The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and left ventricular hypertrophy. Catecholamines play an important role in the pathogenesis of both essential hypertension in humans and in the SHR. Recently, we obtained evidence that the SHR harbors a variant in the gene for dopamine beta hydroxylase (Dbh) that is associated with reduced adrenal expression of Dbh mRNA and reduced DBH enzymatic activity which correlated negatively with blood pressure. In the current study, we used a transgenic experiment to test the hypothesis that reduced Dbh expression predisposes the SHR to hypertension and that augmentation of Dbh expression would reduce blood pressure. We derived 2 new transgenic SHR-Dbh lines expressing Dbh cDNA under control of the Brown Norway (BN) wild type promoter. We found modestly increased adrenal expression of Dbh in transgenic rats versus SHR non-transgenic controls that was associated with reduced adrenal levels of dopamine and increased plasma levels of norepinephrine and epinephrine. The observed changes in catecholamine metabolism were associated with increased blood pressure and left ventricular mass in both transgenic lines. We did not observe any consistent changes in brainstem levels of catecholamines or of mRNA levels of Dbh in the transgenic strains. Contrary to our initial expections, these findings are consistent with the possibility that genetically determined decreases in adrenal expression and activity of DBH do not represent primary determinants of increased blood pressure in the SHR model.

Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Zobrazit více v PubMed

CABASSI A, VINCI S, CALZOLARI M, BRUSCHI G, BORGHETTI A. Regional sympathetic activity in prehypertensive phase of spontaneously hypertensive rats. Life Sci. 1998;62:1111–1118. PubMed

CHANG ST, LIU YP, HUANG CL, WANG PY, TUNG CS. Implication of cerebral dopamine-beta hydroxylase for cardiovascular and mood regulation in rats. Chin J Physiol. 2013;56:209–218. PubMed

CHEN Y, WEN G, RAO F, ZHANG K, WANG L, RODRIGUEZ-FLORES JL, SANCHEZ AP, MAHATA M, TAUPENOT L, SUN P, MAHATA SK, TAYO B, SCHORK NJ, ZIEGLER MG, HAMILTON BA, O’CONNOR DT. Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure. J Hypertens. 2010;28:76–86. PubMed PMC

CHEN Y, ZHANG K, WEN G, RAO F, SANCHEZ AP, WANG L, RODRIGUEZ-FLORES JL, MAHATA M, MAHATA SK, WAALEN J, ZIEGLER MG, HAMILTON BA, O’CONNOR DT. Human dopamine β-hydroxylase promoter variant alters transcription in chromaffin cells, enzyme secretion, and blood pressure. Am J Hypertens. 2011;24:24–32. PubMed PMC

CORNISH JL, WILKS DP. A functional interaction between the mesolimbic dopamine system and vasopressin release in the regulation of blood pressure in conscious rats. Neuroscience. 1997;81:69–78. PubMed

DEQUATTRO V, FENG M. The sympathetic nervous system: the muse of primary hypertension. J Hum Hypertens. 2002;16(Suppl 1):S64–S69. PubMed

ESLER M. The sympathetic system and hypertension. Am J Hypertens. 2000;13:99S–105S. PubMed

GROBECKER G, ROIZEN MF, WEISE V, SAAVEDRA JM, KOPIN IJ. Sympathoadrenal medullary activity in young, spontaneously hypertensive rats. Nature. 1975;258:267–268. PubMed

HOWES LG, ROWE PR, SUMMERS RJ, LOUIS WJ. Age related changes of catecholamines and their metabolites in central nervous system regions of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Clin Exp Hypertens A. 1984;6:2263–2277. PubMed

IVICS Z, MÁTÉS L, YAU TY, LANDA V, ZÍDEK V, BASHIR S, HOFFMANN OI, HIRIPI L, GARRELS W, KUES WA, BÖSZE Z, GEURTS A, PRAVENEC M, RÜLICKE T, IZSVÁK Z. Germline transgenesis in rodents by pronuclear microinjection of Sleeping Beauty transposons. Nat Protoc. 2014;9:773–793. PubMed

JIROUT ML, FRIESE RS, MAHAPATRA NR, MAHATA M, TAUPENOT L, MAHATA SK, KŘEN V, ZÍDEK V, FISCHER J, MAATZ H, ZIEGLER MG, PRAVENEC M, HÜBNER N, AITMAN TJ, SCHORK NJ, O’CONNOR DT. Genetic regulation of catecholamine synthesis, storage and secretion in the spontaneously hypertensive rat. Hum Mol Genet. 2010;19:2567–2580. PubMed PMC

NAGATSU T, KATO T, NUMATA Y, KEIKO I, UMEZAWA H. Serum dopamine beta-hydroxylase activity in developing hypertensive rats. Nature. 1974;251:630–631. PubMed

OHLSTEIN EH, KRUSE LI, EZEKIEL M, SHERMAN SS, ERICKSON R, DEWOLF WE, JR, BERKOWITZ BA. Cardiovascular effects of a new potent dopamine beta-hydroxylase inhibitor in spontaneously hypertensive rats. J Pharmacol Exp Ther. 1987;241:554–559. PubMed

ROBERTSON D, HAILE V, PERRY SE, ROBERTSON RM, PHILLIPS JA, 3RD, BIAGGIONI I. Dopamine beta-hydroxylase deficiency. A genetic disorder of cardiovascular regulation. Hypertension. 1991;18:1–8. PubMed

SWOAP SJ, WEINSHENKER D, PALMITER RD, GARBER G. Dbh(−/−) mice are hypotensive, have altered circadian rhythms, and have abnormal responses to dieting and stress. Am J Physiol Regul Integr Comp Physiol. 2004;286:R108–R113. PubMed

TAKAMI T, ITO H, SUZUKI T. Decreased norepinephrine content in the medulla oblongata in severely hypertensive rats. Clin Exp Pharmacol Physiol. 1993;20:161–167. PubMed

VAN DEN BUUSE M. Pressor responses to brain dopaminergic stimulation. Clin Exp Pharmacol Physiol. 1997;24:764–769. PubMed

The abnormalities of adrenomedullary hormonal system in genetic hypertension: Their contribution to altered regulation of blood pressure