Central alpha2B-adrenergic receptor antisense in plasmid vector prolongs reversal of salt-dependent hypertension.
OBJECTIVE
Previous studies have shown that a fully functional alpha(2B)-adrenergic receptor (AR) is necessary for the development of salt-induced hypertension. The current studies were designed to explore the effect of prolonged inhibition of central alpha(2B)-AR gene expression by antisense (AS) DNA on this hypertension.


METHODS
We developed a plasmid vector driven by a cytomegalovirus promoter, containing a green fluorescent protein reporter gene and AS for rat alpha(2B)-AR protein. Subtotally nephrectomized, salt-loaded hypertensive rats received intracerebroventricular injection of 500 microg of either the AS plasmid (n = 9) or sense plasmid (containing cDNA for alpha(2B)-AR), as control (n = 7).


RESULTS
The AS injection produced a fall in SBP from 201 +/- 4 to 171 +/- 5 mmHg within 12 h. The level of BP in the 3 days post-injection was 174 +/- 6, 181 +/- 4 and 184 +/- 6 mmHg on day 1, day 2 and day 3, respectively (P < 0.05), and returned gradually towards baseline in subsequent days, although it remained significantly lower for the 8 days of observation. The control sense plasmid injections produced no significant changes in blood pressure (BP). Neither group had histological evidence of neural tissue disruption.


CONCLUSIONS
These results indicate that protracted translational inhibition of the alpha(2B)-AR gene in the central nervous system can be obtained by AS DNA delivered via plasmid vector and lead to decreased generation of alpha(2B)-AR protein, which can partly reverse salt-induced hypertension for several days.
Kintsurashvili
Ekaterina
E
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Johns
Conrado
C
Ignjacev
Ivana
I
Gavras
Irene
I
Gavras
Haralambos
H
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000494:pharmacology*; D049452:Green Fluorescent Proteins; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007202:Indicators and Reagents; D007276:Injections, Intraventricular; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000187:drug effects; D008297:Male; D008955:Models, Cardiovascular; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D010957:Plasmids / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism*; D011991:Receptors, Virus / Q000187:drug effects / Q000378:metabolism; D013599:Systole / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014162:Transfection
C547773:Adra2b protein, rat; D007202:Indicators and Reagents; D008164:Luminescent Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D018341:Receptors, Adrenergic, alpha-2; D011991:Receptors, Virus; C064084:cytomegalovirus receptor; D049452:Green Fluorescent Proteins