Zdenka Dobešová

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.

Antihypertensive Mechanisms of Chronic Captopril or N -Acetylcysteine Treatment in L-NAME Hypertensive Rats

Hypertension due to chronic inhibition of NO synthase (NOS) by Nω-nitro-L-arginine methyl ester (L-NAME) administration is characterized by both impaired NO-dependent vasodilation and enhanced sympathetic vasoconstriction. The aim of our study was to evaluate changes in the participation of major vasoactive systems in L-NAME–treated rats which were subjected to simultaneous antihypertensive (captopril) or antioxidant (N-acetylcysteine, NAC) treatment. Three-month-old Wistar males treated with L-NAME (60 mg/kg/day) for 5 weeks were compared to rats in which L-NAME treatment was combined with simultaneous chronic administration of captopril or NAC. Basal blood pressure (BP) and its acute responses to consecutive i.v. injections of captopril (10 mg/kg), pentolinium (5 mg/kg), L-NAME (30 mg/kg), tetraethylammonium (TEA, 16 mg/kg) and nitroprusside (NP, 20 μg/kg) were determined in conscious rats at the end of the study. The development of L-NAME hypertension was prevented by captopril treatment, whereas NAC treatment caused only a moderate BP reduction. Captopril treatment normalized the sympathetic BP component and significantly reduced residual BP (measured at full NP-induced vasodilation). In contrast, chronic NAC treatment did not modify the sympathetic BP component or residual BP, but significantly enhanced NO-dependent vasodilation. Neither captopril nor NAC treatment influenced the compensatory increase of TEA-sensitive vasodilation mediated by endothelium-derived hyperpolarizing factor in L-NAME–treated rats. Chronic captopril treatment prevented L-NAME hypertension by lowering of sympathetic tone, whereas chronic NAC treatment attenuated L-NAME hypertension by reduction in the vasodilator deficit due to enhanced NO-dependent vasodilation.

Vasoactive systems in L-NAME hypertension: the role of inducible nitric oxide synthase.

Objectives The contribution of the renin–angiotensin system (RAS) and the sympathetic nervous system (SNS) to blood pressure (BP) maintenance was evaluated in rats with Nω-nitro-l-arginine methyl ester (L-NAME) hypertension. Furthermore, we studied the extent of nitric oxide (NO) synthesis inhibition and the participation of remaining NO in the counterbalance of pressor systems, with a special reference to inducible nitric oxide synthase (iNOS). Methods Wistar rats subjected to chronic L-NAME treatment (40 mg/kg per day for 4 weeks) were used. A consecutive blockade of RAS (captopril) and SNS (pentolinium) was followed by acute L-NAME injection. Dimethylguanidine or aminoguanidine were used to affect NO synthesis by iNOS. Results L-NAME hypertensive rats had borderline augmentation of depressor response to captopril injection, but their BP fall after pentolinium was considerably enhanced compared with controls. Residual BP (recorded after simultaneous blockade of the RAS and the SNS) was elevated by 20–40% in hypertensive rats. Pronounced inhibition of NO synthase activity (50% reduction in the aorta and myocardium) was detected in L-NAME hypertensive rats in which the BP rise elicited by acute L-NAME injection was considerably attenuated (by 60–80%). In contrast, acute administration of dimethylguanidine [mixed endothelial NO synthase (eNOS)/iNOS inhibitor] to hypertensive rats induced a major BP rise similar to that caused by L-NAME injection in controls. Aminoguanidine (a selective iNOS inhibitor) caused a substantial BP rise in L-NAME hypertensive rats only. Conclusion The contribution of SNS to BP maintenance in L-NAME hypertension is more important than that of RAS. In L-NAME hypertensive rats the iNOS becomes a major source of hemodynamically important NO production, which is still insufficient to compensate prevailing vasoconstriction.

Chronic N-acetylcysteine administration prevents development of hypertension in N(omega)-nitro-L-arginine methyl ester-treated rats: the role of reactive oxygen species.

The aim of this study was to evaluate the production of superoxide anions as well as their role in the induction and/or maintenance of high blood pressure in rats with Nω-nitro- L-arginine methyl ester (L-NAME)-induced hypertension. In the preventive study, we compared adult Wistar rats treated with L-NAME for 4 weeks with L-NAME-treated rats that were simultaneously given N-acetylcysteine (NAC) in their drinking water. Basal blood pressure, superoxide production, conjugated dienes concentration and NO synthase (NOS) activity were measured at the end of the experiment. Chronic NOS inhibition by L-NAME treatment increased blood pressure, enhanced superoxide production in the aorta and elevated the concentration of conjugated dienes in the heart and kidney. All these changes were prevented by simultaneous NAC administration, which augmented NOS activity in L-NAME-treated rats. In the therapeutic study, the effects of chronic NAC treatment were studied in rats with established hypertension which developed during 4 weeks of L-NAME administration. The blood pressure effects of chronic NAC treatment in established L-NAME hypertension were only moderate, although this treatment also restored NOS activity and lowered conjugated dienes in the heart and kidney. Since chronic NAC treatment had better preventive than therapeutic effects, it seems that reactive oxygen species play a more important role in the induction than in the maintenance of L-NAME hypertension.

Nifedipine-sensitive noradrenergic vasoconstriction is enhanced in spontaneously hypertensive rats: the influence of chronic captopril treatment

Aim:  The relationship between increased sympathetic tone and enhanced activity of L‐type voltage‐dependent Ca2+ channels (L‐VDCC) in spontaneously hypertensive rats (SHR) was studied using in vivo and in vitro approaches.

The effect of chronic l-carnitine treatment on blood pressure and plasma lipids in spontaneously hypertensive rats

The effect of chronic L-carnitine treatment on blood pressure and plasma lipids was studied in spontaneously hypertensive rats (SHR). L-Carnitine treatment for 6 weeks lowered significantly both the systolic and mean arterial pressure of SHR but its influence on diastolic and pulse pressure was only modest. L-Carnitine did not influence the relative heart and kidney weight of SHR. However, L-carnitine completely abolished the age-dependent rise of plasma total cholesterol, triglycerides and uric acid seen in untreated SHR. On the other hand, L-carnitine treatment had no significant effects on blood pressure, relative organ weight and plasma lipids in normotensive Wistar-Kyoto rats. Our results suggest that L-carnitine might prevent some cardiovascular alterations by its influence on lipid metabolism.

The Prague Hypertensive Rat: A New Model of Genetic Hypertension

Several animal models of genetic hypertension have been developed but not all of them possess a closely related control strain. Therefore, a new model based on Wistar rats is described in which both hypertensive and normotensive lines were bred from a single parental pair. Several basic data on the two lines (called the Prague Hypertensive Rat, PHR, and the Prague Normotensive Rat, PNR) are given. PNR had a longer survival compared with PHR. At the age of 7 weeks, systolic blood pressure was 161 +/- 14 mmHg in PHR males and 109 +/- 9 mmHg in PNR males. Its further increase with age was very slow in PNR but very steep in PHR. Typical left ventricular cardiac hypertrophy developed in PHR in which cardiac output was not significantly different from that of PNR but total peripheral resistance was higher. Kidney weight was also greater in PHR than in PNR. There was no difference in basic renal functions except of proteinuria which was higher in PHR than in PNR. No differences were observed in extracellular and interstitial fluid volumes whereas plasma and blood volumes were slightly but significantly greater in PHR than in PNR suggesting a shift of extracellular fluid towards the intravascular compartment. This hypertensive model the parameters of which resemble to those of human essential hypertension should be especially suitable for cross-transplantation studies.

Chronic endothelin A receptor blockade attenuates contribution of sympathetic nervous system to salt hypertension development in adult but not in young Dahl rats

Endothelin‐1 (ET‐1) plays an important role in the pathogenesis of salt‐dependent forms of hypertension in adult rats, but its participation in salt hypertension elicited in immature rats is still unknown. Therefore, we compared ET‐1 role in the development or the maintenance of salt hypertension induced in young (4‐week‐old) or adult (12‐week‐old) Dahl rats.

Plasma Triglycerides and Red Cell Ion Transport Alterations in Genetically Hypertensive Rats

Ion transport abnormalities in essential hypertension are often associated with concomitant changes of lipid metabolism, but this information is missing in rats with genetic hypertension. We therefore studied the alterations of red cell Na+ and K+ transport and their relationship to blood pressure and plasma lipids (cholesterol and triglycerides) in Prague hereditary hypertriglyceridemic (HTG) rats, Lyon hypertensive (LH) rats, and HTG x Lewis F2 hybrids. In both hypertensive models and F2 hybrids, red cell Na+ content (Na+(i)) was positively related to plasma triglycerides but not to plasma cholesterol levels. Na+(i) elevation was more pronounced in HTG than in LH rats, probably due to higher plasma triglycerides in the former strain. The two hypertensive strains differed in bumetanide-sensitive Na+ transport, which was augmented in HTG rats with low plasma cholesterol but suppressed in LH rats characterized by high cholesterol levels. In the two genetic models, there was a positive association of blood pressure with Na+ leak, and this was also confirmed by the cosegregation of these parameters in F2 hybrids. We conclude that the enhancement of Na+ leak represents the major ion transport abnormality in rats with genetic hypertension. The alterations in plasma lipids are important determinants of abnormal red cell ion transport in hypertensive models studied. Although the detailed mechanism of their participation in ion transport regulation is still not completely understood, triglyceride-dependent changes in membrane microviscosity seem to be responsible for the modulation of particular ion transport pathways.

Chronic antioxidant therapy lowers blood pressure in adult but not in young Dahl salt hypertensive rats: the role of sympathetic nervous system

It is well‐known that salt hypertension is associated with increased oxidative stress. Since the development of salt hypertension is age‐dependent, we were interested whether young and adult salt hypertensive Dahl rats differ in oxidative stress level and/or in the effects of chronic antioxidant therapy on blood pressure (BP) level and on the participation of particular vasoconstrictor/vasodilator systems in BP maintenance.