Comparison of the effects of indapamide and captopril on the development of spontaneous hypertension.

OBJECTIVES: The effects of indapamide, a thiazide-like diuretic, and captopril, an angiotensin-converting enzyme inhibitor, on spontaneous hypertension and the development of left ventricular hypertrophy (LVH), nitric oxide generation and oxidant status were investigated. METHODS: Six-week-old male spontaneously hypertensive rats (SHR) were treated with indapamide (1 mg/kg per day) or captopril (10 mg/kg per day) or a combination of indapamide plus captopril. After the 6-week treatment, nitric oxide synthase (NOS) activity, the expression of NOS isoform proteins, conjugated dienes concentration and relaxation responses of the femoral artery were analyzed. RESULTS: Indapamide and captopril partly prevented a blood pressure increase in young SHR. Captopril in contrast to indapamide reduced LVH. The effect of the combined indapamide and captopril treatment on the prevention of hypertension was additive. Combined indapamide and captopril treatment increased NOS activity and endothelial NOS protein expression in the aorta and decreased conjugated dienes concentration in the kidney compared with the indapamide monotherapy group. Indapamide and indapamide and captopril treatment increased acetylcholine-induced relaxation of the femoral artery. CONCLUSION: Whereas captopril reduced LVH, indapamide enhanced NOS activity and decreased oxidative damage in the case of the combined treatment. It is concluded that the complex protective effects of the combined indapamide plus captopril treatment on hypertension may be exerted via its effects on blood pressure, hypertrophy and vasorelaxation.

Effect of chronic apocynin treatment on nitric oxide and reactive oxygen species production in borderline and spontaneous hypertension.

The purpose of this study was to investigate the effect of NAD(P)H oxidase inhibitor - apocynin (4-hydroxy-3-methoxyacetophenone) on the increase of systolic blood pressure (SBP) in borderline (BHR) and spontaneously hypertensive rats (SHR). Young 6-week-old male BHR (offspring of SHR dams and Wistar Kyoto sires) and SHR were treated with apocynin (30 mg/kg/day) for six weeks. SBP was measured by tail-cuff plethysmography. Nitric oxide synthase (NOS) activity was determined in the left ventricle and aorta. Protein expression of nuclear factor kappa B (NF-kappaB) and NAD(P)H oxidase subunits p67phox and p22phox as well as concentration of cGMP were determined for the left ventricle. Apocynin significantly decreased SBP in all groups investigated. Administration of apocynin had no effect on NOS activity in either tissue studied. However, apocynin decreased protein expression of NF-kappaB (p65) and NAD(P)H oxidase subunit p22phox in both hypertensive groups and p67phox subunit in the SHR group. Moreover, apocynin was able to prevent a decrease in cGMP concentration in the left ventricle of both hypertensive groups. In conclusion, our study demonstrated that apocynin treatment partially prevented SBP rise in borderline and spontaneously hypertensive rats, yet without increasing activity of NOS in the left ventricle and aorta. However, apocynin was able to decrease production of reactive oxygen species in hypertensive rats; thus preventing the decrease in cGMP formation.

The effect of N-acetylcysteine and melatonin in adult spontaneously hypertensive rats with established hypertension.

The attenuated nitric oxide (NO) formation and/or elevated production of reactive oxygen species are often found in experimental and human hypertension. We aimed to determine possible effects of N-acetylcysteine (1.5 g/kg/day) and N-acetyl-5-methoxytryptamine (melatonin, 10 mg/kg/day) in adult spontaneously hypertensive rats (SHR) with established hypertension. After a six-week-treatment, blood pressure was measured and NO synthase (NOS) activity, concentration of conjugated dienes, protein expression of endothelial NOS, inducible NOS and nuclear factor-kappaB (NF-kappaB) in the left ventricle were determined. Both treatments improved the NO pathway by means of enhanced NOS activity and reduced reactive oxygen species level as indicated by decreased conjugated diene concentrations and lowered NF-kappaB expression. N-acetylcysteine (but not melatonin) also increased the endothelial NOS protein expression. However, only melatonin was able to reduce blood pressure significantly. Subsequent in vitro study revealed that both N-acetylcysteine and melatonin lowered the tone of phenylephrine-precontracted femoral artery via NO-dependent relaxation. Nevertheless, melatonin-induced relaxation also involved NO-independent component which was preserved even after the blockade of soluble guanylate cyclase by oxadiazolo[4,3-a]quinoxalin-1-one. In conclusion, both N-acetylcysteine and melatonin were able to improve the NO/reactive oxygen species balance in adult SHR, but blood pressure was significantly lowered by melatonin only. This implies that a partial restoration of NO/reactive oxygen species balance achieved by the antioxidants such as N-acetylcysteine has no therapeutic effect in adult rats with established hypertension. The observed antihypertensive effect of melatonin is thus mediated by additional mechanisms independent of NO pathway.

Possible role of nitric oxide in the locomotor activity of hypertensive rats.

We aimed to analyze whether hypertension and changes in nitric oxide (NO) generation are associated with alterations of locomotor activity in rats. Male Wistar rats treated with an inhibitor of NO synthase, NG-nitro-L-arginine methyl ester (L-NAME, 40 mg/kg/day) for 6 weeks, control Wistar rats, spontaneously hypertensive rats (SHR), and control Wistar Kyoto rats (WKY) aged 18 weeks were investigated. Locomotor activities were tested by the open field method. NO synthase activity (NOS), concentration of cGMP and conjugated dienes (CD) as well as protein expression of nuclear factor NF-kappaB were determined in the cerebral cortex, cerebellum and brainstem. NOS activity in the brain parts investigated was not changed in SHR in comparison with the normotensive WKY. L-NAME treatment resulted in the decreased NOS activity in comparison with Wistar rats. The concentration of CD and expression of NF-kappaB protein, markers of reactive oxygen species, were higher and the concentration of cGMP was lower in hypertensive animals and more pronounced in SHR as well. Thus, the concentration of NO in the brain parts of SHR might be lower than in the L-NAME treated rats. L-NAME treatment increased horizontal (by 28%) and vertical (by 80%) motor activity. Similarly, in SHR both locomotor activities were increased by 105% and 148%, respectively, in comparison with WKY. In conclusion, decreased level of NO was associated with increased locomotor activity indicating that in addition to genetic differences which may determine changes in locomotor activity in hypertensive rats, the role of a signalling pathway mediated by NO may be supposed.

Effect of chronic N-acetylcysteine treatment on the development of spontaneous hypertension.

The imbalance between NO (nitric oxide) and ROS (reactive oxygen species) is an important factor in the development of hypertension. The aim of the present study was to determine the preventive and therapeutic effects of NAC (N-acetylcysteine) in SHRs (spontaneously hypertensive rats). Young and adult SHRs and WKY (Wistar-Kyoto) rats were treated with NAC (20 g/l in the drinking water). After 8 weeks of treatment, BP (blood pressure) and NOS (NO synthase) activity, conjugated dienes and GSH (reduced glutathione) in the kidney and left ventricle were determined. Protein expression of eNOS (endothelial NOS), inducible NOS and NF-kappaB (nuclear factor kappaB) were also determined in the left ventricle and kidney. Chronic NAC treatment partially attenuated the rise in BP in young SHRs (179+/-6 compared with 210+/-8 mmHg in untreated animals), but it had no significant effect on BP in adult SHRs. The antioxidant action of NAC, measured as a decrease of the concentration of conjugated dienes or inhibition of NF-kappaB expression, was greater in young than in adult SHRs. Similarly, eNOS protein expression was attenuated more in young than in adult SHRs, although NAC treatment increased NOS activity to a similar extent in both young and adult rats. In conclusion, both decreased ROS production and increased NOS activity appear to participate in the BP changes after NAC treatment in young SHRs. In adult SHRs with established hypertension, however, the secondary alterations (such as pronounced structural remodelling of resistance vessels) might attenuate the therapeutic effect of NAC.