Dopamine receptor blockade and synthesis inhibition during exaggerated natriuresis in spontaneously hypertensive rats

Hansell , P. & Sjöquist , M. 1992. Dopamine receptor blockade and synthesis inhibition during exaggerated natriuresis in spontaneously hypertensive rats. Acta Physiol Scand 144 , 269–276. Received 21 September 1990, accepted 11 October 1991. ISSN 0001–6772. Department of Physiology and Medical Biophysics, Biomedical Centre, University of Uppsala, Sweden. The influence of dopamine receptor blockade and synthesis inhibition on natriuresis induced by isotonic saline volume expansion was investigated in anaesthetized spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. The aim of the study was to elucidate the mechanisms underlying the phenomenon of exaggerated natriuresis during volume expansion that has been observed in spontaneously hypertensive rats. Volume expansion, at 5 % of body weight, resulted in a larger and faster natriuretic response in spontaneously hypertensive rats than in Wistar-Kyoto rats. Sixty minutes after commencement of volume expansion the natriuretic response (accumulated sodium excretion) in Wistar-Kyoto rats (n = 8) was only 24% of that in spontaneously hypertensive rats (n = 17). When spontaneously hypertensive rats were pretreated with the dopamine receptor blockers haloperidol (n= 14, 1 mg kg^-1), SCH23390 (n = 8, 30 μg h^-1 kg^-1) or the dopamine synthesis inhibitor benserazide (n = 8, 50 mg kg^-1; n = 5, 100 mg kg^-1), the natriuretic response to volume expansion was only 16, 35, 59 and 42%, respectively, of that in untreated SHR. The corresponding proportion in the haloperidol-treated (n= 8) compared with untreated Wistar-Kyoto rats was 22%. In conclusion, isotonic volume loading results in more pronounced natriuresis in spontaneously hypertensive than in Wistar-Kyoto rats. Dopamine receptor blockade and synthesis inhibition attenuate the expansion of exaggerated natriuresis in spontaneously hypertensive rats and reduces the volume expansion natriuresis in Wistar-Kyoto rats, indicating that the dopamine system plays an important role.     

Aldosterone in the exaggerated natriuresis of spontaneously hypertensive rats

The effect of mineralocorticoid hormones on the urinary responses of spontaneously hypertensive and normotensive rats to oral salt loading was determined. In response to a control salt load, the increase was determined. In response to a control salt load, the increase in urinary sodium excretion by the spontaneously hypertensive rats was significantly greater than that of the normotensive rats [48 +/- 6 (SE) mueq/h vs. 26 +/- 4 mueq/h]. Treatment with spironolactone did not significantly alter the natriuretic response of the spontaneously hypertensive rats (43 +/- 8 mueq/h) to another salt load, but increased the natriuretic response of the normotensive rats (55 +/- 7 mueq/h) to that of the hypertensive rats. D-Aldosterone suppressed the natriuretic response to salt loading of the hypertensive rats to a level which was not significantly different from that of the normotensive rats. Plasma aldosterone concentration was significantly lower in the spontaneously hypertensive rats than in the normotensive rats (18.0 +/- 3.3 and 52.1 +/- 5.2 ng/100 ml, respectively). Neither extracellular fluid volume nor total body water in spontaneously hypertensive and normotensive rats were significantly different. The data support the hypothesis that the exaggerated natriuresis in the spontaneously hypertensive rats is mediated by a relative lack by these rats of aldosterone-mediated distal tubular sodium reabsorption.     

Renal nerve activity and exaggerated natriuresis in conscious spontaneously hypertensive rats

Exaggerated natriuresis upon volume loading occurs in both human and animal hypertension and is mainly due to suppressed tubular reabsorption. To explore whether altered renal sympathetic activity contributes to this response, conscious male spontaneously hypertensive rats (SHR) were exposed to isotonic saline loading in comparison with normotensive male Wistar Kyoto rats (WKR). After a 60 min control hydropenic period, during which mean arterial pressure, heart rate, renal sympathetic nerve activity and urinary sodium excretion were followed, a 60 min period of intravenous volume expansion with isotonic saline (0.2 ml/minx 100 g b. w.) was started followed by a 60 min hydropenic recovery period. Already during the control period sodium excretion was significantly higher in SHR. During the volume load and subsequent recovery period a clearly exaggerated natriuresis occurred in SHR compared with WKR. Further, volume loading reduced renal sympathetic nerve activity in all animals, but significantly more in SHR. Moreover, volume loading reduced mean arterial pressure and heart rate in both groups. It is suggested that the accentuated reflex inhibition of renal sympathetic activity in SHR upon volume loading emanates from cardiac mechanoreceptors and partly explains the exaggerated natriuresis in SHR. This augmented ‘volume’ reflex response is probably due to reduced systemic venous compliance in SHR with a consequently increased central filling and cardiac receptor activation.     

Renal dopamine and noradrenaline excretion during CNS-induced natriuresis in spontaneously hypertensive rats: influence of dietary sodium

Abnormalities in dopamine (DA) and noradrenaline (NA) activities and sodium handling may be involved in the pathogenesis of hypertension. The present study was designed to investigate whether any differences exist between normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in urinary excretion of DA, NA and sodium after 15 weeks on a low, medium or high sodium diet and during a subsequent elevation of the cerebroventricular fluid sodium concentration (CNS-induced natriuresis). Seven features were noted: (1) Basal sodium and DA excretion after the diet regimen was correlated to the dietary sodium content in both strains, except that sodium and DA excretion in SHR showed no further increase after the high sodium diet over and above that after medium sodium diet. (2) For any given sodium diet, SHR excreted more DA and NA as compared with WKY. (3) Blood pressure in SHR, as opposed to that in WKY, was higher after medium and high sodium diet than after low sodium diet. (4) During CNS-induced natriuresis NA excretion decreased or remained unchanged in WKY, but increased in SHR. (5) The DA/NA excretion ratio during CNS-induced natriuresis increased in WKY while decreased in SHR, which would not favour a natriuretic/vasodilatory response in the latter. (6) The ability of SHR to respond with CNS-induced natriuresis was attenuated after high sodium diet. (7) The magnitude of CNS-induced natriuresis was in both strains correlated to the sodium diet; the higher the dietary sodium content, the greater the natriuretic response. In conclusion, the study shows some clear differences in the catecholamine and sodium handling between WKY and SHR which may be involved in the pathogenesis of hypertension in SHR. Furthermore, increased sodium in the diet sensitizes the brain and kidney to increase the ability to respond with natriuresis for a given sodium stimulus.     

Renal dopamine and noradrenaline excretion during CNS‐induced natriuresis in spontaneously hypertensive rats: influence of dietary sodium

Abnormalities in dopamine (DA) and noradrenaline (NA) activities and sodium handling may be involved in the pathogenesis of hypertension. The present study was designed to investigate whether any differences exist between normotensive Wistar–Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in urinary excretion of DA, NA and sodium after 15 weeks on a low, medium or high sodium diet and during a subsequent elevation of the cerebroventricular fluid sodium concentration (CNS‐induced natriuresis). Seven features were noted: (1) Basal sodium and DA excretion after the diet regimen was correlated to the dietary sodium content in both strains, except that sodium and DA excretion in SHR showed no further increase after the high sodium diet over and above that after medium sodium diet. (2) For any given sodium diet, SHR excreted more DA and NA as compared with WKY. (3) Blood pressure in SHR, as opposed to that in WKY, was higher after medium and high sodium diet than after low sodium diet. (4) During CNS‐induced natriuresis NA excretion decreased or remained unchanged in WKY, but increased in SHR. (5) The DA/NA excretion ratio during CNS‐induced natriuresis increased in WKY while decreased in SHR, which would not favour a natriuretic/vasodilatory response in the latter. (6) The ability of SHR to respond with CNS‐induced natriuresis was attenuated after high sodium diet. (7) The magnitude of CNS‐induced natriuresis was in both strains correlated to the sodium diet; the higher the dietary sodium content, the greater the natriuretic response. In conclusion, the study shows some clear differences in the catecholamine and sodium handling between WKY and SHR which may be involved in the pathogenesis of hypertension in SHR. Furthermore, increased sodium in the diet sensitizes the brain and kidney to increase the ability to respond with natriuresis for a given sodium stimulus.     

Reflex inhibition of sympathetic activity during volume load in awake normotensive and spontaneously hypertensive rats

The reflex inhibition of the sympathetic activity in the splanchnic nerves was recorded upon volume expansion with blood in awake spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto rats (WKR) at an age of 16–20 weeks. At 10% blood volume expansion SHR showed a significantly greater nerve inhibition (43 %) in comparison with WKR (33 %). This augmented reflex response was not caused by the arterial baroreceptors, because the sensitivity of the arterial baroreceptor reflex arch, if anything, tended to be lower in SHR and the increase in arterial blood pressure upon volume load was also lower in SHR. It is suggested that the reason for this increased reflex inhibition in SHR is an augmented low pressure receptor response. The mechanism behind this is discussed. The most likely explanation is a decreased distensibility of the venous system, the systemic andlor the pulmonary veins.     

Skeletal muscle adaptation to physical training and beta-adrenergic blockade in spontaneously hypertensive rats

Summary The effects of training alone or in combination with long-term, non-selective, -adrenergic blockade on histochemical and biochemical properties of fast-twitch [extensor digitorum longus muscle (EDL)] and slow-twitch [soleus muscle (Sol)] muscle were analyzed in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto strain rats (WKY). Fiber type distribution of Sol was drastically modified in SHR with fewer type I fibers and more type IIA fibers. No such histochemical alterations were observed in EDL. While prolonged swimming training remained ineffective in inducing both histochemical and biochemical improvement in WKY, SHR displayed a significant enhancement of capillarization and oxidative capacity in both Sol and EDL. However, in long-term -blocks rats training failed to improve significantly the oxidative capacity of SHR muscles, suggesting that -adrenoreceptor stimulation is necessary for a fully efficient adaptation of muscular metabolism to physical training.     

Immunological depression in spontaneously hypertensive rats.

Cell-mediated immunity was investigated in spontaneously hypertensive rats (SHR). The thymuses of young SHR rats before developing hypertension had reduced numbers of immature T lymphocytes which were detected by the rosette formation test with guinea-pig erythrocytes in the presence of foetal bovine serum, whereas the thymuses of eight other rat strains tested contained about 60% of rosetting cells. The number of rosetting cells decreased progressively with age. The blastogenic responses to PHA and Con A of the SHR rats' lymphocytes was depressed to less than one-fifth when compared to those of othe rat strains including W/7k rats, the original colony of the SHR rats. Eight-month-old SHR rats showed fewer mitogenic responses than those of 2-month-old SHR rats. Other cell-mediated immune responses, including delayed hypersensitivity, allograft rejections, and a co-operation of T and B lymphocytes to produce humoral antibody formation were depressed significantly when compared to those of other rat strains. Possible mechanisms of immunological depression in the SHR rats in relation to the devleopment of hypertension are discussed.     

Renal tubular reabsorption in spontaneously hypertensive rats.

We characterized renal tubular reabsorption before and during acute expansion in anesthetized 12-wk-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Although mean arterial pressure was higher in euvolemic, nondiuretic SHR than in WKY, 158 vs. 114 mmHg, kidney and nephron glomerular filtration rate (GFR) as well as fluid reabsorption by the proximal convoluted tubule, loop of Henle, and distal convoluted tubule-collecting duct were similar. In euvolemic SHR with aortic constriction (SHR-AC), an acute decrease in renal perfusion pressure to 114 mmHg reduced sodium and water excretion. Kidney and nephron GFR and fluid reabsorption by segments along the nephron resembled values for SHR and WKY. Infusion of isotonic saline (3 ml.100 g body wt-1.h-1) produced similar increases in fractional sodium and water excretion by SHR and WKY, whereas SHR-AC exhibited a blunted natriuresis and diuresis. During expansion, fluid reabsorption by the nephron segments did not differ appreciably among the three groups. The effect(s) of perfusion pressure on reabsorption by superficial nephrons may be covert and was not unmasked, or may be manifested preferentially by deeper nephrons. We conclude that kidneys of SHR require a higher arterial pressure than kidneys of WKY to excrete a given amount of salt and water.     

Renal and nephron hemodynamics in spontaneously hypertensive rats.

Renal and nephron hemodynamics were compared between anesthetized, nondiuretic, spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Although the mean arterial pressure was higher in SHR than in WKY, 158 VS. 114 mmHg, glomerular filtration rate (GFR) and renal blood flow (RBF) were similar in both groups. So were intrarenal hydrostatic pressures, single nephron GFR (SNGFR), and single nephron blood flow (SNBF). Accordingly, the increased renal vascular resistance (RVR) in SHR was due to predominant preglomerular vasoconstriction. In a second group of SHR, SHR-AC, the femoral arterial pressure was reduced acutely to 114 mmHg by means of aortic constriction above the renal arteries. The mean values for GFR, RBF, SNGFR, SNBF, and intrarenal hydrostatic pressures resembled those in SHR, whereas RVR was less in SHR-AC. These autoregulatory adjustments of RVR were again largely limited to the preglomerular vasculature. Efferent arteriolar resistance was similar in all three groups. We conclude that the enhanced RVR in 12-wk-old SHR is primarily a consequence of a physiological, autoregulatory response of afferent arteriolar resistance to the elevated arterial pressure. Further, RVR in SHR is not fixed and constant but responds appropriately to reductions in renal perfusion pressure.     

Kidney and bladder calculi in spontaneously hypertensive rats.

Naturally occurring kidney stones are rare in animals. The Japanese strains of spontaneously hypertensive rats (SHR) are normotensive at birth but develop high blood pressure, hyperglycaemia and hyperlipidaemia as they mature. The SHR strain is prone to develop kidney stones. A unique sub-strain of SHR has been developed in which some animals develop hypothalamic obesity concomitantly with their rising blood pressure, i.e. Obese/SHR. The Obese/SHR characteristically develop microscopic kidney stones which become detached at an early stage of formation, migrate to the bladder, and grow by concretion into huge, rounded calculi. The stone nidus starts as a subepithelial cyst-like focus containing oedema, colloidal acidic mucoprotein, and red and white blood cells suspended on a delicate network of fibrils. THe nidi grow by concretion of an admixture of calcium and acidic protein in a lamellar arrangement. The disparate morphogenesis and anatomic location of kidney stones in Obese is opposed to non-obese/SHR suggest that calculus formation may be governed by specific differences in genetic programming. The incidence of kidney stones parallels the severity and chronicity of the hypertension in SHR, non-obese and Obese/SHR, and the Cushingoid habitus in the Obese/SHR.     

Cerebral function during hypotensive haemorrhage in spontaneously hypertensive rats and Wistar Kyoto rats

Studies on cerebral function during cerebral ischaemia are usually performed on conscious animals after ligation of a major vessel supplying the brain. In this work, we studied somatosensory evoked potentials (SEP) in chloralose-anaesthetized Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) during hypotensive haemorrhage, with the main emphasis on the SHR which are more vulnerable. The main purpose was to see whether haemorrhaged SHR could be used for studies of cerebral function during relative cerebral ischaemia in anaesthetized rats. The mean arterial pressure (MAP) was rapidly lowered to 45-50 mm Hg and maintained at that level by adjustments of bleeding and transfusion. This resulted in pronounced sympathetic inhibition and bradycardia in all rats. In SHR, this sympatho-inhibitory response was usually reversed after about 20 min. In one group of hypertensive rats (SHRt, n = 24), MAP was raised to 75 mm Hg by partial re-transfusion, when heart rate (HR) had returned to the pre-bleeding level and MAP was maintained at that level for the rest of the experiment. All the other rats (SHR, n = 12; WKY, n = 11) were kept at 45-50 mm Hg for 32 min, after which WKY were bled further to a MAP of 30 mm Hg for 8 min. SEP amplitudes decreased after haemorrhage in all groups but more so in SHR. In the WKY group, SEP were only modestly attenuated during the first 32 min, but after further bleeding to 30 mm Hg the amplitudes were reduced to the same extent as in SHR. Some SHR showed flat SEP immediately upon haemorrhage and were excluded from the SHRt group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renin-angiotensin system in stroke-prone spontaneously hypertensive rats.

The development of malignant hypertension was studied in stroke-prone spontaneously hypertensive rats (SHR) kept on 1% NaCl as drinking water. Along with salt-loading, blood pressure gradually increased and reached a severe hypertensive level (greater than 230 mmHg), which was followed by increases in urinary protein (greater than 100 (mg/250 g body wt)/day) and plasma renin concentration (PRC, from 18.9 +/- 0.1 to 51.2 +/- 19.4 (ng/ml)/h, mean +/- SD). At this stage, renal small arteries and arterioles showed severe sclerosis and fibrinoid necrosis. Stroke was observed within a week after the onset of these renal abnormalities. The dose of exogenous angiotensin II (AII) producing 30 mmHg rise in blood pressure increased with the elevation of PRC, from 22 +/- 12 to 75 +/- 36 ng/kg, which was comparable to that in rats on water. The fall of blood pressure due to an AII inhibitor, [1-sarcosine, 8-alanine]AII (10(microgram/kg)/min for 40 min) became more prominent with the increase in PRC in salt-loaded rats, but was not detected in rats on water. These findings suggest that the activation of renin-angiotensin system participates in malignant hypertension of salt-loaded stroke-prone SHR rats that show stroke signs, proteinuria, hyperreninemia, and renovascular changes.     

Lentivirus mediated IL-17R blockade improves diastolic cardiac function in spontaneously hypertensive rats

Background

Hypertension causes cardiac fibrosis characterized by low-grade inflammation. We hypothesized that proinflammatory cytokine, interleukin-17 (IL-17) is important in hypertensive cardiac fibrosis. The pre-ligand assembly domain (PLAD) of IL-17 receptor A (IL-17RA) mediates receptor–chain associations essential for signaling. This study was designed to explore the role of IL-17 RA PLAD in hypertension-induced cardiac fibrosis.

Methods

Eight-week-old male spontaneously hypertensive rats (SHRs) were divided into 2 groups, depending on receiving IL-17RA PLAD-Ig or green fluorescent protein (GFP) lentivirus. Age-matched Wistar Kyoto rats served as controls. Cardiac function was determined by echocardiography. Cardiac hypertrophy and fibrosis were histopathologically examined. Matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP) expression were quantified by immunoblotting. Collagen content was quantified.

Results

Both cardiac systolic and diastolic function and myocardial fibrosis in SHRs was improved significantly by the IL-17RA PLAD. Expression of MMP-2 and MMP-9, TIMP-1 and − 2, type I and type III collagen were statistically decreased by IL-17RA PLAD-Ig treatment. Collagen quantitation, as well as collagen concentration and collagen cross-linking, were reduced by IL-17/IL-17R signal blockade.

Conclusions

IL-17/IL-17RA signaling plays an important role in myocardial collagen metabolism in hypertension-induced diastolic dysfunction.     

Brain catecholamines in spontaneously hypertensive and DOCA-salt hypertensive rats

The concentrations and alpha-methyl-p-tyrosine (alpha-MPT) induced disappearance of catecholamines, adrenaline, noradrenaline and dopamine, were measured in selected areas of the brainstem and hypothalamus of spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The catecholamine levels were measured by a sensitive radioenzymatic assay method combined with microdissection of the rat brain. The adrenaline concentration was higher in the area A1 of young SHR, but not in adult SHR, than in age-matched control rats. Noradrenaline concentrations and the alpha-MPT induced noradrenaline disappearance were less in the rostral part of the nucleus tractus solitarii (NTS) and the nucleus hypothalamic anterior of young SHR, and in the rostral part of the NTS of adult SHR. On the other hand in DOCA-salt hypertensive rats, the concentrations of adrenaline and noradrenaline were the same as in control rats in the examined areas. The alpha-MPT induced noradrenaline disappearance was less in the rostral part of the NTS of DOCA-salt hypertensive rats. Dopamine concentrations and the alpha-MPT induced dopamine disappearance were the same in the examined areas of SHR and DOCA-salt hypertensive rats. The results suggest that SHR have a change in adrenergic neural activity in the brainstem and a decrease in noradrenergic neural activity in the brainstem and hypothalamus while DOCA-salt hypertensive rats have a decrease in noradrenergic neural activity in the brainstem. Such changes in brain catecholaminergic neurons may have played an important role in the development of hypertension in these rats.     

Vascular prostaglandin synthesis in the spontaneously hypertensive rat.

Vascular prostaglandin synthesis was studied in tissues (aorta and inferior vena cava) obtained from spontaneously hypertensive rats (SHRs) of the Aoki-Okamoto strain and age-matched Wistar-Kyoto (WKYs) controls. PGE2 synthesis in aortas from SHRs was significantly enhanced at 10 wk of age (5.3 +/- 0.7 nmol PGE2/mg protein per 10 min vs. 1.9 +/- 0.03 nmol PGE2/mg protein per min in the WKYs, P less than 0.001) and increased progressively until 22 wk of age; PGE2alpha synthesis in SHRs was not significantly different from WKYs. In the venous walls from SHRs, PGF2alpha was the prostaglandin predominantly synthesized (7.1 +/- 0.6 vs. 1.9 +/- 0.05 nmol PGE2alpha/mg protein per 10 min in the WKY controls, P less than 0.01). The activities of 15-hydroxy prostaglandin dehydrogenase and PGE 9-ketoreductase were also compared in the two groups of animals. The only difference detected was a significant increase in venous PGE 9-ketoreductase of SHR's (7.3 +/- 0.06 vs. 4.8 +/- 0.04 nmol PGF2alpha/mg per min, P less than 0.01). The results suggest that increased vascular synthesis of prostaglandins accompanies the development of spontaneous hypertension and may serve to attenuate the effects of blood pressure elevation.     

Behavioral reactivity in spontaneously hypertensive rats

Spontaneously hypertensive rats of the Okamoto strain (SHR) were compared with inbred normotensive rats of the Wistar-Kyoto strain (WKY) and with normally bred Wistar rats (NT) in tests on the audiogenic immobility reaction (freezing), open-field behavior in a dark and an enlightened arena respectively, auditory startle response and male sexual behavior. Compared to the WKYs the SHRs showed increased locomotion and rearing in the open-field situations, reduced startle response and shortened immobility reaction. The SHRs differed in the same way from the NT rats with the exception for motor activity in the dark arena, where no differences were observed. The WKY rats showed less motor activity than the NT animals. Both SH and WKY rats showed shorter latency time for ejaculation than the NT rats. The characteristics of the behavior patterns displayed by the SH rats were interpreted as indicating a reduced propensity for fear reactions in this strain of rats compared to the WKY and NT strains used in the present study.     

Matrix metalloproteinase-9 in spontaneously hypertensive hyperlipidemic rats.

The presence of hypertension and hyperlipidemia accelerates atherosclerosis and increases the risk of ocular disease. Since there were few rat models for atherosclerosis, spontaneously hypertensive rats (SHRs) and spontaneously hyperlipidemic rats (HLRs) were crossbred to obtain a new model: the spontaneously hypertensive hyperlipidemic rat (SHHR). Matrix metalloproteinases (MMPs) play an important role in ocular degeneration. The purpose of this study is to investigate changes in the MMP activities in vitreous and plasma as well as MMP expression in the retinas of SHHRs, which served as a model of vascular degeneration. We used 8-month-old Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats, SHRs, HLRs, and SHHRs. The MMP-2 and MMP-9 activities in plasma and vitreous were examined by zymography. The mRNA expression of MMP-2, MMP-9, and tissue inhibitor of metalloproteinases-3 (TIMP-3) in retina was examined by quantitative PCR. The localized expression of MMP-9 in the retinas was examined by immunostaining. The MMP-9 activity increased significantly in SHHRs compared with all other rats. MMP-9 was observed mainly at the superficial layer of the retina on immunostaining. The MMP-2, MMP-9, and TIMP-3 mRNA in retina was not significantly different in SHHRs as compared with all other rats. Increased MMP-9 activity in vitreous was influenced more intensely from plasma than retina because there was no change in MMP-9 expression in retina, and MMP-9 immunostaining was observed mainly at the surface of the retina, where blood vessels are present. In this study, the complications of hypertension and hyperlipidemia induced increased MMP-9 activity in vitreous and plasma. It is therefore suggested that MMP-9 may be involved in causing this result and in the development of retinal disease.     

Mineral balance and bone histology in spontaneously hypertensive rats.

SHRs (9 weeks old) were fed diets with or without extra NaCl (2%) and were given water or saline (1%) for 7 weeks. Food and liquid intakes were measured weekly. Blood pressure was determined at 9, 11, 13, 15, and 16 weeks of age. The values for body weight gain and food intake were not influenced by any treatment. Liquid intake greatly increased with the surplus of dietary NaCl. The blood pressure increased with age in all treatments. The increase in blood pressure was enhanced by the addition of NaCl to diet and water. Urinary potassium and calcium excretions were enhanced by added dietary NaCl and saline. Calcium content in the femoral bone was not changed by any treatment, although the number of osteoclast and the area of bone marrow were increased by saline supplementation.     

Regional blood flow in normotensive and spontaneously hypertensive rats.

Regional distribution of cardiac output in unanesthetized spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) and Wistar NR male rats (10 each group; average age 21 wk) was determined using two 15-mum microspheres (141Ce and 85Sr) injected 10 min apart through a left ventricular (LV) cannula. Fractional flow distribution was expressed as percentage activity of injected dose (average of the two measurements). Despite differences in body and organ weights, organ flow distribution did not vary between SHR and WKY, except for heart and testes (P less than 0.025). However, differences did not exist between SHR and NR with respect to heart, brain, lungs, spleen, and adrenal flows (P less than 0.05).