1,2-Diacylglycerol content in myocardium from spontaneously hypertensive rats during the development of hypertension

Summary 1,2-Diacylglycerol (DAG) has been considered to play an important role as an activator of protein kinase C in the signal transduction of inositol phospholipid metabolism. To examine the relation of 1,2-DAG in heart tissues to cardiac hypertrophy associated with hypertension, we measured the amount of 1,2-DAG in spontaneously hypertensive rat (SHR) hearts at 4,10 and 20 weeks of age, and in age-matched normotensive Wistar-Kyoto (WKY) rat hearts using thin-layer chromatography with flame ionization detection (TLC-FID). Significant cardiac hypertrophy was found in 4-week-old SHR, while SHR did not yet have significant hypertension. Major phospholipids such as phosphatidylcholine and phosphatidylethanolamine increased from 4 to 20 weeks in the myocardium, but there was no difference between the two strains. The cholesterol levels of 4- and 20-week-old SHR were significantly higher than WKY rats. The 1,2-DAG contents of SHR hearts were significantly higher than WKY rats at 4 weeks. An increase in the RNA contents of SHR hearts were significantly higher than WKY rats at 4 weeks. An increase in the RNA content was also observed in 4-week-old SHR hearts. However, analysis of the fatty acid composition of 1,2-DAG revealed no difference between the two strains. However, there was no significant difference in the 1,2-DAG content or in its fatty acid composition between SHR and WKY rat hearts at 10 and 20 weeks of age. It is suggested that an increase in the 1,2-DAG content of SHR hearts during the early stages appears related to the initiation of cardiac hypertrophy in SHR hearts before developed hypertension.     

Pravastatin affects blood pressure and vascular reactivity

Summary To investigate the effect of endogenous cholesterol synthesis on blood pressure and vascular response, a HMG CoA reductase inhibitor, pravastatin (1 or 10mg/kg per day) was administered orally for 2 or 4 weeks to spontaneously hypertensive rats (SHR/lzm) and normotensive Wistar-Kyoto (WKY/lzm) rats. Blood pressure was significantly increased in the pravastatin-treated groups of both strains, occurring in WKY after a longer treatment period than in SHR. The thoracic aortas from SHR and WKY were pretreated with pravastatin (10^–4M). The vascular response to norepinephrine in terms of both contractility and sensitivity, was increased in the pravastatin-treated SHR aorta but not in the WKY aorta. The increased response was not observed in the presence of mevalonate. Acetylcholine-induced vascular relaxation in the aortas from both strains was not affected by pravastatin pretreatment. These results suggest that the vascular response to norepinephrine may be affected by the intracellular cholesterol synthesis pathway.     

Pulse pressure, aortic reactivity, and endothelium dysfunction in old hypertensive rats

The reactivity of old hypertensive rat aortas has not been investigated in relation to each phenotype of the blood pressure curve, mean arterial pressure (MAP), and pulse pressure (PP). Aortic reactivities from 3- to 78-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were studied with the use of organ chambers and invasive blood pressure, carotid diameter, and histomorphometry. MAP and PP were elevated in SHR, but at 78 weeks, a selective increase of PP without further MAP increase was observed for the same carotid diameter as WKY. Aortic relaxation in response to carbamylcholine decreased similarly with age in both strains. With (+) or without (-) endothelium (E), maximal developed tension (MDT) under KCl increased linearly with age in SHR, proportionally to wall thickness and MAP increase. Under norepinephrine (NE), MDT of E(-) aortas from SHR and controls increased with age and reached plateaus at 12 weeks, whereas MDT of E(+) aortas from SHR increased linearly with age. Because the NE-induced MDT was higher for E(-) than E(+), the difference estimated endothelial function. This difference reached plateaus from 12 to 78 weeks in WKY but was abolished beyond 12 weeks in SHR, a finding also observed under NO-synthase inhibition. In old hypertensive rats, (1) increased KCl reactivity is endothelium independent but influenced by the MAP-dependent aortic hypertrophy with resulting increased vascular smooth muscle reactivity, whereas (2) increased NE reactivity is endothelium dependent in association with increased PP, altered endothelial function, and extracellular matrix, with resulting enhanced intrinsic arterial stiffness.     

Changes in cardiac energy metabolism during early development of female SHR

We investigated effects of hypertension and early development on myocardial energy metabolism as reflected by maximal enzyme activities, glucose transporter content, and endogenous substrates in female Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Left ventricular hypertrophy and systolic hypertension were evident in SHR at 6 weeks of age and these differences increased at 14 and 22 weeks of age. 3-Hydroxyacyl-CoA dehydrogenase (HOAD) activity in the left ventricle was 18% lower in 6-week-old rats than both 14- and 22-week-old rats, but not different between WKY rats and SHR. Hexokinase activity was 15% lower in 6-week-old SHR than WKY rats and decreased progressively with age in both strains. Glucose transporter (GLUT) 1 content was nearly twofold greater in 6-week-old rats than both 14- and 22-week-old rats. We found no difference in citrate synthase activity or GLUT4 content among groups. Glycogen concentration was 44% lower in SHR than WKY rats, whereas triglyceride was slightly (16%) higher in SHR than WKY rats. Older animals had higher levels both glycogen and triglyceride than younger animals. We conclude that the left ventricle of both SHR and WKY rats may change from predominantly glucose to fatty acid oxidation for energy production during early development.     

Increases in flow reduce the release of endothelium-derived relaxing factor in the aorta of normotensive and spontaneously hypertensive rats

Experiments were designed to compare basal and acetylcholine-induced release of endothelium-derived relaxing factor at different flow rates in the aorta of the normotensive (Wistar-Kyoto; WKY) and spontaneously hypertensive (SHR) rat. Aortic segments (with endothelium) of either WKY or SHR were perfused at different flow rates (1 or 4 mL/min) with modified Krebs-Ringer solution; the relaxing activity of the perfusate from the two types of segments was bioassayed by measuring the isometric force in rings (without endothelium, and contracted with norepinephrine) of aortas of both WKY and SHR. All studies were performed in the presence of indomethacin to prevent endothelial production of prostacyclin and other vasodilator prostanoids. The basal release of endothelium-derived relaxing factor was not significantly affected by the flow rate in either the WKY or the SHR aortas. At the two flow rates, and with both types of bioassay rings, the basal release of endothelium-derived relaxing factor was smaller with SHR than with WKY aortas, but this reached significance only at 4 mL/min using the SHR-aorta as bioassay tissue. Both with WKY and SHR aortas the release of endothelium-derived relaxing factor evoked by acetylcholine was significantly larger at 1 than at 4 mL/min; no significant differences in responsiveness to acetylcholine were noted between WKY and SHR segments. There was also no difference in responsiveness of WKY and SHR bioassay rings to acetylcholine and acetylcholine-induced release of endothelium-derived relaxing factor. These experiments suggest that prolonged exposure to increases in shear stress reduces the ability of the endothelium to release endothelium-derived relaxing factor in responses to muscarinic activation.     

Endothelium-derived contracting factor released by serotonin in the aorta of the spontaneously hypertensive rat.

Contractions to serotonin are augmented in aortas with endothelium from spontaneously hypertensive rats (SHR) compared to normotensive controls (WKY). Experiments were designed to determine whether this is due to the release of a vasoconstrictor prostanoid from the endothelium. Rings of aortas with and without endothelium were taken from SHR and WKY and suspended in organ chambers for isometric tension recording. Contractions to serotonin were similar in rings without endothelium from both strains. The presence of the endothelium reduced the contractions to all concentrations of serotonin in the WKY; in the SHR the endothelium inhibited only the response to lower concentrations of serotonin. Indomethacin (or meclofenamate) reduced the contractions to high concentrations of serotonin only in rings from SHR with endothelium; it did not affect the response in SHR rings without endothelium or in rings from WKY (with and without endothelium). The endothelium inhibited contractions to norepinephrine only in the presence of indomethacin in both strains. These experiments suggest that serotonin stimulates the release of vasoconstrictor prostanoids from the endothelium of the SHR but not from the WKY aorta. Norepinephrine may release endothelium-derived contracting factor(s) in both strains.     

Norepinephrine overflow in perfused mesenteric arteries of spontaneously hypertensive rats

We examined the overflow of endogenous norepinephrine with electrical stimulation, the associated pressor response, and rate of initial neuronal uptake of [3H]norepinephrine in perfused mesenteric arteries of 7- and 13-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. The tissues of two rats, a spontaneously hypertensive and a WKY control rat, were simultaneously processed and subjected to the same electrical stimulation. Both absolute and fractional overflow of endogenous norepinephrine during periarterial nerve stimulation (5 and 10 Hz for 1 minute) in the tissue of 7-week-old SHR was significantly greater whereas overflow of 13-week-old SHR was equivalent as compared with that of the age-matched WKY rats. The tissue content of norepinephrine was 20-25% higher in SHR of both ages. There was significantly enhanced [3H]norepinephrine uptake in the tissues of young SHR, but no difference was observed in the older SHR. The pressor response to periarterial nerve stimulation was significantly enhanced in 7-week-old SHR and much more so at the older age as compared with the WKY control rats. Exogenous norepinephrine dose-response curves in the tissues of 7-week-old SHR exhibited a parallel leftward shift, characteristic of a change in sensitivity, whereas that of 13-week-old SHR showed a much steeper slope as compared with the respective WKY control rats. This finding suggests that in addition to smooth muscle supersensitivity, structural alterations had occurred in vasculature of 13-week-old SHR. These data indicate that in SHR both the exocytotic release of norepinephrine and the responsiveness of the vascular smooth muscle cells are enhanced in the developmental stage of hypertension whereas smooth muscle supersensitivity to norepinephrine and nonspecific structural alterations primarily contribute to the maintenance of hypertension at 13 weeks of age.     

A comparison of CNS angiotensin II binding in the hypothalamus-thalamus-septum-midbrain region of developing spontaneously hypertensive and normotensive rats

Specific angiotensin II (ANG II) binding was studied in brain homogenates from the hypothalamus-thalamus-septum-midbrain (HTSM) region of age-matched 4-, 8-, 12- and 16-week spontaneously hypertensive rats (SHR) and their normotensive controls, Wistar-Kyoto (WKY) rats, using 125I-angiotensin II. Scatchard analysis revealed that the dissociation constants (Kd) ranged from 0.36 to 0.73 nmol/l, although these values were not significantly different at any given age period between the SHR and WKY rats. In contrast, a statistically significant increase in ANG II receptor binding was seen between the SHR and WKY rat at 4 weeks of age. However, this difference was not observed at older age periods. Furthermore, both the SHR and WKY rat showed a decrease in ANG II receptor levels during development, with the most marked reductions occurring between 12 and 16 weeks of age for both strains. These findings suggest that ANG II receptors in the HTSM region of both the SHR and WKY rat are down-regulated during development, that receptor loss is more significant in the SHR than in its normotensive control and that binding capacity differences between the two strains are only seen before the onset of measureable increases in the arterial pressure of the SHR. We conclude that there is a significant difference in the ANG II binding capacity during the development of hypertension in the SHR as compared with the WKY rat and therefore it may play a role in the pathogenesis of this disorder.     

Differential development of vascular and cardiac hypertrophy in genetic hypertension. Relation to sympathetic function

We compared blood pressure, hindquarter vascular resistance properties, left ventricular weight, and norepinephrine kinetics, in spontaneously hypertensive rats (SHR) and weight-matched normotensive Wistar-Kyoto (WKY) rats at 4, 9, 14, 20, 30, and 50 weeks of age. At 4 weeks, systolic and mean blood pressure measurements were the same in both strains, but the vascular resistance of the fully dilated hindquarter bed was significantly higher in SHR than in WKY rats, with a much larger difference during maximum constriction. Plots of resistance at maximum dilatation and at maximum constriction against body weight suggest that a component of the increase in vascular muscle mass in SHR occurred in the neonatal period preceding hypertension followed by a later component related to the rise in blood pressure. By contrast, left ventricular hypertrophy was minimal at 4 weeks and most of its development paralleled the rise in blood pressure. Sympathetic activity, assessed by norepinephrine fractional rate constant, was higher in SHR than in WKY rats in the left ventricle and kidney through most of the period between 4 and 50 weeks, but was similar in both strains in the muscle bed. This pattern of sympathetic activity will accentuate hypertension once cardiac and vascular hypertrophy are fully established. In all regions, norepinephrine tissue concentration was higher in young SHR and could potentiate the trophic effects of growth factors in early vascular hypertrophy. We suggest that the initial (primary) component of vascular hypertrophy precedes the rise in blood pressure and may be critical in the pathogenesis of hypertension. Possible reasons for the short delay in the rise in blood pressure in young SHR, once the vascular "amplifier" has been established, include high vascularity, immaturity of smooth muscle, and delay in the development of left ventricular hypertrophy.     

Altered gene expression of prostacyclin synthase and prostacyclin receptor in the thoracic aorta of spontaneously hypertensive rats.

OBJECTIVE: The aim of this study was to evaluate the possible role of prostacyclin (PGI2) in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). METHODS: Measurement of mRNA and protein levels of PGH synthase (PGHS)-1, PGI2 synthase and the PGI2 receptor, in the thoracic aorta was performed in SHR aged 5, 10, 20, and 40 weeks old and in age-matched normotensive Wistar-Kyoto (WKY) rats with a competitive polymerase chain reaction method and immunoblotting. Aortic production of 6-keto-PGF1 alpha, the main metabolite of PGI2, was also measured. RESULTS: Compared with age-matched WKY rats, PGHS-1 mRNA and protein levels in the thoracic aorta of SHR increased with age, reaching three- and twofold higher than WKY rats at 40 weeks old, respectively. PGI2 synthase mRNA and protein levels in SHR were significantly higher than in WKY rats at 20 and 40 weeks old. In contrast, PGI2 receptor mRNA levels in SHR were consistently lower than in WKY rats at all ages. CONCLUSIONS: These results provide evidence that hypertension elicits alterations in levels of arachidonic acid metabolites, including PGH2 and PGI2. They also suggest that the decreased expression of PGI2 receptor mRNA in prehypertensive SHR could be one of the causes of hypertension in SHR.     

A high phosphate diet lowers blood pressure in spontaneously hypertensive rats

Plasma phosphate values are significantly lower in spontaneously hypertensive rats (SHR) than in normotensive Wistar-Kyoto rats (WKY). In this study, we increased plasma phosphate in SHR by a dietary phosphate intake and followed the effects on blood pressure. Fifteen male WKY and 15 male SHR were housed from 4 weeks of age up to 26 weeks. At 4 weeks of age all SHR manifested a hypophosphatemia compared with age-matched WKY (F = 62, p less than 0.0003). At 5 weeks of age, the rats were divided into three diet groups: a control group, a group receiving 1.41% (wt/vol) KCl in drinking water, and a group receiving 2% (wt/vol) K2HPO4 X KH2PO4 in drinking water. In the control (F = 16.2, p less than 0.02) and KCl groups, (F = 36.3, p less than 0.03), hypophosphatemia persisted throughout the study. The phosphate-supplemented diet normalized plasma phosphate level in SHR but did not change plasma phosphate level in WKY. As a consequence, no difference in plasma phosphate level between WKY and SHR was present in the group receiving additional phosphate from that time on (F = 1.2, p greater than 0.41). The phosphate-supplemented diet significantly decreased systolic blood pressure in both strains. In phosphate-supplemented SHR, a significant decline in systolic blood pressure was observed from 20 weeks of age on (at 20 weeks of age: 222 +/- 3 mm Hg for control SHR vs 198 +/- 5 mm Hg for phosphate-supplemented SHR; p less than 0.0003).(ABSTRACT TRUNCATED AT 250 WORDS)     

Norepinephrine release and reuptake by hypothalamic synaptosomes of spontaneously hypertensive rats

We compared the overflow of endogenous norepinephrine during electrical field stimulation, the norepinephrine content, and the rate of initial neuronal uptake of [3H]norepinephrine in synaptosomes isolated from hypothalamus and brainstem of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at 7 and 13 weeks of age. The synaptosomes of two rats, a SHR and a WKY rat control, were simultaneously processed and subjected to the same electrical field stimulation. The overflow of endogenous norepinephrine during electrical stimulation (2 Hz, 2 minutes) in the hypothalamic synaptosomes of 7-week-old SHR was significantly greater, whereas the overflow of 13-week-old SHR was equivalent to the age-matched WKY rat. The norepinephrine content of synaptosomes was about the same in SHR and age-matched controls. There was also significantly enhanced [3H]norepinephrine uptake in the hypothalamic synaptosomes of young SHR, but neither the hypothalamic nor the brainstem samples of 13-week-old SHR showed any significant difference in their rate of [3H]norepinephrine uptake. These data are similar to those we observed (unpublished observations) in perfused mesenteric artery system in which norepinephrine release was significantly elevated during periarterial nerve stimulation only in young SHR. Thus, these results suggest that a parallel enhancement of norepinephrine release in hypothalamus with that of peripheral nervous system may play an important role during development of hypertension in young SHR.     

Enalapril can prevent vascular amplifier development in spontaneously hypertensive rats

Three groups of spontaneously hypertensive rats (SHR) were given enalapril (25 mg/kg/day) from 4 to 9 weeks, 4 to 14 weeks, and 14 to 20 weeks of age. The drug was stopped and observations continued for another 16-21 weeks. At selected times, we measured blood pressure, in vitro hindquarter vascular resistance properties, left ventricular weight/body weight ratio, and skeletal muscle vessel norepinephrine kinetics in treated and untreated SHR and in Wistar-Kyoto (WKY) rats. At the end of each treatment period, all cardiovascular variables were close to values of WKY rats and well below those of untreated SHR, and the norepinephrine or fractional rate constant was about 25% below those levels. After enalapril was stopped, blood pressure and left ventricular weight/body weight ratio increased in parallel to levels ranging from 30% to 50% of the normal difference between untreated SHR and WKY rats. However, in SHR treated from 4 to 9 weeks and from 4 to 14 weeks of age, hindquarter resistance properties remained close to WKY rat levels for the entire observation period of 16-21 weeks after treatment, suggesting suppression of the enhanced resistance responses of SHR (amplifier properties). In SHR treated from 14 to 20 weeks of age, suppression of amplifier properties was more transient, and they redeveloped partially 5-6 weeks after cessation of therapy. When enalapril was given up to 14 weeks of age, the long-term suppression of amplifier properties was probably mainly through prevention of smooth muscle hypertrophy in resistance vessels and possibly through other mechanisms (e.g., "rarefaction").(ABSTRACT TRUNCATED AT 250 WORDS)     

Age-related changes in neuropeptide Y immunoreactivity (NPY-ir) in the cortex and spinal cord of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats

The concentrations of neuropeptide Y immunoreactivity (NPY-ir) were measured in the cortex and cervical, thoracic and lumbar spinal cord of 8-, 18- and 31-week-old normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). This peptide was measured using a highly sensitive and specific radio-immunoassay (RIA) developed in our laboratory. The concentrations of NPY-ir in the cortex, cervical and thoracic spinal cord were significantly different between the two strains, with the levels being consistently lower in the SHR strain independent of age. While there was no obvious change in the levels of NPY-ir in the cortex with increasing age, there was a general trend for the levels to fall in all three spinal cord regions. The rate of decrease of NPY-ir in the thoracic spinal cord appeared greater in the SHR compared with the WKY rats. These biochemical differences observed in the cortex and thoracic spinal cord of SHR and WKY rats may be related to the behavioural and blood pressure differences observed in these strains.     

The measurement of central noradrenergic activity in spontaneously hypertensive rats: a comparison of free 3,4-dihydroxyphenylethyleneglycol levels with FLA-63 induced noradrenaline depletion

Noradrenergic activity was measured in the brainstem, hypothalamus and thoracic spinal cord of male and female spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats at 6 and 28-36 weeks of age. Two techniques were used, measurement of a major noradrenaline (NA) metabolite, free 3,4-dihydroxyphenylethyleneglycol (DHPG), and measurement of the rate of decline in brain NA levels following dopamine-beta-hydroxylase (DBH) inhibition by FLA-63. There was a good correlation between the changes with age in NA turnover measured by the two techniques. NA levels and NA turnover measured by both techniques fell with age in brainstem and thoracic spinal cord in both SHR and WKY rats. In both strains these falls in turnover were associated with increases in blood pressure. However, the increase in blood pressure in the SHR was greater than in the WKY, even though NA turnover fell to a similar extent in both strains. These data show a difference in the pattern of change in NA levels and turnover in the brainstem and thoracic spinal cord compared to other brain regions and may therefore be related to the development of higher levels of blood pressure in older rats in both strains. They do not offer a simple explanation for the much higher blood pressures seen at all ages in the SHR.     

Heart size in inbred strains of rats. Part 2. Cardiovascular DNA and RNA contents during the development of cardiac enlargement in rats

Enlargement and nucleic acid content of the cardiovascular system of several strains (SHRSP/N, SHR/N, OM/N, M520/N) of rats were compared with the WKY/N strain in an attempt to characterize cardiac enlargement. Cardiac enlargement in rats can be due to either hypertrophy (increase in myocyte size), hyperplasia (increase in cell number including supporting tissue), or a combination of both. The sum of the indices of the degree of hypertrophy and hyperplasia calculated from the difference of the heart and aorta deoxyribonucleic acid (DNA) concentration and total DNA content between each strain and the WKY/N was almost equal to the degree of heart and aorta enlargement. The SHRSP/N revealed a striking hypertrophy of myocardial cells from the prehypertensive stage, and hyperplasia appeared gradually with the elevation of blood pressure. In contrast, the SHR/N developed a marked hyperplasia with some hypertrophy at the prehypertensive stage. Cardiac enlargement of the OM/N was attributed to both hypertrophy and hyperplasia. A large heart weight of the M520/N was recognized at only a young age, and was due almost entirely to hyperplasia. Aortic enlargements were related to hyperplasia. An increased ribonucleic acid (RNA) concentration was observed in both ventricles of the SHRSP/N, SHR/N, and M520/N rats at 4 weeks of age, and in all of the four strains at 16 weeks of age. A significantly higher RNA concentration was indicated in the aorta of three hypertensive strains of SHRSP/N, SHR/N, and OM/N at established hypertensive stage. These changes might be related to manifestations of genetic or other factors such as the effect of elevated blood pressure.     

Contractions to Endothelin in Normotensive and Spontaneously Hypertensive Rats: Role of Endothelium and Prostaglandins

Contractions to endothelin-1 in aortas of the spontaneously hypertensive rats (SHR) were compared with those of normotensive controls (WKY); rings with and without endothelium were studied in organ chambers. Contractions to endothelin were smaller in aortas of SHR compared to WKY, whether the endothelium was present or not. The presence of a functional endothelium reduced contractions to the peptide in both strains. Endothelium-dependent relaxations to acetylcholine and endothelium-independent relaxations to nitric oxide were observed in rings from both strains during contraction with endothelin. Indomethacin reduced the contractions to endothelin in the aorta from SHR with endothelium, but not in those without endothelium; it did not significantly affect endothelin-induced contractions in rings of WKY with or without endothelium. These experiments demonstrate that contractions of the vascular smooth muscle to endothelin are reduced in the aorta of the SHR. The basal and stimulated release of endothelium-derived relaxing factor inhibits contractions to endothelin in the aorta from both strains. The inhibitor of cyclooxygenase indomethacin does not prevent the response of the vascular smooth muscle to endothelin; however, endothelin may stimulate the release of an indomethacin-sensitive endothelium-derived contracting factor in the SHR aorta.     

In vivo DNA synthesis is not uniformly increased in arterial smooth muscle of young spontaneously hypertensive rats.

We compared the distribution of DNA synthesis over the arterial tree of young normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) with marginally elevated blood pressure. Six-week-old male SHR and WKY rats were therefore infused with 5-bromo-2'-deoxyuridine (BrdUrd) for 2 days and the nuclear incorporation of the thymidine analogue in the media of various arteries was determined by immunohistochemistry. In WKY rats, 2.5% of the arterial smooth muscle nuclei in elastic, muscular and resistance arteries incorporated BrdUrd. In SHR, DNA synthesis was more marked in large arteries than in resistance arteries. It was in addition significantly larger in the aorta, superior mesenteric, renal and femoral arteries of the SHR than in those of the WKY rats. However, nuclear incorporation of BrdUrd in vivo did not differ between SHR and WKY rats in aortic endothelium, carotid arterial smooth muscle, nor in mesenteric or renal resistance arteries. Between 6 and 20 weeks of age, the number of nuclear profiles per media cross-section did not increase in large arteries of WKY rats and SHR. During this period of time, however, carotid artery and thoracic aorta weight and DNA content increased. SHR large arteries gained more DNA than those of WKY rats. These data indicate that DNA synthesis is uniformly distributed over the arterial system in young WKY rats and that DNA synthesis is elevated in the smooth muscle of large arteries of 6-week-old SHR but not in their resistance arteries.     

Thymectomy delays the development of hypertension in Okamoto spontaneously hypertensive rats

Previous studies in rats have demonstrated that immune system dysfunction contributes to the aetiology of spontaneous hypertension. Chronic immunosuppression with cyclophosphamide attenuated the level of hypertension in Okamoto spontaneously hypertensive rats (SHR) by approximately 50%. Also, neonatal thymic implants delayed the development of spontaneous hypertension and significantly attenuated its level at the age of 22 weeks in SHR. In the present study, the effect of thymectomy at the age of 4 weeks on blood pressure was investigated in SHR and Wistar-Kyoto (WKY) rats. The removal of the thymus gland in 4-week-old SHR produced a significant reduction in systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and mean arterial pressure (MAP) when rats were 16-19 weeks old, while no pressure reduction was observed in WKY rats. The decrease in arterial pressure of 16-week-old SHR was associated with a significant reduction in lymphocyte count at this age as compared with the control group. In 1-year-old SHR, thymectomized at the age of 4 weeks, there was no significant difference in arterial pressure or lymphocyte count compared with controls. These data support the hypothesis that an immune imbalance may be important in the development of spontaneous hypertension. We conclude that thymectomy at a young age (4 weeks) delays the development of hypertension in SHR.     

Noradrenergic mechanisms in the brain and peripheral organs of normotensive and spontaneously hypertensive rats at various ages

Previous studies of noradrenergic mechanisms in spontaneously hypertensive rats (SHR) have yielded conflicting results, as many have used: 1) rats of only one age; 2) a single organ such as heart or brain; or 3) either Wistar-Kyoto (WKY) or an outbred normotensive control rat. We have studied the turnover of norepinephrine (NE) in three brain areas (cortex, hypothalamus, brain stem) and three peripheral organs (duodenum, skeletal muscle, kidney) of SHR, WKY, and Wistar rats at 5, 9, and 18 weeks of age. The rate of decline of norepinephrine [NE] in tissue was determined with a fluorescence assay at 0, 2, 4, and 8 hours after inhibition of tyrosine hydroxylase with alpha-methyltyrosine. Differences in NE turnover were inferred by comparing slopes of regression lines calculated for the plot of log [NE] (expressed as a percent of the initial concentration) vs time. Systolic arterial pressure of SHR was similar to that of WKY and Wistar rats at 5 weeks of age, but increased to 150 mm Hg by 9 weeks and reached an average of 190 mm Hg by 18 weeks. The turnover of NE in 5-week-old SHR compared to two normotensive strains was significantly lower in the cortex and significantly higher in the kidney and skeletal muscle. By 9 weeks, in SHR, NE turnover had increased significantly in the hypothalamus and brain stem, while decreasing significantly in the kidney and duodenum. No such changes were seen in these organs of WKY or Wistar rats when comparing turnover of NE at 5 and 9 weeks. At 18 weeks, there were no further differences in the organs of SHR when compared to values obtained at 9 weeks. These data support the hypothesis that the turnover of NE may be altered in central and peripheral organs of young SHR, and may initiate or contribute to the development of hypertension. Changes in turnover of NE in the brain and peripheral organs between 5 and 9 weeks in SHR suggest compensatory responses to increasing arterial pressure; however, similar changes in turnover were not seen between 9 and 18 weeks, although arterial pressure continued to increase.