Enhanced blood pressure sensitivity to DOCA-salt treatment in endothelin ET(B) receptor-deficient rats

The role of endothelin ET(B) receptor-mediated action in the development and maintenance of deoxycorticosterone acetate (DOCA)-salt-induced hypertension was evaluated using the spotting-lethal (sl) rat which carries a naturally occurring deletion in the ET(B) receptor gene. Homozygous (sl/sl) rats treated with DOCA-salt for 1 week exhibited an earlier onset of hypertension than heterozygous (sl/+) and wild-type (+/+) rats (systolic blood pressure, SBP; 156.7+/-3.4 versus 128.8+/-5.3 and 132.9+/-3.7 mmHg, respectively). Four weeks after the start of DOCA-salt treatment, homozygous rats developed marked hypertension, with a SBP of 206. 0+/-4.5 mmHg, compared with 184.8+/-10.7 mmHg in heterozygous and 164.3+/-4.8 mmHg in wild-type rats. Cardiovascular hypertrophy and renal dysfunction observed after 4-weeks treatment with DOCA-salt were more severe in homozygous rats, compared to wild-type and heterozygous animals. These evidences support strongly the view that ET(B) receptor-mediated actions are a protective factor in the pathogenesis of DOCA-salt-induced hypertension.     

SODIUM INTAKE MODULATES RENAL VASCULAR REACTIVITY TO ENDOTHELIN-1 IN DAHL RATS

1. The systemic and renal haemodynamic responses to endothelin-1 (ET1) were evaluated and compared to Angiotensin II (AII) in anaesthetized Dahl salt-sensitive (DS) and salt-resistant (DR) rats on either low (0.1% NaCl in diet) or high (8% NaCl in diet) salt intake. 2. Baseline mean arterial pressure on low salt diet was similar in both strains, while on high salt diet it was 73 +/- 4 mmHg in DR rats and 119 +/- 8 mmHg in DS rats (P less than 0.05). Baseline renal blood flow (RBF) and renal vascular resistance (RVR) were similar in all groups. 3. AII in bolus injection induced a short, dose-dependent increase in blood pressure and renal vascular resistance and a fall in renal blood flow. The maximal pressure increase was significantly greater in DS rats on high salt diet than that in each of the other groups (P less than 0.05). The fall in renal blood flow and the increase in renal vascular resistance were attenuated in both strains on low salt diet. 4. ET1 induced an initial decrease followed by a prolonged increase in blood pressure; both phases were similar in all groups. However, renal vascular reactivity to ET1 was markedly modulated by salt intake. On low salt diet, following a bolus injection of ET1 (1 nmol/kg), RBF decreased by 34% in DR and by 20% in DS rats, while on high salt diet RBF decreased by 76% in DR and by 80% in DS rats (P less than 0.05 high vs low salt).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of endothelin ETA receptor blocker LU 135252 on cardiac remodeling and survival in a hypertensive rat model of chronic heart failure

AIM: To investigate whether the endothelin ETA receptor blocker provides similar benefit on cardiac remodeling and survival in a hypertensive rat model of chronic heart failure (CHF). METHODS: Male stroke-prone spontaneously hypertensive (SHR-SP) rats were subjected to permanent ligation of the left coronary artery and were treated for 6 weeks with the endothelin ETA receptor blocker LU 135252 (30 mg.kg(-1).d(-1)) starting 24 h after ligation or untreatment. Sham-operated rats served as normal controls. The mean arterial blood pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular contractility (LV dp/dt(max)), left ventricular inner diameter (LVD) and circumference (LVC), septal thickness, left ventricular interstitial collagen content (ICC) and heart weight (HW) were measured at the end of the treatment. RESULTS: Compared with the untreated group, LU 135252 tended to increase HW (1.43 +/-0.03 vs 1.38 +/-0.04 g; P> 0.05), increased LVD (7.65+/-0.24 mm vs 6.58+/-0.14 mm; P<0.05), markedly increased LVC (30.11+/-0.83 mm vs 24.82+/-0.85 mm; P< 0.01) and reduced left ventricular ICC (3.79%+/-0.09% vs 6.71%+/-0.11%; P< 0.01), slightly lowered MAP (132+/-6 mmHg vs 142+/-4 mmHg; P>0.05), reduced LVEDP (14 4 mmHg vs 27+/-4 mmHg; P<0.05) and improved LV dp/dtmax (4230+/-450 mmHg/s vs 1950+/-400 mmHg/s; P<0.05); survival was not prolonged significantly (13% vs 11%; P=NS). CONCLUSION: In this hypertensive rat model of CHF, chronic endothelin ETA receptor blockade with LU 135252 improves cardiac hemodynamics, however, it does not affect long-term survival and worsens cardiac remodeling. Thus, endothelin ETA receptor antagonists are unlikely to have an important role in the management of patients with CHF.     

EFFECTS ON SHEEP BLOOD PRESSURE OF TREATMENT WITH ANGIOTENSIN, STEROIDS AND SALT

1. Angiotensin II (AII, 0.22 microgram/min) infused for 7-14 days, into adult unanaesthetized wethers, caused a rise in blood pressure of 7 +/- 3/7 +/- 3 mmHg (mean +/- s.e.m.) from control values of 90 +/- 5/54 +/- 3 mmHg (P less than 0.05, n = 11). Cardiac output and pulse interval were not affected. A high salt intake had no effect on blood pressure, cardiac output and pulse interval, nor did it potentiate the action of AII. 2. Ethinyl oestradiol (EE, 20 mg/week) caused a small fall in systolic and diastolic pressure of 6 +/- 3/6 +/- 5 mmHg (n = 7, P less than 0.1, P less than 0.05). When AII (0.22 microgram/min) was given with EE, it still caused a significant rise in blood pressure (P less than 0.01). The synthetic progestin (1 mg of norethisterone [NE] for 8-18 days) plus a high salt diet had no effect on arterial pressure and cardiac output but pulse interval rose significantly (P less than 0.05). 3. Therefore the reduction in vascular reactivity to angiotensin seen in human pregnancy is probably not related to high levels of oestrogen. Further, NE combined with a high salt diet does not cause hypertension in sheep.     

Reversal of cardiac dysfunction by selective ET-A receptor antagonism

The effectiveness of a selective endothelin receptor-A (ET-A) antagonist, A-127722 (approximately 10 mg kg(-1) day(-1) as 200 mg kg(-1) powdered food), to reverse existing cardiac remodelling and prevent further remodelling was tested in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Uninephrectomised rats (UNX) administered DOCA (25 mg every fourth day s.c.) and 1% NaCl in drinking water for 28 days developed hypertension (systolic blood pressure (BP): UNX 128+/-6 mmHg, DOCA-salt 182+/-5* mmHg; *P<0.05 vs UNX), left ventricular hypertrophy (UNX 1.99+/-0.06 mg kg(-1) body wt, DOCA-salt 3.30+/-0.08* mg kg(-1) body wt), decreased left ventricular internal diameter (UNX 6.69+/-0.18 mm, DOCA-salt 5.51+/-0.37* mm), an increased left ventricular monocyte/macrophage infiltration together with an increased interstitial collagen from 2.7+/-0.3 to 11.7+/-1.3%, increased passive diastolic stiffness (UNX 21.1+/-0.5, DOCA-salt 30.1+/-1.3*), prolongation of the action potential duration at 20 and 90% of repolarisation (APD20-UNX 6.8+/-1.1, DOCA-salt 10.1+/-1.5* ms; APD90-UNX 34.4+/-3.5 ms, DOCA-salt 64.3+/-10.4* ms) and vascular dysfunctions (2.6-fold decrease in maximal contractile response to noradrenaline, 3.5-fold decrease in maximal relaxation response to acetylcholine). Administration of A-127722 for 14 days starting 14 days after surgery attenuated the increases in systolic BP (150+/-6** mmHg, **P<0.05 vs DOCA-salt), left ventricular wet weight (2.65+/-0.06** mg kg(-1) body wt) and internal diameter (6.39+/-0.31** mm), prevented left ventricular monocyte/macrophage accumulation, attenuated the increased left ventricular interstitial collagen (7.6+/-1.3%**), reversed the increased passive diastolic stiffness (22.1+/-1.2**), attenuated the action potential duration prolongation (APD20 - 7.6+/-1.4**, APD90 - 41.5+/-6.9** ms) and normalised changes in vascular function. ET-A receptor antagonism both reverses and prevents the cardiac and vascular remodelling in DOCA-salt hypertension and improves cardiovascular function.     

Recombinant adeno-associated virus-mediated delivery of antisense angiotensin II receptor 1 gene attenuates hypertension development

Aim：The renin-angiotensin system plays a crucial role in the development and establishment of hypertension, and the pharmacological blockade of the system results in a reduction in blood pressure. In the present study, we investigated whether the effects of a novel, double-stranded, recombinant adeno-associated virus vector （rAAV）-mediated antisense angiotensin Ⅱ receptor 1 （AT1R） gene efficiently prevents the development of hypertension induced by a high-salt diet in adult, male Sprague-Dawley （SD） rats. Methods：A rAAV was prepared with a cassette containing a cytomegalovirus promoter and partial cDNA （660 base pairs） for the AT1R inserted in the antisense direction （rAAV-AT1-AS）. A single tail vein injection of the rAAV-AT1-AS or rAAV-GFP （green fluorescent protein, a reporter gene） was performed in adult, male SD rats. Two weeks after injection, the animals were fed a diet containing 8% NaCl, and the systolic blood pressure was measured weekly using the tail-cuff method for 12 weeks. Results： The high-salt diet induced a significant rise in systolic blood pressure in the rAAV-GFP-treated animals; however, the rAAV-AT1-AS treatment attenuated the rise in blood pressure （142.7±4.5 mmHg vs 117±3.8 mmHg, P〈0.01）, and the hypotensive effect was maintained until the experiments ended at 12 weeks. In the rAAV-GFP-treated animals AT1 was overexpressed in various tissues, especially in the aorta and kidney at mRNA levels; in contrast, rAAV-AT1-AS treatment markedly attenuated AT1 expression. Furthermore, rAAV-AT1-AS treatment prevented target organ damages from hypertension, including cardiac dysfunction and renal injury compared to the rAAV-GFP group. Conclusion：These results suggest that rAAVmediated anti-AT1 delivery attenuates the development of hypertension and protects against renal injury and cardiac remodeling.     

Increase in blood pressure with enhanced Na+, K+ -ATPase activity in stroke-prone spontaneously hypertensive rats after 4-weeks intake of rapeseed oil as the sole dietary fat

Twenty stroke-prone spontaneously hypertensive rats were divided into 2 groups of 10 animals each, and fed a defatted diet and orally administered rapeseed (canola) oil or soybean oil at 10 (w/w)% of the consumed diet once a day for 4 weeks. At the 4th week of administration, the systolic blood pressure in the canola oil group was higher (235 +/- 2 mmHg, mean +/- S.E.M., N=10) than that in the soybean oil group (225 +/- 4 mmHg, N=10, P<0.05). In isolated, perfused mesenteric bed from these rats, the increase in perfusion pressure by norepinephrine, ATP, arachidonic acid, endothelin-1, angiotensin II or serotonin showed no between-group differences. There were also no between-group differences in the production of thromboxane A2 and prostaglandin 12 in the outflow by arachidonic acid injection. On the other hand, in the isolated aortic ring from the canola oil group, developed tension in potassium-free solution was enhanced with activation of Na+, K+ -ATPase. These results suggest that canola oil intake as the sole dietary fat increases systolic blood pressure of stroke-prone spontaneously hypertensive rats. The changes in vascular responsiveness to vasoconstrictors and production of prostanoids are unlikely to have relevance to the elevation of blood pressure. However, altered Na+, K+ -ATPase activity may play a role in the promotion of blood pressure elevation.     

Role of endothelin ETB receptor in partial ablation-induced chronic renal failure in rats

We investigated the role of endothelin ET(B) receptor in the remnant kidney model of chronic renal failure, by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the endothelin ET(B) receptor gene. After 5/6 nephrectomy, systolic blood pressure and renal functional parameters were measured for 12 weeks. At the end of the experimental period, arterial blood sample, remnant kidney, heart and aorta were collected and used for biochemical measurements and histopathological studies. The ET(B)-deficient sl/sl rats exhibited earlier and higher increases in systolic blood pressure, urinary protein excretion, blood urea nitrogen and plasma creatinine concentration, compared with cases in wild-type rats. Histopathologic examination of the kidney revealed glomerular and tubular lesions, alterations of which were more severe in sl/sl than in wild-type rats. While aortic endothelin-1 contents were increased similarly in both groups, the level of renal endothelin-1 content was significantly elevated in sl/sl rats, but not in the wild-type rats. These results suggest that enhanced endothelin-1 production is at least partly responsible for the increased susceptibility to partial ablation-induced chronic renal failure in ET(B) receptor-deficient rats and that ET(B) receptor-mediated actions are protective against vascular and renal injuries in this disease.     

Is functional upregulation of the 5-HT2B receptor in deoxycorticosterone acetate salt-treated rats blood pressure dependent?

This study tests the hypothesis that the functional upregulation of the arterial 5-hydroxytryptamine (5-HT)2B receptor in arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats depends on the development of high blood pressure. Wistar-Furth and Wistar rats were given sham or DOCA-salt treatment (200 mg/kg DOCA, SC; 1.0% NaCl and 0.2% KCI in drinking water). Systolic blood pressures (4 week; mm Hg) were: Wistar Sham (120+/-3), Wistar DOCA (176+/-6), Wistar-Furth Sham (112+/-3) and Wistar-Furth DOCA (136+/-4). Isolated mesenteric arteries from Wistar DOCA and Wistar-Furth DOCA rats displayed a three- to fivefold leftward shift in contraction to 5-HT that was insensitive to blockade by the 5-HT2A receptor antagonist ketanserin (10 nM) and a significantly increased maximal contraction to the 5-HT2B receptor agonist BW723C86 [Wistar DOCA = 90+/-17% phenylephrine contraction; Wistar Sham = 1+/-1%; Wistar-Furth DOCA = 33+/-8%; Wistar-Furth Sham = 0%]. Arteries from Sprague-Dawley rats receiving salt or DOCA alone displayed similar systolic blood pressures (151+/-11 mm Hg and 144+/-5 mm Hg, respectively), but only tissues from rats receiving DOCA displayed an increased contraction to BW723C86 (DOCA alone = 60.7+/-16% vs. sham = 13+/-5.3%). These data suggest that upregulation of the arterial 5-HT2B receptor is largely independent of an increase in blood pressure.     

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 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.     

INHIBITION OF NO SYNTHESIS HAS AN ADDITIVE EFFECT ON HYPERTENSION INDUCED BY ACTH IN CONSCIOUS RATS

1. The haemodynamic and metabolic effects of oral intake of approximately 30 mg/kg per day N-nitro-L-arginine (NOLA) were examined in sham and adrenocorticotrophin (ACTH, 0.5 mg/kg per day) treated conscious Sprague-Dawley rats (n = 33). 2. NOLA administration produced an increase in systolic blood pressure of 24 +/- 6 mmHg (P < 0.001), but did not alter food or water intake, urine volume or electrolyte excretion in rats not treated with ACTH. 3. Compared with sham injection, ACTH-treated rats demonstrated an increase in systolic blood pressure (water + sham, 3 +/- 1 mmHg; water + ACTH, 16 +/- 3 mmHg; P < 0.001), loss of bodyweight, and increases in water intake and urine volume. 4. The magnitude of the blood pressure rise in ACTH-treated rats was greater in those receiving NOLA than in those drinking water only (water + ACTH, 16 +/- 3 mmHg; NOLA + ACTH, 37 +/- 3 mmHg; P < 0.05). Metabolic changes were similar. 5. Inhibition of nitric oxide is unlikely to be a major determinant of ACTH-induced hypertension in the rat, since NOLA increased blood pressure whether or not ACTH was administered, indicating an additive effect of ACTH and NOLA administration.     

Vasopressin and the pathogenesis of chronic renal failure.

1. Partial (5/6) renal ablation was performed in Long Evans rats treated with vehicle or a vasopressin V1-receptor antagonist, in control Long Evans rats, and in homozygous Brattleboro rats which lack endogenous vasopressin. 2. In control and vasopressin-blocked Long Evans rats, 3 weeks following partial renal ablation, systolic blood pressure was 215 +/- 5 and 199 +/- 9 mmHg and, urinary protein excretion was 54 +/- 4 and 50 +/- 3 mg day-1, respectively. 3. The pressor response to exogenous vasopressin was significantly (P less than 0.05) reduced in rats treated with the V1-receptor antagonist (ED50 mmHg 5.0 +/- 1.6 vs. 0.09 +/- 0.01 micrograms kg-1). 4. In control Long Evans and in Brattleboro rats, 3 weeks following renal ablation, systolic blood pressure was 204 +/- 10 and 191 +/- 7 mmHg, and urinary protein excretion was 97 +/- 27 and 71 +/- 5 mg day-1, respectively. 5. Histological examination of the remaining kidney tissue demonstrated significant glomerular hyalinization following renal ablation but no differences between any of the groups. 6. The data indicate that neither vasopressin nor the urinary concentrating mechanism is likely to be involved in the hypertension and proteinuria associated with partial renal ablation.     

Synergistic actions of enalapril and tempol during chronic angiotensin II-induced hypertension

Experiments were designed to test the hypothesis that antioxidant treatment would increase the anti-hypertensive actions of endogenous kinins during angiotensin converting enzyme (ACE) inhibition. Four groups of rats, all given angiotensin II (Ang II) for 2 weeks, were studied: 1) control, 2) enalapril, 3) tempol or 4) both tempol and enalapril. Ang II significantly increased systolic blood pressure (BP) when compared with the baseline (170+/-8 vs. 128+/-4 mm Hg, P<0.05). Neither enalapril nor tempol alone was able to attenuate the elevation in BP (165+/-7 and 164+/-6 mm Hg, respectively). In contrast, combined administration of tempol and enalapril prevented the increase in BP (137+/-5 mm Hg). Plasma 8-isoprostane increased in Ang II-infused rats when compared with control untreated rats (69+/-14 vs. 23+/-0.5 pg/ml, P<0.05). Tempol alone or tempol plus enalapril significantly attenuated the increase in plasma 8-isoprostane (29+/-6 and 34+/-7 pg/ml, respectively). In additional experiments, we used the bradykinin B(2) antagonist, icatibant to determine if increased B(2) receptor contributes to the anti-hypertensive effect of combined tempol and enalapril in Ang II-infused rats. Icatibant decreased the ability of this combination to lower arterial pressure. Additionally, a significant increase in B(1) receptor protein expression in renal cortex of Ang II-infused rats was observed compared to control suggesting that bradykinin receptor activation could account for the effect of enalapril to enhance the actions of tempol. These data support the hypothesis that combined reduction of superoxide along with enhanced endogenous kinins may facilitate blood pressure lowering in Ang II hypertension.     

Enrasentan improves survival, limits left ventricular remodeling, and preserves myocardial performance in hypertensive cardiac hypertrophy and dysfunction

Evidence suggests that endothelin receptor antagonists may have therapeutic potential for the chronic treatment of heart failure. In the current study, the effects of an orally active mixed endothelin-A/endothelin-B (ETA /ETB ) receptor antagonist (enrasentan) were assessed in a model of cardiac hypertrophy and dysfunction (spontaneously hypertensive stroke prone rats) maintained on a high-salt/high-fat diet. Echocardiography was used to quantify cardiac performance and left ventricular dimensions. Enrasentan (1,200 and 2,400 parts per million in the high-salt/high-fat diet) had no significant effects on body weight and systolic blood pressure. However, increases in heart rate were not observed in the enrasentan-treated groups at 12 weeks (p < 0.05). Enrasentan-treated groups exhibited significantly improved survival (90-95% vs. 30% [control rats] at 18 weeks; p < 0.001). Enrasentan treatments also increased stroke volume (at 8, 12, and 16 weeks) and cardiac index (at 8 and 16 weeks) 33-50% and 45-63%, respectively. Enrasentan treatments reduced the relative wall thickness (14-27% at 8 and 12 weeks), ratio of left ventricular mass to body weight (20% at 12 weeks), and ratio of terminal heart weight to body weight (16-23%, p < 0.05). Finally, circulating aldosterone concentration (54-57%) and proANF fragment (33%) were reduced in enrasentan-treated groups (54-57% and 33%, respectively). Mixed ETA /ETB receptor antagonism improves cardiac performance and attenuates ventricular remodeling and premature mortality in an aggressive hypertension model.     

Renal and systemic effects of chronic blockade of ET(A) or ET(B) receptors in normal rats and animals with experimental heart failure

Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal hemodynamic changes and impaired excretory function in congestive heart failure. It has previously been demonstrated that acute administration of ABT-627 (endothelin-A blocker) abolished systemic and renal vasoconstriction in controls and rats with congestive heart failure induced by a surgically created aortocaval fistula (Abassi et al. Clin Sci (Lond) 2002;103:S245-S248). In contrast, acute endothelin-B blockade by A-192621 exaggerated the ET-1 induced systemic and renal vasoconstriction. The present study examined the renal and systemic effects of chronically administered ABT-627 (24 mg/kg per day) or A-192621 (72 mg/kg per day) for 7 days via osmotic minipumps inserted intraperitoneally on the day of operation of sham controls and rats with congestive heart failure. Tailcuff measurements revealed that ABT- 627 significantly decreased mean arterial pressure from 108 +/- 2 mmHg to 87 +/- 2 mmHg (P < 0.05), whereas A-192621 significantly increased mean arterial pressure from 110 +/- 3 mmHg to 122 +/- 3 mmHg (P < 0.05) in controls. Despite the hypotensive effect of ABT-627, daily sodium excretion dramatically increased, but to a lesser extent in A-192621-treated controls. Furthermore, chronic administration of ABT-627 to controls attenuated the systemic and renal vasoconstriction induced by ET-1 (1 nmol/kg intravenous), whereas A-192621 augmented these effects. Similarly, chronic treatment with ABT-627 totally abolished the systemic and renal vasoconstriction caused by injected ET-1 in rats with congestive heart failure, whereas A192621 potentiated these effects. Chronic treatment of animals with congestive heart failure with ABT-627 did not influence daily sodium excretion, whereas treatment with A192621 significantly improved daily sodium excretion. Interestingly, treatment with either ABT-627 or A192621 significantly decreased cardiac hypertrophy in rats with congestive heart failure. In conclusion, in sham controls endothelin-B receptor mediated vasodilation and natriuresis, probably as a result of tubular action, whereas in congestive heart failure the excretory contribution of endothelin-B receptor was attenuated, resulting in Na+ retention.     

Involvement of the endothelin ET(B) receptor in gender differences in deoxycorticosterone acetate-salt-induced hypertension

1. In the present study, we investigated the role of endothelin ET(B) receptors in gender differences in the development of deoxycorticosterone acetate (DOCA)-salt-induced hypertension by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the ET(B) receptor gene. 2. In wild-type rats, the elevation of systolic blood pressure (SBP) by DOCA-salt treatment for 4 weeks was extremely lower in females than in males, but this gender difference was partially attenuated in ovariectomized (OVX) animals. These alterations of SBP corresponded with vascular superoxide () production. 3. In homozygous (sl/sl) group, the SBP of male, intact female and OVX rats was markedly elevated by DOCA-salt treatment to the same extent, indicating that the gender difference in DOCA-salt-induced hypertension was abolished by the genetic ET(B) receptor deficiency. There were similar increases in the vascular endothelin (ET)-1 content in the three DOCA-salt-treated animal groups, but vascular production in male and OVX rats was much higher than that in intact females. 4. Daily oral administration of ABT-627, an ET(A) receptor antagonist, to sl/sl rats for 2 weeks suppressed the DOCA-salt-induced hypertension more efficiently in intact female rats than in male animals. 5. Thus, vascular oxidative stress is related, at least in part, to differences in the development of DOCA-salt-induced hypertension between male and female rats, but this gender difference is abolished by the genetic ET(B) receptor deficiency, suggesting that ET(B) receptor-mediated vasoprotective actions contribute to the gender differences seen. In addition, in both sexes, vascular ET-1 overproduction and the ET(A) receptor-mediated action seem to be responsible for the enhanced susceptibility to DOCA-salt hypertension in genetic ET(B) receptor deficiency.     

Inhalation of the endothelin-A receptor antagonist LU-135252 at various doses in experimental acute lung injury

We studied the effects of the inhaled endothelin-A receptor antagonist LU-135252 at different doses on hemodynamics and gas exchange in an animal model of acute lung injury. Thirtysix piglets (27 +/- 1 kg) were anesthetized, mechanically ventilated (FiO2 1.0), and surfactant-depleted by repeated lung lavage. The animals were randomly assigned to receive either nebulized LU- 135252 for 30 minutes at a dose of 0.3 mg/kg (n = 12), or at a dose of 3.0 mg/kg (n = 12); n = 12 animals received no further treatment (Controls). Induction of acute lung injury decreased PaO2 from 566 +/- 8 mmHg to 53 +/- 2 mmHg (mean +/- SEM) and increased intrapulmonary shunt (QS/QT) from 13 +/- 1% to 57 +/- 2%. Inhalation of LU-135252 at either dose induced a significant and sustained increase in PaO2 (0.3 mg/kg: 349 +/- 39 mmHg; 3.0 mg/kg: 219 +/- 40 mmHg), and a significant decrease in QS/QT (0.3 mg/kg: 19 +/- 2%; 3.0 mg/kg: 27 +/- 3%) when compared with Controls (PaO2: 50 +/- 3 mmHg, QS/QT: 50 +/- 5%) (P < 0.05; values at 4 hours). Mean pulmonary artery pressure in LU-135252-treated animals (0.3 mg/kg: 31 +/- 2 mmHg; 3.0 mg/kg: 30 +/- 1 mmHg) was significantly lower than in Controls (40 +/- 2 mmHg), while there were no differences in mean arterial pressure and cardiac output. We conclude that inhalation of LU-135252 at either dose improved gas exchange and hemodynamics comparably, indicating that the lower dose was already sufficient to block the majority of endothelin-A receptors in ventilated regions of the injured lung.     

Cyclo-oxygenase-2 inhibition increases blood pressure in rats

1 It is known that nonselective cyclo-oxygenase (COX) inhibitors have small but significant effects on blood pressure (BP), most notably in hypertensive patients on antihypertensive medication. Whether selective COX-2 inhibitors also interfere with BP regulation is not well understood. Therefore, we aimed to examine the effect of chronic treatment with a selective COX-2 inhibitor (rofecoxib) on systolic blood pressure (sBP) in normotensive Wistar-Kyoto rats (WKY) and on the developmental changes of sBP in young spontaneously hypertensive rats (SHR). In addition, we investigated a possible influence of salt intake on the effects of COX-2 inhibition on BP in these two rat strains. 2 Rofecoxib dose dependently increased sBP and decreased plasma levels of 6-keto prostaglandin (PG)F(1alpha) in WKY rats fed a normal salt diet (0.6% NaCl, wt wt(-1)), without affecting serum thromboxane (TX)B(2) levels. 3 Rofecoxib significantly elevated sBP in both rat strains fed normal salt or high salt diet (8% NaCl, wt wt(-1)), but not in rats on low salt intake (0.02% NaCl, wt wt(-1)). 4 Rofecoxib significantly decreased plasma levels of 6-keto PGF(1alpha) in both rat strains fed normal or high salt diet, but not in rats during low salt intake. 5 Rofecoxib exerted no influence on the changes of body weight nor on water intake. Plasma renin activity (PRA) and renocortical renin mRNA abundance were not changed by rofecoxib, but plasma aldosterone concentration (PAC) was significantly reduced. 6 These results suggest that chronic inhibition of COX-2 causes an increase of blood pressure that depends on prostacyclin synthesis. Furthermore, this increase is independent on genetic predisposition and can be prevented by salt deprivation. Since water intake and body weight gain were not changed by rofecoxib, fluid retention appears not to be a major reason for the development of hypertension. Similarly, an activation of the renin-angiotensin-aldosterone axis appears to be an unlikely candidate mechanism.     

Nifedipine effectively lowers salt-induced high blood pressure in diabetic rats.

This study examined the antihypertensive efficacy of nifedipine (a calcium channel blocker) in salt-loaded alloxan-diabetic rats. Significant increases in basal mean arterial blood pressures were observed after six weeks of high salt (8% NaCl) feeding in both diabetic (p < 0.05) and nondiabetic (p < 0.05) rats. The values were 129.95+/-3.14 mmHg for control (C); 149.22+/-8.83 mmHg for nondiabetic salt-fed (N-SF) and 150.60+/-8.01 mmHg for diabetic salt-fed (D-SF) groups. The non-salt-fed diabetic group (D) had a pressure of 136.75+/-6.66 mmHg. The maximum mean arterial blood pressures in response to noradrenaline (10(-9)-10(-5) M) infusion were significantly (p < 0.05) higher in the N-SF and D-SF groups than in the control. Nifedipine (100 microg/Kg) reduced significantly the pressures (both before and following noradrenaline infusion) in the salt-fed groups (p < 0.001). The inhibitory effect of nifedipine was more marked (p < 0.01) in the diabetic salt-fed than in the nondiabetic salt-fed. It is therefore suggested that nifedipine is effective in lowering salt-induced high blood pressure in diabetic rats.