Hypertension is a major risk factor in the development of cardiovascular disease. Adenovirus gene transfer of endothelin-1 (Ad.CMV.ET-1) in rats produced significant (5-fold) increases in plasma ET-1 and systemic blood pressure (46%) 4 days after viral administration, compared with β-galactosidase (Ad.CMV.β-gal) injected as control. The density (Bmax) of the ET receptor ETA measured in aortas was reduced significantly by more than 50% to 17±2 fmol·mg-1 of protein for the Ad.CMV.ET-1 group compared with 39±6 fmol·mg-1 of protein for the control. There was no change in the density of the smaller population of the ETB sub-type. In agreement, the ratio of ETA mRNA to cyclophilin mRNA (a housekeeping gene) measured by Northern analysis was reduced in Ad.CMV.ET-1 rats compared with controls. The ratio of m RNA encoding the ETB subtype did not change. ET-1 vasoconstriction was significantly reduced (P < 0.05) in aortas from Ad.CMV.ET-1-treated rats [pD2 = 8.67±0.14 (where pD2 is -log10EC50); n = 11] versus the control (pD2 = 9.11±0.06; n = 14) but there was no significant difference in the potency of two other vasoconstrictors tested (noradrenaline and Arg-vasopressin), indicating this was a specific effect on ET receptors. There was no change in the affinity of ET-1 binding to either receptor subtype in the experimental group compared with the control, demonstrating that the attenuation in the constrictor response is the result of the reduced density of receptors rather than a change in affinity. The results show that ETA (but not ETB) receptors are modulated in this experimental model of hypertension and provide further evidence for selective blockade of the ETA receptor as a therapeutic strategy.
|Original language||English (US)|
|Issue number||SUPPL. 48|
|State||Published - Aug 1 2002|
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