UMLS:C0004135 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Gene therapy for hypertension is needed for the next generation of antihypertensive drugs. Current drugs, although effective, have poor compliance, are expensive and short-lasting (hours or one day). Gene therapy offers a way to produce long-lasting antihypertensive effects (weeks, months or years). We are currently using two strategies: antisense oligodeoxynucleotides (AS-ODN), an dantisense DNA delivered in viral vectors, to inhibit genes associated with vasoconstrictive properties. It is not necessary to know all the genes involved in hypertension, since many years of experience with drugs show which genes need to be controlled. AS-ODNs are short, single-stranded DNA that can be injected in naked form or in liposomes. AS-ODNs, targeted to AT1 receptors (AT1R), angiotensinogen (AGT), angiotensin converting enzyme (ACE) and beta 1-adrenergic receptors effectively reduce hypertension in rat models (SHR, 2K-1C and cold-induced) hypertension. The effects can last up to one month when delivered with liposomes. No side effects or toxic effects have been detected and repeated injections can be given. For the vector, adeno-associated virus (AAV) is used with a construct to include a CMV promoter, antisense DNA to AGT or AT1R and a reporter gene. Results in SHR demonstrate reduction and slowing of hypertension development with a single dose administration. Left ventricular hypertrophy is also reduced by AAV-AS-AGT treatment. Double transgenic mice (human renin plus human AGT) with high angiotensin II (Ang II) causing high blood pressure, treated with AAV-AT1R-AS, show a normalisation of blood pressure for over 6 months with a single injection of vector. We conclude that ODNs will probably be developed first because they can be treated like drugs for the treatment of hypertension with long-term effects. Viral vector delivery needs more engineering to be certain of its safety but one day may be used for a very prolonged control of blood pressure.
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PMID:Gene therapy for hypertension: sense and antisense strategies. 1172 1

In wild-type mice, 2-wk administration of losartan, an angiotensin (Ang) II type 1 (AT1) receptor antagonist, along with dietary sodium restriction, resulted in an elevation of plasma aldosterone greater than that seen with sodium restriction alone (2.75 +/- 0.35 vs. 1.38 +/- 0.16 ng/ml, P < 0.01). Plasma potassium increased in sodium-restricted, losartan-treated mice (6.0 +/- 0.2 mEq/liter), while potassium remained unchanged in mice with sodium restriction alone. To study the effect of Ang II on glomerulosa cells that may operate independently of plasma potassium in situ, we used chimeric mice made of cells with or without the intact AT1A gene (Agtr1a). When animals were fed a normal diet or chronically infused with Ang II, the aldosterone synthase mRNA was detectable only in Agtr1a+/+ but not Agtr1a-/- zona glomerulosa cells. After 2 wk of sodium restriction, plasma aldosterone increased (1.51 +/- 0.27 ng/ml) and potassium remained on average at 4.5 +/- 0.2 mEq/liter, with aldosterone synthase mRNA expressed intensively in Agtr1a+/+, but not detectable in Agtr1a-/- cells. Simultaneous sodium restriction and losartan treatment caused increases in plasma potassium (5.5 +/- 0.1 mEq/liter) and aldosterone (1.84 +/- 0.38 ng/ml), with both Agtr1a-/- and Agtr1a+/+ cells intensively expressing aldosterone synthase mRNA. Thus, aldosterone production is regulated by Ang II in the adrenal gland during chronic alterations in extracellular fluid volume when plasma potassium is maintained within the normal range. In the light of a previous observation that dietary potassium restriction superimposed on sodium restriction abolished secondary hyperaldosteronism in angiotensinogen null-mutant mice, the present findings demonstrate that when the renin-Ang system is compromised, plasma potassium acts as an effective alternative mechanism for the volume homeostasis through its capacity to induce hyperaldosteronism.
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PMID:In situ demonstration of angiotensin-dependent and independent pathways for hyperaldosteronism during chronic extracellular fluid volume depletion. 1173 22

Since pharmacological interactions of the renin-angiotensin system appear to alter the neurological outcome of stroke patients significantly, we examined the effect of elevated levels of angiotensin II and the role of its receptor subtype AT1 in brain infarction in transgenic mice after focal cerebral ischemia. Angiotensinogen-overexpressing and angiotensin receptor AT1 knockout mice underwent 1 h or 24 h permanent middle cerebral artery occlusion (MCAO). The current study revealed a much smaller penumbra size, i.e., brain tissue at risk, in angiotensinogen-overexpressing animals compared with their wild-type subgroup after 1 h MCAO, but an enlarged infarct size after 24 h. In contrast, a smaller lesion area of energy failure and a much larger penumbral area were found in AT1 knockout mice compared with wild-type littermates. Lower perfusion thresholds for ATP depletion and protein synthesis inhibition after MCAO in AT1-deficient mice and reduced cell damage in an in vitro model using embryonic neurons of AT1 knockout mice suggest injury mechanisms independent of arterial blood pressure. Our data, therefore, demonstrate a direct correlation between brain angiotensin II and the severity of ischemic injury in experimental stroke.
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PMID:Ischemic injury in experimental stroke depends on angiotensin II. 1181 64

In spite of several drugs for the treatment of hypertension, there are many patients with poorly controlled high blood pressure. This is partly due to the fact that all available drugs are short-lasting (24 hr or less), have side effects, and are not highly specific. Gene therapy offers the possibility of producing longer-lasting effects with precise specificity from the genetic design. Preclinical studies on gene therapy for hypertension have taken two approaches. Chao et al. have carried out extensive studies on gene transfer to increase vasodilator proteins. They have transferred kallikrein, atrial natriuretic peptide, adrenomedullin, and endothelin nitric oxide synthase into different rat models. Their results show that blood pressure can be lowered for 3-12 weeks with the expression of these genes. The antisense approach, which we began by targeting angiotensinogen and the angiotensin type 1 receptor, has now been tested independently by several different groups in multiple models of hypertension. Other genes targeted include the beta 1-adrenoceptor, TRH, angiotensin gene activating elements, carboxypeptidase Y, c-fos, and CYP4A1. There have been two methods of delivery antisense; one is short oligodeoxynucleotides, and the other is full-length DNA in viral vectors. All the studies show a decrease in blood pressure lasting several days to weeks or months. Oligonucleotides are safe and nontoxic. The adeno-associated virus delivery antisense to AT1 receptors is systemic and in adult rodents decreases hypertension for up to 6 months. We conclude that there is sufficient preclinical data to give serious consideration to Phase I trials for testing the antisense ODNs, first and later the AAV.
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PMID:Gene therapy for hypertension: the preclinical data. 1188 75

We aimed to study the mechanisms and the significance of the influence exerted by the renin-angiotensin system (RAS) on the pineal melatonin production. Pineal melatonin and other indoles were determined by HPLC with electrochemical detection after angiotensin AT1-receptor blockade with Losartan in vivo or in cultured glands. N-acetyltransferase (NAT) activity was radiometricaly measured. To test the in vivo relevance of the local RAS, pineal melatonin and its indole precursors were determined in transgenic rats with inhibited production of angiotensinogen exclusively in astrocytes, TGR(ASrAOGEN). Tryptophan hydroxylase (TPH) and NAT mRNA levels were determined by real-time RT-PCR. Pineal melatonin content was significantly decreased by AT1-receptor blockade in vivo, in cultured glands and in TGR(ASrAOGEN) (35%, 32.4% and 17.5% from control, respectively). Losartan produced a significant decrease of pineal 5-hydroxytryptophan, serotonin, 5-hydroxyindole acetic acid and N-acetylserotonin in pineal cultures. Also, the pineal content of the precursor indoles in TGR(ASrAOGEN) rats was significantly lowered. The reduction of 5-hydroxytryptophan levels by 33-75% in both in vivo and in vitro studies suggests a decreased activity of TPH. Moreover, the TPH mRNA levels in TGR(ASrAOGEN) rats were significantly lower than control rats. On the other hand, NAT activity was unaffected by Losartan in pineal culture and its expression was not significantly different from control in TGR(ASrAOGEN) rats. Our results demonstrate that a local pineal RAS exerts a tonic modulation of indole synthesis by influencing the activity of TPH via AT1-receptors.
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PMID:Locally synthesized angiotensin modulates pineal melatonin generation. 1190 23

1. The present review provides an update on evidence of the neurotransmitter pathways and location of receptors within the nucleus tractus solitarii (NTS) mediating the baroreflex and other haemodynamic actions of angiotensin (Ang) II. 2. A series of studies suggests a significant role for substance P in the acute cardiovascular and carotid sinus chemoreceptor facilitatory actions of AngII in the NTS. The use of antisense oligonucleotides to AT1 receptors indicates both pre- and post-synaptic AngII receptors are likely to be involved in these actions. 3. With respect to baroreceptor reflex actions, it is clear that endogenous AngII impairs the gain for operation of the baroreceptor reflex, because AT1 receptor antagonists facilitate reflex function. This effect is either independent of substance P or involves inhibition of release. Moreover, initial data obtained using antisense oligonucleotides to AT1 receptors suggest that, in the NTS, the effect of endogenous AngII on the baroreceptor reflex is mainly due to presynaptic actions on vagal or carotid sinus afferent fibres. In contrast, the level of endogenous AngII within the NTS appears to have variable effects on activation of cardiopulmonary vagal afferent fibres by phenylbiguanide. These results indicate a divergence of effects of AngII on reflexes evoked by these two different types of sensory input. 4. Use of transgenic rats with alterations in brain angiotensin peptides allowed us to assess the effect of long-term alterations in brain Ang peptides on reflex function. We studied (mRen2)27 transgenic rats (TGR(mRen2)) with high brain medulla AngII levels and transgenic rats with angiotensinogen (Aogen) antisense linked to glial fibrillary acidic protein promoter (TGR(ASrAogen)) with greatly reduced brain Aogen. The reflex evoked by activation of cardiac vagal chemosensitive afferent fibres was enhanced in TGR(ASrAogen), whereas the baroreceptor reflex control of heart rate was attenuated in TGR(mRen2), further confirming a divergence of effects of AngII on these two sensory modalities. 5. The overall results are consistent with a sustained inhibitory effect of AngII on the baroreceptor reflexes, with dose-dependent or activation-dependent effects on cardiac vagal afferent fibre activation. Moreover, alterations in substance P pathways may contribute to the actions of AngII on reflex function.
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PMID:Angiotensin peptides as neurotransmitters/neuromodulators in the dorsomedial medulla. 1201 Jan 95

Recent studies have linked fetal exposure to a suboptimal intrauterine environment with adult hypertension. The aims of this study were twofold: 1) to see whether cortisol treatment administered to the ewe for 2 days at 27 days of gestation (term approximately 150 days) resulted in high blood pressure in offspring; 2) to study the effect of the same treatment on gene expression in the brain at 130 days of gestation and in lambs at 2 months of age. Mean arterial pressure was significantly higher in the adult female and male offspring of sheep treated with cortisol than in the control group (females: 89+/-2 mmHg vs. 81+/-2; P<0.05 and males: 102+/-4 mmHg vs. 91+/-3; P<0.05). Prenatal cortisol treatment led to up-regulation of angiotensinogen, AT1, MR, and GR mRNA in the hippocampus in fetuses at 130 days of gestation but not in the animals at 2 months of age. This is the first evidence that short prenatal exposure to cortisol programmed high blood pressure in the adult female and male offspring of sheep. Altered gene expression in the hippocampus could have a significant effect on the development of the hippocampus, and on postnatal behavior.
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PMID:Programming effects of short prenatal exposure to cortisol. 1208 63

Accumulating evidence suggests that angiotensin II (ANG II) plays an important role in the complex affair of renal organogenesis. The renin-angiotensin system (RAS) is up-regulated during renal development and in the perinatal period. On the other hand, inhibition of the RAS, for example by angiotensin-converting enzyme (ACE) inhibitors, may produce specific renal abnormalities including abnormal renal vessels, failure to develop a renal pelvis and tubular atrophy associated with expansion of the interstitium. AT2 receptors are expressed abundantly during fetal development and are down-regulated markedly after birth, whereas the abundance of AT1 receptors increases as maturation proceeds. Mice with targeted deletions of genes for angiotensinogen or ACE revealed severe renal abnormalities. In contrast, AT1A, AT1B and AT2 receptor knockout animals exhibited milder abnormalities of the kidney. These findings suggest that AT1 and AT2 receptors are both involved in the development of the nephron, and that ANG II provides signals through both receptors. ANG II exerts in vitro growth-stimulatory effects on tubular cells. Moreover, ANG II induces synthesis of collagen type IV in tubular cells, a necessary prerequisite for successful basement membrane formation. These effects are mediated through AT1 receptors. Thus, it is feasible that blockade of the RAS during kidney organogenesis leads to a decrease in the growth factor ANG II that may be pivotal for tubular growth and differentiation. On the other hand, ANG II's growth-stimulatory effects through AT1 receptors may be counterbalanced by AT2 receptor-mediated apoptosis and growth inhibition. Therefore, alterations in AT2 receptor signalling may alter the delicate balance between growth stimulation and inhibition, leading to alterations in tubular formation.
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PMID:Angiotensin II and tubular development. 1238 87

OBJECTIVE: To investigate the relation of renin-angiotensin system (RA3) gene polymorphisms and expressions with the clinical efficacy of antihypertensive drugs. METHODS: This randomized, single-blind study consisted of 90 patients with essential hypertension, who were divided into losartan, lisinopril and nisodipine groups with corresponding medications as indicated. The genotypes of angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T polymorphism and expressions of ACE and AT1 receptor genes were examined individually. RESULTS: The basal level of mRNA expression of AT1 receptor was lower in patients with MM genotype of AGT gene than those in patients with MT 1 and TT genotypes, but between the latter two, no significant differences were found. The three antihypertensive drugs, when significantly lowering the blood pressure, reduced AT1 receptor mRNA expression concurrently. Losartan and lisinopril both decreased ACE mRNA expression levels that were positively correlated with the difference of the diastolic blood pressure whereas nisodipine elevated ACE mRNA expression, showing inverse correlation to the difference of thediastolic blood pressure. CONCLUSION: For patients with hypertension who have elevated basal levels of AT1 mRNA expression and AGT T allele or who retain high basal expression levels of ACE mRNA AT1 antagonists and ACE inhibitors that execute their action through RAS are preferentially selected, and in cases of low basal levels of ACE mRNA calcium antagonists are preferred.
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PMID:Relation of renin-angiotensin system gene polymorphisms and expressions with the efficacy of antihypertensive drugs. 1242 59

There are several controversies concerning the enhanced gene expression of cardiac renin-angiotensin system components in spontaneously hypertensive rats (SHR) compared with their normotensive control Wistar-Kyoto (WKY) rats. We hypothesized that these discrepancies arise from circadian fluctuations in gene expression. We examined the circadian mRNA expression of renin, angiotensinogen, ACE, and angiotensin type 1a (AT1a) and type 2 (AT2) receptors in the hearts of SHR and WKY rats by real-time quantitative reverse transcription-polymerase chain reaction. The cardiac mRNA expression of the renin-angiotensin system components showed circadian oscillations in both SHR and WKY rats. The amplitudes of these circadian fluctuations were greater in the SHR than in the WKY rats. The mRNA levels of the renin-angiotensin system components were also increased in the SHR compared with the WKY rats at many time points (especially during the dark phase). However, the levels of ACE, AT1a receptor, and AT2 receptor mRNA in the SHR and WKY rats were almost the same during the late light phase. In contrast to mRNA expression, ACE activity was similar both at the time of maximum and minimum mRNA expression. The AT1 receptor antagonist candesartan upregulated AT1a receptor mRNA and downregulated ACE mRNA at specific time points only in the SHR group. Our findings of differential diurnal expression of cardiac renin-angiotensin system genes in SHR and WKY rats appear to explain the discrepancies between prior studies. However, the physiological relevance of the differential circadian mRNA expression of the renin-angiotensin system components remains to be elucidated.
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PMID:Augmented diurnal variations of the cardiac renin-angiotensin system in hypertensive rats. 1246 65

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