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 pharmacology   MeSH
• Antihypertensive Agents pharmacology   MeSH
• Sodium Chloride MeSH
• Clonidine pharmacology   MeSH
• Hypertension * chemically induced   drug therapy   MeSH
• Hypotension * MeSH
• Blood Pressure MeSH
• Rats MeSH
• Sodium Chloride, Dietary MeSH
• Rats, Inbred Dahl MeSH
• Rats, Transgenic MeSH
• Renin MeSH
• Sympathetic Nervous System MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Angiotensin II MeSH
• Antihypertensive Agents MeSH
• Sodium Chloride MeSH
• Clonidine MeSH
• Sodium Chloride, Dietary MeSH
• Renin MeSH

The aim of the present study was to perform kidney messenger ribonucleic acid (mRNA) analysis in normotensive, Hannover Sprague-Dawley (HanSD) rats and hypertensive, Ren-2 renin transgenic rats (TGR) after doxorubicin-induced heart failure (HF) with specific focus on genes that are implicated in the pathophysiology of HF-associated cardiorenal syndrome. We found that in both strains renin and angiotensin-converting enzyme mRNA expressions were upregulated indicating that the vasoconstrictor axis of the renin-angiotensin system was activated. We found that pre-proendothelin-1, endothelin-converting enzyme type 1 and endothelin type A receptor mRNA expressions were upregulated in HanSD rats, but not in TGR, suggesting the activation of endothelin system in HanSD rats, but not in TGR. We found that mRNA expression of cytochrome P-450 subfamily 2C23 was downregulated in TGR and not in HanSD rats, suggesting the deficiency in the intrarenal cytochrome P450-dependent pathway of arachidonic acid metabolism in TGR. These results should be the basis for future studies evaluating the pathophysiology of cardiorenal syndrome secondary to chemotherapy-induced HF in order to potentially develop new therapeutic approaches.

• Keywords
• chemotherapy-induced heart failure, cytochrome P-450, doxorubicin, endothelin system, hypertension, kidney, renal adrenergic system, renin-angiotensin-aldosterone system,
• MeSH
• Doxorubicin adverse effects   MeSH
• Hypertension complications   genetics   physiopathology   MeSH
• Rats MeSH
• Kidney drug effects   physiopathology   MeSH
• RNA, Messenger genetics   MeSH
• Kidney Diseases chemically induced   genetics   physiopathology   MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Antibiotics, Antineoplastic adverse effects   MeSH
• Gene Expression Regulation drug effects   MeSH
• Renin-Angiotensin System drug effects   MeSH
• Renin genetics   MeSH
• Heart Failure chemically induced   genetics   physiopathology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Doxorubicin MeSH
• RNA, Messenger MeSH
• Antibiotics, Antineoplastic MeSH
• Ren2 protein, rat MeSH Browser
• Renin MeSH

Recent studies have shown that the renal CYP450 (cytochrome P450) metabolites of AA (arachidonic acid), the vasoconstrictor 20-HETE (20-hydroxyeicosatetraenoic acid) and the vasodilator EETs (epoxyeicosatrienoic acids), play an important role in the pathophysiology of AngII (angiotensin II)-dependent forms of hypertension and the associated target organ damage. The present studies were performed in Ren-2 renin transgenic rats (TGR) to evaluate the effects of chronic selective inhibition of 20-HETE formation or elevation of the level of EETs, alone or in combination, on the course of hypertension and hypertension-associated end-organ damage. Both young (30 days of age) prehypertensive TGR and adult (190 days of age) TGR with established hypertension were examined. Normotensive HanSD (Hannover Sprague-Dawley) rats served as controls. The rats were treated with N-methylsulfonyl-12,12-dibromododec-11-enamide to inhibit 20-HETE formation and/or with N-cyclohexyl-N-dodecyl urea to inhibit soluble epoxide hydrolase and prevent degradation of EETs. Inhibition in TGR of 20-HETE formation combined with enhanced bioavailability of EETs attenuated the development of hypertension, cardiac hypertrophy, proteinuria, glomerular hypertrophy and sclerosis as well as renal tubulointerstitial injury. This was also associated with attenuation of the responsiveness of the systemic and renal vascular beds to AngII without modifying their responses to noradrenaline (norepinephrine). Our findings suggest that altered production and/or action of 20-HETE and EETs plays a permissive role in the development of hypertension and hypertension-associated end-organ damage in this model of AngII-dependent hypertension. This information provides a basis for a search for new therapeutic approaches for the treatment of hypertension.

• MeSH
• Amides pharmacology   therapeutic use   MeSH
• Angiotensin II pharmacology   MeSH
• Antihypertensive Agents pharmacology   therapeutic use   MeSH
• Hypertension complications   drug therapy   physiopathology   MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• 8,11,14-Eicosatrienoic Acid analogs & derivatives   metabolism   MeSH
• Hydroxyeicosatetraenoic Acids biosynthesis   MeSH
• Multiple Organ Failure etiology   prevention & control   MeSH
• Norepinephrine pharmacology   MeSH
• Rats, Sprague-Dawley MeSH
• Rats, Transgenic MeSH
• Drug Evaluation, Preclinical methods   MeSH
• Renal Circulation drug effects   MeSH
• Sulfones pharmacology   therapeutic use   MeSH
• Vasoconstrictor Agents pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• 11,12-epoxy-5,8,14-eicosatrienoic acid MeSH Browser
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid MeSH Browser
• Amides MeSH
• Angiotensin II MeSH
• Antihypertensive Agents MeSH
• DDMS MeSH Browser
• 8,11,14-Eicosatrienoic Acid MeSH
• Hydroxyeicosatetraenoic Acids MeSH
• Norepinephrine MeSH
• Sulfones MeSH
• Vasoconstrictor Agents MeSH