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The aim of the present study was to establish a convenient clinically applicable assay method for chymase-dependent angiotensin II forming activity of circulating mononuclear leukocytes (CML), which was potentially a marker of tissue chymase activity. Using this method, association between CML chymase activity and clinical parameters was determined. Cardiovascular outpatients (n = 170) without taking antihypertensive medication were recruited. An ELISA for chymase-dependent angiotensin II-forming activity in CML was established using Nma /Dnp-modified angiotensin I. Logistic regression analysis revealed that age and male gender were significant independent determinants of the increased CML chymase activity. After adjustment by age and gender, the CML chymase activity was positively correlated with systolic blood pressure, pulse rate, and the brain natriuretic peptide level. The relation between blood pressure and CML chymase activity suggests that it might reflect that increased tissue chymase activity contributes to systemic high blood pressure and heart rate because plasma chymase is inactive due to inhibitory plasma inhibitors. [ABSTRACT FROM AUTHOR]

The heart adapts to increased pressure overload by hypertrophic growth of terminally differentiated cardiomyocytes. At the genetic level, the hypertrophic response is characterized by the reprogramming of gene expression, i.e. upregulation of immediate early genes, natriuretic peptide genes and genes encoding structural proteins. In the present study, we characterized the early changes in gene expression with cDNA expression arrays in response to increase in blood pressure produced by arginine8-vasopressin infusion (0.05 µg/kg/min, i.v.) for 30 min and 4 h in conscious normotensive rats. Expression profiling revealed differential expression of 14 genes in the left ventricle, and several novel factors of immediate early genetic response to pressure overload were identified, such as growth arrest and DNA damage inducible protein 45 (GADD45α), epidermal fatty acid-binding protein (E-FABP) and Bcl-X. Administration of angiotensin II (Ang II) for 6 h by osmotic minipumps also increased left ventricular GADD45α, E-FABP and Bcl-X gene expression. Furthermore, the induction of GADD45α and Bcl-X gene expression by Ang II was blocked by angiotensin II type 1 receptor antagonist losartan. In summary, our analysis provided new insights into the pathogenesis of pressure overload-induced hypertrophy by suggesting the existence of novel regulators of the immediate early gene expression program. [ABSTRACT FROM AUTHOR]

Purpose. To evaluate the ocular hypotensive effect of topical CS-088, an angiotensin AT1 receptor antagonist, and the effect of CS-088 on aqueous humor dynamics. Methods. The effects of CS-088 on intraocular pressure (IOP) were studied in 2 models of rabbit ocular hypertension. Experimental ocular hypertension was induced in albino rabbits by injecting α-chymotrypsin into the anterior chamber (α-chymotrypsin rabbit). The effects of the single application of CS-088 were examined. Additionally, CS-088 was repeatedly administered over a period of 3 weeks to hereditary ocular hypertensive rabbits (buphthalmic rabbits, JWHR bu/bu) and the IOPs were monitored throughout the experiment. The effects of CS-088 on aqueous humor dynamics were also examined in normal rabbits. In this study, the methods of IOP recovery rate, two-level constant pressure perfusion and fluorescein-dextran perfusion were used respectively to determine the aqueous inflow, outflow facility and uveoscleral outflow (USF). Results. CS-088 at 1% and 2% significantly lowered the IOP in the α-chymotrypsin rabbits with a maximum IOP reduction of 10.1 mmHg. The maximum effect obtained with 2% CS-088 was no greater than that with 1% CS-088. In the buphthalmic rabbits, 2% CS-088 also lowered IOP significantly. Timolol was effective in both models. In the study on aqueous humor dynamics, a slight increase in USF (17%) was seen after a topical application of CS-088 whereas changes in aqueous inflow or outflow facility were not observed. Conclusions. Topical CS-088 can decrease IOP in rabbits. Despite the USF change, the ocular hypotensive mechanism by CS-088 was not fully determined. [ABSTRACT FROM AUTHOR]

Objective: Angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism influence the circulating and cellular levels of ACE and has been shown to be a risk factor in a number of diseases including IgA nephropathy. We have investigated the association of ACE gene I/D polymorphism with the clinical presentation of idiopathic nephrotic syndrome (INS) in Kuwaiti children. Materials and methods: The genotypes for ACE gene I/D polymorphism were determined in 102 subjects (54 INS cases and 48 healthy controls) using a PCR method. Results: The distribution of DD, ID and II genotypes was 70%, 20% and 10% in INS cases compared with 52%, 46% and 2% in the controls. The mean age of onset of the disease was significantly lower in the INS cases with DD genotype (37 months) compared with cases with II genotype (65 months, p < 0.05). The clinical manifestation of the disease was considerably severe in cases with DD genotypes compared with cases having ID and II genotypes. The INS cases with DD genotype also showed a significantly higher incidence of steroid sensitivity and steroid dependence. Seventy-three per cent of the INS cases with minimal change lesion had a DD genotype. Also 70% of the cases which needed cytotoxic drugs had DD genotype. Conclusion: Our data suggest an association of the D-allele of the ACE gene I/D polymorphism with the clinical manifestation of INS in Kuwaiti Arab children. [ABSTRACT FROM AUTHOR]

Aims: Renal medullary blood flow is important in blood pressure regulation and is surprisingly unaffected by the vasoconstrictor action of angiotensin II (Ang II). This study tested if the effect of Ang II on the renal papillary circulation is modulated by bradykinins, prostaglandins or NO (NO). In anaesthetised Wistar rats, total renal blood flow (RBF) was measured, as was cortical (CBF) and papillary (PBF) blood flow, using the laser-Doppler technique, in responses to Ang II (30 ng kg[sup -1] min[sup -1]) alone and after ACE inhibition (enalapril) or bradykinin/prostaglandin synthesis inhibition (ketoprofen, aprotinin). PBF was also measured after blockade of NO formation with or without pretreatment with an Ang II receptor antagonist (losartan). Major findings: (i) PBF did not change in response to Ang II infusion but MAP increased (+10%) and RBF and CBF decreased. (ii) Treatment with aprotinin and ketoprofen left MAP, RBF and CBF unchanged but decreased PBF. Ang II did not decrease PBF further but a significant increase in MAP was seen. (iii) Enalapril treatment left PBF unchanged but decreased MAP and increased RBF and CBF. When Ang II was infused PBF and MAP increased markedly. (iv) L-NAME reduced PBF independently of losartan treatment. Principal conclusion: Bradykinin and prostaglandins do not appear to cause the lack of renal papillary vasoconstriction to Ang II. However, the increase in PBF to Ang II seen after enalapril treatment suggests that enalapril treatment, possibly via its effects on kinin break-down and subsequent NO formation, might affect the sensitivity of renal papillary autoregulation. This may be an important aspect of the blood pressure lowering effect of ACE inhibitors. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme inhibitors (ACEI) block degradation of bradykinin, and bradykinin stimulates prostacyclin synthesis. Therefore, we set out to determine whether the effects of ACE inhibitors on prostaglandin production in essential hypertensive patients are class effects or are dependent on ACE inhibitor structure. In addition, we studied whether hypertensives show an impaired capacity to synthesize vasodilator prostaglandins. To address these questions, we compared the effects of captopril (sulfhydryl-containing inhibitor), enalapril and ramipril (carboxyl-containing inhibitors) and fosinopril (phosphoryl-containing inhibitor) on blood pressure and urinary excretion of 6-keto-prostaglandin (PG) F1-α (the breakdown product of prostacyclin) in 44 mild-to-moderate essential hypertensive subjects before and 8 weeks after administration of an ACEI. We also studied prostacyclin excretion in 15 normotensive healthy controls. Levels of urinary 6-keto-PGF1-α (pg/ml) were measured by specific radioimmunoassay. Hypertensive subjects showed a lower excretion of 6-keto-PGF1-α than normotensive controls (212 ± 147 vs 353 ± 98 pg/ml, p < 0.001). All ACEI induced a significant decrease in MAP and increased the rate of excretion of the prostacyclin metabolite: C, 211 ± 200 to 338 ± 250 pg/ml, p < 0.05; E, 202 ± 133 to 296 ± 207 pg/ml, p < 0.05; R, 205 ± 127 to 342 ± 211 pg/ml, p < 0.05; F, 235 ± 128 to 347 ± 241 pg/ml, p < 0.05. In hypertensives (n = 44) the decrease in blood pressure correlated negatively with the rise in 6-keto-PGF1-α excretion (r = -0.51, p < 0.001). These data suggest that impaired prostacyclin biosynthesis in hypertensive patients could account for haemodynamic changes leading to the hypertensive state. Moreover, the hypotensive mechanisms of ACEI may be mediated by an increase in prostacyclin production; this effect seems to be class-dependent. [ABSTRACT FROM AUTHOR]