Sympathetic hyperactivity and relative NO deficiency are characteristic alterations in both genetic and salt hypertension. The contribution of these abnormalities to blood pressure (BP) maintenance can be determined in conscious rats using a consecutive blockade of particular vasoactive systems. Thus, the contribution of pressor effects of angiotensin II to the maintenance of high BP is usually small, but the role of renin-angiotensin system in the development of hypertension mediated by central and peripheral effects of angiotensin II on sympathetic activity is highly important. This is even true in angiotensin-dependent hypertension of heterozygous Ren-2 transgenic rats in which sympathetic hyperactivity is increasing with age. Central sympathoexcitation in this hypertensive model can be inhibited by lower losartan doses than peripheral angiotensin II-dependent vasoconstriction. This experimental model also yielded important knowledge on nephroprotective effects of new therapeutic drugs - endothelin receptor type A blockers. A considerable part of sympathetic vasoconstriction is dependent on the interaction of Ca2+ sensitization (RhoA/Rho kinase pathway) and Ca2+ influx (through L-VDCC). The blockade of these pathways prevents a major part of sympathetic vasoconstriction. Ca2+ sensitization seems to be attenuated in genetic hypertension in order to compensate increased Ca2+ influx. In contrast, enhanced Ca2+ sensitization is a hallmark of salt sensitivity in Dahl rats in which salt hypertension is dependent on increased Ca2+ influx. The attention should also be paid to the impairment of arterial baroreflex sensitivity which permits enhanced BP responses to pressor or depressor stimuli. Some abnormalities can be studied in blood vessels isolated from hypertensive rats but neither conduit arteries nor mesenteric resistance arteries represent the vascular beds decisive for the increased peripheral resistance and high BP. Keywords: Sympathetic vasoconstriction, NO-dependent vasodilatation, Calcium sensitization, Calcium influx, Arterial baroreflex, Spontaneously hypertensive rats, Salt hypertensive Dahl rats, Ren-2 transgenic rats, RAS blockade, SNS blockade, NOS inhibition, Endothelin, Vascular contraction and relaxation, Isolated conduit and resistance arteries, EDCF, PGI2, BKCa channels.

• MeSH
• hypertenze * patofyziologie   metabolismus   MeSH
• krevní tlak fyziologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• renin-angiotensin systém fyziologie   MeSH
• sympatický nervový systém * patofyziologie   metabolismus   MeSH
• vazodilatace * fyziologie   účinky léků   MeSH
• vazokonstrikce * fyziologie   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The agonists of alpha(2)-adrenergic receptors such as clonidine, rilmenidine or monoxidine are known to lower blood pressure (BP) through a reduction of brain sympathetic outflow but their chronic antihypertensive effects in rats with low-renin or high-renin forms of experimental hypertension were not studied yet. Moreover, there is no comparison of mechanisms underlying BP reduction elicited by chronic peroral (po) or intracerebroventricular (icv) clonidine treatment. Male salt-sensitive Dahl rats fed 4% NaCl diet and Ren-2 transgenic rats were treated with clonidine administered either in the drinking fluid (0.5 mg/kg/day po) or as the infusion into lateral brain ventricle (0.1 mg/kg/day icv) for 4 weeks. Basal BP and the contributions of renin-angiotensin system (captopril 10 mg/kg iv) or sympathetic nervous system (pentolinium 5 mg/kg iv) to BP maintenance were determined in conscious cannulated rats at the end of the study. Both peroral and intracerebroventricular clonidine treatment lowered BP to the same extent in either rat model. However, in both models chronic clonidine treatment reduced sympathetic BP component only in rats treated intracerebroventricularly but not in perorally treated animals. In contrast, peroral clonidine treatment reduced angiotensin II-dependent vasoconstriction in Ren-2 transgenic rats, whereas it lowered residual blood pressure in Dahl rats. In conclusions, our results indicate different mechanisms of antihypertensive action of clonidine when administered centrally or systemically.

• MeSH
• angiotensin II farmakologie   MeSH
• antihypertenziva farmakologie   MeSH
• chlorid sodný MeSH
• clonidin farmakologie   MeSH
• hypertenze * chemicky indukované   farmakoterapie   MeSH
• hypotenze * MeSH
• krevní tlak MeSH
• krysa rodu Rattus MeSH
• kuchyňská sůl MeSH
• potkani inbrední Dahl MeSH
• potkani transgenní MeSH
• renin MeSH
• sympatický nervový systém MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• angiotensin II MeSH
• antihypertenziva MeSH
• chlorid sodný MeSH
• clonidin MeSH
• kuchyňská sůl MeSH
• renin MeSH

INTRODUCTION: Previous studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ETA) receptor blockade retards chronic kidney disease (CKD) progression. This prompted us to evaluate if this progression will be alleviated by the addition of sEH inhibitor and ETA receptor antagonist to the standard complex blockade of RAS (angiotensin-converting enzyme inhibitor plus angiotensin II type 1 receptor blocker) in rats with established CKD. METHODS: The treatment regimens were initiated 6 weeks after 5/6 NX in TGR, and the follow-up period was 60 weeks. RESULTS: The addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance - all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ETA receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, also abolished the beneficial effects of adding sEH inhibitor to the RAS blockade. CONCLUSION: These data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to further extend this therapeutic regimen should be made with extreme caution.

• Klíčová slova
• 5/6 Renal mass reduction, Chronic kidney disease, Endothelin A receptor blocker, Hypertension, Renin-angiotensin system, Soluble epoxide hydrolase inhibitor,
• MeSH
• antagonisté endotelinového receptoru A farmakologie   MeSH
• chronická renální insuficience prevence a kontrola   MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• hypertenze MeSH
• krysa rodu Rattus MeSH
• nefrektomie MeSH
• potkani transgenní MeSH
• receptor endotelinu A MeSH
• renin-angiotensin systém účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antagonisté endotelinového receptoru A MeSH
• epoxid hydrolasy MeSH
• receptor endotelinu A MeSH