Effects of chronic oral treatment with imidapril and TCV-116 on the responsiveness to angiotensin II in ventrolateral medulla of SHR.

OBJECTIVE: To examine whether chronic oral treatment with an angiotensin-converting enzyme inhibitor imidapril and an angiotensin II type 1 receptor antagonist TCV-116 would alter the response to angiotensin II in the rostral ventrolateral medulla. METHODS: Twelve-week-old spontaneously hypertensive rats (SHR) were treated with imidapril (20 mg/kg per day, n = 7), TCV-116 (5 mg/kg per day, n = 8) or vehicle (n = 8) for 4 weeks. Wistar- Kyoto rats (WKY) (n = 8) served as normotensive controls. At 16 weeks of age, angiotensin II (100 pmol) was microinjected into the rostral ventrolateral medulla of anaesthetized rats. RESULTS: Blood pressure decreased significantly in the rats treated with either imidapril or TCV-116. Pressor responses to angiotensin II microinjected into the rostral ventrolateral medulla were comparable in the untreated SHR, the imidapril-treated SHR and WKY (12 +/- 2, 15 +/- 4 and 10 +/- 1 mmHg, respectively), but were abolished in SHR treated with TCV-116 (0 +/- 2 mmHg, P< 0.01). Angiotensin-converting enzyme activity in the brain stem was significantly lower in SHR treated with imidapril (0.70 +/- 0.06 nmol/mg per h), but significantly higher in SHR treated with TCV-116 (1.62 +/- 0.04 nmol/mg per h) than in the untreated SHR (1.37 +/- 0.05 nmol/mg per h). CONCLUSIONS: Chronic oral treatment with imidapril and TCV-116 may have divergent influences on the renin-angiotensin system within the brain stem. TCV-116, but not imidapril, abolishes the pressor effect of angiotensin II in the rostral ventrolateral medulla.     

Role of Angiotensin II in Reflex Tachycardia During Hypotension Caused by a Calcium Channel Blocker

Blood pressure and heart rate were measured by telemetry in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) to investigate the contribution of angiotensin II to the reflex tachycardia resulting from exaggerated hypotension caused by a high dose of a calcium channel blocker. Pre-treatment with TCV-116, an angiotensin II AT1 receptor antagonist, or enalapril partially attenuated the reflex tachycardia induced by manidipine, but TCV-116 had almost no effect on the sinus tachycardia induced by isoproterenol. The suppressive effects of TCV-116 against the reflex tachycardia tended to be more obvious in WKY than in SHR, though the difference was not statistically significant. Concurrent administration of propranolol almost completely inhibited both the reflex tachycardia and the sinus tachycardia in SHR and WKY, indicating that the sympathetic nervous system contributes to both types of tachycardia. We demonstrated that angiotensin II may be involved in the reflex tachycardia induced by calcium channel blockers probably via activation of some component of the sympathetic nervous system other than postsynaptic factors at the sinus node.     

Renal angiotensin II receptor regulation and renin-angiotensin system inhibition in one-kidney, one clip hypertensive rats

OBJECTIVE: To characterize glomerular and preglomerular vascular angiotensin II receptors during the acute phase of nonrenin-dependent one-kidney, one clip hypertension in rats, using the angiotensin II antagonists losartan and PD 123319, and to investigate their regulation after renin-angiotensin system blockade with either an angiotensin converting enzyme inhibitor, captopril, or an angiotensin II receptor antagonist, TCV-116. MATERIALS AND METHODS: One-kidney, one clip hypertension was produced in male Sprague-Dawley rats by placing a silver clip (internal diameter 0.2 mm) on the left renal artery and removing the contralateral kidney. After 1, 2 or 4 weeks, the rats were killed, and their glomerular and preglomerular vascular membranes were purified. Competitive binding studies were performed using specific angiotensin II antagonists. Similarly, one-kidney, one clip hypertension was allowed to develop for 2 weeks before treatment with captopril or TCV-116 for 2 weeks. RESULTS: Competitive binding studies showed that only the angiotensin II type 1 (AT1) receptor was detected on both glomeruli and preglomerular vessels of all groups. The vascular AT1 receptor density was significantly higher in the 1 and 2 week one-kidney, one clip groups, but the glomerular receptor density was not different in these rats compared with age-matched uninephrectomized controls. The glomerular receptor density was significantly higher in captopril-treated rats and significantly lower in TCV-116-treated rats compared with untreated and control rats, but no significant changes were detected in any groups in vascular AT1 receptor density. CONCLUSIONS: Angiotensin II receptors on preglomerular vessels and glomeruli are differentially regulated during the early phase of hypertension and after renin-angiotensin system blockade. Vascular angiotensin II receptors are upregulated in the early phase of hypertension whereas glomerular angiotensin II receptors are not However, after renin-angiotensin system blockade, glomerular but not vascular angiotensin II receptors were differentially regulated according to the type of blockade.     

Chronic antisense therapy for angiotensinogen on cardiac hypertrophy in spontaneously hypertensive rats

OBJECTIVE: We examined the effect of the suppression of plasma angiotensinogen (AGT) by the intravenous injection of antisense oligodeoxynucleotides (ODNs) against AGT targeted to the liver on cardiac remodeling in spontaneously hypertensive rats (SHR). The ODNs against rat AGT were coupled to asialoglycoprotein (ASOR) carrier molecules, which serve as an important method for regulating liver gene expression. METHODS: Male SHR (n = 18), and age-matched male Wistar-Kyoto rats (WKY, n = 6) were used for this study. At 10 weeks of age, the SHR were divided into three groups (each group n = 6), and the systolic blood pressure (SBP) did not significantly change among them. The control SHR and WKY groups received saline, the sense SHR group was injected with the sense ODNs complex and the antisense SHR group was injected with the antisense ODNs complex, from 10 to 20 weeks of age. ASOR-poly(L)lysine-ODNs complex was injected via the tail veins twice a week. RESULTS: At the end of the treatment, a reduction of hepatic AGT mRNA, cardiac angiotensin II type 1 receptor mRNA and the plasma AGT concentration was only observed in the antisense-injected SHR but not in the other groups of SHR and WKY. This antisense therapy did not significantly change the mRNA expression for angiotensin converting enzyme, angiotensin II type 2 receptor and AGT in the left ventricle (LV) among all three groups. Although the plasma angiotensin II (Ang II) concentration significantly decreased to the level of WKY after the antisense therapy, the SBP, LV to body weight ratio and % collagen volume fraction also showed a reduction, however, these findings were still larger than in the WKY than in either the sense-injected SHR or control SHR. CONCLUSION: The plasma AGT is considered to play a role in the development of cardiac hypertrophy in SHR, but it has not a complete effects on cardiac remodeling even if the plasma Ang II levels are inhibited because of an insufficient suppression of hypertension.     

Comparison of the antihypertensive effects of the new angiotensin II (AT1) receptor antagonist candesartan cilexetil (TCV-116) and the angiotensin converting enzyme inhibitor enalapril in rats.

Antihypertensive effects of an angiotensin (Ang) II receptor antagonist, candesartan cilexetil (TCV-116), were compared with those of an angiotensin converting enzyme (ACE) inhibitor, enalapril, in spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive rats (2K, 1C-HR) and 1-kidney, 1-clip hypertensive rats (1K, 1C-HR). CV-11974, the active form of TCV-116, had no inhibitory activity for plasma ACE. In rats, TCV-116 inhibited the pressor responses to Ang I, Ang II, and Ang III without an effect on the bradykinin (BK)-induced depressor response. Enalapril inhibited only the Ang I-response and potentiated the BK-response. In SHR, the antihypertensive effect of TCV-116 (10 mg/kg) was larger than the maximum antihypertensive effect of enalapril and was not intensified by combination with enalapril. Administration of CV-11974 potentiated the maximum antihypertensive effect of enalapril. Although both agents reduced blood pressure in 2K, 1C-HR, only TCV-116 had a marked antihypertensive effect in 1K, 1C-HR. These findings indicate that TCV-116 is more effective than enalapril in reducing blood pressure in SHR and 1K, 1C-HR, and that the BK- and/or prostaglandin-potentiating effect of enalapril contributes little to its antihypertensive mechanism in SHR.     

Vascular angiotensin II receptors in SHR

We investigated the density (Bmax) of angiotensin II (ANG II) receptors in the mesenteric vascular bed of spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) control rats. In 12-week-old SHR, the Bmax and the dissociation constant (Kd) of ANG II binding sites were not different from those of WKY rats in the sodium replete state or after sodium depletion. In prehypertensive (4- and 6-week-old) SHR, the Bmax of the vascular ANG II receptors was significantly higher (p less than 0.05) than in age-matched WKY rats. This result could not be attributed entirely to differences in the circulating renin-angiotensin-aldosterone system in 4-week-old-rats. In 6-week-old WKY rats, the plasma renin activity was significantly higher (p less than 0.05), which may account in part for the higher density of ANG II binding sites in SHR. There was an age-related decrease in the number of ANG II receptors in SHR. The increased density of vascular ANG II receptors in young SHR may play a role in the development of high blood pressure in this model of spontaneous hypertension. The higher number of ANG II binding sites in young SHR is not selective for ANG II receptors, since an increased density of alpha 1-adrenergic receptors was also found in the mesenteric arteries of 4-week-old SHR.     

Rostral ventrolateral medulla neurons of neonatal Wistar-Kyoto and spontaneously hypertensive rats

We compared the electrophysiological properties of neurons in the rostral ventrolateral medulla (RVLM) of neonatal Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), and responses to angiotensin II and its type 1 receptor antagonist candesartan. Using the whole-cell patch-clamp technique, we examined the characteristics of RVLM neurons in brainstem-spinal cord preparations with a preserved sympathetic neuronal network. The baseline membrane potential of irregularly firing neurons was less negative (-50.1+/-0.6 versus -52.0+/-0.6 mV) and the firing rate was faster (3.0+/-0.2 versus 2.0+/-0.2 Hz) in SHR (n=56) than in WKY (n=38). Superfusion with angiotensin II (6 micromol/L) significantly depolarized the RVLM bulbospinal neurons in SHR (5.4+/-1.1 mV, n=15) but not in WKY. In contrast, candesartan (0.12 micromol/L) induced a significant membrane hyperpolarization (-3.7+/-0.4 mV; n=14) and a decrease in the firing rate in RVLM bulbospinal neurons of SHR but not of WKY. These results suggest that endogenously generated angiotensin II binds to type 1 receptors on RVLM bulbospinal neurons, thus tonically contributing to a higher membrane potential and a faster firing rate in SHR. The electrophysiological properties of RVLM neurons and their responses to angiotensin II and candesartan differ between neonatal WKY and SHR. These differences in RVLM neurons suggest a mechanism that possibly leads to elevation in blood pressure.     

Increases in renal angiotensin II content and tubular angiotensin II receptors in prehypertensive spontaneously hypertensive rats

To examine the role of the intrarenal renin-angiotensin system in the development of hypertension in spontaneously hypertensive rats (SHR), we measured angiotensin II contents and tubular 125I-angiotensin II binding sites in the kidney of SHR and age-matched Wistar-Kyoto rats (WKY). In prehypertensive (4-week-old) SHR, not only the kidney angiotensin II content but also the angiotensin II receptor density in brush border membranes were significantly higher than in the WKY. In contrast, angiotensin II levels in the 20-week-old SHR kidneys were significantly lower than in the WKY. Acceleration of the intrarenal renin-angiotensin system and the increased density of tubular angiotensin II receptors in young SHR may therefore play an important role in the development of high blood pressure in SHR.     

Significance of brain renin for pathogenesis of hypertension: effect of antihypertensive drugs on active and inactive renins in the brain of spontaneously hypertensive rat

Relationship between blood pressure and brain renin was studied in four groups of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY); as controls (n = 5), administered captopril (n = 5), trichlormethiazide (n = 5) and atenolol (n = 5). 1) Inactive renin in the hypothalamus of captopril-administered SHR was significantly lower than that of control SHR and captopril-administered WKY. On the other hand, active renin in the hypothalamus, thalamus and striatum of captopril-administered SHR was significantly lower than that of control SHR and captopril-administered WKY. 2) Inactive renin in the hypothalamus of trichlormethiazide administered SHR was significantly lower than that of control SHR and trichlormethiazide-administered WKY. On the other hand, active renin in the hypothalamus, thalamus and midbrain of trichlormethiazide-administered SHR was significantly lower than that of control SHR and trichlormethiazide-administered WKY. 3) Inactive renin in the hypothalamus of atenolol-administered SHR was significantly lower than that of control SHR and atenolol-administered WKY. On the other hand, active renin in the hypothalamus, thalamus and midbrain of atenolol-administered SHR was significantly lower than that of control SHR and atenolol-administered WKY. These results suggest that the production and/or activation of renin in the hypothalamus, thalamus, midbrain and striatum play an important role in the initiation and/or development of hypertension of SHR by the local generation of angiotensin II.     

Cysteinyl leukotrienes are involved in angiotensin II-induced contraction of aorta from spontaneously hypertensive rats

OBJECTIVE: Non specific lipoxygenase inhibitors have been reported to reduce the in vitro constrictor response and the in vivo pressor effect of angiotensin II in rats. The aim of this study was to assess the role of cysteinyl leukotrienes, in the vascular response to angiotensin II in spontaneously hypertensive rats (SHR). METHODS: Rings of thoracic aorta from SHR and normotensive Wistar-Kyoto rats (WKY) were compared in terms of contractile responses and release of cysteinyl leukotrienes in response to angiotensin II. RESULTS: Pretreatment with the specific 5-lipoxygenase inhibitor AA861 10 microM reduced the efficacy of angiotensin II in intact and endothelium-denuded aorta from SHR (% inhibition vs. control: 65+/-12.6% with endothelium (n=6), P<0.05; 43+/-7.2% without endothelium (n=6), P<0.05) but not in aorta from WKY. In addition, in aorta from SHR, the CysLT(1) receptor antagonist MK571 1 microM reduced by 55+/-6.1% (n=6, P<0.05) the contractile effects of angiotensin II in rings with endothelium but not in endothelium-denuded rings. Angiotensin II induced a 8.6+/-2.1-fold increase in cysteinyl leukotriene production in aorta rings from SHR with endothelium which was prevented by the AT(1) receptor antagonist losartan 1 microM but not by the AT(2) receptor antagonist PD123319 0.1 microM. In aorta rings from WKY, cysteinyl leukotriene production remained unchanged after exposition to angiotensin II. The cysteinyl leukotrienes (up to 0.1 microM) induced contractions in aorta rings from SHR but not from WKY. CONCLUSIONS: These data suggest that cysteinyl leukotrienes, acting at least in part on endothelial CysLT(1) receptors, are involved in the contractile response to angiotensin II in isolated aorta from SHR but not from WKY.     

Angiotensin II Antagonism and Pre-Glomerular Arterial Wall Dimensions in the Kidney of the Spontaneously Hypertensive Rat

The effects of the angiotensin II type 1 receptor antagonist TCV-116 on the wall dimensions of the interlobular and arcuate arteries have been studied. SHR rats were treated with TCV-116 between 4 and 10 weeks, at which time their kidneys were perfusion-fixed and examined using stereological techniques. TCV-116 reduced arterial pressure and left ventricle/body weight ratio, but did not reduce renal arterial wall dimensions. For both arcuate and interlobular arteries, wall density/kidney ratio was significantly greater in the TCV-116 treated SHR than in untreated SHR and wall:lumen ratio was also significantly greater for the interlobular arteries in the TCV-116 treated rats. These findings are similar to those obtained previously using enalapril, and indicate that hypertrophy of the walls of these intra-renal arteries is not secondary to the elevated arterial pressure, unlike in other vascular beds.     

Dietary sodium restriction and the renin-angiotensin system in young spontaneously hypertensive rats

Severe dietary sodium restriction initiated early in life is required to prevent development of hypertension in spontaneously hypertensive rats (SHR). Moderate sodium restriction does not affect hypertension development. This relative insensitivity to sodium restriction may be related to compensatory increases in other pressor mechanisms, specifically the renin-angiotensin system. We evaluated this possibility by measuring plasma renin activity, the blood pressure response to the angiotensin converting enzyme inhibitor captopril as well as blood pressure responsiveness to exogenous angiotensin II in SHR and Wistar-Kyoto rats (WKY) raised from birth until 6 or 16 weeks on control (101 mumol Na+/g food), moderate (26 mumol/g) or two severe (17 or 9 mumol/g) sodium-restricted diets. Moderate sodium restriction did not affect development of hypertension, but also did not cause significant increases in PRA or the blood pressure response to captopril in SHR or WKY. In contrast, severe sodium restriction blunted or prevented the development of hypertension in SHR and was associated with (1) marked increases in plasma renin activity (2) increased maintenance of blood pressure by the renin-angiotensin system (as assessed by captopril), and (3) a marked decrease in the blood pressure response to angiotensin II. We conclude that the relative insensitivity of hypertension development in SHR to dietary sodium restriction does not relate to a compensatory increase in the activity of the renin-angiotensin system. The moderate sodium restriction employed (26 mumol/g) may rather represent the lower end of the normal range.     

Brain angiotensin in the developing spontaneously hypertensive rat

There are several factors in the manifestation of high blood pressure in spontaneously hypertensive rats (SHR) which implicate a central role for brain angiotensin II (Ang II). We have measured levels of angiotensin in the brain of SHR and rats of the Wistar-Kyoto strain (WKY). The experiments were carried out in 2-, 4-, 14- and 20-week-old rats. Areas of brain from rats were homogenized and purified with SepPak C-18 cartridges. The levels were measured by radio-immunoassay whose detection limit was 1.95 pg/tube. Significant differences were found between the different age groups and between SHR and controls. In the hypothalamus, there was a consistent elevation of brain Ang II in SHR as compared to WKY in all age groups. Cerebellum also had higher levels in SHR, especially in rats at 2 and 4 weeks of age. Brainstem levels were significantly higher in SHR only in the 14-week-old age group. Plasma levels during these time periods did not differ significantly between the strains. The results demonstrate changes in brain Ang II with development. At an early age, there are high levels of Ang II in the hypothalamus and cerebellum which do not correlate with hypertension but may be important for the development of hypertension. The higher levels of brain Ang II in SHR support the hypothesis that hypertension in SHR is related to brain Ang II activity.     

Role of oxidative stress in the sex differences in blood pressure in spontaneously hypertensive rats

OBJECTIVE: The hypothesis was tested that differences in oxidative stress play a role in the sex differences in the development and maintenance of hypertension in spontaneously hypertensive rats (SHR). DESIGN AND METHODS: Male and female SHR [and Wistar-Kyoto (WKY) rats in the long-term study] (n = 6-12 per group) received tempol (30 mg/kg per day) or tap water for 6 weeks from 9 to 15 weeks of age or from birth until 15 weeks of age. Blood pressure [mean arterial pressure (MAP)] and kidney tissue F2-isoprostane (IsoP) were measured at 15 weeks of age. RESULTS: In SHR given tempol for 6 weeks, blood pressure and IsoP were reduced in males, but not in females. In SHR given tempol from birth, MAP was higher in SHR than WKY rats (SHR males, 181 +/- 2 mmHg; SHR females, 172 +/- 3 mmHg; WKY males, 100 +/- 2 mmHg; WKY females, 101 +/- 2 mmHg, P < 0.01), and tempol reduced MAP by 14% (156 +/- 3) and 26% (127 +/- 4) in male and female SHR, respectively, but had no effect on WKY rats. IsoP was higher in SHR than WKY rats and higher in male SHR than female SHR (SHR males, 5.18 +/- 0.23 ng/mg; SHR females, 3.71 +/- 0.19 ng/mg, P < 0.01; WKY males, 1.72 +/- 0.45 ng/mg; WKY females, 2.21 +/- 0.08 ng/mg, P < 0.05, compared with SHR). Tempol reduced IsoP in SHR to levels found in WKY rats, but had no effect on IsoP in WKY rats. CONCLUSIONS: Development of hypertension in SHR is mediated in part by oxidative stress independent of sex. Also, tempol is effective in reducing blood pressure in females only when given prior to the onset of hypertension.     

Genetic abnormalities in cultured cutaneous fibroblasts in SHR rats

Skin fibroblasts were isolated from newborn spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY) to study their cell growth and reactivity in culture. SHR fibroblasts exhibited an enhanced growth rate in presence of 10 per cent fetal calf serum and a marked increase in 3H thymidine incorporation compared to WKY cells, when confluent quiescent fibroblasts were stimulated by 2, 5, 10 or 15 per cent serum as well as by 10 ng/ml EGF. Inositol phosphate formation determined by exchange chromatography in presence of 20 mM LiC1, was stimulated by serum, 1 microM angiotensin II, I microM bradykinin and 0.1 microM vasopressin in both type of cells labelled with 3H myoinositol. Significantly higher levels were produced in SHR cells by angiotensin II, serum and bradykinin compared to WKY fibroblasts. No difference between the two cell groups was observed with vasopressin. The intracellular pH (pHi) of isolated SHR and WKY fibroblasts was measured in bicarbonate-free medium using the fluorescent dye BCECF. The identical pHi values (7.03 +/- 0.10, n = 5 and 7.04 +/- 0.07, n = 6 for WKY and SHR respectively agree with an absence of Na+/H+ antiport activation in unstimulated cells. This study allows to conclude that skin fibroblasts isolated from newborn SHR, similarly to vascular smooth muscle cells, exhibit an hyperresponsiveness to serum, EGF and angiotensin II. These results demonstrate the presence of an intrinsic cellular developing capacity.     

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 effects of angiotensin II type-1 receptor antisense oligonucleotides on renal function in spontaneously hypertensive rats

The effect of selectively decreasing renal angiotensin II type 1 (AT1) receptor expression on renal function and blood pressure has not been determined. Therefore, we studied the consequences of selective renal inhibition of AT1 receptor expression in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in vivo. Vehicle, AT1 receptor antisense oligodeoxynucleotides (AS-ODN), or scrambled oligodeoxynucleotides were infused chronically into the cortex of the remaining kidney of conscious, uninephrectomized WKY and SHR on a 4% NaCl intake. Basal renal cortical membrane AT1 receptor protein was greater in SHR than in WKY. In WKY and SHR, AS-ODN decreased renal but not cardiac AT1 receptors. AT1 receptor AS-ODN treatment increased plasma renin activity to a greater extent in WKY than in SHR. However, plasma angiotensin II and aldosterone were increased by AS-ODN to a similar degree in both rat strains. In SHR, sodium excretion was increased and sodium balance was decreased by AS-ODN but had only a transient ameliorating effect on blood pressure. Urinary protein and glomerular sclerosis were markedly reduced by AS-ODN-treated SHR. In WKY, AS-ODN had no effect on sodium excretion, blood pressure, or renal histology but also modestly decreased proteinuria. The major consequence of decreasing renal AT1 receptor protein in the SHR is a decrease in proteinuria, probably as a result of the amelioration in glomerular pathology but independent of systemic blood pressure and circulating angiotensin II levels.     

Lesion of the area postrema region attenuates hypertension in spontaneously hypertensive rats

To determine whether the area postrema contributes to the development of hypertension in spontaneously hypertensive rats (SHR), sham or electrolytic lesions of the area postrema (AP) were made in 4-week-old SHR and Wistar-Kyoto (WKY) controls. From weeks 5 through 16, systolic pressure was measured via tail plethysmography. While blood pressure rose markedly in sham-operated SHR, increases in pressure were small in AP-ablated SHR and similar to those seen in all WKY. Subsequent direct measurements of mean arterial pressure in the same rats showed a significant correlation (r = 0.87, p less than 0.01) with the pressure data acquired via weekly tail-cuff measurement, thereby confirming that hypertension in AP-ablated SHR had indeed been attenuated. Analysis of several hundred computer-acquired measurements of mean arterial pressure from each rat showed that AP ablation shifted the distribution of mean arterial pressure to a lower range in SHR but not WKY. Ablation of the AP also decreased resting heart rate in SHR but not WKY. Suppression of heart rate in response to intravenous phenylephrine was equivalent in sham-operated and AP-ablated rats, suggesting that baroreflex-mediated slowing of heart rate was not impaired. In response to intravenous angiotensin II, suppression of heart rate was similar in sham and AP-ablated SHR, and actually was enhanced in AP-ablated WKY. Histological evaluation of the lesions indicated that visible damage to the adjacent nuclei of the solitary tracts was confined to a small portion of the commissural nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transforming growth factor-beta1 modulates angiotensin II-induced calcium release in vascular smooth muscle cells from spontaneously hypertensive rats

OBJECTIVES: To investigate the role of transforming growth factor-beta1 (TGF-beta1) on Ca2+-dependent mechanisms elicited by angiotensin II in aortic vascular smooth muscle cells (VSMC) of Wistar- Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). METHODS: Cai2+ release induced by angiotensin II (1 micromol/ l) was studied in cultured VSMC isolated from the aortas of 6-week-old WKY rats and SHR. Intracellular Ca2+ (Cai2+) was assessed in Fura-2 loaded cells using fluorescent imaging microscopy. Angiotensin II receptors were analysed by binding studies. RESULTS: Pretreatment of VSMC for 24 h with TGF-beta1 significantly increased angiotensin II-induced Cai2+ mobilization from internal stores in SHR, while Ca2+ influx was not altered. This effect involves tyrosine kinase and is not due to an increase in angiotensin II binding sites, or a change in the affinity of the receptors. By contrast, TGF-beta1 did not modify the response of VSMC from WKY rats to angiotensin II. CONCLUSIONS: These results help our understanding of the interactions between the pathways activated by TGF-beta1 and the G protein-coupled receptor signalling pathway, and their role in genetic hypertension.     

Neonatal Diethylstilbestrol Alters Blood Pressure and CNS Drinking Response in SHR and WKY Rats

ABSTRACT

Neonatal SHR and WKY rats were treated with diethylstilbestrol or propylene glycol (controls). Control SHR had higher blood pressures than WKY rats. Neonatal diethylstilbestrol treatment delayed the onset and full expression of hypertension in the male SHR but had no effect on blood pressure in the other animals. Neonatal diethylstilbestrol treatment had an adverse effect on body weights of male SHR and WKY rats through 98 days of age (not statistically decreased thereafter). Adult female SHR and WKY rats treated neonatally with diethylstilbestrol had body weights significantly greater than the control females. Neonatal treatment with diethylstilbestrol resulted in precocious puberty in female SHR and WKY rats. Control female SHR and WKY rats and female SHR treated neonatally with diethylstilbestrol had attenuated angiotensin - II induced drinking response from the central administration of estrogen in adulthood. The angiotensin II - induced drinking response was not siqnificantly attenuated by central estrogen in adult WKY females exposed neonatally to diethylstilbestrol. Neonatal diethylstilbestrol treatment of WKY female rats appears to have altered neuroendocrine secretions that control CNS drinking behavior.