Fifty years ago, Lewis K. Dahl has presented a new model of salt hypertension – salt-sensitive and salt-resistant Dahl rats. Twenty years later, John P. Rapp has published the first and so far the only comprehensive review on this rat model covering numerous aspects of pathophysiology and genetics of salt hypertension. When we summarized 25 years of our own research on Dahl/Rapp rats, we have realized the need to outline principal abnormalities of this model, to show their interactions at different levels of the organism and to highlight the ontogenetic aspects of salt hypertension development. Our attention was focused on some cellular aspects (cell membrane function, ion transport, cell calcium handling), intra- and extrarenal factors affecting renal function and/or renal injury, local and systemic effects of renin-angiotensin-aldosterone system, endothelial and smooth muscle changes responsible for abnormal vascular contraction or relaxation, altered balance between various vasoconstrictor and vasodilator systems in blood pressure maintenance as well as on the central nervous and peripheral mechanisms involved in the regulation of circulatory homeostasis. We also searched for the age-dependent impact of environmental and pharmacological interventions, which modify the development of high blood pressure and/or organ damage, if they influence the salt-sensitive organism in particular critical periods of development (developmental windows). Thus, severe self-sustaining salt hypertension in young Dahl rats is characterized by pronounced dysbalance between augmented sympathetic hyperactivity and relative nitric oxide deficiency, attenuated baroreflex as well as by a major increase of residual blood pressure indicating profound remodeling of resistance vessels. Salt hypertension development in young but not in adult Dahl rats can be attenuated by preventive increase of potassium or calcium intake. On the contrary, moderate salt hypertension in adult Dahl rats is attenuated by superoxide scavenging or endothelin-A receptor blockade which do not affect salt hypertension development in young animals.

Idebenone (IDE), a synthetic analog of coenzyme Q, strongly activates glycerol phosphate (GP) oxidation in brown adipose tissue mitochondria. GP oxidase, GP cytochrome c oxidoreductase and GP dehydrogenase activities were all significantly stimulated by 13 muM IDE. Substituted derivatives of IDE acetyl- and methoxyidebenone had similar activating effects. When succinate was used as substrate, no activation by IDE could be observed. The activation effect of IDE could be explained as release of the inhibition of glycerol phosphate dehydrogenase by endogenous free fatty acids. NADH oxidoreductase activity and oxidation of NADH-dependent substrates were inhibited by IDE. The extent of the inhibition and IDE concentration dependence varied when various substrates were tested, being highest for pyruvate and lowest for 2-oxoglutarate. This study thus showed that the effect of IDE on various mitochondrial enzymes is very different and thus its therapeutic use should take into account its specific effect on various mitochondrial dehydrogenases in relation to particular defects of mitochondrial respiratory chain.

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 N S S S S-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.

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