angiotensin-i and Cerebrovascular-Disorders

Electroacupuncture (EA) can effectively alleviate anxiety disorders and memory impairments caused by various neurodegenerative diseases; however, the molecular mechanisms underlying its neuroprotective effects are unclear. Previous studies have shown that the renin-angiotensin system (RAS) comprises of two axes with mutual antagonism: the classical angiotensin converting enzyme/angiotensin II/angiotensin II type 1 receptor (ACE/Ang II/AT1R) axis and the protective angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor (ACE2/Ang-(1-7)/MasR) axis. In this study, we observed that chronic cerebral hypoperfusion (CCH) mediated anxiety-like behavior and memory impairments in spontaneously hypertensive rats (SHR) via upregulation of the hippocampal classical axis (ACE/Ang II/AT1R) and the partial hippocampal protective axis (ACE2/Ang-(1-7)). However, Ang II levels were much higher than those of Ang-(1-7), indicating that the ACE/Ang II/AT1R axis plays a dominant role in the comorbidity of CCH and hypertension. Moreover, candesartan cilexetil (Canc) and perindopril (Peril) were used as positive control drugs. We found that EA, Canc, and Peril attenuated CCH-induced anxiety-like behavior and memory impairments in SHR, potentially via downregulation of the hippocampal classical axis (ACE/Ang II/AT1R) and upregulation of the whole hippocampal protective axis (ACE2/Ang-(1-7)/MasR). These results suggest that EA therapy for CCH with hypertension may be mediated by two hippocampal RAS axes.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Anxiety; Cerebrovascular Disorders; Down-Regulation; Electroacupuncture; Hippocampus; Male; Memory Disorders; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction; Up-Regulation

We evaluated the renal effects of the new angiotensin II type 1 (AT ) receptor antagonist, HR 720, in the stroke-prone spontaneously hypertensive rat. Rats were treated with either vehicle, HR 720, MK-954 (a selective AT1 receptor antagonist) or enalapril for 6 weeks. Blood pressure was decreased to a similar extent by HR 720, MK-954 and enalapril (203 +/- 4, 202 +/- 5 and 190 +/- 4 vs. 247 +/- 4 mm Hg for control). Urinary protein secretion was also decreased (5.2 +/- 0.3, 5.3 +/- 0.2 and 5.5 +/- 0.6 vs. 25.2 +/- 4.6 mg/100g/24h). The glomerular hypertensive change was improved in each drug-treated group (2.0 +/- 0.2, 3.3 +/- 0.3 and 1.6 +/- 0.1 vs. 17.6 +/- 1.5%; p < 0.0001). These results show that, in addition to its antihypertensive effect, HR 720 has a beneficial effect on renal function.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Body Weight; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Imidazoles; Kidney; Kidney Function Tests; Kidney Glomerulus; Losartan; Organ Size; Proteinuria; Rats; Rats, Inbred SHR; Receptors, Angiotensin; Tetrazoles; Tissue Embedding

1. The protective effect of ME3221, a surmountable AT1 antagonist, on the hypertension and its concomitant complications in aged (32 week old) stroke-prone spontaneously hypertensive rats (SHRSP) was studied following long-term (32 weeks) oral administration, and compared with those of losartan (metabolite EXP3174 is an insurmountable AT1 antagonist) and enalapril. 2. During the treatment period, ME3221, at a dose of 10 mg/kg per day steadily reduced the systolic blood pressure, and no tolerance was developed to the fall in blood pressure. The reference drugs showed similar activity, but the antihypertensive effect of ME3221 was more potent. 3. In the control group, rats began to die from 52 weeks of age and all rats had died by 64 weeks of age. In contrast, no rats treated with ME3221, losartan or enalapril died before 64 weeks of age. 4. ME3221, losartan and enalapril suppressed the hypertensive complications observed in control SHRSP, that is, cerebral apoplexy (stroke and cerebral oedema), renal injury (increased proteinuria, total N-acetyl-beta-D-glucosaminidase activity and ascites) and heart failure (cardiac hypertrophy and pleural effusion). 5. These results indicate that ME3221 has a stable anti-hypertensive effect, prevents hypertensive complications and prolongs survival in aged SHRSP equally as well as losartan and enalapril.

Topics: Aging; Angiotensin I; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Cerebral Hemorrhage; Cerebrovascular Disorders; Hypertension; Longevity; Male; Organ Size; Rats; Rats, Inbred SHR; Survival Rate; Tetrazoles

Linkage studies have shown that the gene locus for angiotensin converting enzyme (ACE) is associated with the expression of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). We tested the hypothesis that the conversion of angiotensin I (Ang I) to angiotensin II (Ang II) in blood vessels is elevated in SHRSP.. We measured the conversion rate of Ang I to Ang II during one pass through an isolated resistance vessel bed. We used the same substrains of SHRSP and Wistar-Kyoto control rats (WKY) that had been employed in the earlier linkage studies.. Isolated hindquarters from young and adult (10- to 12- and 36- to 38-week-old) rats were perfused with an artificial medium and then infused with Ang I at 0.5 and 2 pmol/ml. Ang I and II were measured with high-performance liquid chromatography and radioimmunoassay in hindquarter effluent and in blank control channels. Conversion and extraction rates were calculated from angiotensin levels in hindquarter and blank perfusion channels, respectively.. The conversion rates of Ang I to Ang II did not differ between SHRSP and WKY in young or in adult rats. Captopril completely abolished the formation of Ang II in all groups of rats. During infusion at the higher dose of Ang I, the extraction of Ang I was significantly decreased in SHRSP compared with WKY.. Our results are consistent with the notion that the metabolism of angiotensin is decreased in spontaneously hypertensive rats. However, we found no support for the hypothesis that vascular ACE is responsible for high blood pressure in SHRSP. These findings suggest that other genes close to the ACE locus or the hyperexpression of the enzyme in other areas may contribute to hypertension in these rats.

Topics: Aging; Angiotensin I; Angiotensin II; Animals; Cerebrovascular Disorders; Chromatography, High Pressure Liquid; Hindlimb; Hypertension; Male; Radioimmunoassay; Rats; Rats, Inbred SHR; Rats, Inbred WKY

1. The angiotensin converting enzyme (ACE) activity of spontaneously hypertensive (SHR) and spontaneously hypertensive stroke-prone (SHRSP) rats was compared to the ACE activity of normotensive Wistar-Kyoto rats (WKY). 2. ACE activity was assessed indirectly in conscious unrestrained rats using the equipressor response end point to simultaneously calculate the extent of conversion of angiotensin I (AI) to angiotensin II (AII) and the pulmonary degradation of bradykinin (BK). 3. The pulmonary degradation of BK was significantly elevated (99.4%) in SHR rats whereas the elevation was not significant in SHRSP rats (99.2%) compared to WKY rats, even though the pulmonary inactivation of BK in WKY rats was higher (98.6%) than in normotensive Wistar rats (95.6% and 97.5%) previously studied. 4. Blood pressure responsiveness to intra-aortically injected BK (bolus injection and infusion) was markedly increased in SHR and SHRSP rats with no change in reactivity to sodium nitroprusside. 5. Conversion of AI to AII assessed by the equipressor doses of the hormones which produced a 20-mmHg rise in blood pressure was markedly elevated in SHR (86 +/- 4%) and SHRSP (80 +/- 7%) rats when compared to WKY rats (38 +/- 4%). 6. The marked increase in conversion of AI to AII in hypertensive animals, accompanied by an increased pulmonary degradation of BK in SHR rats, suggests that ACE activity is increased in conscious SHR and SHRSP rats and may participate in the genesis of hypertension in this model of genetic hypertension.

Topics: Angiotensin I; Angiotensin II; Animals; Blood Pressure; Bradykinin; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Hypertension; Lung; Male; Nitroprusside; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Angiotensin(Ang) contents in the adrenal gland of stroke-prone spontaneously hypertensive rats(SHRSP) and age-matched Wistar Kyoto rats(WKY) were determined using reverse phase high performance liquid chromatography combined with a specific radioimmunoassay. In normotensive 5 wk-old SHRSP, the adrenal renin activity was about 3 times higher than that of age-matched WKY while the adrenal Ang I and Ang II concentrations did not differ from those of WKY. In the severely hypertensive 25 wk-old SHRSP, the adrenal Ang II and Ang I, and plasma aldosterone concentrations were about 5-fold, 2-fold and 4-fold, respectively, increased compared with levels in the WKY. In the 25 wk-old SHRSP 24 h after bilateral nephrectomy, the adrenal Ang II and plasma aldosterone levels were not decreased and were 10 and 3 times, respectively, higher than those of nephrectomized control WKY. Thus, the enhanced local generation of Ang II in the adrenal gland may contribute to the increased release of aldosterone in SHRSP with malignant hypertension.

Topics: Adrenal Glands; Aging; Aldosterone; Angiotensin I; Angiotensin II; Animals; Cerebrovascular Disorders; Chromatography, High Pressure Liquid; Hypertension; Hypertension, Malignant; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin