Genetic influences on cardiovascular responses to an acoustic startle stimulus in rats

1. The aim of the present study was to assess the cardiovascular differences among five inbred rat strains (n=16 per strain), including spontaneously hypertensive rats (SHR), Wistar Kyoto (WKY) rats, Wistar Furth (WF) rats, Fischer (F344) rats and Lewis (Lew) rats and the usual outbred Wistar (W) rat strain (n=25). 2. These strains were compared under resting conditions for blood pressure (BP) and heart rate (HR) levels and for their baroreceptor-HR reflex sensitivity. In addition, their responses to an acoustic startle stimulus were measured. 3. A consistent rise in BP was observed among the groups as a result of the noise stimulus. This rise in systolic BP (SBP) averaged (+/-SEM) 37 +/- 2 mmHg in the SHR and 34 +/- 4 mmHg in F344 rats, while the response was only 23 +/- 3 mmHg in WKY rats. Pulse pressure (PP) was increased following noise in all groups. The delay for the BP response for all groups combined was 1.6 +/- 0.1 s. 4. Most animals had minimal HR variations, except F344 rats, responding with a 42 +/- 13 b.p.m. decrease 3.0 s after the stimulus (i.e. 1.3 s after the maximal 34 +/- 4 mmHg SBP rise). 5. The highest SBP (160 +/- 3 mmHg) and diastolic BP (104 +/- 3 mmHg) were observed in inbred SHR. Other groups were normotensive. Resting PP was elevated for SHR (56 +/- 2 mmHg) compared with the other groups (40 +/- 2 mmHg). The highest HR was found in F344 and WF rats, with 389 +/- 11 and 372 +/- 7 b.p.m., respectively. The lowest HR was observed in SHR and Lewis rats, with 335 +/- 7 and 323 +/- 7 b.p.m., respectively. The least sensitive baroreflex function was observed in SHR (0.8 +/- 0.1 b.p.m./mmHg) compared with the other strains (1.4 +/- 0.2 b.p.m./mmHg). 6. The present study confirms the importance of genetic factors on the cardiovascular responses of rats to a noise startle stimulus. Two inbred normotensive rat strains, namely F344 and WKY rats, which exhibit a substantial difference in pressor response to noise, may be used to unravel the mechanisms of sympathetic activation.     

Nitric oxide inhibition accelerates hypertension and induces perivascular inflammation in rats

1. Inflammatory changes in peripheral arteries have been reported in animal models of hypertension. Whether they occur in cerebral arteries (CA) with hypertension induced by deprivation of endogenous nitric oxide (NO) remains unknown. 2. In the present study, we compared the arteriolar injury score (AIS) and perivascular inflammation in CA between hypertensive and normotensive rats following NO deprivation with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Five-week-old male spontaneously hypertensive rats (SHR) and Wistar -Kyoto (WKY) rats were fed with L-NAME (1 mg/mL) for 4 weeks. 3. Nitric oxide deprivation resulted in time-dependent elevations in tail-cuff pressure (representing systolic blood pressure (SBP)) in both SHR and WKY rats. The magnitude of increase in SBP was larger in SHR (+81.0 +/- 3.2 vs+25.0 +/- 2.2 mmHg; P < 0.01). Arteriolar hyalinosis and AIS in various segments of the CA were assessed with periodic acid-Schiff staining and inflammatory cells were immunostained with the antibody against macrophage/monocyte marker (ED1). The ED1+ cells appeared in the middle CA of L-NAME-treated SHR as early as 2 weeks after treatment. These cells were not observed in L-NAME-treated WKY rats and untreated SHR. More ED1+ cells were found in L-NAME-treated SHR than L-NAME-treated WKY rats after 4 weeks treatment. 4. The AIS and number of ED1+ cells around the perivascular area of the internal carotid artery were significantly higher in L-NAME-treated compared with untreated rats (AIS: 137 +/- 28 vs 46 +/- 10 for WKY rats, respectively; 169 +/- 18 vs 53 +/- 6 for SHR, respectively (P < 0.01); ED1+ cells: 7.9 +/- 0.6 vs 1.3 +/- 0.9 for WKY rats, respectively; 13.6 +/- 2.7 vs 2.1 +/- 0.9 for SHR, respectively (P < 0.01)), although SBP was higher in untreated SHR than in L-NAME-treated WKY rats (170 +/- 4 vs 137 +/- 4 mmHg, respectively; P < 0.05). 5. These findings suggest that ED1+ cells appeared in the middle CA of L-NAME-SHR as early as 2 weeks after treatment. Chronic inhibition of NO accelerates hypertension and induces perivascular inflammation.     

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.     

Sex-differences in circadian blood pressure variations in response to chronic angiotensin II infusion in rats

1. The aim of this study was to investigate the effect of chronic angiotensin II (AngII) infusion on the circadian rhythms of arterial blood pressure, heart rate (HR) and locomotor activity (ACT) in male and female rats. 2. Radiotelemetry probes were implanted into the aorta in male and female rats and allowed 10 days for recovery. Control levels for mean arterial pressure (MAP), HR and ACT were recorded for 3 days, then AngII (400 ng/kg per min s.c. via osmotic minipump) or vehicle (saline) was infused for 10 days (n = 6 per group). Further recordings of MAP, HR and ACT were made during days 8, 9 and 10 of the infusion period. 3. In response to AngII infusion, night and day-time MAP increased significantly in female (18 +/- 2 mmHg; 28 +/- 7 mmHg) and male (27 +/- 4 mmHg; 30 +/- 3 mmHg) rats, respectively. The degree of elevation in MAP in response to AngII was attenuated in the females during the night period (P(sex) < 0.05) but not the day (P(sex) = 0.2). Control night-day differences in MAP, HR and ACT averaged 7 +/- 1 mmHg, 58 +/- 5 b.p.m. and 30 +/- 4 units in the female and 6 +/- 1 mmHg, 43 +/- 3 b.p.m. (P(sex) < 0.05) and 14 +/- 2 units (P(sex) < 0.05) in male rats, respectively. AngII infusion disrupted MAP circadian rhythm in female (-4 +/- 2 mmHg) and male rats (1 +/- 2 mmHg; P(treat) < 0.01), but did not affect heart rate or locomotor activity. 4. In conclusion, sex differences in the circadian rhythm of heart rate and locomotor activity, but not arterial pressure exist under basal conditions. Circulating AngII modulated the circadian rhythm of MAP in female and male rats but not heart rate or locomotor activity. These findings have important implications for our understanding of circadian blood pressure rhythms in states of activation of the renin angiotensin system.     

Effects of trans-resveratrol on hypertension-induced cardiac hypertrophy using the partially nephrectomized rat model

trans-Resveratrol (resveratrol) has been shown to have beneficial effects on the cardiovascular system in a number of studies. It is, however, unclear whether this naturally occurring compound can protect against cardiac hypertrophy. The aim of the present study was to investigate the effects of resveratrol on cardiac hypertrophy in vivo and the potential underlying mechanisms involving endothelin (ET), angiotensin (Ang) II and nitric oxide (NO) in partially nephrectomized rats. Animal models bearing cardiac hypertrophy were replicated in male Sprague-Dawley rats following partial nephrectomy (PNX). Resveratrol (10 or 50 mg/kg) was administered to rats by gavage for 4 weeks. Simultaneous PNX and sham operation controls were simultaneously established in the present study. The systolic blood pressure (SBP) of rats was measured at baseline and, along with heart weight, after 4 weeks treatment. Serum ET-1, AngII and NO concentrations were determined. In the present study, it was shown that, compared with rats in the sham-operated group, rats in the PNX group had significantly higher SBP (154.1 +/- 22.7 mmHg), heart weight (1.69 +/- 0.24 g) and serum ET-1 (125.70 +/- 26.27 pg/mL) and AngII serum concentrations (743.63 +/- 86.50 pg/mL), whereas serum NO concentrations were lower (21.1 +/- 6.9 micromol/L; all P < 0.05). These values in the sham control group were 114 +/- 10 mmHg, 1.28 +/- 0.13 g, 52.44 +/- 21.85 pg/mL, 528.7 +/- 158.5 pg/mL and 53.21 +/- 23.87 micromol/L, respectively. After 4 weeks treatment with 50 mg/kg resveratrol, SBP, heart weight and ET-1 and AngII concentrations had decreased to 135.4 +/- 15.8 mmHg, 1.39 +/- 0.15 g, 97.11 +/- 26.74 pg/mL and 629.64 +/- 116.18 pg/mL, respectively. However, the serum NO concentration had increased to 40.1 +/- 14.6 micromol/L. These values were significantly different from those obtained for the PNX group. In conclusion, trans-resveratrol appears to be able to protect against the increase in SBP and subsequent cardiac hypertrophy in vivo and the mechanisms responsible may involve, at least in part, modulation of NO, AngII and ET-1 production.     

Contribution of the renin-angiotensin system to short-term blood pressure variability during blockade of nitric oxide synthesis in the rat.

1. The aim of this study was to investigate, by use of spectral analysis, (1) the blood pressure (BP) variability changes in the conscious rat during blockade of nitric oxide (NO) synthesis by the L-arginine analogue NG-nitro-L-arginine methyl ester (L-NAME); (2) the involvement of the renin-angiotensin system in these modifications, by use of the angiotensin II AT1-receptor antagonist losartan. 2. Blockade of NO synthesis was achieved by infusion for 1 h of a low-dose (10 micrograms kg-1 min-1, i.v., n = 10) and high-dose (100 micrograms kg-1 min-1, i.v., n = 10) of L-NAME. The same treatment was applied in two further groups (2 x n = 10) after a bolus dose of losartan (10 mg kg-1, i.v.). 3. Thirty minutes after the start of the infusion of low-dose L-NAME, systolic BP (SBP) increased (+10 +/- 3 mmHg, P < 0.01), with the effect being more pronounced 5 min after the end of L-NAME administration (+20 +/- 4 mmHg, P < 0.001). With high-dose L-NAME, SBP increased immediately (5 min: +8 +/- 2 mmHg, P < 0.05) and reached a maximum after 40 min (+53 +/- 4 mmHg, P < 0.001); a bradycardia was observed (60 min: -44 +/- 13 beats min-1, P < 0.01). 4. Low-dose L-NAME increased the low-frequency component (LF: 0.02-0.2 Hz) of SBP variability (50 min: 6.7 +/- 1.7 mmHg2 vs 3.4 +/- 0.5 mmHg2, P < 0.05), whereas the high dose of L-NAME not only increased the LF component (40 min: 11.7 +/- 2 mmHg2 vs 2.7 +/- 0.5 mmHg2, P < 0.001) but also decreased the mind frequency (MF: 0.2-0.6 Hz) component (60 min: 1.14 +/- 0.3 mmHg2 vs 1.7 +/- 0.1 mmHg2, P < 0.05) of SBP. 5. Losartan did not modify BP levels but had a tachycardic effect (+45 beats min-1). Moreover, losartan increased MF oscillations of SBP (4.26 +/- 0.49 mmHg2 vs 2.43 +/- 0.25 mmHg2, P < 0.001), prevented the BP rise provoked by the low-dose of L-NAME and delayed the BP rise provoked by the high-dose of L-NAME. Losartan also prevented the amplification of the LF oscillations of SBP induced by L-NAME; the decrease of the MF oscillations of SBP induced by L-NAME was reinforced after losartan. 6. We conclude that the renin-angiotensin system is involved in the increase in variability of SBP in the LF range which resulted from the withdrawal of the vasodilating influence of NO. We propose that NO may counterbalance LF oscillations provoked by the activity of the renin-angiotensin system.     

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.     

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.     

Upregulated function of phosphatidylinositol-3-kinase in genetically hypertensive rats: a moderator of arterial hypercontractility

1. The growth enzyme phosphatidylinositol 3-kinase (PI3K) was recently implicated in the mediation of arterial spontaneous tone, an event observed in arteries from hypertensive, but not normotensive, subjects that contributes to changes in total peripheral resistance in the hypertensive state. We have shown this occurrence in experimentally induced models of hypertension. However, because the majority of hypertension is genetically based, it is important to demonstrate a similar change in genetically hypertensive animals. 2. Aorta from spontaneously hypertensive rats (SHR; systolic blood pressure = 183 +/- 4 mmHg) and Wistar Kyoto (WKY) rats (115 +/- 2 mmHg) were isolated for the measurement of isometric contractile force. Aorta from SHR displayed small increases (approximately 5% maximum phenylephrine (PE)-induced contraction) in spontaneous tone, whereas aorta from WKY rats displayed none. The non-selective PI3K inhibitor LY294002 (20 micromol/L) and the selective inhibitor of the p110delta catalytic subunit of PI3K IC87114 (20 micromol/L) caused a fall of basal tone in SHR aorta (20 +/- 7 and 24 +/- 6% of the initial PE contraction, respectively), but did not alter tone in arteries from WKY rats. LY294002, but not IC87114, normalized the increased potency of noradrenaline (NA) observed in aorta from SHR (-log EC50 values for NA in the presence of vehicle in WKY rats and SHR 7.5 +/- 0.1 and 7.8 +/- 0.1, respectively (P < 0.05); -log EC(50) values for NA in the presence of LY294002 in WKY rats and SHR 7.0 +/- 0.1 and 7.0 +/- 0.1, respectively). 3. Biochemical expression of the p110 catalytic and p85 regulator subunits of PI3K in western analyses revealed no difference in expression of the regulatory p85alpha or p110alpha protein subunits between WKY rats and SHR; p110gamma was not detected. In contrast, p110delta expression was increased greater than 30% in aorta from SHR compared with WKY rats (827.6 +/- 88.5 vs 576.8 +/- 53.4 arbitrary densitometry units, respectively). Immunohistochemical analyses revealed expression of the p110delta isoform in the smooth muscle of arteries. 4. These data underscore the relevance of an enzyme historically classified as one committed to growth/anti-apoptosis in modifying contractility and supports involvement of PI3K in genetically based hypertension.     

Dissociation of blood pressure and sympathetic activation of renin release in sinoaortic-denervated rats

1. Blood pressure (BP) and heart rate (HR) increase 6 and 24 h after sinoaortic baroreceptor denervation (SAD), whereas plasma renin activity (PRA) and renal renin mRNA levels remain unchanged. We postulated that a simultaneous rise in BP could offset the expected activation of renin associated with an increased renal sympathetic discharge secondary to SAD. 2. To test this hypothesis, the increase in BP associated with the onset of SAD was prevented by a continuous infusion of sodium nitroprusside (SNP; 30 microg/kg per h). Changes were measured in five groups of conscious adult male Wistar rats: (i) sham; (ii) SAD; (iii) SAD rats in which the BP was prevented from increasing by infusion of SNP; (iv) sham rats in which the BP was increased by 30% by infusion of phenylephrine (PE; 1.5-2.0 mL/h); and (v) SNP + PE for 3 h by infusion as above. 3. As expected, BP and heart rate (HR) increased significantly following SAD compared with sham rats (152 +/- 4 vs 116 +/- 3 mmHg, respectively, for BP and 503 +/- 6 vs 345 +/- 13 b.p.m., respectively for HR; n = 5; P < 0.05) but remained unchanged when SNP was infused for 3 h (106 +/- 1 mmHg and 455 +/- 9 b.p.m., respectively; n = 5; P < 0.05). 4. Similarly, BP and HR increased with PE infusion compared with PE + SNP (138 +/- 9.9 vs 113 +/- 2.3 mmHg for BP, respectively, and 325 +/- 9 vs 423 +/- 18 b.p.m. for HR, respectively; n = 5; P < 0.05). 5. Plasma renin activity remained unchanged in SAD compared with sham rats (1.67 +/- 0.35 vs 1.05 +/- 0.17 ng angiotensin (Ang) I/mL per h), but increased significantly when hypertension was prevented (5.86 +/- 0.77 ng AngI/mL per h; n = 5; P < 0.05). Renin mRNA levels in the kidneys were unchanged in all groups. 6. These results show that an elevation in BP appears to offset increased renal sympathetic discharge with no change in PRA.     

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.     

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.     

Anterior hypothalamic beta-adrenoceptors in chronic aortic-coarctated hypertensive rats: an interaction with central angiotensin II receptors

1. The aim of the present study was to investigate the activity of anterior hypothalamic beta-adrenoceptors and angiotensin (Ang) II receptors on blood pressure in normotensive rats and aortic-coarctated (ACo) animals at a chronic stage of hypertension. A possible interaction between beta-adrenoceptors and AngII pressor activity was also investigated. 2. Injection of isoproterenol (0.1-10 nmol) in the anterior hypothalamic area induced a dose-dependent decrease in mean arterial pressure (MAP) in sham-operated (SO), but not in ACo, animals. Isoproterenol (1 nmol) reduced blood pressure in SO rats (DeltaMAP -10.1+/-1.4 mmHg; n=10) but not in ACo animals (DeltaMAP -0.9+/-1.6 mmHg; n=10; P<0.05 vs SO rats). Whereas previous administration of atenolol (40 nmol) enhanced the cardiovascular effect of isoproterenol (1 nmol) in ACo rats but not in SO animals, propranolol (40 nmol) prevented the hypotensive action of isoproterenol in both experimental groups. Intrahypothalamic administration of clenbuterol decreased MAP in a dose-dependent manner; however, the depressor response to clenbuterol (10 nmol) was greater in ACo rats than in SO rats (DeltaMAP -26.8+/-3.2 vs -14.4+/-2.4 mmHg, respectively; n=5 for both; P<0.05). When AngII (50 ng) was injected into the anterior hypothalamic area, a greater pressor response was observed in ACo rats than in SO rats (DeltaMAP 19.6+/-1.1 vs 11.3+/-0.6 mmHg, respectively; n=5 for both; P<0.05). Atenolol (40 nmol) pretreatment partially and significantly prevented the pressor response to AngII in ACo rats, but not in SO rats. 3. In conclusion, these results provide pharmacological evidence for the existence of a beta1-adrenoceptor-mediated pressor mechanism in the anterior hypothalamic area of ACo rats that is absent in SO rats. The enhanced depressor beta2-adrenoceptor activity observed in chronic ACo rats could be a compensatory adjustment to pressor beta1-adrenoceptor activity. Conversely, pressor overactivity of AngII was observed in the anterior hypothalamic area of ACo rats at a chronic hypertensive stage; this enhancement could be explained, at least in part, by the pressor beta1-adrenoceptor activity.     

Inhibitory effects of angiotensin II on barosensitive rostral ventrolateral medulla neurons of the rat

1. The brain renin-angiotensin system can influence arterial baroreceptor reflex control of blood pressure (BP) through both direct and indirect effects on sympathetic premotor neurons of the rostral ventrolateral medulla (RVLM). The present study examined the direct effect of angiotensin (Ang) II applied by microiontophoresis on the ongoing activity of single RVLM neurons. 2. In 26 urethane-anaesthetized Wistar rats, recordings of single unit activities of barosensitive RVLM neurons were made from one barrel of a six-barrel micropipette assembly. The other five barrels were filled with either L-glutamate, AngII, valsartan (an AT1 receptor antagonist), PD 123177 (an AT2 receptor antagonist) and saline. All drugs were applied by microiontophoresis. 3. Mean BP was 83 +/- 3 mmHg. Application of AngII inhibited the ongoing activity of RVLM neurons, identified as barosensitive because their activity was inhibited by a phenylephrine- induced increase in BP, from 12.6 +/- 1.5 to 5.4 +/- 1.1 Hz (n=24; P < 0.001). Angiotensin II also inhibited the glutamate-evoked excitation of barosensitive RVLM neurons from 15 +/- 3 to 5.8 +/- 2.0 Hz (n=6; P < 0.001). Valsartan significantly increased neuronal activity from 9.5 +/- 2.3 to 13.5 +/- 3.2 Hz (n=7, P < 0.01), whereas PD 123177 significantly decreased neuronal activity from 13.5 +/- 3.5 to 9.9 +/- 2.8 Hz (n=13; P < 0.01). 4. The results suggest that AngII exerts a tonic inhibitory effect on barosensitive RVLM neurons, which is presumably mediated through AT1 receptor stimulation.     

Effects of morin on blood pressure and metabolic changes in fructose-induced hypertensive rats

High fructose (HF) feeding induces a moderate increase in blood pressure in rats, which is associated with insulin resistance, hyperinsulinemia, and hypertriglyceridemia. In the present study, we examined the chronic effect of morin, a flavonoid isolated from medicinal plants, on blood pressure, lipid profiles, and serum insulin and glucose in HF-induced hypertensive rats. Rats were divided into control group and HF-fed group during the first three weeks of experiments. Then, rats were further divided into four groups and treated for 4 more weeks as follows: 1) control group; 2) morin-treated (intraperitoneal 5 mg/kg/d) control group; 3) HF-fed group; 4) morin-treated, HF-fed group (n=8, each group). Morin-treated HF-fed group showed lower systolic blood pressure (SBP) (132.0+/-2.5 mmHg vs. 142.8+/-2.2 mmHg, p<0.05), lower serum insulin level (1.21+/-0.27 vs. 2.73+/-0.30 microIU/dl, p<0.05), and lower plasma triglycerides (47.8+/-5.0 vs. 65.5+/-5.0 mg/dl, p<0.05) than those of HF-fed group. Morin treatment also suppressed mRNA expression of endothelin-1 (ET-1) in the thoracic aorta from HF-induced hypertensive rats. Moreover, decreased renal sodium excretion in HF-induced hypertensive rats was ameliorated by morin treatment. In conclusion, the results of this study demonstrate that morin has an anti-hypertensive effect in HF-induced hypertensive rats. This effect of morin may be associated with the suppression of serum insulin and plasma triglyceride level, with the down-regulation of ET-1 in the thoracic aorta, and with the partial amelioration of renal dysfunctions in HF-induced hypertensive rats.     

The bradykinin B1 receptor and the central regulation of blood pressure in spontaneously hypertensive rats.

1. We evaluated if the brain bradykinin (BK) B1 receptor is involved in the regulation of blood pressure (BP) in conscious rats. 2. Basal mean BP and HR were 115 +/- 2 and 165 +/- 3 mmHg and 345 +/- 10 and 410 +/- 14 beats min in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), respectively. Intracerebroventricular (i.c.v.) injection of 1 nmol B1 receptor agonist Lys-desArg9-BK significantly increased the BP of WKY and SHR by 7+/-1 and 19+/-2 mmHg, respectively. One nmol Sar[D-Phe8]-desArg9-BK, a kininase-resistant B1 agonist, increased the BP of WKY and SHR by 19+/-2 and 17+/-2 mmHg, respectively and reduced HR in both strains. 3. I.c.v. injection of 0.01 nmol B1 antagonists, LysLeu8-desArg9-BK or AcLys[D-betaNal7,Ile8]-desArg9-BK (R715), significantly decreased mean BP in SHR (by 9+/-2 mmHg the former and 14+/-3 mmHg the latter compound), but not in WKY. In SHR, the BP response to R715 was associated to tachycardia. 4. I.c.v. Captopril, a kininase inhibitor, increased the BP of SHR, this response being partially prevented by i.c.v. R715 and reversed into a vasodepressor effect by R715 in combination with the B2 antagonist Icatibant. 5. I.c.v. antisense oligodeoxynucleotides (ODNs) targeted to the B1 receptor mRNA decreased BP in SHR, but not in WKY. HR was not altered in either strain. Distribution of fluorescein-conjugated ODNs was detected in brain areas surrounding cerebral ventricles. 6. Our results indicate that the brain B1 receptor participates in the regulation of BP. Activation of the B1 receptor by kinin metabolites could participate in the pathogenesis of hypertension in SHR.     

香荚兰乙酮对DOCA盐高血压大鼠血压及大动脉结构的影响

目的观察香荚兰乙酮对醋酸脱氧皮质酮(DOCA)盐高血压大鼠血压及大动脉结构的影响。方法 34只SD大鼠分为假手术组(n=10),DOCA盐高血压模型组(模型组,n=13)和香荚兰乙酮治疗组(治疗组,n=11),模型组和治疗组大鼠于左肾切除术1 wk后开始给药(DOCA 12.5 mg.wk-1皮下注射,1%NaCl饮水;治疗组饮水中加入1.5 mmol.L-1香荚兰乙酮),共5 wk。所有动物在术后wk 2,4,6测定尾动脉血压;6 wk后通过超声活体观察颈总动脉内膜-中膜厚度(IMT),并取胸主动脉测定血管中层厚度。结果模型组大鼠血压呈逐步升高趋势,wk 6治疗组大鼠血压明显下降[(140.6±10.5)mmHg vs.(166.6±13.5)mmHg,P<0.01],胸主动脉中层厚度[(165.52±33.65)μm vs.(194.25±17.91)μm,P<0.05]及颈动脉IMT[(53.33±10.22)μm vs.(78.00±12.96)μm,P<0.05]均显著降低。结论香荚兰乙酮干预可明显降低DOCA盐高血压大鼠尾动脉血压,抑制颈动脉内IMT的增厚,降低胸主动脉中层厚度。     

Atorvastatin prevented and partially reversed adrenocorticotropic hormone-induced hypertension in the rat

1. Adrenocorticotropic hormone (ACTH)-induced hypertension is associated with nitric oxide (NO) deficiency and increased oxidative stress. Atorvastatin (Ato), an HMG-Co-enzyme-A reductase inhibitor has been reported to enhance availability of NO. The aim of the study was to assess whether pretreatment with Ato would prevent the development of ACTH-induced hypertension and whether established ACTH-induced hypertension could be reversed with subsequent administration of Ato in rats. 2. Male Sprague-Dawley rats (n = 60) were treated with Ato (30 mg/kg per day in drinking water) or tap water for 15 days. ACTH (0.2 mg/kg per day s.c) or saline was started 4 days after Ato treatment or non-treated rats and continued for 11-13 days (prevention study). In the reversal study, Ato was given on day 8 of ACTH/Saline treatment for 5 days. Systolic blood pressure (SBP) was measured on alternate days using the tail cuff method. 3. Adrenocorticotropic hormone treatment increased SBP (110 +/- 2-136 +/- 2 mmHg, P < 0.001) and aortic superoxide production (P < 0.001). Ato alone did not alter SBP, but Ato pretreatment prevented ACTH-induced hypertension compared with that in rats treated with ACTH alone (118 +/- 2 and 136 +/- 2 mmHg, respectively, P cent < 0.01). Ato partially reversed ACTH-induced hypertension (124 +/- 3 and 136 +/- 2 mmHg, respectively, P cent < 0.05). Plasma nitrate/nitrite (NOx) was decreased in ACTH-treated rats compared with saline treated rats (6.6 +/- 0.4 saline and 4.5 +/- 0.5 micromol/L ACTH, P < 0.001). Atorvastatin affected neither plasma NOx nor aortic superoxide production. 4. Atorvastatin prevented and partially reversed ACTH-induced hypertension in the rat.     

Aminoguanidine prevents age-related deterioration in left ventricular-arterial coupling in Fisher 344 rats

In recent studies, aminoguanidine (AG), an inhibitor of advanced glycation endproducts, has been identified as a prominent agent that can prevent the age-related aortic stiffening and cardiac hypertrophy. The aim of this study was to determine whether AG had effects on the left ventricular (LV)-arterial coupling in aged Fisher 344 rats in terms of the ventricular and arterial chamber properties. Normotensive rats were treated from 18 to 24 months with AG (1 g l(-1) in drinking water) and compared with a control group. LV pressure and ascending aortic flow signals were recorded to construct the ventricular and arterial end-systolic pressure-stroke volume relationships to calculate LV end-systolic elastance (Ees) and effective arterial volume elastance (Ea), respectively. The optimal afterload (Qload) determined by the ratio of Ea to Ees was used to measure the efficiency of mechanical energy transferred from the left ventricle to the arterial system. In comparison with the 6-month-old rats, the 24-month-old animals had decreased Ees, at 567.4 +/- 26.7 vs 639.0 +/- 20.7 mmHg ml(-1), decreased Ea, at 411.5 +/- 18.6 vs 577.9 +/- 15.7 mmHg ml(-1), and decreased Q(load), at 0.9428 +/- 0.0024 vs 0.9962 +/- 0.0014. Treatment with AG for 6 months did not significantly affect Ees; however, when normalized to LV weight (i.e., Eesn = Ees/LV weight), Eesn showed a significant rise of 22.8%, suggesting that AG may retard the aging process on the intrinsic contractility of the left ventricle. On the other hand, the decrease in Ea in aging rats was prevented by AG, as reflected in the increase of 19.7% in this variable (P < 0.05). The 24-month-old treated rats also exhibited a significant rise of 21.6% in Ea/Ees, causing an increase of 5.2% in Qload (P < 0.05). We conclude that in healthy older Fisher 344 rats without diabetes, long-term treatment with AG may improve both the arterial and ventricular function and optimize the matching condition for the left ventricular-arterial coupling.     

DIETARY Ng-NITR0-l-ARGININE INDUCES SUSTAINED HYPERTENSION IN NORMOTENSIVE WISTAR-KYOTO RATS

1. Prolonged oral administration of NG-nitro-L-arginine (L-NNA) for a period of 5 weeks in 8 week old male normotensive Wistar-Kyoto (WKY) rats (n = 10), induced hypertension in all animals. Hypertension was characterized by a sharp initial increase in both systolic blood pressure (SBP) and mean blood pressure (MBP) until the third day (from 126 +/- 3 mmHg to 160 +/- 6 mmHg and from 95 +/- 3 mmHg to 133 +/- 6 mmHg, respectively). This was followed by a gradual and steady increase until the fourth week (163 +/- 4, 171 +/- 3 and 189 +/- 8 mmHg for SBP in weeks 1, 2 and 4, respectively; and 135 +/- 4, 143 +/- 3 and 157 +/- 5 mmHg for MBP in weeks 1, 2 and 4, respectively). 2. Intravenously L-arginine.HCl (500 mg/kg) administered on the last day of the 5th week abolished the effect of dietary L-NNA on the arterial blood pressure. 3. Dietary L-NNA-induced hypertension in WKY rats is easily obtainable and free of any surgical operation, and can be utilized as a new experimental model to further understand the importance of endothelium-dependent relaxing factor/nitric oxide in blood pressure regulation and to clarify the pathological significance in intact animals where endothelium-dependent relaxing factor/nitric oxide is functionally involved.