Immunologic suppression of carcinogenesis in spontaneously hypertensive rats (SHR) with T cell depression

A strain of spontaneously hypertensive rats (SHR) showed a selective depression of T cell functions brought about by aging. Conversely, this strain had a high NK cell activity as compared to other normal rat strains. This SHR strain was found to be much more sensitive to the carcinogenic activity of low doses of MCA than were WKA rats with normal T cell functions. Allogeneic thymus grafts almost completely restored the T cell functions of SHR, whereas injection of an immunopotentiator, NSP, enhanced NK cell activity and also caused a partial recovering of T cell functions. When immunologic restoration was achieved, generation of killer T cells to syngeneic SMT-5 tumor cells was induced and the cytotoxic activity of NK cells to K-562 cells was also enhanced. But the cytotoxic activity to the SMT-5 cells of NK cells and macrophages from the treated or untreated SHR was not detected. Allogeneic thymus grafts induced a significant transplantation resistance against a syngeneic SMT-5 tumor and injection of NSP enhanced only the survival days of the rats. Allogeneic thymus grafts also significantly suppressed the incidence of tumors induced by MCA, whereas the injection of NSP was not effective in the prevention of tumor development but was effective in prolongation of latency periods. These results support the hypothesis that immune surveillance mediated by T cells is an important mechanism for the control of tumor development.     

Genetic control of blood pressure in spontaneously hypertensive rats (SHR)

Genetic control of blood pressure in the SHR strain was studied by three separate experiments which consist of cross analysis between the SHR and Donryu, two-way selecton for high and low blood pressure levels, and successive backcrosses to the parental strains. The results obtained were as follows. 1. The data from genetic crosses between the SHR and Donryu showed the phenotype segregation ratio of 1:1 at the backcross and 1:2:1 at the F2 generation. 2. Two-way selection for high and low blood pressure levels was performed from the F2 generation onward. The separation between the two lines occurred immediately after the first selection. Thereafter, the difference increased gradually with generation. The blood pressure level at the seventh generation of selection became approximately equal to those of the parental strains. 3. Two types of the successive backcross were performed from the F1 hybrids by mating the males showing the highest blood pressure level to Donryu females and the females showing the lowest blood pressure level to SHR males on the other. Bimodality was observed in the distribution of blood pressure levels at each generation. Their phenotypic segregation ratios were accordant with 1:1 on the whole. At the intercross generation during successive backcrosses, a trimodal distribution was observed. 4. These results confirmed that the hypertensive trait of the SHR is regulated by a single major gene and other several genes with minor effect. A gene symbol ht was proposed for this major gene. Concurrently, a congenic strain having the ht gene on the genetic background of the Donryu was developed by the successive backcross system.     

On the role of NMDA receptors in blood pressure regulation in spontaneously hypertensive rats (SHR)

Summary In the present study the binding of [³H]MK-801 to glutamatergic receptors of the NMDA type was compared in spontaneously hypertensive (SHR) and normotensive (WKY) rats in various brain structures (including nucleus tractus solitarii) by quantitative receptor autoradiography. Additionally, blood pressure changes after treatment with the NMDA antagonist MK-801 were studied in both strains. There were no differences between SHR and WKY rats either in the level of [³H]MK-801 binding or in the hypertensive reaction to MK-801.     

Changes in the blood vessel wall elastin of spontaneously hypertensive (SHR) rats

It has been demonstrated that both elastin and tropoelastin preparations obtained from aortae of spontaneously hypertensive rats at the stage of established hypertension differ in their amino acid composition from age-matching controls. The differences refer to an increased proportion of polar amino acids, particularly aspartic and glutamic acid (about a two-fold increase compared to the controls) and arginine and tyrosine (1.5 times the control value). On the other hand, this increase is compensated for by a decrease in the valine concentration. Furthermore, direct estimation of the number of val-pro sequence in different elastin preparations indicated a drop from 49.3 to 29.2 per 1,000 residues in normotensive controls and preparations obtained from spontaneously hypertensive rats respectively.     

Collagen in the aortae of spontaneously hypertensive (SHR) rats

A biphasic pattern of collagen biosynthesis was found in the aortae of spontaneously hypertensive (SHR) rats; the time course of the rate of biosynthesis is similar to that described in the heart by Sen and Bumpus. In comparison to age-matched controls, collagen biosynthesis is elevated in the SHR rats, diminishes during the first fourteen weeks and rises again at the stage of established hypertension. In the period of established hypertension, the increased rate of collagen biosynthesis was associated with a pronounced rise of the collagen type I to type III ratio. On the other hand, in the pre-hypertensive stage, the proportion of collagen type III clearly exceeds the proportion of collagen type I in SHR rats.     

Long-term intake of edible oils benefits blood pressure and myocardial structure in spontaneously hypertensive rat (SHR) and streptozotocin diabetic SHR

The beneficial effects of edible oils long-term supplementation in blood pressure (BP) and cardiac structure were investigated in spontaneously hypertensive rat (SHR) and streptozotocin diabetic (Db) SHR (45 mg/rat i.p.). Twenty-five 12-week old male SHR were divided into four SHR-Db groups and one SHR group, SHR-Db groups each receiving, respectively, olive oil, palm oil and fish oil, and another SHR-Db group with placebo by gavage on a daily basis for 6 weeks. Myocardial structures were analyzed through light microscopy and stereology. In SHR-Db, the BP and the myocardium were significantly altered by oil supplementation. The BP, the interstitial fibrosis and cardiomyocyte size showed a significant decrease in treated SHR-Db than in SHR or untreated SHR-Db. The myocardial microvasculature and number of cardiomyocytes were higher in all treated groups, especially in fish oil group. Long-term edible oil supplementation showed beneficial effects decreasing BP levels and offsetting adverse myocardial remodeling in diabetic SHR.     

Effect of ibuprofen on systolic blood pressure and aortic PGI2 production in spontaneously hypertensive rats (SHR)

Ibuprofen, at doses of 90, 180, and 360 mg/kg, subcutaneously, produced no statistically significant changes in systolic blood pressure in spontaneously hypertensive rats (SHR) measured over a period of 5–240 minutes, or at 24 hours. Seven-day treatment of SHR with ibuprofen (180 mg/kg, S.C. 2 × day) also had no significant effect. Production of PGI₂-like substance by isolated aortic rings from SHR was inhibited (20–75%) by the drug in concentrations of 1–10 μg/ml. Thus, in doses known to be anti-inflammatory and/or inhibitory of prostaglandin biosynthesis, ibuprofen appears to lack an effect on systolic blood pressure in this paradigm of essential hypertension. This is in contrast to findings indicating other inhibitors of prostaglandin biosynthesis may exacerbate the hypertensive state in SHR and man.     

Changes in elastin composition in aorta of spontaneously hypertensive rats (SHR)

Tropoelastin and elastin preparations obtained from aortae of spontaneously hypertensive rats (SHR) show an increased proportion of polar amino acids (aspartic acid, glutamic acid, arginine and tyrosine). The content of these amino acids is 1.43-3.04 times higher in SHR rats than in similar elastin or tropoelastin preparations obtained from normotensive animals. On the other hand elastin and tropoelastin preparations obtained from SHR rats show a lower frequency of the Val-Pro sequence; this was found to be 35.93 per 1000 amino acid residues in SHR rats as compared to 51.04 per 1000 amino acids in the preparations obtained from control animals. Since similar differences were found not only in elastin preparations but also in tropoelastin, contamination of these preparations with an acidic protein seems unlikely. In general the results obtained are similar to those seen in animals kept on a long term high fat diet. It appears feasible to suggest that these differences are caused by a changed proportion of two different elastin type.     

Antiserum to prolactin lowers blood pressure (BP) in spontaneously hypertensive rats

The role of PRL in the development of hypertension in the SHR was examined by administering PRL antiserum to neonatal SHR. On days 2-7 post partum, male SHR were injected with 50 microliters/day of either antiserum to PRL (which chronically lowers plasma PRL), normal rabbit serum (NRS), or 0.9% NaCl. Heart rate, BP, and body weight were measured biweekly on weeks 6-14 of age. Anti-PRL lowered BP vs. NaCl on weeks 6, 8, 12, and 14 (range 7-17 mm Hg lower). NRS animals showed BP differences from the NaCl group only on weeks 6 and 14, with no consistent effect. Heart rates fell during the study in the NaCl and anti-PRL groups but not in the NRS group. Anti-PRL and NRS groups had higher heart rates than did the NaCl group. Body weights did not differ between groups except on week 14, when the NRS group weighed less than the NaCl group. These results suggest that while PRL is involved in BP regulation in the SHR, it is not involved in the pathogenesis of the genetic hypertension seen in the strain. In addition, the results suggest that the serum treatment may have caused heart damage which led to an elevation in the heart rates of the serum-treated groups.     

Some evidence of enhanced alimentary motivation in spontaneously hypertensive rats (SHR)

The consumption of a wet mash of biscuits or pellets, outside the home cage, was determined in adult spontaneously hypertensive (SHR) and normotensive (NT) Wistar rats. Rats were deprived of food for 24 h or satiated. Regardless of the testing conditions, SHR showed a higher food interest than NT rats, which was reflected in a shorter latency to start eating, a longer time of eating to the first interval as well as to the 30 sec interval which terminated the trial, and a larger amount of food consumed during the test trial. The speed of eating was greater in SHR. In the competition for food SHR won almost all encounters with NT rats. The mean time of eating by SHR increased over the consecutive encounters up to 90%. These findings indicate that alimentary motivation of SHR was higher than that of NT rats. The results are discussed in terms of hyperreactivity of SHR.     

Increased immunoreactive neuropeptide Y in platelets of spontaneously hypertensive rats (SHR)

A high concentration of immunoreactive neuropeptide Y was observed in rat platelets using a specific and sensitive radioimmunoassay for neuropeptide Y. Three kinds of high performance liquid chromatography combined with radioimmunoassay for neuropeptide Y showed that immunoreactive neuropeptide Y in rat platelets is identical to rat authentic neuropeptide Y. To investigate the pathological role of platelet neuropeptide Y in genetic hypertensive rats, the platelet content and plasma concentration of neuropeptide Y were measured by a sensitive radioimmunoassay for rat neuropeptide Y in 5-, 10- and 15-wk old spontaneously hypertensive rat and age-matched Wistar Kyoto rat. Platelet content of immunoreactive neuropeptide Y in 5-, 10- and 15-wk old spontaneously hypertensive rat was higher than that in Wistar Kyoto rat at each age. No difference was observed in plasma concentration of immunoreactive neuropeptide Y between spontaneously hypertensive rat and Wistar Kyoto rat at each age.     

Ontogeny of mitochondrial calcium transport in spontaneously hypertensive (SHR) and WKY rats

The current studies were designed to investigate calcium uptake by intestinal jejunal sacs as well as in intestinal mitochondria of spontaneously hypertensive rats and their genetically matched WKY control rats. Kinetics of jejunal calcium uptake by jejunal sacs of adult SHR and WKY rats showed a significant decrease in Vmax of calcium uptake in SHR (227 +/- 24 versus 423 +/- 22 nmol.g tissue-1.3 min-1) compared to WKY rats P less than 0.001. To explore the intracellular handling of calcium by the intestinal mitochondria, calcium uptake was characterized by intestinal mitochondria before (suckling and weanling periods) and after (adult period) development of hypertension. Calcium uptake by intestinal mitochondria was driven by ATP in the presence of succinate as a respiratory substrate. Calcium uptake was stimulated several fold by the presence of ATP compared to no ATP conditions. Maximal calcium uptake occurred between 15-30 min and was significantly greater in adult SHR and WKY rats compared to corresponding values in weanling and suckling rats. Maximal ATP dependent calcium uptake in adult, weanling and suckling WKY rats was significantly greater compared to corresponding mean values in each age group in SHR (P less than 0.001). Oligomycin (10 micrograms/mg protein) inhibited calcium uptake partially. Ruthenium red (0.25 microM), 1 mM sodium azide and 0.5 mM dinitrophenol inhibited calcium uptake by more than 80% in both SHR and WKY rats. Kinetic parameters for ATP stimulated calcium uptake at 10 s revealed a Vmax of 0.56 +/- 0.6, 3.46 +/- 0.23 and 3.95 +/- 0.52 nmol/mg protein/10 s in suckling, weanling and adult WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic polypeptide (ANP) in the development of spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP)

In order to investigate the pathophysiological role of atrial natriuretic polypeptide (ANP) in genetic hypertensive rats, the atrial content and plasma concentration of ANP were measured by a sensitive radioimmunoassay (RIA) for rat ANP in 5-, 10- and 20-week-old spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) and compared to age-matched Wistar Kyoto rats (WKY). Atrial content of immunoreactive ANP (ir-ANP) tended to be higher in SHR and was already significantly higher in SHRSP than in WKY at 5 weeks of age. Atrial content in the hypertensive strains became significantly higher than in WKY when hypertension developed at 10 and 20 weeks. On the other hand, plasma ir-ANP in SHR was significantly lower than in WKY at 5 weeks, however, it became significantly higher in both SHR and SHRSP than in WKY at 10 and 20 weeks. These findings suggest that ANP release may increase to compensate for the elevation of blood pressure in SHR and SHRSP and that biosynthesis of ANP may be concomitantly stimulated, resulting in an increase in atrial ANP.     

Intestinal calcium transport in spontaneously hypertensive rats (SHR) and their genetically matched WKY rats

Calcium transport across the basolateral membranes of the enterocyte represents the active step in calcium translocation. This step occurs by two mechanisms, an ATP-dependent pump and a Ca2+/Na+ exchange process. These studies were designed to investigate these two processes in jejunal basolateral membrane vesicles (BLMV) of the spontaneously hypertensive rats (SHR) and their genetically matched controls, Wistar-Kyoto (WKY) rats. The ATP-dependent calcium uptake was stimulated several-fold compared with no ATP condition in both SHR and WKY, but no differences were noted between rate of calcium uptake in SHR and WKY. Kinetics of ATP-dependent calcium uptake at concentrations between 0.01 and 1.0 microM revealed a Vmax of 0.67 +/- 0.03 nmol/mg protein/20 sec and a Km of 0.2 +/- 0.03 microM in SHR and Vmax of 0.69 +/- 0.12 and a Km of 0.32 +/- 0.14 microM in WKY rats. Ca2+/Na+ exchange in jejunal BLMV of SHR and WKY was investigated in two ways. First, sodium was added to the incubation medium (cis-Na+). Second, Ca2+ efflux from BLMV was studied in the presence of extravesicular Na+ (trans-Na+). Both studies suggest a decreased exchange of calcium and Na+. Kinetic parameters of Na(+)-dependent Ca2+ uptake at concentrations between 0.01 and 1.0 microM exhibited Vmax of 0.05 +/- 0.01 nanmol/mg protein/5 sec and a Km of 0.21 +/- 0.13 microM in SHR and Vmax of 0.11 +/- 0.02 nanmol/mg protein/5 sec and a Km of 0.09 +/- 0.05 in WKY, respectively. These results confirm that the intestinal BLMV of SHR and WKY rats have two mechanisms for calcium extrusion, an ATP-dependent Ca2+ transport process and a Na+/Ca2+ exchange process. The ATP-dependent process appears to be functional in SHR; however, the Ca2+/Na+ exchange mechanism appears to have a marked decrease in its maximal capacity. These findings suggest that calcium extrusion via Ca2+/Na+ is impaired in the SHR, which may lead to an increase in intracellular calcium concentration. These findings may have relevance to the development of hypertension.     

Depression of T cell-mediated immunity and enhancement of autoantibody production by natural infection with microorganisms in spontaneously hypertensive rats (SHR)

We studied the effects of breeding conditions on the development of immunological abnormalities in spontaneously hypertensive rats (SHR) with congenital T cell depression. The depression of T cell functions, the production of natural thymocytotoxic autoantibody (NTA), and the development of polyarteritis nodosa were more evident in SHR reared under a conventional (CV) environment than in specific-pathogen-free (SPF) SHR bred in a semi-barrier system. Enhancement of these immunologic abnormalities was also observed by the conventionalization of SPF-SHR. A high frequency of antibodies to mouse hepatitis virus (MHV), Sendai virus, and Mycoplasma pulmonis was detected in CV rat sera, whereas no antibodies were detected in SPF-SHR. The experimental infection of Sendai virus induced the enhancement of T cell depression and of NTA production in SPF-SHR. We interpret these results to mean that the natural infection of microorganisms causes an acceleration of immunologic abnormalities in SHR reared in a CV environment.     

Congenital abnormality of pituitary-thyroid axis in spontaneously hypertensive rats (SHR) and stroke-prone rats (SPR).

In an attempt to study whether TSH abnormality was genetically determined in SHR and SPR, plasma T4, T3, TSH and prolactin concentrations were measured in the animals with intervals of 1 to 3 months. Hypertension was found in 6-month-old SHR and SPR, but it was not found in younger animals. In contrast, a decrease of plasma T3 and an increase of plasma TSH were found in 15-day-old SHR. Also, an increase of TSH was found in 1-month-old SPR in spite of normal plasma T3 concentration. These abnormalities in SHR and SPR increased progressively with age. It is suggested that thyroid-pituitary abnormality was genetically determined in SHR and SPR.     

Chronic decrease of blood pressure by rat relaxin in spontaneously hypertensive rats

Relaxin is an ovarian polypeptide hormone which is present in large amounts in the rat during the second half of gestation. During this period, blood pressure declines markedly, especially in spontaneously-hypertensive rats (SHR). To test the hypothesis that relaxin might be implicated in this decrease in blood pressure, we infused the hormone in female non-pregnant rats by means of an osmotic mini pump. Our results show that intravenous infusion of purified rat relaxin (1.8 micrograms/day) markedly reduced systolic blood pressure for at least 5 or 6 days in SHR. This decrease was highly significant from 24 hours after the beginning of the infusion and remained significant after 5 days. Rat relaxin was ineffective in control Wistar-Kyoto rats (WKY). Infusion of purified porcine relaxin (3.0 micrograms/day) also diminished blood pressure in SHR, but the effect was less pronounced and developed more slowly, reaching statistical significance on the fourth day of infusion. SHR not receiving relaxin maintained their original systolic blood pressure throughout the experiment. These results indicate that relaxin is involved in the regulation of blood pressure during gestation.     

Effect of elastase on blood pressure and urinary excretions of prostaglandins and catecholamines in the spontaneously hypertensive rat (SHR)

The effects of elastase on blood pressure (B.P.) and the urinary excretions of prostaglandins (PGs) and catecholamines in the spontaneously hypertensive rat (SHR) were investigated. Male SHRs (n = 20), castrated at 4 weeks of age, were divided into 2 groups. Elastase was then dissolved in saline (5 mg/ml) and injected subcutaneously (10 mg/kg of body weight) into the SHRs of one of the 2 groups (n = 10) at 5 to 13 weeks of age, and the same dose of saline only was injected subcutaneously into the SHRs of the other group (n = 10) as a control during the same period. B.P. was measured by the tail-cuff method every 2 weeks. Urine sampling and measurement of body weight (B.Wt.) were also performed every 2 weeks. The B.P. in the elastase-administered group (184.1 +/- 3.3 mmHg) was found to be significantly lower (p less than 0.02) than that of the control group (198.0. +/- 4.3) at 9 weeks of age. A significant difference (p less than 0.01) in B.P. between the control group (204.0 +/- 4.5) and the elastase-administered group (187.3 +/- 2.7) was also observed at 13 weeks of age. The urinary excretion of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in the control group (5.1 +/- 0.4 ng/day/100 g B.Wt.) at 11 weeks of age was significantly lower (p less than 0.05) than that of the elastase-administered group (10.4 +/- 1.3).(ABSTRACT TRUNCATED AT 250 WORDS)