PJ-414 Prevention of Hypertensive Renal Complication by Monotherapy or Combination of Angiotensin AT1 Receptor Blocker and Sympathetic Antagonists in SHR/Izm.(Kidney/Renal Circulation 2 (H) : PJ69)(Poster Session (Japanese))
Takae AsaiIzumi IchiyamaYoshihiro SatoYasuyuki KitaharaChikura ShiraishiHisao TaguchiHirotaka FujitaAtsuhiko TakahashiFumio SaitoYuji OtsukaToshio KushiroKatsuo Kanmatsuse
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In young spontaneously hypertensive rats (SHR), transient angiotensin II type 1 receptor (AT1R) blockade decreases blood pressure for a prolonged period. We tested the hypothesis that transient AT1R blockade in SHR leads to cardiac protection until advanced age.Wistar-Kyoto rats, SHR and transiently losartan-treated SHR (SHR-Los) (20 mg/kg per day; weeks 4-8 of age) were followed up until week 72 (n=9 each group), including repeated echocardiography, radiotelemetric investigations and 24-h urine collection. End-point measurements comprised left ventricular function parameters, left ventricular histomorphology and molecular biology (types I and III collagen, brain natriuretic peptide, AT1R mRNA) as well as renal morphology.Prehypertensive treatment with losartan, but not with the general vasodilator hydralazine, reduced blood pressure until age 48 weeks. In untreated SHR, the end-diastolic volume increased from week 36 and the left ventricular ejection fraction fell from week 48. In contrast, age-related changes in end-diastolic volume and ejection fraction were comparable in SHR-Los and Wistar-Kyoto rats up to age 60 weeks. At age 72 weeks, the ejection fraction was reduced in SHR-Los but higher than that in untreated SHR (ejection fraction: Wistar-Kyoto rats, 58 +/- 3%; SHR, 39 +/- 3%; SHR-Los, 46 +/- 3%; P < 0.01 and P < 0.05, respectively). The heart weight/body weight ratio (SHR-Los, 4.7 +/- 0.1 g/kg; SHR, 5.2 +/- 0.2 g/kg) and cardiac brain natriuretic peptide mRNA levels were improved by treatment. Left ventricular histomorphology and 24-h albuminuria were significantly improved in SHR-Los (41 +/- 5 mg/day; SHR, 80 +/- 22 mg/day; P < 0.05).In young SHR, transient AT1R blockade, not blood pressure lowering, attenuates the development of hypertension and exerts cardioprotective effects up to age 72 weeks.
Hydralazine
Brain natriuretic peptide
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Objectives It is generally accepted that short-term (4 weeks) inhibition of the renin–angiotensin system (RAS) of young spontaneously hypertensive rats (SHR) in their pre-hypertensive phase confers long-lasting protection from fully hypertensive levels in adulthood. However, there is very little data pertaining to the effects of such treatment in adult SHR with established hypertension. Therefore, we determined the relative effects of angiotensin converting enzyme (ACE) inhibition (perindopril), AT1 receptor blockade (candesartan cilexetil) and RAS-independent vasodilatation (hydralazine) and their withdrawal in adult SHR, on blood pressure measured by radiotelemetry, as well as on cardiac and vascular structure. Methods Adult male SHR were instrumented with radiotelemetry probes to measure blood pressure and heart rate continuously. SHR were given either vehicle, perindopril (1 mg/kg per day), candesartan cilexetil (2 mg/kg per day) or hydralazine (30 mg/kg per day) at equi-effective depressor doses for 4 weeks (treatment study). Separate groups of animals were also given identical treatments but were then monitored for a further 8 weeks after drug withdrawal (withdrawal study). An indirect in-vivo assessment of whole body vascular hypertrophy (mean arterial pressure during maximum vasoconstriction) was made during and after drug withdrawal, as was the pressor activity evoked by angiotensin I and angiotensin II. The effect of antihypertensive treatment on microalbuminuria was also assessed during and after drug withdrawal. Finally, left ventricular : body weight (lv : bw) and mesenteric media : lumen ratios were determined either immediately after 4-week treatment (treatment study) or 8 weeks later (withdrawal study). Results Perindopril persistently lowered blood pressure in adult SHR whereas blood pressure returned to vehicle levels within approximately 4 and 15 days after withdrawal of hydralazine and candesartan cilexetil, respectively. Cardiac hypertrophy was reduced by all three treatments, but to a lesser extent by hydralazine (treatment study), and this regression of cardiac hypertrophy persisted only with both types of RAS inhibition (withdrawal study). Vascular hypertrophy, measured indirectly and directly, was also reduced by all three treatments, with perindopril and candesartan cilexetil causing hypotrophic and eutrophic remodelling, respectively (treatment study), although these changes were generally not maintained after drug withdrawal (withdrawal study). Angiotensin I-induced pressor responses were equally inhibited during treatment with either candesaran cilexetil or perindopril (and were unaffected by hydralazine) but normalized rapidly in both groups (within approximately 2–4 days) after withdrawal of RAS inhibition. In addition, there was a small age-related increase in microalbuminuria over the study period, which was not significantly affected by any treatment. Conclusions Following 4-week treatment, candesartan cilexetil, perindopril and hydralazine caused similar antihypertensive effects; however, only perindopril persistently reduced blood pressure following drug withdrawal. Both types of RAS inhibition and hydralazine caused marked cardiac and vascular remodelling during treatment, whereas only the RAS inhibitors persistently regressed cardiac hypertrophy 8 weeks later. Collectively, these results indicate the importance of the RAS for the maintenance of hypertension and cardiovascular hypertrophy in adult SHR, as well as identifying differential effects of ACE inhibition and AT1 receptor blockade on persistent blood pressure reduction.
Candesartan
Hydralazine
Perindopril
Mesenteric arteries
Plasma renin activity
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Captopril
Carvedilol
Pulse pressure
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The aim of the present study was to investigate the effects of short-term treatment with an AT(1) receptor blocker (ARB) on amelioration of hypertensive end-organ damage in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP were divided into two groups: (i) an ARB-treated group; and (ii) a control group. Candesartan (1 mg/kg per day) was administered orally from 6 to 11 weeks of age. At 20 weeks of age, plasma renin activity (PRA), angiotensin II concentrations, angiotensin-converting enzyme (ACE) activity and hydroperoxide content were measured. Expression of intercellular adhesion molecule (ICAM)-1, renin, AT(1) and AT(2) receptors was investigated by reverse transcription-polymerase chain reaction. Blood pressure in the ARB group was slightly lower at 7, 8, 11, 13-15 and 18 weeks of age, but no significant difference in blood pressure was found between the ARB and control groups at 20 weeks of age. All rats in the control group had cerebral oedema, whereas no lesions were found in the ARB group. In the ARB group, PRA, AII and hydroperoxide content were lower than in the control group. In the ARB-treated group, lower ICAM-1 expression was found in the cerebral cortex and slightly, albeit not significantly, lower expression of renin was found in the kidney. In contrast, AT(1) receptor expression in the cerebrum and kidney was higher in the ARB group compared with the control group. These results indicate that short-term treatment of SHRSP with ARB at a young age is effective in preventing cerebral oedema after maturation. Such beneficial effects of ARB may be due, in part, to decreased blood pressure and is likely mainly due to inhibition of total circulating and local renin-angiotensin systems.
Candesartan
Stroke
Spontaneously hypertensive rat
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Manabe, S.; Okura, T.; Miyoshi, K.; Watanabe, S.; Tang, J.; Fukuoka, T.; Higaki, J. Author Information
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Interactions between the renin‐angiotensin (RAS) and sympathetic nervous systems (SNS) were investigated by examining the influence of acute renal denervation and adrenergic and AT1 receptor blockade in SHR. Thirty (n=30) SHR treated with a combination of carvedilol plus losartan (5 mg/kg p.o + 10 mg/kg, p.o.) for 7 days. On day 8, the rats were anaesthetized and the left kidney was denervated or left intact. The renal vasoconstrictor responses to intrarenal doses of noradrenaline (NA), phenylephrine (PE) and Angiotensin II (Ang II) were determined. Data, mean±SEM were subjected to ANOVA with significance at P<0.05. The magnitudes of the vasoconstrictor responses to NA, PE and Ang II at 50%, 48% and 35% in the control rats were decreased to 44%, 43% and 8% respectively (all P<0.05), after treating them with losartan+carvedilol. However, following renal denervation, the vascular responsiveness to Ang II and adrenergic agonists was blunted to 50% (P<0.05) of their values in rats with intact renal nerves treated with this drug combination. Collectively, these data demonstrate an important influence of the renal sympathetic nerves on the ability of carvedilol and losartan to block renal vasoconstrictions in the SHR and point to an important interaction between Ang II, adrenergic vasoconstriction and the renal nerves.
Carvedilol
Phenylephrine
Sympathetic nervous system
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SUMMARY 1. The angiotensin II type 1 receptor antagonist, losartan, prevented the development of hypertension in spontaneously hypertensive rats (SHR). 2. Losartan also prevented the development of left ventricular hypertrophy and vascular amplifier abnormalities. 3. Part of the hypotensive effect induced by long‐term treatment with losartan persisted for a long time after the withdrawal of treatment. 4. The results support the hypothesis that angiotensin II contributes to the development of hypertension and cardiovascular hypertrophy in SHR.
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Renal circulation
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Attenuating aldosterone (ALDO) effects may be important in slowing kidney and cardiovascular disease progression. This study tested whether ACE inhibitor (I) therapy achieves lower plasma (p) ALDO levels than angiotensin receptor blocker (ARB) therapy when they are used under usual clinical conditions in chronic kidney disease (CKD) patients.Consecutive CKD patients (n = 123) were studied. They were clinically stable and receiving either ACEI (n = 77) or ARB (n = 46) (physician's choice) for > or = 3 months.Mean pALDO in the ACEI cohort was 7.8 +/- 5.7 (SD) ng/dl compared to 12.3 +/- 9.8 ng/dl in the ARB cohort (p = 0.0018, normal ambulatory pALDO 9.4-33.8 ng/dl). The pALDO difference was not explained by differences in age, sex, race, body weight, diagnosis of diabetes; the use of beta-blockers, calcium channel blockers or diuretic; systolic or diastolic blood pressure; plasma renin, serum creatinine, sodium, potassium, or bicarbonate levels; 24-hour urine potassium, sodium, urea or protein excretion; or ACEI or ARB dose.Mean pALDO is about 60% higher with ARB therapy than ACEI therapy when these drugs are customarily used in CKD patients. This difference could be clinically important with regard to kidney and cardiovascular protection.
Calcium channel blocker
Plasma renin activity
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Hermida, R. C.1; Ayala, D. E.1; Mojon, A.1; Fontao, M. J.1; Chayan, L.2; Dominguez, M. J.3; Fernandez, J. R.1 Author Information
Angiotensin Receptor Blockers
Hypertensive disease
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