Normotensive Rat Strains Research Articles

Different changes of N-6 and N-3 fatty acids in adipose tissue from spontaneously hypertensive (SHR) and normotensive rats after diets supplemented with linolenic or eicosapentaenoic acids

In spontaneously hypertensive (SHR) and normotensive rats of the Wistar-Kyoto (WKY) and Wistar-Schönwalde (WSCHOE) strain, diets supplemented with n-3 fatty acids of different chain length α-linolenic acid, LNA- C 18:3, n-3 with linseed oil and eicosapentaenoic acid, EPA - C 20:5, n-3 with cod liver oil) were fed over a period of 22 weeks. After the LNA-rich diet, among the long-chain n-3 fatty acids EPA in epididymal adipose tissue remained unchanged, whereas docosapentaenoic (DPA) and docosahexaenoic acids (DHA) fell. The n-6 fatty acids linoleic (LA) and arachidonic acid (AA) both appeared decreased. After the EPA-rich diet, all n-3 fatty acids, i.e. not only EPA, DPA and DHA, but also LNA were augmented when compared with controls fed commercially available pellets. Among the n-6 fatty acids LA was extremely depressed, whereas AA appeared increased. The p/s-ratio was elevated after the LNA-rich diet, but decreased after the EPA-rich diet. The data indicate a differential effect of dietary n-3 fatty acids of different chain length on the supply of other n-3 fatty acids, of LA and AA as well as on the p/s-ratio in adipose tissue of rats.Blood pressure was not influenced by either diet in either SHR or in both normotensive strains of rats.

Depressor effect of diabetes in the spontaneously hypertensive rat: associated changes in heart performance.

Effects of streptozotocin-induced diabetes (8 weeks) on the performance of perfused hearts from spontaneously hypertensive (SH) rats were compared with effects on normotensive Wistar-Kyoto (WK) and Sprague-Dawley (SD) rat hearts. Diabetes markedly decreased systolic arterial pressure (SAP) of SH rats in vivo but did not affect SAP of either of the normotensive strains. Diabetes also reduced heart size of SH and normotensive rats and reversed absolute left ventricular hypertrophy (wall-to-lumen ratios and left-to-right ventricular weight ratios) of SH rats. Heart perfusion at the end of the 8-week period revealed that diabetes (i) reduced hydraulic work at high pressure loads and efficiency of contraction (work/mu LO2 consumed) of SH rat hearts but not of WK or SD hearts, and (ii) depressed left ventricular pulse pressure development (LVPP) and contractility (LV + dP/dt) of SH hearts more extensively than it reduced these variables in either of the normotensive control groups. Effects of diabetes which were similar in hypertensive and normotensive hearts were reductions in stroke work at high volume loads and depressions in LV-dP/dt. Attendant hypothyroidism probably contributed to the reductions in SAP, heart size, LVPP, LV+ and -dP/dt, and stroke work but not to the decreased efficiency or reversal of hypertrophy of SH rat hearts. Malnutrition of SH rats, like hypothyroidism, also decreased heart size without reversing hypertrophy but had no effect on SAP and only reduced LV-dP/dt. The results show that diabetes reversed hypertrophy and selectively reduced contraction efficiency, contractility, and LVPP of SH hearts, but otherwise the effects of diabetes in hypertensive and normotensive rat strains were similar to each other.(ABSTRACT TRUNCATED AT 250 WORDS)

Proteoglycans and Hypertension I.A Biochemical and Ultrastructural Study of Aorta Glycosaminoglycans in Spontaneously Hypertensive Rats

The extracellular matrix of blood vessel walls contains elastin, collagen, and proteoglycans, all of which can affect vascular resistance and, hence, blood pressure by virtue of their biomechanical properties.In the present study, we have begun to explore the possibility that proteoglycans may play a role in the pathophysiology of hypertension by analyzing, qualitatively and quantitatively, the polysaccharide components of proteoglycans from aorta of two normotensive rat strains, Wistar Kyoto (WKY) and Wistar rats, and from spontaneously hypertensive (SH) rats of the Okamoto strain.The total concentration of aorta glycosaminoglycans in the SH rat was 33% higher than in the WKY rat, due to a 164% increase in chondroitin 4- and 6-sulfate.The content of dermatan sulfate (DS), hyaluronic acid (HA), and heparan sulfate (HS) was similar in the two strains.The 4-wk-old SH rat also had an increase in chondroitin sulfate (CS) compared to the 4-wk-old WKY rat, without any change in DS, HA, or HS.The Wistar rat had approximately the same concentration of CS and DS in the aorta as the WKY rat, but HS and HA were reduced by 62 and 37%, respectively.The galactosaminoglycans (CS and DS) were heterogeneous on cellulose acetate electrophoresis and exhibited a different pattern for each of the three strains.Undersulfated CS accounted for 15 % of the total CS in WKY aorta but was present in only trace amounts in the SH aorta; 2% of the CS from the Wistar aorta was undersulfated.In all three strains, DS was exclusively 4-sulfated, and the CS contained approximately equal amounts of 4- and 6-sulfated galactosamine residues.Ultrastructural studies demonstrated that the HS was localized in the subendothelial matrix and the pericellular region surrounding the medial smooth muscle cells.CS and DS were primarily associated with collagen in the media.In the SH rat aorta the subendothelial matrix was thicker, and there was a relative increase in the CS/DS in the smooth muscle cell pericellular matrix.We suggest that, if similar alterations in CS proteoglycans are present in the resistance vessels, these changes may contribute to the increased peripheral vascular resistance in the hypertensive animal.

Comparison of β-endorphin immunoreactivity in hypothalamic and brainstem nuclei of normotensive and age-matched hypertensive rat strains

The concentration of β-endorphin immunoreactivity was determined in 21 hypothalamic and brainstem nuclei of Sprague-Dawley (SD) and 6 and 14 week Wistar-Kyoto (WKY) and Spontaneously Hypertensive (SH) rats. The concentrations of β-endorphin immunoreactivity were greater in the hypothalamic nuclei than in the brainstem nuclei approximately by a factor of 5. A significant strain-age interaction was observed in the β-endorphin immunoreactivity levels in the anterior hypothalamic area, paragigantocellular reticular nucleus and locus coeruleus of age-matched SH and WKY rats in that immunoreactivity levels fell in the age period studied (6–14 weeks) in WKY rats and rose in SH rats. These biochemical differences are related in time to a growth period during which there are large increases in blood pressure in the SH rat and may thus have a pathogenetic significance.

Allogeneic kidney transplantation after active immunological enhancement: a model to study post-transplantation hypertension in rats.

A model was developed to study post-transplant hypertension after allogeneic kidney transplantation between two inbred normotensive rat strains. Prolongation of graft survival was achieved by 'active immunological enhancement'. Renal function, systolic blood pressure and plasma renin concentration were determined. The systolic blood pressure started to rise in the second week after allogeneic transplantation. The glomerular filtration rate was impaired to a greater extent than the effective renal plasma flow. Histopathological changes occurred indicating immunological reactions in the renal graft. The plasma renin concentration was lower in transplant recipients than in controls. We hypothesize that retention of sodium is mediately involved in the post-transplant hypertension observed in this model.

Serum renotropic activity and renal growth in spontaneously hypertensive rats

Studies performed in the 1950's suggested that a circulating factor controlling renal growth (renotropin) could contribute to hypertension. However, no assay was available to prove its existence. Recently, different assays have been able to demonstrate the presence of a circulating renotropic factor following unilateral nephrectomy in rats. Therefore, we investigated certain aspects of renal growth in SHR, especially serum renotropic activity, and compared these with the same parameters in three strains of normotensive rats (SD, NWR, and WKY). Renal slice and renal DNA synthesis in response to unilateral nephrectomy were not unusual in SHR compared to other strains previously studied. Sera and renal extracts from young SHR following unilateral nephrectomy compared to sera and renal extracts from sham-operated SHR stimulated 3H-thymidine incorporation into the DNA of renal fragments. This pattern was similar to findings when sera and renal extracts from unilaterally nephrectomized SD were investigated, but the sera and extracts from SHR may have shown greater overall stimulation. Interestingly, a relative increase in renotropic activity was found in the serum of untouched SHR (11.1% +/- 1.7 (SEM), P less than 0.001) but not untouched NWR, SD, and WKY. The greatest renotropic activity in SHR was found at 6 to 16 weeks of age (13.5% +/- 2.1 (SEM), P less than 0.001). The previously reported activator found in renal tissue after unilateral nephrectomy was not found to be increased in untouched SHR. No studies were performed on SHR greater than 25 weeks of age. As a first approximation, our investigations are consistent with a previously hypothesis that renotropin may play some role in hypertension.

Reciprocal Embryo Transfer Between Spontaneously Hypertensive and Normotensive Rat Strains: I. Reproductive Characteristics and Transfer Technique

The conditions necessary to achieve successful transfer and development of embryos between two separate genetic lines of Wistar rats, one hypertensive (SHR) and the other normotensive (WKY), were investigated. Prior to determining the technical conditions for transfer, the reproductive characteristics of each strain were studied in order to determine whether they were significantly different. Differences between the two strains were found in ovulation rate, percentage of abnormal pre-implantation embryos and gestation length; litter size and maternal weight gain during pregnancy were not significantly different. For transfers, three protocols for synchrony of embryo and uterine development were tested, and optimal conditions were found to exist with the transfer of day-5 WKY embryos to day-5 SHR pseudopregnant recipients (74% successful pregnancies), and the transfer of day-4 SHH embryos to day-4 pseudopregnant WKY recipients (53% successful pregnancies). The data indicate that some of the reproductive ch...

Effects of hypertension on cardiac performance in rats with myocardial infarction

To determine the effects of hypertension and myocardial infarction on cardiac performance, hemodynamic studies were performed on etheranesthetized, female spontaneously hypertensive rats and on two strains of normotensive rats, Wistar-Kyoto and American Wistar, 26 days after coronary arterial ligation. Baseline measurements of ventricular and arterial pressures and cardiac output (electromagnetic flowmeter) were obtained. Peak cardiac pumping and pressure-generating capacities were determined during a volume load and aortic occlusion, respectively. Infarct size was determined by planimetry. There was a progressive reduction in mean arterial pressure in relation to infarct size in both hypertensive and normotensive rats, but this reduction was twice as great in spontaneously hypertensive rats as in the normotensive rats, such that the arterial pressure of hypertensive rats with a moderate or large infarction decreased to within the “normotensive range.” However, spontaneously hypertensive rats still maintained significantly higher arterial pressures than did normotensive rats at comparable infarct sizes. There was also a progressive reduction in the peak pressure developed during an afterload stress, and this reduction was greater in hypertensive rats than in normotensive rats with a large infarct. Maximal flow-generating capacity was similarly altered in rats with infarction: Peak stroke volume index varied inversely with infarct size and the reduction in this index was significantly greater in spontaneously hypertensive rats than in normotensive rats with a large infarct. Moreover, peak stroke work index was reduced to a greater extent in spontaneously hypertensive rats than in both normotensive strains of rats at any infarct size. Thus, after myocardial infarction, greater reductions in both pressure and flow-generating capacities occurred in hypertensive rats than in normotensive rats.

Urinary prostaglandins in the Lyon strains of hypertensive, normotensive, and low blood pressure rats.

A longitudinal study of the urinary excretion of prostaglandins (PGs) E and F alpha was performed in simultaneously selected hypertensive (LH), normotensive (LN), and low blood pressure (LL) female rats of the Lyon strains aged from 5 to 45 weeks. The urinary excretion of PGE did not significantly differ between LL and LN rats whereas in LH rats it was found to be significantly lower than that of LN or LL rats starting at the age of 32 weeks. The urinary excretion of PGF alpha was significantly reduced in both LL and LH rats; however, this decrease was more marked in LH than in LL animals and, from 9 weeks of age, the urinary PGF alpha were significantly lower in LH than in age-matched LL rats. In addition, both PGE and PGF alpha were found to be significantly and negatively related to the systolic blood pressure level in LH rate (r = -0.56, n = 58, p less than 0.001 for PGE; and r = -0.78, n = 58, p less than 0.001 for PGF alpha) but not in LN of LL animals. In conclusion, it seems unlikely that renal PGs could play a primary role in the spontaneous hypertension observed in the Lyon strain of rats.

Circadian rhythm of circulating glucose, insulin and growth hormone in spontaneously hypertensive rats

Circulating levels of growth hormone (GH), insulin, and glucose were measured at hourly intervals during a 24 h period to establish the diurnal rhythm of these hormones in spontaneously hypertensive rats (SHR). There was no statistically significant correlation between circulating GH levels and pituitary GH content. Serum GH appeared to be higher at night in female SHR and higher during day-light hrs in male SHR. GH levels fluctuated considerably, whereas insulin levels showed much less diurnal variation. Although there was no statistically significant correlation between blood glucose and insulin levels, glucose levels rose and fell considerably during the 24 hr period with a definite decline in blood glucose during the nocturnal hyperactivity observed in SHR. These findings are of interest in that SHR have giant-sized islets of Langerhans, develop hyperglycemia spontaneously, and are growth-retarded compared to most normotensive strains of rat.

Brain aging in normotensive and hypertensive strains of rats. II. Ultrastructural changes in neurons and glia.

A variety of age-related changes occur in the structure of neurons in the cerebral cortex of Wistar-Kyoto and spontaneously hypertensive rats. The most marked alteration associated with increasing age was the deposition of lipofuscin pigment, primarily at the bases of apical dendrites of pyramidal neurons. While no strain-related differences in the amount of lipofuscin pigment were observed in the youngest (3 months) and in the aged (22-27 months) groups of rats, it appeared that hypertensive rats had larger pigment deposits at 12 months of age. At the ultrastructural level, neurons of the aged brains exhibited numerous nuclear invaginations and filamentous nuclear inclusions, increased amounts of Golgi complex and two types of cytoplasmic inclusions. The number of degenerative structures in the neuropil (membranous whorls, dystrophic axons and alterations in myelin sheaths) was also apparently increased in the aged brains. Neurofibrillary tangles were observed in dendritic processes of a 27-month-old Wistar-Kyoto rat. Glial cells accumulated distinctive pigment granules by which the three types of glia could be identified.

Cardiac function and morphology with aging in the spontaneously hypertensive rat.

To determine the effects of a chronic pressure load on cardiac function and morphology, spontaneously hypertensive rats (SHR) and two normotensive strains of Wistar rats (WKY and NWR) were studied under ether anesthesia at 13, 25, 52, and 90 wk of age. Although resting cardiac index of the SHR was comparable to that of WKY and NWR at all ages, the peak cardiac output and peak stroke volume per gram of left ventricle determined during a rapid intravenous infusion of Tyrode solution was markedly reduced in the SHR only at 90 wk of age. Autonomic inhibition did not alter the peak stroke volume attained, but reduced peak cardiac output at all ages in each of the strains. Absolute left ventricular dimensions in the SHR increased out of proportion to body growth, consistent with concentric hypertrophy. As peak pumping ability markedly declined from 52 to 90 wk of age in the SHR, the free wall of the left ventricle greatly thickened whereas the septum remained unchanged. At this time the right ventricle also hypertrophied. This disproportionate thickening of the walls of the left ventricle and the hypertrophy of the right ventricle were reflected in measurements of their fiber diameters. These alterations in ventricular architecture may contribute to the decrease in pumping ability observed in long-standing hypertension.

Ventricular morphology and pumping ability of exercised spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) and two strains of normotensive Wistar rats were subjected to a 5 day/wk swimming program to determine whether the heart of the SHR could respond to an additional stimulus to cardiac growth. Swimming was tolerated well by all rats. Although body weight of the exercised groups was not significantly reduced, both the right and left ventricular weights of all exercised groups were increased. Left ventricular circumference and chamber volume were increased without a change in free wall thickness in all exercised groups. Ventricular performance was assessed by peak cardiac output and stroke volume attained during rapid intravenous volume loading, both before and after autonomic inhibition. After combined cholinergic and beta-adrenergic inhibition, all exercised rats had slower heart rates and higher peak stroke volume than respectively sedentary controls. Thus, exercised SHR had the same alterations in cardiac mass and performance as exercised normotensive rats. Despite the initial presence of left ventricular hypertrophy, the SHR responded appropriately to an additional stimulus for adaptive cardiac growth.

Behavioral suppressant effects of clonidine in strains of normotensive and hypertensive rats

The behavioral effects of orally administered clonidine were investigated in Long—Evans (LE), Sprague—Dawley (SD) or Kyoto Wistar (KW) rats assumed to be normotensive and in NIH spontaneously hypertensive (SH)_ rats. Although clonidine (0.05–1 mg/kg) resulted in the same quanlitative effects, i.e., depression of motor activity, the dose of clonidine required to depress motor activity to 50% of control levels (ED 50) tended to vary according to strain. An analysis of variance of the dose response curves for the foru strains of rats indicated a significant strain effect. When the effects of clonidine on food-reinforced operant responding were investigated, it was observed that SD and SH rats differed with regard to rate and temporal patterning of IRT > 20 sec responding. Although oral administration of clonidine (0.006–.01 mg/kg) procedure similar percentage decreases from control in SH and SD rats, an analysis of the temporal patterning of responding indicated differences in responsiveness to the behavioral effects of clonidine. These studies demonstrate strain-related differences in responsiveness to the behavioral suppressant effects of clonidine. Marked between genetically hypertensive rats and rats assumed to be normotensive were not evident.

Relationship between blood pressure of spontaneously hypertensive rats and alterations in membrane properties of mesenteric arteries.

Spontaneously hypertensive rats (SHR) and two strains of normotensive rats were compared with respect to enzymatic activities and calcium accumulation of plasma membrane and endoplasmic reticulum enriched fractions from their mesenteric arteries. Increased specific activities of alkaline phosphatase, 5'-nucleotidase and Mg2+-ATPase, and increased ATP-dependent calcium accumulation were found in 5- to 6-month-old SHR as compared to both strains fo age-matched normotensive rats. Alkaline phosphatase was increased in 33-day-old "early hypertensive" and 3- to 4-month-old SHR, but 5'-nucleotidase, Mg2+-ATPase, and calcium accumulation were not. Hydralazine treatment of young SHR partially prevented the increase of both alkaline phosphatase activity and blood pressure that develops with age. The relationship between alkaline phosphatase activity and the alterations in vascular reactivity associated with hypertension remains to be determined.

Effect of Timolol on Hydralazine-lnduced Increase in Plasma Renin Activity in Spontaneously Hypertensive and Normotensive Rats

SummaryThe effects ot two β-adrener-gic receptor-blocking agents, timolol and propranolol, on resting PRA and on the hydralazine-induced increase in PRA were studied in SHR and in two strains of normo-tensive rats [Wistar (NWR) and Sprague-Dawley (NSDR)]. With single oral doses, these β-adrenergic-blocking drugs reduced PRA in a dose-dependent manner in SHR but not in NWR or NSDR. After four daily doses, timolol antagonized the hydralazine-induced increase in PRA in SHR and lowered PRA in NWR. Timolol lowered PRA in NSDR only at 10 mg/kg/day p.o. for 4 days. It was concluded that SHR are more sensitive than normotensive rats to the PRA-lowering effects of β-adrenergic-blocking drugs.

Physiological and biochemical concomitants of restraint stress in rats

Restraint stress of 30 min increases plasma CS and lowers hypothalamic NE. Restraints of longer durations are associated with an attenuation of these changes. Daily repetitive restraint enhances the CS response on the second day and progressively diminishes it on subsequent days. Whole brain NE increases on the first day and decreases on Day 2 to 5. The CS response to acute restraint is similar is similar in 5 different normotensive rat strains, but is enhanced in the genetically hypertensive SH rat, its normotensive backbreed WKY, and the DOCA hypertensive Sprague-Dawley rat. Comparison with other stressors (electric foot shock and novel environment) indicate that the responses to restraint are different at least in time course, if not qualitatively.

Regional blood flow and vascular resistance in the spontaneously hypertensive rat.

Blood flow through the superior mesenteric and iliac arteries and the ascending aorta was determined electromagnetically in spontaneously hypertensive rats and in two strains of Wistar normotensive rats (Wistar Kyoto and Wistar Carworth). Regional vascular resistance of the mesenteric and hindlimb circulations and total peripheral resistance were calculated from measurements of blood flow and arterial pressure in pentobarbital anaesthetized male rats 5 to 8 months of age. There was no significant difference between the spontaneously hypertensive rats and either normotensive strain in blood flow index (ml./min/kg) of the superior mesenteric and iliac arteries, or of the ascending aorta. Moreover, the hindlimb/mesenteric resistance ratio was unaltered in the spontaneously hypertensive rats relative to the normotensive controls. These data suggest that a proportionate increase in vascular resistance occurs in the hindlimb and mesenteric circulations of the spontaneously hypertensive rats.

Aggressive behavior in hypertensive and normotensive rat strains

Shock induced fighting, mouse killing, and jump thresholds were measured in gentically hypertensive or hypertensive-prone rat strains and in normotensive and surgically induced (renal) hypertensive rats. Differences in levels of shock induced agression and jump thresholds were observed, but were not a direct effect of hypertension and appeared to be traits genetically separate from the susceptibility to hypertension.

Reactivity to norepinephrine and nature of the alpha adrenergic receptor in vascular smooth muscle of a genetically hypertensive rat

Aortic smooth muscle from the so-called spontaneously hypertensive rat (SHR) did not exhibit supersensitivity or hyperreactivity to norepinephrine compared with two strains of normotensive Wistar rats. The dissociation constant K B of phentolamine reacting with alpha-adrenergic receptors in the aorta of the SHR was very similar to values reported for other alpha receptors. Thus, the adrenergic receptors mediating vascular contraction appear to be nearly identical in both SHRs and normotensive animals. Aortic strips from one strain of normotensive Wistar rat developed about as twice as much tension as either the other normotensive strain or the SHR. If two strains of normotensive rat had not been used as controls, an attempt to relate the degree of tension developed to hypertension in the SHR might have been made. It is clear that studies ulilizing the SHR to analyze mechanisms involved in hypertension must use multiple strains of normotensive rats in order to insure adequate controls.