培哚普利,普萘洛尔与双氢氯噻嗪对自发性高血压大鼠心血管结？…

AIM: To investigate the effects of perindopril, propranolol, and dihydrochlorothiazide on artery wall thickening, left ventricular hypertrophy, and cardiac fibrosis in spontaneously hypertensive rats (SHR). METHODS: After measurement of systolic blood pressure (SBP), 16-wk-old Male SHR were randomly divided into 3 groups (each n = 10), given perindopril (Per, 5 mg.kg-1.d-1), propranolol (Pro, 40 mg.kg-1.d-1), dihydrochlorothiazide (DCT, 100 mg.kg-1.d-1) respectively by gavage for 12 wk. Sex-, age-, and number-matched untreated SHR and normotensive Wistar Kyoto rats (WKY) served as controls. When the treatment finished, body weights (BW) and SBP were measured before decapitation of the rats. The heart was excised rapidly, the left ventricle was weighed and then subjected to collagen content analysis. Vascular wall and lumen ratio from aorta, renal arteries and branch III vessels of mesenteric arteries were determined morphometrically. RESULTS: Treated rats in 3 groups showed a lower SBP and the ratio of left ventricle weight to body weight (LVW/BW) compared with WKY. Artery wall thickening was similarly inhibited in the treated groups. Per and Pro inhibited cardiac fibrosis, but collagen concentration increased in DCT treated SHR [collagen volume fraction (CVF): 19 +/- 4 vs SHR 14 +/- 4, P < 0.05; perivascular collagen fraction(PVCF): 84 +/- 7 vs SHR 79 +/- 5, P < 0.05]. CONCLUSION: Per and Pro inhibited, but DCT promoted, cardiac fibrosis.     

Effect of polyphenol-containing azuki bean (Vigna angularis) extract on blood pressure elevation and macrophage infiltration in the heart and kidney of spontaneously hypertensive rats

1. Hypertension is a major risk factor for myocardial infarction and renal damage, and it has also been shown to have pro-inflammatory actions that increase the formation of reactive oxygen species. Macrophage infiltration has been suggested to play a role in the pathogenesis of hypertension. Azuki beans are known to contain pro-anthocyanidins, a group of polyphenolic bioflavonoids with remarkable radical-scavenging activities in vitro. Therefore, the aim of the present study was to investigate the effect of polyphenol-containing azuki bean extract (ABE) on systolic blood pressure (SBP) and macrophage infiltration in the heart and kidney of spontaneously hypertensive rats (SHR). 2. Spontaneously hypertensive rats and control normotensive Wistar-Kyoto (WKY) rats were divided into two groups fed either 0 or 0.8% ABE in their diets. Tail SBP and macrophage kinetics in the heart and kidney were examined. 3. The SBP of the SHR group was higher than that of age-matched WKY rats throughout the treatment period. After 8 weeks of treatment, the increased SBP in ABE-treated SHR was significantly less than that in untreated SHR. 4. Nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH)-stimulated superoxide (O2-) production was enhanced in the kidney and heart in SHR and WKY rats compared with levels in the absence of NADH or NADPH. The NADPH-stimulated superoxide (O2-) levels in the kidney in untreated SHR was significantly higher than that in untreated WKY rats. The (O2-) levels in ABE-treated SHR were significantly decreased compared with the untreated SHR group. 5. In immunohistochemical analyses, the number of macrophages in the heart and in the glomeruli and tubulointerstitium of the kidney was significantly higher in ABE-untreated SHR than in ABE-untreated WKY rats. Conversely, there was a significant decrease in the number of macrophages in ABE-treated SHR compared with the untreated SHR. There were significant positive correlations between SBP and the number of ED1-positive macrophages in the heart and tubulointerstitial and glomerular areas of the kidney in WKY rats and SHR. 6. In conclusion, the results of the present study suggest that ABE attenuates the elevation of SBP and macrophage infiltration in the heart, as well as in the glomeruli and tubulointerstitium of the kidney, in our SHR model.     

Centrally produced neuronal nitric oxide in the control of baroreceptor reflex sensitivity and blood pressure in normotensive and spontaneously hypertensive rats

We studied the effect of chronic nitric oxide synthase (NOS) blockade in the brain on mean arterial pressure [MAP (mmHg)], heart rate [HR (bpm)] and baroreceptor reflex sensitivity [BRS (mean slope: bpm/mmHg)] in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Intracerebroventricular (i.c.v.) infusion of the nonselective NOS inhibitor N-Nitro-L-arginine-methylester (L-NAME) (50 microg/kg per day, 11-12 days) increased MAP in WKY and SHR (125+/-2.1 vs 118+/-1.1 controls, P<0.01 and 179+/-3.59 vs 156+/-4.0 controls, P<0.001, respectively) without affecting HR. In L-NAME-treated WKY, BRS to bradycardia was suppressed (-0.79+/-0.09 vs -1.76+/-0.17 controls, P=0.001), whereas in SHR, L-NAME did not affect BRS to bradycardia. BRS to tachycardia remained unaffected in either strain. In WKY, 7-nitroindazole (7-NI x Na+) (34 microg i.c.v./kg per day, 11-12 days), a selective nNOS inhibitor, did not affect MAP or HR, but BRS to bradycardia and tachycardia was decreased (-0.37+/-0.20 vs -0.97+/-0.41 controls, P<0.01 and -1.78+/-0.20 vs -2.52+/-0.40 controls, P=0.05, respectively). In SHR, the same dose of 7-NI x Na+ increased resting MAP (171+/-5.00 vs 150+/-7.00 controls, P<0.05) without affecting HR or BRS to bradycardia or tachycardia. Thus in WKY, BRS to acute changes in systemic blood pressure (BP) is regulated by NO produced by nNOS in the brain, serving as a neurotransmitter in sympathetic and parasympathetic efferent pathways. In SHR, systemic BP is regulated in part by NO released by the type I NOS isoenzyme in the brain.     

Thromboxane A2 and the development of hypertension in spontaneously hypertensive rats

Osmotic minipumps containing OKY-046 (15-20 mg/kg per day), to inhibit thromboxane (TX) A2 synthase, were implanted into 43-day-old SHR and age-matched Wistar-Kyoto rats (WKY) to study the role of TXA2 in the development of hypertension in SHR. Inhibition of TXA2 synthase with OKY-046 did not affect urine volume, sodium excretion, potassium excretion, food and water intake or body weight in either WKY or SHR during the two weeks of study. In the first week systolic blood pressure (SBP) was significantly lower in SHR receiving OKY-046 in comparison to SHR which received no OKY-046 (127 +/- 3 vs. 110 +/- 4 mm Hg, P less than 0.01). OKY-046 did not affect SBP in WKY. By the second week SBP in SHR and WKY receiving OKY-046 did not differ from their respective controls despite an 85% reduction in serum immunoreactive TXB2 (iTXB2; the stable hydrolysis product of TXA2) and a 45% reduction in urinary iTXB2 excretion. These results support a possible role for TXA2 in the developmental stage of hypertension in SHR and other factors in the sustained elevation of blood pressure.     

Effect of cross-fostering on renal anti-oxidant/oxidant status and development of hypertension in spontaneously hypertensive rats

1. The hypotensive effect of cross-fostering in spontaneously hypertensive rats (SHR) is thought to involve adjustments in renal function. However, its association with renal anti-oxidant/oxidant balance during cross-fostering is not known. 2. The present study examined the effect of cross-fostering and in-fostering of 1-day-old offspring between SHR and Wistar-Kyoto (WKY) dams on renal anti-oxidant/oxidant status and systolic blood pressure (SBP). Renal anti-oxidant/oxidant status and SBP were determined in the offspring from 4-16 weeks of age. 3. Cross-fostered SHR had significantly lower SBP than in-fostered SHR at 6, 8 and 12 weeks, but not at 16 weeks (127 ± 1 vs 144 ± 2, 138 ± 1 vs 160 ± 1, 174 ± 2 vs 184 ± 2 and 199 ± 2 vs 194 ± 3 mmHg at 6, 8, 12 and 16 weeks, respectively). No differences in SBP were evident between cross-fostered and in-fostered WKY rats. There were no significant differences in levels of thiobarbituric acid-reactive substances (TBARS), protein carbonyl and total anti-oxidant status (TAS) or superoxide dismutase, catalase, glutathione peroxidase (GPx), glutathione S-transferase and glutathione reductase activity between cross-fostered and in-fostered SHR or WKY offspring. However, compared with WKY rats, catalase activity was higher at 6 and 16 weeks, TAS was higher at 16 weeks and GPx activity and TBARS were lower at 16 weeks in SHR. 4. It appears that cross-fostering of SHR offspring to WKY dams during the early postnatal period causes a transient delay in the rise in blood pressure in SHR and that this does not involve the renal anti-oxidant/oxidant system.     

Amlodipine ameliorates endothelial dysfunction in mesenteric arteries from spontaneously hypertensive rats

1. Endothelial dysfunction plays a critical role in the development and progression or pathogenesis of hypertension. Amlodipine, a calcium channel blocker, is an effective antihypertensive agent. We investigated the effects of amlodipine on endothelial dysfunction in mesenteric arteries from spontaneously hypertensive rats (SHR). 2. Eight-week-old SHR were treated with amlodipine (10 mg/kg per day) for 8 weeks. Control SHR and Wistar-Kyoto (WKY) rats were treated with saline. Systolic blood pressure (SBP) was measured by the tail-cuff method. Isometric tension changes of isolated mesenteric arterial rings were recorded continuously by a myograph system. Serum contents of malondialdehyde (MDA) and total nitrate/nitrite (NO(x) ) were determined. Vascular superoxide anion production was analysed with dihydroethidium (DHE) fluorescence. 3. The contractile responses to KCl and phenylephrine were greater in untreated SHR than in WKY. Acetylcholine (ACh)-induced relaxation was significantly impaired in untreated SHR. Amlodipine treatment reduced the contractions and improved relaxation to ACh. In WKY, relaxation to ACh was inhibited by N(G) -nitro-l-arginine methyl ester (l-NAME) and not changed by ascorbic acid. In untreated SHR, the response to ACh was unaffected by l-NAME, whereas it was improved by ascorbic acid. Amlodipine restored the inhibitory effect of l-NAME on ACh-induced relaxation, but ascorbic acid no longer exerted its facilitating effect. Amlodipine prevented the rise in SBP and ameliorated abnormalities in serum MDA and NO in untreated SHR. DHE assay showed an increased intravascular superoxide generation in untreated SHR, which was abrogated by amlodipine. 4. Treatment of SHR with amlodipine resulted in amelioration of endothelial dysfunction by anti-oxidant activity and improvement in NO availability.     

22Na+ and 86Rb+ transport in vascular smooth muscle of SHR, Wistar Kyoto, and Wistar rats

To gain further insight into differences in cellular Na+ and K+ regulation between the spontaneously hypertensive rat (SHR), Wistar Kyoto (WKY), and American Wistar (W) rats, 22Na+ and 86Rb+ washouts were performed under steady-state conditions in cultured vascular smooth muscle cells from the three rat strains. SHR vascular smooth muscle cells showed significantly higher bumetanide sensitive 86Rb+ washout rate constant (x 10(-4)/min; mean +/- SEM) than WKY cells (-38.6 +/- 2.84 and -23.8 +/- 3.58, respectively; p less than 0.005). SHR vascular smooth muscle cells also exhibited significantly higher values than WKY cells in the total 22Na+ washout rate constant (x 10(-2)/min) (-61.0 +/- 1.57 vs. -53.8 +/- 1.24; p less than 0.005). The amiloride sensitive component of the 22Na+ washout rate constant accounted for these differences (-18.6 +/- 1.04 for SHR and -12.1 +/- 2.00 for WKY; p less than 0.05). There were no apparent differences in cellular Na+ concentrations between WKY and SHR cells. In general, the 86Rb+ and 22Na+ washout parameters of W rat cells were quite similar to those of cells from SHR. We conclude that the bumetanide-sensitive 86Rb+ washout (the Na+ K+-cotransport), the overall, and the amiloride-sensitive 22Na+ washout (the latter primarily represents the Na+/H+ antiport) are higher in SHR than WKY rat vascular smooth muscle cells. These findings indicate innate differences in cellular Na+ and K+ transport in vascular smooth muscle cells of the SHR and WKY rat. The mechanisms responsible for these differences are yet to be determined.     

Reduced basal nitric oxide bioavailability and platelet activation in young spontaneously hypertensive rats

OBJECTIVE: To investigate the role of basal nitric oxide (NO) bioavailability for platelet activation in young spontaneously hypertensive rats before onset of hypertension. Phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) in platelets was used as a sensitive monitor of in vivo NO bioavailability. METHODS AND RESULTS: Whole blood samples were taken from 10-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In vivo surface-expression of P-selectin and platelet-binding of fibrinogen were assessed by flow cytometry. Platelet VASP-phosphorylation at its serine 239 (Ser239) and serine 157 (Ser157) residues was assessed using specific antibodies to determine NO bioavailability in vivo, and compared with endothelial vasomotor function. The increment in vascular tone following inhibition of NO-synthase in slightly preconstricted aortic rings was reduced indicating less NO formation under physiological stimulation (WKY 71.1+/-4.1%; SHR 57.8+/-2.4%, P<0.05). In vivo platelet VASP-phosphorylation was significantly reduced at both phosphorylation sites in SHR (mean fluorescence for Ser239: WKY: 15.2+/-0.6; SHR: 11.7+/-0.5, P<0.01; Ser157: WKY: 53.0+/-3.0; SHR: 35.0+/-3.5, P<0.05). Surface-expression of P-selectin and membrane-bound fibrinogen were significantly enhanced in SHR compared with WKY (P-selectin: WKY: 23.2+/-3.4; SHR 58.3+/-7.9, P<0.001; platelet-bound fibrinogen: WKY: 8.6+/-0.5; SHR: 13.5+/-1.1, P<0.001). In vitro preincubation of platelets with the NO donor sodium nitroprusside normalized platelet surface-expression of P-selectin in SHR. CONCLUSION: Using VASP-phosphorylation as a sensitive monitor of in vivo NO bioavailability, these data provide evidence that reduced vascular NO formation in vivo contributes to increased platelet activation in young SHR.     

Nitric oxide in mesenteric vascular reactivity: a comparison between rats with normotension and hypertension

1. Nitric oxide (NO) plays an important role in various physiological functions. The continuous formation of endogenous NO from endothelial cells maintains a vasodilator tone and regulates blood flow and pressure. However, the role of NO in hypertension remains controversial. 2. In the present study, we used an in situ mesenteric perfusion system. The primary objectives of the study were to examine whether or not mesenteric vasoreactivity is changed by alterations in perfusion pressure and to assess the role of NO in changes of vascular reactivity in hypertension. 3. Spontaneously hypertensive rats (SHR; 12-15 weeks of age) and age-matched normotensive Wistar-Kyoto (WKY) rats were used as the experimental and control groups, respectively. Endothelium-dependent and -independent vasodilation was detected by acetylcholine (ACh) or NO donors (sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP)). Dose-dependent reactivity to these agents (10(-6) to 10(-4) mol/L) was detected by bolus intra-arterial injections of 10 microL of the test agents at 5 min intervals. Dose-dependent responses to vasoconstrictor drugs, such as noradrenaline (NA) and phenylephrine (PE; 10(-6) to 10(-4) mol/L) were also observed. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg) was given to examine the contribution of NO to the vasoreactivity of the mesenteric bed. 4. Acetylcholine, SNP and SNAP produced dose-dependent vasodilation in both WKY rats and SHR. The magnitude of the vasodilation was significantly greater in SHR than in WKY rats. It was also greater at high than low flow rates in SHR. The increase in mesenteric perfusion pressure following L-NAME was significantly higher in SHR than in WKY rats. However, there were no differences in responses to L-NAME between low and high flow rates in SHR. Endothelium-independent vasoconstriction (NA and PE) was dose dependent in both SHR and WKY rats. The magnitude of the endothelium-independent vasoconstriction was greater in SHR than in WKY rats. 5. The results suggest that endothelium-dependent or -independent mesenteric vasoconstriction and vasodilation is enhanced in SHR compared with WKY rats, supporting the concept of enhancement of NO function in the hypertensive state. Flow-induced shear stress is also a key factor in the regulation of peripheral resistance depending on NO formation in hypertension.     

Alterations of renal vasopressin V1A and V2 receptors in spontaneously hypertensive rats

To elucidate the role of arginine vasopressin (AVP) in a hypertensive state, the characteristics of renal cortex V(1A) and medulla V(2) receptors in young spontaneously hypertensive rats (SHR) during the developmental phase of hypertension were compared with those of age-matched Wistar-Kyoto (WKY) rats using the radioligand receptor assay technique. The systolic blood pressure of 8-week-old SHR was statistically significantly higher than that of WKY rats (142 +/- 1 vs. 125 +/- 2 mm Hg). The plasma AVP levels were also significantly higher in SHR than in WKY rats (3.20 +/- 0.41 vs. 1.96 +/- 0.34 pg/ml). In SHR, the maximum capacity of (3)H-d(CH(2))(5)Tyr(Me)AVP binding to cortical V(1A) receptors (B(max)) was statistically significantly higher than that of WKY rats (39.7 +/- 2.7 vs. 22.4 +/- 0.9 fmol/mg protein). Furthermore, the B(max) values of (3)H-AVP binding to medullary V(2) receptors in SHR were also significantly higher than in WKY rats (40.2 +/- 1.9 vs. 28.3 +/- 1.3 fmol/mg protein). However, the apparent dissociation constant (K(d)) values of renal cortex V(1A) and medulla V(2) receptors in SHR and WKY rats were not significantly different. These results indicate that increased amounts of renal cortex V(1A) and medulla V(2) receptors in SHR play an important role in the pathophysiology of hypertension.     

INCREASED Na+/H+ EXCHANGE ACTIVITY IN VASCULAR SMOOTH MUSCLE CELLS OF SPONTANEOUSLY HYPERTENSIVE RATS AND POSSIBLE INVOLVEMENT OF PROTEIN KINASE C

1. Na+ influx into cultured vascular smooth muscle cells (VSMC) obtained from spontaneously hypertensive rats (SHR) and from Wistar-Kyoto rats (WKY) was measured. Na+ influx via the Na+/H+ exchange system was measured as the rate of 22Na+ influx into cultured VSMC sensitive to ethylisopropylamiloride (EIPA), a specific inhibitor of the exchange system. 2. The total 22Na+ influx rate in SHR was significantly higher than in WKY (6.08 +/- 0.16 vs 4.13 +/- 0.09 nmol/min per mg protein; P less than 0.001; n = 14). The EIPA (1 X 10(-4) mol/L)-sensitive 22Na+ influx rate in SHR was significantly higher than that in WKY (4.32 +/- 0.27 vs 2.17 +/- 0.14 nmol/min per mg protein; P less than 0.001; n = 14). There was no difference in EIPA-insensitive 22Na+ influx between SHR and WKY. The EIPA-sensitive 22Na+ influx rate into VSMC was significantly decreased in SHR but not in WKY by the addition of 1 X 10(-4) mol/L 1-(5-isoquinoline-sulfonyl)-methylpiperazine (H-7), an inhibitor of protein kinase C (PK-C). 3. These results suggest that the increase in Na+ influx in SHR may be due to elevation of the Na+/H+ exchange activity, and possible involvement of PK-C in the increased Na+/H+ exchange activity in VSMC from SHR.     

Mechanisms of augmented vasoconstriction induced by 5-hydroxytryptamine in aortic rings from spontaneously hypertensive rats

Background and purpose:To test whether development of enhanced vasoconstriction to 5-hydroxytryptamine (5-HT; serotonin) in SHR was temporally related to hypertension, elevated vascular superoxide (O(2)(-)) levels, decreased NO bioavailability, or increased contractile effects of cyclooxygenase or rho-kinase and/or PKC.Experimental approach:We examined systolic blood pressure (SBP), vascular O(2)(-), and 5-HT-induced contractile responses of aortic segments from 4- and 8-week-old WKY and SHR.Key results:SBP was 35% higher in SHR than WKY at 4 weeks and 60% higher at 8 weeks. Contractile responses to 5-HT were similar in WKY and SHR at 4 weeks, but were markedly augmented in SHR at 8 weeks. The NO synthase inhibitor, L-NAME, enhanced contractile responses to 5-HT markedly in both strains at 4 weeks and in WKY at 8 weeks, but only very modestly in SHR at 8 weeks. These functional differences were associated with higher O(2)(-) levels in SHR versus WKY at 8 weeks, but not at 4 weeks. The rho-kinase inhibitor, Y-27632, and the PKC inhibitor, Ro 31-8220, each only modestly attenuated contractions in WKY and SHR in each age group, and their effects in each strain were more pronounced at 8 weeks. The cyclooxygenase inhibitor, indomethacin, had no effect on contractile responses.Conclusions and implications:Development of augmented vascular contractile responses to 5-HT in SHR is preceded by hypertension. It is associated with increased vascular O(2)(-) levels and reduced modulatory effects of NO, and is unlikely to be due to enhanced activity of rho-kinase, PKC or cyclooxygenase.British Journal of Pharmacology (2008) 155, 210-216; doi:10.1038/bjp.2008.247; published online 16 June 2008.     

Changes in autonomic activity and baroreflex sensitivity with the hypertension process and age in rats

1. Autonomic activity and baroreflex sensitivity (BRS) were compared in age-matched conscious groups of Wistar Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP). 2. Male WKY rats, SHR and SHRSP aged 4-30 weeks were used. Autonomic activity and BRS were estimated by power spectral and cross-spectral analysis of systolic blood pressure (SBP) and SBP-SBP (SS) interval fluctuations, respectively. 3. The time-course of heart rate (HR), SBP, the amplitude of the low-frequency component of SBP fluctuation (SBP-LF; prazosin-sensitive index) and the amplitude of the high-frequency component of the SS interval fluctuation (SS-HF; atropine-sensitive index) consisted of two periods. In the first period (up to 10 or 15 weeks of age), BP, SBP-LF and SS-HF increased with age. The order of SBP-LF was SHRSP > SHR > WKY rats throughout this period. During the second period, BP was sustained at certain levels in all strains, but changes in SBP-LF and SS-HF with age were different among strains. In particular, in SHRSP, SBP-LF markedly decreased with age after 10 weeks. Baroreflex sensitivity in WKY rats increased gradually with age, whereas the BRS in SHR and SHRSP decreased before 6 weeks of age and remained lower than that in WKY rats. 4. In conclusion, the present study shows that both prazosin-sensitive and atropine-sensitive indices are associated with the elevation of BP in all strains studied. However, hypertension after 15 weeks of age in SHRSP is sustained despite a paradoxical reduction in sympathetic activity with an abnormal control of BRS. Therefore, the contribution of autonomic activity to hypertension may be discussed separately as a developmental period and a sustained period.     

卡托普利早期治疗自发性高血压大鼠阻止遗传性高血压形成的机理

本文探讨早期卡托普利治疗阻止高血压形成的机制。自发性高血压大鼠（ＳＨＲ）宫内期给药（１００ｍｇ·ｋｇ－１·ｄ－１）到１６周龄，４０ｗｋ处死。测定收缩压，血管壁／腔面积比（Ｍ／Ｌ），血管收缩（后肢灌注Ｆｏｌｋｏｗ模型）和舒张（动脉环体外实验）功能。卡托普利治疗显著降低血压，停药后２４ｗｋ，血压仍维持在相对低的水平（２１．１±１．１ｋＰａ，对照２８．５±１．１ｋＰａ。Ｐ＜０．０１）．治疗能明显减少Ｍ／Ｌ并接近正常ＷＫＹ大鼠水平。治疗组ＳＨＲ大鼠主动脉对硝普钠舒张敏感性及最大舒张反应明显比８ＨＲ增高，后肢阻力血管苯福林灌注显示ＳＨＲ最小灌注压，最大灌注压，曲线最大斜率都明显比ＷＫＹ大，ＥＣ５０明显较小，治疗的ＳＨＲ以上四个指标几乎达到与ＷＫＹ相同水平。结论：卡托普利持久地阻止高血压形成，持久降压的机理可能是在抑制血管肥厚基础上，减弱末梢血管阻力，改善血管舒张功能。关键词     

Withdrawal reveals lack of effect of prolonged antihypertensive treatment on intrinsic aortic wall stiffness in senescent spontaneously hypertensive rats

1. Chronic antihypertensive treatment lowers cardiovascular morbidity and mortality. The beneficial effect on the blood vessel wall may be due to the lowering of blood pressure (BP) and, hence, wall stress (WS), or to a treatment-induced change in wall structure. 2. We have previously shown that, when evaluated at the same level of BP and WS, the stiffness of the aortic wall of old spontaneously hypertensive rats (SHR) is higher than that of young and adult SHR and that of age-matched Wistar-Kyoto (WKY) rats. In the present study, we tested the hypothesis that the intrinsic changes in wall composition and mechanics in old SHR can be modulated by long-term treatment with an angiotensin I-converting enzyme inhibitor (captopril; 40 mg/kg per day) combined with a diuretic (hydrochlorothiazide; 20 mg/kg per day) and that treatment withdrawal would reveal whether such changes are maintained when BP and WS return to pretreatment levels. 3. We evaluated aortic structure and mechanics in SHR following 1 week withdrawal of oral antihypertensive treatment from 3 to 15 months of age (n = 8). Results were compared with age-matched SHR that were maintained on treatment (n = 12) or were not treated (n = 13) and with WKY rats (no treatment n = 11; maintained n = 11; withdrawn n = 10). 4. Isobaric aortic wall stiffness was estimated from the ratio of baseline aortic pulse wave velocity (PWV) to BP and the slope relating aortic PWV to BP following sodium nitroprusside-induced hypotension. Relative wall stiffening was estimated as the ratio of elastic modulus (EM) to WS. We argued that if treatment produced a change in wall elastin or collagen content, with a subsequent decrease in isobaric wall stiffness, then this would be maintained when BP increased following withdrawal of treatment. 5. In old SHR, treatment lowered isobaric wall stiffness (baseline PWV/BP 4.6 +/- 0.3 cm/s per mmHg; slope relating PWV to BP 6.7 +/- 0.4 x 10-3 cm/s per mmHg and EM/WS 4.1 +/- 0.4 vs 6.1 +/- 0.4 cm/s per mmHg, 9.7 +/- 0.9 x 10-3 cm/s per mmHg and 8.9 +/- 1.1, respectively, without treatment; all P < 0.05). After 1 weeks treatment withdrawal, the indices (5.7 +/- 0.2 cm/s per mmHg, 9.1 +/- 0.2 x 10-3 cm/s per mmHg and 7.2 +/- 0.6) increased in parallel with the increase in WS to levels similar to those observed in untreated SHR. There were no significant differences among the WKY rat groups. 6. Treatment increased the elastin and collagen contents of the aortic wall in both SHR (196 +/- 13 and 128 +/- 5 vs 111 +/- 9 and 86 +/- 4 mg/g wet weight, respectively, in untreated; P < 0.05) and WKY rats (190 +/- 19 and 135 +/- 4 vs 115 +/- 7 and 114 +/- 5 mg/g wet weight, respectively, in untreated; P < 0.05). This increase remained following withdrawal (213 +/- 26 and 118 +/- 4 vs 161 +/- 14 and 127 +/- 4 mg/g wet weight in SHR and WKY rats, respectively). 7. In summary, 1 year of treatment with captopril plus hydrochlorothiazide increases wall elastin content and reduces WS and stiffness in old SHR. Following withdrawal, elastin content remains high, but wall stiffness parallels WS in a manner similar to that in untreated SHR.     

Comparison of angiotensin II-induced blood pressure and structural changes in Fischer 344 and Wistar Kyoto rats

1. The purpose of the present study was to evaluate the blood pressure (BP) response, the BP and heart rate (HR) components of the startle reaction and the structure of the carotid artery and the aorta during chronic infusion of angiotensin (Ang) II in Fischer 344 (F344) compared with Wistar Kyoto (WKY) rats, two in-bred normotensive contrasted strains. 2. Osmotic mini-pumps filled with saline vehicle or AngII (120 ng/kg per min) were implanted subcutaneously in 8-week-old normotensive rats and infused for 4 weeks in F344 rats (saline, n = 10; AngII, n = 10) and WKY rats (saline, n = 10; AngII, n = 9). Basal BP, HR and the responses to an acoustic startle stimulus (duration 0.7 s, 115 dB) were recorded in conscious rats. The structure of the carotid artery and aorta was determined in 4% formaldehyde-fixed arteries. 3. Compared with WKY rats, vehicle-treated F344 rats had lower bodyweight (BW; 266 +/- 7 vs 299 +/- 9 g; P < 0.05) and heart weight (0.80 +/- 0.02 vs 0.98 +/- 0.04 g; P < 0.05) and higher aortic systolic BP (SBP; 131 +/- 1 vs 123 +/- 5 mmHg; P < 0.001) and diastolic BP (98 +/- 3 vs 89 +/- 2 mmHg; P < 0.001). In F344 rats, compared with the WKY rats, the wall thickness/BW ratio was increased in the carotid artery (156 +/- 9 vs 131 +/- 6 nm/g; P < 0.05) and abdominal aorta (264 +/- 13 vs 217 +/- 12 nm/g; P < 0.05) and decreased in the thoracic aorta (246 +/- 13 vs 275 +/- 8 nm/g; P < 0.05). There was no difference in elastin and collagen density. Angiotensin II differentially enhanced BP in both strains: (SBP: 163 +/- 5 and 132 +/- 4 mmHg in F344 and WKY rats, respectively; P(strain x treatment) < 0.05). Circumferential wall stress was increased in the aorta of F344 rats compared with WKY rats (1176 +/- 39 vs 956 +/- 12 kPa (P < 0.001) and 1107 +/- 42 vs 813 +/- 12 kPa (P < 0.001) in thoracic and abdominal aortas, respectively). The startle response was amplified in F344 rats, with enhanced increases in SBP and pulse pressure (PP) and bradycardia compared with responses of WKY rats (+44 +/- 9 mmHg, +10 +/- 2 mmHg and -40 +/- 17 b.p.m., respectively, in F344 rats vs+28 +/- 4 mmHg, + 4 +/- 2 mmHg and -19 +/- 10 b.p.m. in WKY rats, respectively; P(strain) < 0.05 for BP and PP). The startle response was not affected by AngII. 4. These results indicate a higher BP producing an increase in wall thickness in F344 rats compared with WKY rats. We propose that an increase in sympathetic nervous activity causes these haemodynamic differences, as suggested by the excessive increase in BP during an acoustic startle stimulus. Angiotensin II increased BP in F344 rats, but did not exaggerate the increase in BP during the startle reaction.     

Effects of early perturbation of the renin-angiotensin system on cardiovascular remodeling in spontaneously hypertensive rats

RATIONALE: The goal of this study was to analyze cardiovascular (CV) remodeling in early, short-term CAP treated SHR and their offspring. METHODS: We treated SHR with Captopril (CAP, 100 mg/kg) from in utero to 1 month of age (OCAP). Some of these rats were mated at 3-4 months of age and we used their offspring (2nd G). Controls were untreated SHR, normotensive Wistar Kyoto rats (WKY) and SHR maintained on CAP (SCAP). At 12-14 months of age, rats were cannulated for mean arterial blood pressure (MAP) measurements. An image analysis system was used to quantitate changes in cardiac and vascular (wall-to-lumen ratios, w/l) morphology and fibrosis. RESULTS: Early, short-term CAP treatment prevented the full expression of hypertension in treated rats and their offspring. MAPs were: SHR (180+/-2.2 mm Hg); WKY 125+/-3 mm Hg); SCAP 112+/-2.5mm Hg; OCAP 138+/-2.3 mm Hg; and 2nd G (145+/-2.0 mm Hg). There were significant decreases in heart weight/body weight ratios, large and small vessel morphology, and interstitial and perivascular fibrosis in CAP-treated animals and their offspring in comparison to untreated SHR. CONCLUSIONS: The CV protective properties of early, short-term CAP treatment were not solely due to a reduction in MAP. Although MAP was higher in OCAP and 2nd G, CV structure resembled that found in WKY and SCAP. The effects of our early treatment appear to be due to chronic blockade of the renin-angiotensin system and its effects on growth of CV tissues and the development of fibrosis.     

Delayed hypotensive effect of the thromboxane A2/prostaglandin H2 receptor antagonist S-1452 in spontaneously hypertensive rats

1. Several lines of evidence indicate that thromboxane (Tx) A2 may contribute to the development and maintenance of hypertension. The present study was undertaken to evaluate the role of TxA2 in the development of hypertension in spontaneously hypertensive rats (SHR) by using an orally active, highly specific TxA2/prostaglandin H2 receptor antagonist S-1452. 2. Vehicle (1% arabic gum solution) alone was given orally to Wistar-Kyoto (WKY) rats (n = 15) and SHR (n = 14), while S-1452 (10 mg/kg per day, twice daily) was administered orally to SHR (n = 16) for 18 weeks (from 5 to 23 weeks of age). 3. No significant difference was observed in tail-cuff blood pressure (BP) between vehicle- and S-1452-treated SHR before and at 5 and 11 weeks after treatment. Thereafter, BP was further elevated in vehicle-treated SHR, but was significantly blunted in SHR treated with S-1452 at 15 (224+/-8 vs 211+/-13 mmHg; P < 0.01) and 18 weeks (227+/-9 vs 206+/-10 mmHg; P < 0.001); this was associated with reduced proteinuria. 4. Urinary TxB2 in vehicle-treated SHR, especially during the early period, was significantly greater than that in WKY rats, while no significant difference was observed in urinary 6-ketoprostaglandin F1alpha (6-keto-PGF1alpha) between the two groups. Treatment with S-1452 reduced urinary excretion of TxB2 at 18 weeks. 5. The present study shows that S-1452, at the dose used, does not reduce BP during the early period of the development of hypertension. These results suggest that the role of enhanced TxA2 production in the development of hypertension is small, if any, in SHR. Delayed response of BP may be independent of the direct pharmacological effects of S-1452.     

替米沙坦对高血压大鼠血管ACE2表达及氧化应激水平的影响

目的探讨替米沙坦干预对自发性高血压大鼠(SHR)血管组织血管紧张素转换酶2(ACE2)基因表达、一氧化氮(NO)及氧化应激水平的影响。方法选取10周龄SHR及其同源对照WKY大鼠,分别给予替米沙坦(5、10 mg.kg-1.d-1)或安慰剂,为期10周。采用Western blot检测治疗后大鼠主动脉组织中ACE2蛋白及内皮型NO合酶(eNOS)磷酸化水平。分别采用硝酸还原酶比色法与硫代巴比妥酸比色法测定大鼠主动脉组织中NO和丙二醛(MDA)含量。结果与WKY对照组相比,SHR大鼠主动脉组织中ACE2蛋白和Ser1177-eNOS磷酸化水平明显降低(ACE2:0.39±0.05vs 1.00±0.06;p-eNOS:0.43±0.06 vs 1.00±0.04;P值均<0.01),伴NO水平下调及MDA含量增加(NO mmol.g-1protein:11.5±2.1 vs 27.8±4.9;MDA nmol.g-1 protein:393.9±17.9 vs 186.3±14.5;P值均<0.01),而经替米沙坦治疗后SHR低、高剂量治疗组大鼠主动脉组织中ACE2蛋白和Ser1177-eNOS磷酸化水平增加(ACE2:0.62±0.06,0.65±0.07 vs 0.39±0.05;p-eNOS:0.68±0.07,0.71±0.06 vs0.43±0.06;P值均<0.05),伴NO水平升高(19.2±3.3,23.9±3.2 vs 11.5±2.1 mmol.g-1protein;P值均<0.05)与MDA含量下调(271.9±16.1,249.2±19.6 vs 393.9±17.9nmol.g-1protein;P值均<0.05)。结论长期替米沙坦治疗通过提升高血压大鼠血管ACE2表达及eNOS磷酸化水平,可促使血管NO生成及氧化应激水平改善,提示替米沙坦对高血压具有一定的血管保护功效。     

Role of cardiac hypertrophy in reducing the sensitivity of cardiopulmonary reflex control of renal sympathetic nerve activity in spontaneously hypertensive rats

The gain of the volume-sensitive cardiopulmonary reflex (VSCR) is impaired in spontaneously hypertensive rats (SHR). Sensitivity of VSCR control of efferent renal sympathetic nerve activity (RSNA) in SHR is restored when cardiac hypertrophy and hypertension are reduced by enalapril treatment. The present study investigated which of these two parameters, cardiac hypertrophy or hypertension, has more influence on the impairment of VSCR control of RSNA in SHR. Rats (SHR or Wistar-Kyoto (WKY) rats) were treated with enalapril (10 mg/kg per day; SHRE and WKYE groups, respectively) or hydralazine (5 mg/kg per day; SHRH and WKYH groups, respectively) mixed in their food for 1 month. Control SHR and WKY rats were fed a normal diet. After the treatment regimen, the VSCR was evaluated by determining the decrease in RSNA elicited by acute isotonic saline volume expansion. Mean arterial pressure (MAP) was assessed via an intrafemural catheter and cardiac hypertrophy was determined by the left ventricular (LV) weight/bodyweight (BW) ratio. Afferent baroceptor nerve activity (BNA) was also evaluated during volume expansion to verify participation of the baroreflex. Volume expansion produced an attenuated renal sympathoinhibitory response in SHR compared with WKY rats. Enalapril treatment restored the volume expansion-induced decrease in RSNA in SHRE (-41 +/- 8%) compared with WKY rats (-44 +/- 3%). Although both enalapril and hydralazine treatment reduced MAP in SHR (P < 0.01; 126 +/- 5, 133 +/- 6 and 160 +/- 6 mmHg in SHRE, SHRH and SHR, respectively), hydralazine did not restore the sensitivity of VSCR control of RSNA in SHRH. Spontaneously hypertensive rats with established hypertension had a higher LV/BW ratio compared with WKY rats (3.22 +/- 0.14 vs 1.98 +/- 0.06 mg/g, respectively; P < 0.01). Enalapril reduced the LV/BW ratio in SHRE (2.30 +/- 0.07 mg/g; P < 0.01). Although hydralazine reduced LV hypertrophy, there was a weaker reduction in SHRH (2.68 +/- 0.04 mg/g; P < 0.05) compared with SHRE. There was no statistically significant difference among the WKY rat, WKYE and WKYH groups (P > 0.05). There was no change in afferent BNA during volume expansion in normal or hypertensive animals. Taken together, these results indicate that the impairment of VSCR control of RSNA in the SHR model of hypertension correlates better with the magnitude of cardiac hypertrophy than the level of arterial pressure.