploring either the outer membrane leaflet (TMA-DPH anisotropy) or the membrane lipid core (DPH anisotropy) were used in platelets of HTG rats. DPH (diphenylhexatriene) fluorescence anisotropy was decreased in platelets of fructose-treated HTG animals with highly elevated plasma triglyceride levels, whereas it was increased in gemfibrozil-treated HTG rats in which triglyceride levels were almost normalized. On the contrary, TMA-DPH (trimethylamino-diphenylhexatriene) anisotropy was not substantially altered in platelets from HTG rats by the above modifications of circulating triglycerides. No changes of plasma cholesterol or blood pressure were associated with the triglyceride-dependent modifications of membrane core microviscosity. Our interventional study demonstrates a major causal role of circulating triglycerides in the control of the microviscosity of membrane lipid core.     

Comparison of endothelial function in the carotid artery between normal and short-term hypercholesterolemic rabbits

The present study was undertaken to investigate and compare the vascular function in carotid arteries isolated from normal short-term hypercholesterolemic rabbits. Rabbits were fed normal or 0.5% cholesterol chow for 5 weeks. The tension of isolated carotid artery rings was measured isometrically. Serum lipid levels were measured and morphometric analysis was performed. And content of nitrate/nitrite in the carotid artery was also determined. In the carotid artery precontracted by phenylephrine, the cholesterol chow diet administered for 5 weeks decreased acetylcholine-induced relaxation at only middle concentrations, though it significantly increased the content of nitrate/nitrite, the sum of stable nitric oxide metabolites, in the carotid artery. Cholesterol chow for 5 weeks had no influence on sodium nitroprusside-induced relaxation in the carotid artery. The N(G)-nitro-L-arginine- and indomethacin-resistant endothelium-dependent relaxation induced by acetylcholine was significantly decreased in rabbits receiving the cholesterol chow as compared to rabbits receiving the control diet. The resistant part of acetylcholine-induced relaxation was significantly inhibited when the carotid artery was treated with glibenclamide, a selective inhibitor of ATP-sensitive K(+) channels, 4-aminopyridine, an inhibitor of voltage-dependent K(+) channels, or charybdotoxin, an inhibitor of large and intermediate conductance Ca(2+)-activated K(+) channels, and it was significantly inhibited by tetraethylammonium, a non-selective inhibitor of Ca(2+)-activated K(+) channels and N,N-di-ethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF 525a), a nonselective cytochrome P-450 monooxygenase (CYP) inhibitor, or ketoconazole, a selective CYP3A inhibitor in only normal rabbits. These results suggest that short-term hypercholesterolemia decreased EDHF-induced relaxation mediated through K(+) channels in rabbit carotid artery and that it may be due partially to the inhibition of CYP3A system in the carotid artery at an early stage of hypercholesterolemia.     

Response of aorta connective tissue matrix to injury caused by vassopressin-induced hypertension or hypercholesterolemia.

The aim of the study was to investigate the effect of two various atherogenic stimuli (vasopressin-induced hypertension or hypercholesterolemia) on the collagen and glycosaminoglycan (GAG) content in the internal or external part of both thoracic and abdominal aorta, which are differently susceptible to atherosclerosis. Experimental rabbits were divided into four groups: controls, animals injected with physiological saline or vasopressin at the dose of 1 IU/kg from the 1 st to the 25 th day of experiment, respectively. The animals from group 4 were maintained on food, containing 0.25% cholesterol. Only in the vasopressin-treated group, the systolic blood pressure was elevated from 110 mmHg at the beginning, to 166 mmHg at the end of the study. After 14 weeks the aorta was dissected into internal and external parts. GAG fractions were separated and estimated as uronic acids. Collagen was evaluated as the hydroxyproline content in the tissue. Augmented total GAG and heparan sulphate (HS) level, plus no changes in the collagen content were seen in the internal part of the thoracic aorta in rabbits with hypercholesterolemia or hypertension. In the hypertensive animals, the changes were extended to the external part of the aorta and, additionally, comprised the elevation of the chondroitin-4 sulphate (C-4S) content. The two atherogenic stimuli increased the collagen level with no elevation of the GAG content in the abdominal aorta. A convergent effect of the injury, caused by hypertension or hypercholesterolemia on the collagen, total GAG and HS content was shown in the respective parts of the rabbit aortas. The common GAG, increased in the thoracic aorta, stand for the HS, in both hypertensive and hypercholesterolemic rabbits. As the sensitivity to atherosclerosis development in different segments of the aorta varies, they express various responses of the connective tissue matrix to injuries, caused by hypertension or hypercholesterolemia.     

Evolving biaxial mechanical properties of mouse carotid arteries in hypertension

Quantifying the time course of load-induced changes in arterial wall geometry, microstructure, and properties is fundamental to developing mathematical models of growth and remodeling. Arteries adapt to altered pressure and flow by modifying wall thickness, inner diameter, and axial length via marked cell and matrix turnover. To estimate particular biomaterial implications of such adaptations, we used a 4-fiber family constitutive relation to quantify passive biaxial mechanical behaviors of mouse carotid arteries 0 (control), 7-10, 10-14, or 35-56 days after an aortic arch banding surgery that increased pulse pressure and pulsatile flow in the right carotid artery. In vivo circumferential and axial stretches at mean arterial pressure were, for example, 11% and 26% lower, respectively, in hypertensive carotids 35-56 days after banding than in normotensive controls; this finding is consistent with observations that hypertension decreases distensibility. Interestingly, the strain energy W stored in the carotids at individual in vivo conditions was also less in hypertensive compared with normotensive carotids. For example, at 35-56 days after banding, W was 24%, 39%, and 47% of normal values at diastolic, mean, and systolic pressures, respectively. The energy stored during the cardiac cycle, W(sys)-W(dias), also tended to be less, but this reduction did not reach significance. When computed at normal in vivo values of biaxial stretch, however, W was well above normal for the hypertensive carotids. This net increase resulted from an overall increase in the collagen-related anisotropic contribution to W despite a decrease in the elastin-related isotropic contribution. The latter was consistent with observed decreases in the mass fraction of elastin.     

Hypertension,Thrombosis, and Atherosclerosis in the Rat

A simple high fat diet containing cholic acid has been devised for producing hyperlipemia and an increased incidence of thrombosis in the small coronary vessels of the rat, but without producing significant atherosclerotic lesions. The influence on this syndrome induced by six weeks of desoxycorticosterone administration, 2 mg. daily, and 10 weeks of oral saline (1%) ingestion was investigated in 30 115-g. male rats. Marked hypertension developed only when it was induced prior to beginning the dietary feeding. In comparison to the control groups, the group that was both hyperlipemic and hypertensive had severer hypertension, severer hyperlipemia, double the mortality due to thrombosis and fatty streaks in the aorta but very few lesions of periarteritis nodosa. However, the early atherosclerotic lesions did not seem to be responsible for the increased production of thrombosis. It is therefore probable that under these experimental conditions hypertension has a more direct action on the production of thrombotic effect than that of worsening the atherosclerotic lesions.     

Renal thrombotic microangiopathy in a genetic model of hypertension in mice

Our goal was to develop a model of accelerated hypertension with renal microangiopathy. Transgenic mice that are hypertensive because of overexpression of human renin (R+ mice) and human angiotensin (A+ mice) genes were studied. To increase arterial pressure to levels comparable to those that may be seen in malignant hypertension, high salt was added to the diet and/or the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methylester (L-NAME), was added to the drinking water. Renal lesions, decline in renal function, and proteinuria developed within 10 weeks in R+/A+ mice given both L-NAME and a high-salt diet, and within 24 weeks in mice given either L-NAME or a high-salt diet. Renal morphology showed features of severe thrombotic microangiopathy, with extensive vascular and glomerular lesions in all R+/A+ mice on high salt, L-NAME, or high salt plus L-NAME. Vascular lesions included fibrin thrombi and onion skinning of the vessel walls, whereas glomerular lesions included segmental sclerosis, mesangiolysis, fibrin thrombi within glomerular capillaries, and double-contour formation of glomerular capillary walls. Renal morphology was normal in control mice fed high salt and/or L-NAME. No R+/A+ mice fed a normal diet developed vascular lesions, whereas a few mice developed mild focal glomerular lesions. In summary, these studies characterize vascular and glomerular lesions in R+/A+ mice fed high salt, L-NAME, or both high salt and L-NAME, and provide a murine model of malignant hypertension with renal thrombotic microangiopathy.     

Increased Renal Iron Accumulation in Hypertensive Nephropathy of Salt-Loaded Hypertensive Rats

Although iron is reported to be associated with the pathogenesis of chronic kidney disease, it is unknown whether iron participates in the pathophysiology of nephrosclerosis. Here, we investigate whether iron is involved in the development of hypertensive nephropathy and the effects of iron restriction on nephrosclerosis in salt- loaded stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were given either a normal or high-salt diet for 8 weeks. Another subset of SHRSP were fed a high-salt with iron-restricted diet. SHRSP given a high-salt diet developed severe hypertension and nephrosclerosis. As a result, survival rate was decreased after 8 weeks diet. Importantly, massive iron accumulation and increased iron content were observed in the kidneys of salt-loaded SHRSP, along with increased superoxide production, urinary 8-Hydroxy-2′-deoxyguanosine excretion, and urinary iron excretion; however, these changes were markedly attenuated by iron restriction. Of interest, expression of cellular iron transport proteins, transferrin receptor 1 and divalent metal transporter 1, was increased in the tubules of salt-loaded SHRSP. Notably, iron restriction attenuated the development of severe hypertension and nephrosclerosis, thereby improving survival rate in salt-loaded SHRSP. Taken together, these results suggest a novel mechanism by which iron plays a role in the development of hypertensive nephropathy and establish the effects of iron restriction on salt-induced nephrosclerosis.     

Arteriolar and systemic autoregulatory responses during the development of hypertension in the spontaneously hypertensive rat

Pressure-flow curves were constructed to determine whether acute autoregulation in rat skeletal muscle was altered during the development of hypertension in the spontaneously hypertensive rat (SHR). Under chloralose:urethane anesthesia, hindlimb blood flow and pressure, plus diameter changes of gracilis muscle arterioles, were simultaneously measured in the 6- and 9-week Wistar-Kyoto (WKY) and SHR. Femoral blood flow was measured by electromagnetic flowmetry and hindlimb pressure controlled with an hydraulic occluder. Arteriolar diameters were measured using image shearing techniques. Acute autoregulatory capacity was assessed by comparing the closed-loop gain and the regression lines over the regulated and passive pressure ranges of the pressure-flow curves. The lower pressure limit of autoregulation (LPLAR) shifted upward as the blood pressure increased in the SHR with age; it did not shift in the WKY. Resting hindlimb flow, elevated in the SHR at 6 weeks, was also elevated at the LPLAR. At 9 weeks hindlimb blood flow was comparable in the WKY and SHR. As blood pressure was increased autoregulation was accompanied by vasoconstriction of gracilis arterioles. However, neither the gain of the autoregulatory system nor the regression lines describing the pressure-flow curves were different between the hypertensive and normotensive animals at either age. These results indicate that the acute autoregulatory response mechanism was not affected by the developing hypertension in the SHR, and is consistent with a structural basis for the chronic maintenance of the elevated peripheral vascular resistance.     

Beta-adrenergic receptor alterations in hypertension--physiological and molecular correlates

In hypertensive animals, there is physiological and biochemical evidence that beta-adrenergic responsiveness is diminished. In contrast, in man the physiological evidence of reduced beta-adrenergic responsiveness is not completely convincing and few biochemical studies have been reported. The lymphocyte has been widely used as a model for the human beta-adrenergic receptor complex. In studies comparing young normotensive and mild hypertensive subjects we demonstrated a reduction in beta-adrenergic mediated adenylate cyclase activity in lymphocytes from hypertensive subjects. A parallel reduction in beta-adrenergic receptor affinity for agonists was also seen. These changes are consistent with a functional uncoupling of the receptor from the adenylate cyclase complex. To determine the role of dietary sodium intake on beta-adrenergic receptor properties in hypertension we studied lymphocytes from hypertensive and normotensive subjects fed either a low (10 mequiv.) or high (400 mequiv.) NaCl diet. We demonstrated that a low NaCl diet corrected the defect in lymphocyte beta-adrenergic responsiveness in hypertension. These studies emphasize the utility of biochemical approaches to the study of alterations in beta-adrenergic responsiveness in human hypertension and suggest an important role of dietary sodium in the reduction in beta-adrenergic responsiveness in the hypertensive state.