| Background The sympathetic nervous system plays a crucial role in the regulation of blood pressure(BP), mainly through activating α- and P-adrenergic receptors (β1-ARs) in the effector organs, including heart, kidney, and blood vessels. Since the introduction of propranolol in 1965, β-blockers have become major first-line drugs for hypertension. Through the inhibition of β1- ARs in heart and kidney, p-blockers lower high blood pressure via decreasing cardiac output and plasma renin activity owing to the reduced response to the sympathetic nervous system. Antisense oligodeoxynucleotides(AS-ODN) are short lengths of synthetically made nucleotides (DNA)designed to hybridize with a specific sequence of mRNA, which can effectively downregulate the expression of target proteins through a number of mechanisms. Zhang et al have used an AS-ODN complementary to rat β1-AR mRNA (β1-AS-ODN) and witnessed its ability to reduce BP in spontaneously hypertensive rats. However, the effects of β1-AS-ODN on BP, left ventricular hypertrophy and endothelial function in two-kidney one-clip hypertensive rats have never been reported before.Objective To investigate the effects of β1-AS-ODN delivered by the cationic liposomes (DOTAP/DOPE) on the BP, hemodynamics, left ventricular hypertrophy and endothelial function in renal hypertensive rats.Methods The two-kidney and one-clip(2K1C)rat models were established and divided into five groups: the sham-operated group, the 2K1C group, the 2K1C+inverted ODN(IN-ODN)group, the 2K1C+antisenseoligodeoxynucleotide(AS-ODN)group and the 2KlC+carvedilol group. Single intravenous injection of ODN 0.5 mg·kg-1 was given after four weeks of operation and carvedilol 10 mg·kg-1·d-1 was administrated for 30 days. Blood pressure was measured regularly. Hemodynamic parameters, Left ventricular mass index (LVMI), collagen volume fraction (CVF), ratio of perivascular collagen area to vessel luminal cross-sectional area (PVCA), circulating and myocardial levels of endothelin-1(ET-1) and nitric oxide (NO) were measured on 30th day after administration. The linear correlation between LVMI, CVF, PVCA and ET-1, NO were analyzed.Results (1) Compared with the sham-operated group, SBP, LVSP, LVEDP, LVMI, CVF, PVCA, circulating and myocardial levels of ET-1 all increased(PO.Ol); ±dp/dtmax and circulating and myocardial levels of NO decreased in the 2K1C group and the IN-ODN group. (2) Compared with the IN-ODN group, p>AS-ODN significantly decreased SBP by up to 39mmHg for 27 days (30.44±6.50, PO.01) , increased ±dp/dtmax (PO.01) and had an obvious suppressive effect on LVSP(P<0.05), LVEDP(P<0.01), LVMI(P<0.05), CVF(PO.Ol), PVCA(P<0.01), circulating levels of ET-1 (PO.01) and myocardial levels of ET-l(P<0.05). Carvedilol significantly increased circulating and myocardial levels of NO, on which pVAS-ODN had no effect. (3) LVMI positively correlated with circulating and myocardial levels of ET-l(r=0.749, 0.788, PO.01) and negatively correlated with circulating and myocardial levels of NO(r= -0.881, PO.01, r= -0.615, PO.05). CVF and PVCA positively correlated with myocardial levels of ET-1 (r= 0.644, PO.05, r= 0.778, PO.01).Conclusions (1) The imbalance between ET-1 and NO may play an important role in the development of hypertension and left ventricular hypertrophy of renal hypertensive rats. (2) Pi-AS-ODN mediated by the cationic liposomes has an effective long-term antihypertensive effect with single intravenous injection. It can also improve the hemodynamics, attenuate left ventricular hypertrophy, decrease circulating and myocardial levels of ET-1 and improve endothelial function.
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