Inhibition of Hypertension by Peripheral Administration of Antisense Oligodeoxynucleotides
| Autor: | Shawn Toffolo, Donna Wielbo, Amy Simon, M. Ian Phillips |
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| Rok vydání: | 1996 |
| Předmět: |
Male
medicine.medical_specialty Transcription Genetic medicine.medical_treatment Prohormone Angiotensinogen Blood Pressure In Vitro Techniques law.invention Rats Sprague-Dawley Confocal microscopy law Rats Inbred SHR Internal medicine Renin–angiotensin system Internal Medicine Animals Medicine RNA Messenger Drug Carriers Chemotherapy Liposome business.industry Oligonucleotide Angiotensin II Oligonucleotides Antisense In vitro Rats Endocrinology Liver Data Interpretation Statistical Protein Biosynthesis Hypertension Liposomes business medicine.drug |
| Zdroj: | Hypertension. 28:147-151 |
| ISSN: | 1524-4563 0194-911X |
| DOI: | 10.1161/01.hyp.28.1.147 |
| Popis: | We administered liposome-encapsulated antisense oligodeoxynucleotide targeted to angiotensinogen mRNA peripherally to spontaneously hypertensive rats to test whether peripheral angiotensinogen reduction would lower their hypertensive blood pressures and to determine the role of peripheral angiotensinogen in the modulation of hypertension. Using in vitro translation techniques, we tested the sequence specificity of the antisense sequence. The selected antisense sequence decreased angiotensinogen production in vitro, enabling us to distinguish between specific and nonspecific effects. To increase the efficiency of peripheral and hepatic antisense delivery, oligonucleotides were liposome encapsulated for intra-arterial administration. Confocal microscopy was used for determination of the hepatic distribution of fluorescently labeled antisense. Encapsulated antisense molecules were seen to be distributed within liver tissue 1 hour after injection; however, little or no uptake was observed with the unencapsulated oligonucleotides. We also determined the physiological effects of antisense oligodeoxynucleotide targeted to liver angiotensinogen mRNA. Administration of liposome-encapsulated antisense significantly decreased hypertensive blood pressures to normotensive levels compared with scrambled control oligonucleotides, unencapsulated antisense, and empty liposomes ( P =.013). These data were supported by biochemical changes elicited by the antisense treatment. Rats receiving liposome-encapsulated antisense had significantly lowered peripheral angiotensinogen and angiotensin II levels compared with control groups ( P |
| Databáze: | OpenAIRE |
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