Antisense Oligonucleotides for in Vivo Studies of Angiotensin Receptors

Department of Physiology, College of Medicine, University of Florida, Gainesville 32610-0274, USA.
Advances in Experimental Medicine and Biology (Impact Factor: 1.96). 02/1996; 396:79-92. DOI: 10.1007/978-1-4899-1376-0_9
Source: PubMed
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    ABSTRACT: It has been reported that intracerebroventricularly injected antisense oligonucleotide to angiotensinogen reduces arterial pressure in spontaneously hypertensive rats (SHR), but the mechanism and the sites of action remain unclear. In the present study, we examined whether injection of antisense oligonucleotide to angiotensinogen into the paraventricular hypothalamic nucleus (PVN) would influence arterial pressure and vasopressin release. For this purpose, 12-week-old male SHR were cannulated into the bilateral PVN. One week later, we injected antisense or sense oligonucleotide to angiotensinogen into the bilateral PVN (0.2 nmol/200 nl each side). After 24 h, we directly monitored arterial pressure, and then took blood samples to measure plasma vasopressin, catecholamines and renin activity. Mean arterial pressure did not change in either group (from 144+/-3 to 154+/-4 mmHg for the antisense oligonucleotide group, n=11; from 147+/-4 to 156+/-3 mmHg for the sense oligonucleotide group, n=11). Antisense oligonucleotide attenuated vasopressin release compared with sense oligonucleotide (1.30+/-0.28 vs. 3.29+/-0.60 pg/ml, respectively, P<0.01). Plasma catecholamines also decreased in the antisense oligonucleotide group compared with the sense oligonucleotide group. However, the plasma renin activity did not differ between the groups. In the additional experiment, we examined the neurohormonal and cardiovascular effects of intracerebroventricularly injected antisense oligonucleotide to angiotensinogen in SHR. Mean arterial pressure, plasma vasopressin and plasma norepinephrine were significantly lower in the antisense oligonucleotide group than in the sense oligonucleotide group. These results suggest that angiotensinogen in PVN plays important roles in vasopressin release and sympathetic nerve activity, but may not contribute to the maintenance of arterial pressure in SHR.
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    ABSTRACT: beta-Blockers are widely used for hypertension treatment but must be taken daily. We have developed a novel beta-blocker by targeting beta(1)-adrenergic receptor (beta(1)-AR) mRNA with antisense oligodeoxynucleotides (beta(1)-AS-ODN). A single intravenous injection of beta(1)-AS-ODN significantly reduced cardiac contractility and blood pressure (38+/-5 mm Hg, P<0.05) in spontaneously hypertensive rats for 3 weeks. In the present study, we improved the antihypertensive effect of beta(1)-AS-ODN by delivery with the cationic liposomes DOTAP/DOPE and studied its impact on the peripheral renin-angiotensin system. Five charge ratios (+/-) of liposome/ODN from 0 to 3.5 were tested to deliver 0. 5 mg/kg beta(1)-AS-ODN intravenously in spontaneously hypertensive rats (n=30). On the basis of the magnitude and duration of hypotension, 2.5 was determined to be the optimal charge ratio, which decreased blood pressure by up to 35 mm Hg for 20 to 33 days (P<0.05). The effects were specific for beta(1)-AR, because radioligand binding assay and quantitative autoradiography showed a 35% reduction in beta(1)-AR levels in kidney but no change in beta(2)-AR. beta(1)-AS-ODN diminished the preprorenin mRNA levels in renal cortex by 37% 4 days after administration. This transient effect was followed by a delayed yet marked diminution of plasma renin activity and plasma angiotensin II levels on days 10 and 17 (P<0.01). The results show that beta(1)-AS-ODN has an effective long-term antihypertensive effect up to 33 days with a single intravenous injection. The mechanism appears to be through reduced beta(1)-AR number specifically and reduced cardiac contractility. The inhibition of the renin-angiotensin system is probably a second mechanism to produce the sustained antihypertensive effect of beta(1)-AS-ODN.
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    ABSTRACT: With advances in genetic manipulation and molecular biological and physiological techniques, the mouse has become the animal model of choice for studying the genetic basis of human diseases. The two most commonly used methods for analyzing the function of a gene in vivo, overexpression (transgenic mouse) and deletion (knockout mouse), have been extremely useful in establishing the importance of genes in genetic disorders. The renin-angiotensin system (RAS) is one of the most widely studied systems controlling blood pressure. Although the primary site of Ang-II production is the plasma, all the components of the RAS cascade are expressed in many tissues, including the brain. This review briefly summarizes systemic and tissue-specific transgenic and knockout mouse models of the RAS for determining the role of this system in the regulation of blood pressure and in the pathogenesis of hypertension, with a focus on the RAS in the brain.
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