An Antisense β1-Reducer: Repeated Administration Reduces Hypertension and Cardiac Hypertrophy Persistently Without Toxicity or Immune Response
In order to overcome the adverse effects associated with conventional β-blockers in treating hypertension, we have developed a novel β1-reducer by specifically targeting β1-adrenoceptor mRNA with an antisense oligonucleotide (β1-AS-ODN). A single intravenous injection of β1-AS-ODN deliverd with cationic liposomes caused a profound (25-35 mmHg) and prolonged (20-30 days) reduction in blood pressure in spontaneously hypertensive rats (SHR) without central effects. To be clinically useful the β1-AS-ODN would have to be effective with repeated injections and non-toxic. In this study, we have examined the effects of repeated administration of β1-AS-ODN on blood pressure and cardiac hypertrophy. Toxicity and immune response were assessed. Injections of 1mg/kg β1-AS-ODN (n=9) i.v. at 15, 20 and 26 days maintained systolic blood pressure of SHR at 20-30 mmHg lower than controls for more than 2 months (P<0.05). There was no loss in the antihypertensive efficacy with repeated injections. Instead, the intensity and duration of blood pressure reduction were greater with the second and third treatments. Control animals treated with control inverted-ODN (n=7) or saline (n=7) had no change in blood pressure with repeated injections. Left ventricular hypertrophy normalized by body weight was significantly attenuated 2 months after β1-AS-ODN treatment (P<0.05). Analysis of serum following each antisense delivery revealed no abnormalities in liver transaminase levels (ALT, AST) or hematology parameters (WBC, platelets, hematocrit). No antibodies to ODN/liposome complex were detected in gel immunodiffusion assay. Histological examination of heart, liver, kidney and spleen revealed no immunopathology or organ damage. These results demonstrate that β1-AS-ODN i.v. can be given repeatedly to achieve a sustained reduction of hypertension and reduces cardiac hypertrophy without causing toxic effects or immune stimulation. These data, together with results of our previous studies, show β1-AS-ODN is viable as a potentially new prolonged antihypertensive agent with benefits on cardiac remodeling.