Antisense Inhibition of Brain Renin-Angiotensin System Decreased Blood Pressure in Chronic 2-Kidney, 1 Clip Hypertensive Rats

Kagiyama, Shuntaro; Varela, Adrian E.; Phillips, M. Ian; Galli, Sara M.

doi:10.1161/01.hyp.37.2.371

Cited by 56 publications

(42 citation statements)

References 45 publications

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“…18 Similar results were obtained for other experimental model, namely, 2-kidney-1-clip. 27 Our findings agree with those of Pachori et al, 19 who found moderate antihypertensive effects of AS therapy in young TGR that were accompanied by attenuated cardiac hypertrophy. Our data also demonstrated positive effects of AS therapy on cardiac hypertrophy, as indicated by the decrease in the relative heart weight.…”

Section: Antisensesupporting

confidence: 93%

The effects of repeated delivery of angiotensin II AT1 receptor antisense on distinct vasoactive systems in Ren-2 transgenic rats: young vs. adult animals

et al. 2012

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Although Ren-2 transgenic rat (TGR) is defined as a model of angiotensin II-dependent hypertension, we studied whether the renin-angiotensin system (RAS) is really the main contributor to blood pressure (BP) elevation in hetero-and homozygous TGRs. Moreover, we examined whether repeated antisense (AS) therapy against AT 1 receptors would have a similar effect on the BP and the contribution of the principle vasoconstrictor/vasodilator systems to BP regulation in young and adult TGRs. From the age of 30 (young) and 100 (adult) days, rats were injected with AS for 40 days in 10-day intervals. After 10 and 40 days of AS therapy, the basal BP and acute BP responses to the sequential blockade of the RAS, sympathetic nervous (SNS) and nitric oxide systems were determined in conscious rats. The RAS system was the major system maintaining elevated BP in young homozygous animals, whereas there was an increasing contribution of the SNS in heterozygous TGR with age. The AS therapy in the young TGR had a transient BP-lowering effect that was associated with reduced cardiac hypertrophy; the AS therapy was most effective in young homozygous TGR, causing a substantial reduction of angiotensin-dependent vasoconstriction. In heterozygous rats, AS therapy at earlier stages was related to an inhibition of sympathetic vasoconstriction, whereas to RAS inhibition in established hypertension. In conclusion, repeated AS therapy had transient antihypertensive effects exclusively in young TGR. The contribution of the RAS to BP maintenance is highly important only in homozygous TGRs, whereas it is surpassed by SNS in heterozygous TGR. Keywords: AT 1 receptor; BP regulation; gene therapy; oligodeoxynucleotides; vasodilator and vasoconstrictor systems INTRODUCTION Ren-2 transgenic rat (TGR) is a typical monogenic form of hypertension and represent a well-established model of angiotensin II (ANG II)-dependent hypertension, with a sustained local activation of the renin-angiotensin system (RAS). 1 However, the exact pathophysiological mechanisms responsible for the development and maintenance of hypertension in this model remain unclear. The homozygous line develops severe hypertension and typical signs, that is, impaired kidney and cardiac functions, lead to a high mortality at a young age. Therefore, experiments in homozygous animals can be performed only until 2-3 months of age. In contrast, heterozygous animals become hypertensive at the age of 7-8 weeks, and they survive normally. Originally, TGRs were characterized as a low-renin form of hypertension, 1-3 with similar levels of ANG II in the TGRs and their normotensive Hannover Sprague-Dawley (HanSD) controls. However, controversial findings of either increased or decreased ANG II levels were reported in the plasma and kidneys of anesthetized animals. Recently, Huskova et al. 4 have found that the ANG II levels were increased in conscious TGR, as compared with age-matched HanSD, showing that the increased activity of the RAS might contribute to the

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Section: Antisensesupporting

confidence: 93%

The effects of repeated delivery of angiotensin II AT1 receptor antisense on distinct vasoactive systems in Ren-2 transgenic rats: young vs. adult animals

et al. 2012

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“…There is considerable evidence that ANG II in the brain plays an important role in maintaining a high level of sympathetic activity in a number of models of experimental hypertension (20,24,44,45). In particular, as mentioned above, very recent studies indicate that, at least in SHR and in the Dahl salt-sensitive hypertensive rat, endogenous ANG II has a tonic excitatory action on presympathetic neurons in the RVLM that is not evident in normotensive animals (1,21,22).…”

Section: Perspectivesmentioning

confidence: 98%

Blockade of AT₁ receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions

Sheriff¹,

Fontes²,

Killinger³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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The role of ANG type 1 (AT1) receptors in the rostral ventrolateral medulla (RVLM) in the maintenance of sympathetic vasomotor tone in normotensive animals is unclear. In this study, we tested the hypothesis that AT 1 receptors make a significant contribution to the tonic activity of presympathetic neurons in the RVLM of normotensive rats under conditions where the excitatory input to these neurons is enhanced, such as during systemic hypoxia. In urethane-anesthetized rats, microinjections of the AT1 receptor antagonist candesartan in the RVLM during moderate hypoxia unexpectedly resulted in substantial increases in arterial pressure and renal sympathetic nerve activity (RSNA), whereas under normoxic conditions the same dose resulted in no significant change in arterial pressure and RSNA. Under hypoxic conditions, and after microinjection of the GABA A receptor antagonist bicuculline in the RVLM, subsequent microinjection of candesartan in the RVLM resulted in a significant decrease in RSNA. In control experiments, bilateral microinjections in the RVLM of the compound [Sar 1 ,Thr 8 ]ANG II (sarthran), which decreases sympathetic vasomotor activity via a mechanism that is independent of AT 1 receptors, significantly reduced arterial pressure and RSNA under both normoxic and hypoxic conditions. The results indicate that, at least under some conditions, endogenous ANG II has a tonic sympathoinhibitory effect in the RVLM, which is dependent on GABA receptors. We suggest that the net effect of endogenous ANG II in this region depends on the balance of both tonic excitatory and inhibitory actions on presympathetic neurons and that this balance is altered in different physiological or pathophysiological conditions. brain stem; angiotensin receptors; arterial pressure; chemoreceptor reflex; sympathetic vasomotor tone; angiotensin type 1 receptor THE ROSTRAL PART OF THE ventrolateral medulla (RVLM) contains a group of sympathoexcitatory neurons that play a major role in the tonic and phasic regulation of sympathetic activity and arterial blood pressure (8, 16). These neurons project directly to sympathetic preganglionic neurons in the spinal cord and are an essential component of the central pathways mediating cardiovascular reflex responses to stimulation of baroreceptors, chemoreceptors, and many other peripheral receptors (8, 16).There is considerable evidence suggesting a role for endogenous ANG peptides in the regulation of RVLM neurons. Studies using in vitro autoradiography have demonstrated a high density of ANG II receptor binding sites in the RVLM of most species studied, including humans (2). These receptors are primarily of the ANG type 1 (AT 1 ) subtype (2), and recent studies using an antibody against the AT 1 receptor has confirmed the existence of these receptors on neurons in the RVLM of the rat, including catecholamine neurons of the C1 group (19). Microinjection of ANG II in the RVLM results in an increase in arterial pressure and sympathetic activity, an effect that is mediated by AT 1 receptors (3,14...

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“…This has been tested centrally with intracerebroventricular and intravenous injections. It has been tested in SHR 37 and also in 2-kidney, 1-clip (2K1C) animals 26 and environmentally induced hypertension. 27 In these 3 different models of hypertension-genetic, surgical, and environmental-the antisense produces a decrease in blood pressure within 24 hours of administration.…”

Section: At 1 R As-odnmentioning

confidence: 99%

[1] Gene therapy for hypertension: The preclinical data

Phillips¹

2002

Methods in Enzymology

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Abstract-Despite several drugs for the treatment of hypertension, there are many patients with poorly controlled high blood pressure. This is partly because all of the available drugs are short-lasting (Յ24 hours), have side effects, and are not highly specific. Gene therapy offers a possibility of producing longer-lasting effects with precise specificity based on the genetic design. Preclinical studies on gene therapy for hypertension have taken 2 approaches. Chao et al have performed extensive studies on gene transfer to increase vasodilator proteins. They have transferred kallikrein, atrial natriuretic peptide, adrenomedullin, and endothelin NO synthase into different rat models. Their results show that blood pressure can be lowered for 3 to 12 weeks with the expression of these genes. The antisense approach, which we began by targeting angiotensinogen and the angiotensin type 1 (AT 1 ) receptor, has now been tested independently by several different groups in multiple models of hypertension. Other genes targeted include the ␤ 1 -adrenoceptor, thyrotropinreleasing hormone, angiotensin gene-activating elements, carboxypeptidase Y, c-fos, and CYP4A1. There have been 2 methods of delivering antisense: one is by oligodeoxynucleotides, and the other is with full-length DNA in viral vectors.All the studies show a decrease in blood pressure lasting several days to weeks or months. Oligos are safe and nontoxic and could be delivered orally or eventually by skin patches. Systemic delivery of recombinant adeno-associated virus with DNA antisense to AT 1 receptors 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 some of the antisense oligodeoxynucleotides, although testing the viral vectors needs much more work.

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Antisense Inhibition of Brain Renin-Angiotensin System Decreased Blood Pressure in Chronic 2-Kidney, 1 Clip Hypertensive Rats

Cited by 56 publications

References 45 publications

The effects of repeated delivery of angiotensin II AT1 receptor antisense on distinct vasoactive systems in Ren-2 transgenic rats: young vs. adult animals

The effects of repeated delivery of angiotensin II AT1 receptor antisense on distinct vasoactive systems in Ren-2 transgenic rats: young vs. adult animals

Blockade of AT₁ receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions

[1] Gene therapy for hypertension: The preclinical data

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Antisense Inhibition of Brain Renin-Angiotensin System Decreased Blood Pressure in Chronic 2-Kidney, 1 Clip Hypertensive Rats

Cited by 56 publications

References 45 publications

The effects of repeated delivery of angiotensin II AT1 receptor antisense on distinct vasoactive systems in Ren-2 transgenic rats: young vs. adult animals

The effects of repeated delivery of angiotensin II AT1 receptor antisense on distinct vasoactive systems in Ren-2 transgenic rats: young vs. adult animals

Blockade of AT1 receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions

[1] Gene therapy for hypertension: The preclinical data

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Blockade of AT₁ receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions