In vivo effects of partial phosphorothioated AT1 receptor antisense oligonucleotides in spontaneously hypertensive and normotensive rats.
Partial phosphorothioate (PS) antisense oligodeoxynucleotides (ODNs) targeted against rat AT1 receptor mRNA have been used to control blood pressure in normotensive (WKY) and spontaneously hypertensive (SHR) rats. Molecules were injected intracerebroventricularly (i.c.v., right lateral ventricle) in freely moving animals. The antisense ODN lowered the mean arterial pressure (MAP) 24 hours (-43 mmHg+/-10) and 48 hours (-30 mmHg+/-13) after injection, while the control ODN molecule had no significant effects. The observed decrease of blood pressure was due to a specific inhibition of AT1 receptor gene expression, since the level of its mRNA, monitored by reverse transcription (RT)- polymerase chain reaction (PCR), was significantly reduced by antisense molecule (-40%), compared to sense one. In normotensive rats no effect on MAP have been observed, while AT1 receptor gene expression is reduced (-40%) by antisense treatment. It is known that SHRs have an enhanced basal activity of the central renin-angiotensin system that induces an increase in central sympathetic outflow. Instead in WKY rats the central sympathetic outflow is not conditioned by the enhanced activity of brain renin-angiotensin system. Therefore in normotensive rats although partial PS ODN reduces the AT1 mRNA level this will not result in a modification of the sympathetic outflow and no change in MAP level would be observed.
Piegari
E
E
Institute of Pharmacology and Toxicology, School of Medicine, Second University of Naples, Italy.
Galderisi
U
U
Berrino
L
L
Di Bernardo
G
G
Cipollaro
M
M
Esposito
F
F
Rossi
F
F
Cascino
A
A
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D016376:Oligonucleotides, Antisense; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin