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Biomedical subjects

S Iyer

Publications and source records attributed to S Iyer.

At least 55 records · Page 3Linked to original sources
PubMed1999

Extracranial vertebral artery stent placement: in-hospital and follow-up results.

OBJECT: The authors summarize their experience with stent deployment in the treatment of vertebrobasilar artery (VBA) insufficiency. This is an underdiagnosed condition, and the incidence of significant vertebral artery (VA) stenosis has been underappreciated. Medical therapy has been the mainstay of treatment because of the high rate of morbidity associated with surgical correction of VA stenosis. Recently, some authors have reported acceptable results with the use of percutaneous transluminal angioplasty, but this technique has significant weaknesses such as elastic recoil and problems in achieving safe treatment of dissections. METHODS: The authors investigated the feasibility, safety, and outcome of VA stent placement in 50 patients in whom 55 vessels were treated using stents. Technical success was achieved in 54 (98%) of 55 vessels, with no procedure-related complications. However, one patient (2%) died of nonneurological causes, and one (2%) suffered a stroke that occurred within the 30-day postprocedural period and was related to a complicated coronary intervention. Clinical follow-up review performed at a mean of 25 +/- 10 months revealed two patients (4%) with recurrence of VBA symptoms. Six-month angiographic follow up was completed in 90% of eligible patients, with a 10% incidence of restenosis as defined by greater than 50% luminal narrowing. CONCLUSIONS: Vertebral artery stent placement is feasible in patients who have significant VA stenosis, with predictably good angiographically demonstrated and clinical results. The 6-month angiographically confirmed restenosis rate appears to be low, as does the clinical recurrence rate. This technique solves the problems of elastic recoil and the treatment of angioplasty-induced dissections. Further prospective comparison with medical preventive strategies is warranted.

Adult↗
PubMed1999

Involvement of PARP and poly(ADP-ribosyl)ation in the early stages of apoptosis and DNA replication.

We have focused on the roles of PARP and poly(ADP-ribosyl)ation early in apoptosis, as well as during the early stages of differentiation-linked DNA replication. In both nuclear processes, a transient burst of PAR synthesis and PARP expression occurs early, prior to internucleosomal DNA cleavage before commitment to apoptosis as well as at the round of DNA replication prior to the onset of terminal differentiation. In intact human osteosarcoma cells undergoing spontaneous apoptosis, both PARP and PAR decreased after this early peak, concomitant with the inactivation and cleavage of PARP by caspase-3 and the onset of substantial DNA and nuclear fragmentation. Whereas 3T3-L1, osteosarcoma cells, and immortalized PARP +/+ fibroblasts exhibited this early burst of PAR synthesis during Fas-mediated apoptosis, neither PARP-depleted 3T3-L1 PARP-antisense cells nor PARP -/- fibroblasts showed this response. Consequently, whereas control cells progressed into apoptosis, as indicated by induction of caspase-3-like PARP-cleavage activity, PARP-antisense cells and PARP -/- fibroblasts did not, indicating a requirement for PARP and poly(ADP-ribosyl)ation of nuclear proteins at an early reversible stage of apoptosis. In parallel experiments, a transient increase in PARP expression and activity were also noted in 3T3-L1 preadipocytes 24 h after induction of differentiation, a stage at which approximately 95% of the cells were in S-phase, but not in PARP-depleted antisense cells, which were consequently unable to complete the round of DNA replication required for differentiation. PARP, a component of the multiprotein DNA replication complex (MRC) that catalyzes viral DNA replication in vitro, poly(ADP-ribosyl)ates 15 of approximately 40 MRC proteins, including DNA pol alpha, DNA topo I, and PCNA. Depletion of endogenous PARP by antisense RNA expression in 3T3-L1 cells results in MRCs devoid of any DNA pol alpha and DNA pol delta activities. Surprisingly, there was no new expression of PCNA and DNA pol alpha, as well as the transcription factor E2F-1 in PARP-antisense cells during entry into S-phase, suggesting that PARP may play a role in the expression of these proteins, perhaps by interacting with a site in the promoters for these genes.

3T3 Cells↗
PubMed1999

RDP1258, a new rationally designed immunosuppressive peptide, prolongs allograft survival in rats: analysis of its mechanism of action.

Peptides derived from the HLA class I heavy chain (a.a. 75-84) have been shown to modulate immune responses in vitro and in vivo in a non-allele-restricted fashion. In vivo studies in rodents have demonstrated prolonged allograft survival following peptide therapy. The immunomodulatory effect of these peptides has been correlated with peptide-mediated modulation of heme oxygenase 1 activity (HO-1). Recently, we used a rational approach for designing novel peptides with enhanced immunosuppressant activity. These peptides were also more potent inhibitors of HO-1 activity in vitro. Here we evaluated one of these peptides, RDP1258, for its ability to prolong heterotopic heart graft survival in rats. The peptide mediated effect on HO-1 was analyzed in vitro and in vivo. Peptide RDP1258 was shown to inhibit rat HO-1 in vitro in a dose-dependent fashion. However, RDP1258, like other HO-inhibitors, when administered to rats, secondarily resulted in an up-regulation of splenic HO-1 activity. Up-regulation of HO-1 was associated with prolonged heart allograft survival (6.6 +/- 0.6 vs. 2/14 > 100 days and 12/14 16.2 +/- 1.7 days; p < 0.001). The analysis of graft infiltrating cells on day 5 after transplantation showed a significant decrease in the number of graft infiltrating cells in RDP1258-treated recipients compared to untreated ones (14.8 vs. 32.7%; p < 0.01). In addition, grafts from peptide-treated animals showed significantly decreased expression of TNF-alpha mRNA and increased levels of iNOS mRNA. Our results are consistent with the recent observation that up-regulation of HO-1 results in the inhibition of several immune effector functions. Modulation of HO-1 activity may enable the development of novel immunomodulatory strategies in humans.

Adjuvants, Immunologic↗
PubMed1998

Induction of apoptosis in proliferating human endothelial cells by the tumor-specific antiangiogenesis agent combretastatin A-4.

The antiangiogenic, tubulin-binding drug combretastatin A-4 exhibits a selective toxicity for proliferating endothelial cells in vitro and induces vascular shutdown in tumor models in vivo. The mechanism of combretastatin A-4 cytotoxicity has now been investigated with cultured proliferating human umbilical vein endothelial cells by examining various markers of apoptosis. Incubation of cells with 0.1 mM combretastatin A-4 induced the conversion (first detected after 6 h) of the CPP32 proenzyme to active caspase-3, a cysteine protease that plays an important role in apoptosis in many cell types; the drug also increased caspase-3 activity. Another early event observed was the binding of annexin V to 50% of the cells 8 h after drug treatment. Internucleosomal DNA fragmentation, another hallmark of apoptosis, was detected in cells incubated with 0.1 mM combretastatin A-4 for 24 h. Staining with Hoechst 33258 revealed that about 75% of cells exhibited a nuclear morphology characteristic of apoptosis after incubation with drug for 24 h. Incubation of cells for up to 8 h with combretastatin A-4 did not induce the release of lactate dehydrogenase or increase the uptake of propidium iodide, both indicators of membrane integrity. These results indicate that the selective cytotoxic effect of combretastatin A-4 is mediated by the induction of apoptosis rather than by necrosis and may provide an enhanced clinical strategy in cancer chemotherapy with this new agent.

Animals↗
PubMed1998

The E7 protein of human papillomavirus type 16 sensitizes primary human keratinocytes to apoptosis.

The 'high risk' human papillomaviruses are associated with the development of anogenital carcinomas and their E6 and E7 genes possess immortalizing and transforming functions in several in vitro culture systems. Recently the E6 gene has also been shown to enhance the apoptosis of human mammary epithelial cells. To determine the apoptotic activity of these oncogenes in the natural host cell, we infected genital keratinocytes with retroviruses expressing either HPV-16 E6, E7, or both the E6 and E7 (E6/7) genes. Apoptosis was quantitated under normal growth conditions or when induced by tumor necrosis factor alpha/cycloheximide or sulfur mustard. In contrast to previous findings with mammary epithelial cells, the E6 gene did not significantly augment either spontaneous or induced apoptosis. E6 also did not suppress apoptosis in normal keratinocytes (despite dramatically reducing their p53 levels), suggesting that p53-independent events mediated this effect. In contrast, E7 increased both spontaneous and induced apoptosis as well as the cellular levels of p53 and p21 protein. Interestingly, co-expression of E6 abrogated E7-facilitated apoptosis by tumor necrosis factor alpha nearly completely, but had only a minor protective effect on sulfur mustard induced apoptosis in these cells, demonstrating at least in part the p53-dependence and -independence of these two apoptotic pathways. Finally, our results indicate that the apoptosis of normal and E7-expressing keratinocytes is differentially affected by E6 expression and that E7, when unaccompanied by E6, sensitizes keratinocytes to apoptosis.

Apoptosis↗
PubMed1998

Transient poly(ADP-ribosyl)ation of nuclear proteins and role of poly(ADP-ribose) polymerase in the early stages of apoptosis.

A transient burst of poly(ADP-ribosyl)ation of nuclear proteins occurs early, prior to commitment to death, in human osteosarcoma cells undergoing apoptosis, followed by caspase-3-mediated cleavage of poly(ADP-ribose) polymerase (PARP). The generality of this early burst of poly(ADP-ribosyl)ation has now been investigated with human HL-60 cells, mouse 3T3-L1, and immortalized fibroblasts derived from wild-type mice. The effects of eliminating this early transient modification of nuclear proteins by depletion of PARP protein either by antisense RNA expression or by gene disruption on various morphological and biochemical markers of apoptosis were then examined. Marked caspase-3-like PARP cleavage activity, proteolytic processing of CPP32 to its active form, internucleosomal DNA fragmentation, and nuclear morphological changes associated with apoptosis were induced in control 3T3-L1 cells treated for 24 h with anti-Fas and cycloheximide but not in PARP-depleted 3T3-L1 antisense cells exposed to these inducers. Similar results were obtained with control and PARP-depleted human Jurkat T cells. Whereas immortalized PARP +/+ fibroblasts showed the early burst of poly(ADP-ribosyl)ation and a rapid apoptotic response when exposed to anti-Fas and cycloheximide, PARP -/- fibroblasts exhibited neither the early poly (ADP-ribosyl)ation nor any of the biochemical or morphological changes characteristic of apoptosis when similarly treated. Stable transfection of PARP -/- fibroblasts with wild-type PARP rendered the cells sensitive to Fas-mediated apoptosis. These results suggest that PARP and poly(ADP-ribosyl)ation may trigger key steps in the apoptotic program. Subsequent degradation of PARP by caspase-3-like proteases may prevent depletion of NAD and ATP or release certain nuclear proteins from poly(ADP-ribosyl)ation-induced inhibition, both of which might be required for late stages of apoptosis.

3T3 Cells↗
PubMed1998

Characterization and biological significance of immunosuppressive peptide D2702.75-84(E --> V) binding protein. Isolation of heme oxygenase-1.

This is the first report on peptidic inhibitors of heme oxygenase. Such peptides were originally developed from the immunomodulatory peptide 2702.75-84 which corresponds to amino acid residues 75 to 84 of the alpha1-helix of HLA-B2702 (2702.75-84) and has been shown to be immunosuppressive in vitro and in vivo. In vitro, 2702.75-84 inhibited cytotoxic T- and natural killer cell- mediated target cell lysis, and in vivo peptide therapy resulted in prolongation of heart and skin allograft survival in mice. The peptide was also shown to bind to heat shock protein 70. However, D-enantiomers of 2702.75-84 and derivatives thereof, while still being immunosuppressive, did not bind to heat shock protein 70. This study was designed to identify proteins binding to peptide D2702.75-84(E --> V) (rvnlrialry) consisting of D-amino acids. Compared with 2702.75-84 (RENLRIALRY), glutamic acid residue 76 (E) was replaced with valine (V). Affinity chromatography using immobilized D2702.75-84(E --> V) and mouse and human cell extracts, resulted in the isolation of heme oxygenase-1 (HO-1). Peptide D2702.75-84 inhibited HO activity in vitro in a dose dependent manner. Similar to what has been observed with other inhibitors of HO, administration of peptide into mice resulted in an up-regulation of HO-1 mRNA and protein, as well as enzyme activity in liver, spleen and kidney. Other peptides derived from 2702.75-84 with similar immunomodulatory activity displayed similar effects. In contrast, inactive derivatives of 2702.75-84 had no effect on HO activity. Therefore, the immunosuppressive effects of the described immunomodulatory peptides are similar to those of cobalt-protoporphyrin, a known up-regulator of HO-1. Our results suggest that HO-1 modulation may be a novel mechanism of immunomodulation.

Adjuvants, Immunologic↗
PubMed1998

Stress protein-induced immunosuppression: inhibition of cellular immune effector functions following overexpression of haem oxygenase (HSP 32).

This is the first report on suppression of immune effector functions following upregulation of heat shock protein 32 (HSP 32), known as haem oxygenase (HO-1). Here we evaluated the effect of cobalt-protoporphyrin (CoPP)-induced HO-1 expression on cell-mediated immune responses. Administration of CoPP to CBA mice resulted in overexpression of HO-1 in the spleen, liver and kidneys. In vitro measurements of T cell-mediated and NK-cell-mediated cytotoxicity in spleens from CoPP-treated animals demonstrated a severe suppression of their effector functions while administration of Zn-PP or vitamin B12 had no effect. Furthermore, CoPP therapy decreased the lymphoproliferative alloresponse and differentiation of cytotoxic T cells. Inhibition of proliferation appeared to be due to cell growth arrest with an increased number of cells staying in G0/G1 phase. Despite the suppressed proliferative response, IL-2 production in the MLR was not inhibited. In contrast, CoPP decreased the production of IL-10, IFN-gamma and TNF-alpha. In vivo, CoPP prolonged the survival of heterotopic heart allografts in mice. The immunosuppressive effects following CoPP-mediated upregulation of HO-1 were similar to those observed after peptide-mediated upregulation of HO-1. The results indicate that overexpression of HO results in the inhibition of several immune effector functions and thus provides an explanation for stress-induced immunosuppression.

Animals↗
PubMed1998

Computer-assisted rational design of immunosuppressive compounds.

We describe the rational design of immunosuppressive peptides without relying on information regarding their receptors or mechanisms of action. The design strategy uses a variety of topological and shape descriptors in combination with an analysis of molecular dynamics trajectories for the identification of potential drug candidates. This strategy was applied to the development of immunosuppressive peptides with enhanced potency. The lead compounds were peptides, derived from the heavy chain of HLA class I, that modulate immune responses in vitro and in vivo. In particular, a peptide derived from HLA-B2702, amino acids 75-84 (2702.75-84) prolonged skin and heart allograft survival in mice. The biological activity of the rationally designed peptides was tested in a heterotopic mouse heart allograft model. The molecule predicted to be most potent displayed an immunosuppressive activity approximately 100 times higher than the lead compound.

Animals↗
PubMed1998

Sulfur mustard induces markers of terminal differentiation and apoptosis in keratinocytes via a Ca2+-calmodulin and caspase-dependent pathway.

Sulfur mustard (SM) induces vesication via poorly understood pathways. The blisters that are formed result primarily from the detachment of the epidermis from the dermis at the level of the basement membrane. In addition, there is toxicity to the basal cells, although no careful study has been performed to determine the precise mode of cell death biochemically. We describe here two potential mechanisms by which SM causes basal cell death and detachment: namely, induction of terminal differentiation and apoptosis. In the presence of 100 microM SM, terminal differentiation was rapidly induced in primary human keratinocytes that included the expression of the differentiation-specific markers K1 and K10 and the cross-linking of the cornified envelope precursor protein involucrin. The expression of the attachment protein, fibronectin, was also reduced in a time- and dose-dependent fashion. Features common to both differentiation and apoptosis were also induced in 100 microM SM, including the rapid induction of p53 and the reduction of Bcl-2. At higher concentrations of SM (i.e., 300 microM), formation of the characteristic nucleosome-sized DNA ladders, TUNEL-positive staining of cells, activation of the cysteine protease caspase-3/apopain, and cleavage of the death substrate poly(ADP-ribose) polymerase, were observed both in vivo and in vitro. Both the differentiation and the apoptotic processes appeared to be calmodulin dependent, because the calmodulin inhibitor W-7 blocked the expression of the differentiation-specific markers, as well as the apoptotic response, in a concentration-dependent fashion. In addition, the intracellular Ca2+ chelator, BAPTA-AM, blocked the differentiation response and attenuated the apoptotic response. These results suggest a strategy for designing inhibitors of SM vesication via the Ca2+-calmodulin or caspase-3/PARP pathway.

Apoptosis↗
PubMed1998

Different frequency of gene targeting events by the RNA-DNA oligonucleotide among epithelial cells.

A unique hybrid oligonucleotide composed of both RNA and DNA has been shown to correct a point mutation in a site-specific and inheritable manner in extrachromosomal and chromosomal targets. In order to develop new gene therapeutics for skin, we tested two oligonucleotides that were shown to create a point mutation in alkaline phosphatase and beta-globin genes in several epithelial cell types. Highly transformed epithelial cells (HeLa) exhibited a conversion frequency of 5% by both RNA-DNA oligonucleotides. In comparison, other immortalized epithelial cells (HaCaT) or human primary keratinocytes did not show any detectable level of gene conversion by the restriction fragment length polymorphism analysis, indicating less than 1% conversion frequency. The concentration of the oligonucleotide in the nuclei of HeLa cells was similar to that of HaCaT or human primary keratinocytes measured by a radiolabeled or a fluorescein-conjugated oligonucleotide. Moreover, the RNA-DNA oligonucleotide exhibited a prolonged stability in the nucleus. Thus, neither uptake nor nuclear stability of the oligonucleotide appears to be a limiting factor in gene targeting events under our experimental conditions. These results indicate that the frequency of gene targeting varies among different cells, suggesting that cellular recombination and DNA repair activities may be important.

Alkaline Phosphatase↗
PubMed1998

Abdominal aortic aneurysm repair via percutaneous endovascular stenting in the swine model.

Abdominal aortic aneurysms (AAAs) are the 13th leading cause of death in the United States. Endovascular stent grafts are currently being investigated in clinical trials as an alternative method for treatment of AAA. Twelve pigs underwent creation of AAA using the abdominus rectus fascia. Postoperatively, all 12 animals underwent angiography, which demonstrated turbulent flow within the created aneurysms. Four of the animals were not stented and served as controls. Eight animals underwent subsequent percutaneous placement of a covered endovascular stent via a right femoral sheath, and the stents were deployed between the renal arteries and the aortic bifurcation. The animals were maintained for 120 days before sacrifice and necropsy. Unstented animals (4) died within 6 days, 3 from rupture. Eight animals underwent endovascular stenting: 5 survived without complications, 3 deaths within 2 days were related to technical complications. The 5 surviving animals were sacrificed at 120 days, and necropsy was conducted with in situ dissections of the aorta and intact stent: 3 experimental animals had correct anatomic positioning of the stent, and 2 had inexact stent placement but survived 120 days with AAA thrombosis. Treatment of AAA in this swine model has been demonstrated via placement of a percutaneous covered stent.

Animals↗
PubMed1997

Immunosuppression by D-isomers of HLA class I heavy chain (amino acid 75 to 84)-derived peptides is independent of binding to HSC70.

BACKGROUND: Peptides derived from the class I heavy chain were shown to modulate immune responses in vitro and in vivo. A peptide derived from HLA-B2702 (2702.75-84) inhibited differentiation of cytotoxic T cells as well as T cell and natural killer cell-mediated cytotoxicity in vitro. Peptide-mediated immunomodulation seemed to be independent of the MHC proteins expressed by responder and stimulator cells. In vivo studies in rodents demonstrated prolongation of heart and skin allograft survival after peptide therapy. Here, the correlation between the peptide's biological activity and its amino acid sequence was analyzed using peptides derived from amino acid 75-84 of several mouse, rat, and human MHC class I proteins as well as peptides with single amino acid substitutions in the 2702.75-84 sequence. METHODS: Peptides consisting of both L- and D-amino acids were tested for inhibition of murine and human T cell-mediated and lymphokine-activated killer cell-mediated cytotoxicity, binding to hsc70, and prolongation of heart allograft survival in vivo. RESULTS: Replacement of glutamic acid residue (E) at position 75 with valine (V) resulted in a peptide [2702.75-84(E>V)] with increased in vitro and in vivo activity but unchanged affinity for hsc70. Surprisingly, both L- and D-isomers of 2702.75-84 and 2702.75-84(E>V) inhibited cytotoxic cells in vitro and prolonged heart allograft survival in vivo. However, as expected, the peptides consisting of D-amino acids did not bind to hsc70. CONCLUSION: Assuming that both D- and L-isomers modulate immune responses by similar mechanisms, these results suggest that the peptides' effect is independent of binding to hsc70.

Adenosine Triphosphatases↗
PubMed1997

Elective stenting of the extracranial carotid arteries.

BACKGROUND: Surgical endarterectomy has been shown to be superior to medical management in the management of severe carotid stenosis in both symptomatic and asymptomatic patients. Endarterectomy, although effective, does have limitations, and percutaneous techniques may offer an alternative method of treatment. METHODS AND RESULTS: The feasibility and safety of percutaneous carotid angioplasty and elective (primary) stenting was evaluated prospectively in a consecutive series of 107 patients. One hundred twenty-six carotid arteries with significant stenosis were treated. This series represented a high-risk subset that included patients with previous ipsilateral endarterectomy and severe medical comorbidity. Forty-five percent of the patients were referred by surgeons. Patients had independent neurological examinations before and after the procedure and follow-up cerebral angiography at 6 months. The mean (+/- SD) stenosis was reduced from 78 +/- 14% to 2 +/- 5%. There were 7 minor strokes, 2 major strokes, and 1 death during the initial hospitalization and first 30 days after the procedure. For the combined end point of all strokes and death, the incidence was 7.9%. For ipsilateral major stroke and death, the incidence was 1.6%. There were no strokes during the follow-up period. Mean angiographic stenosis at 6 months in 81 patients was 18 +/- 16% (range, -21% to 57%). Four (4.9%) of these 81 patients had asymptomatic restenosis. Five asymptomatic patients had repeat intervention: 2 had angioplasty for restenosis, 2 had angioplasty for stent deformation, and 1 had endarterectomy for restenosis. CONCLUSIONS: In a high-risk group of patients, percutaneous carotid angioplasty and stenting are feasible and can be performed with low restenosis and repeat intervention rates.

Aged↗
PubMed1997

A genetic and mosaic analysis of a locus involved in the anesthesia response of Drosophila melanogaster.

We describe a genetic and behavioral analysis of several alleles of har38, a mutant with altered sensitivity to the general anesthetic halothane. We obtained a P-element-induced allele of har38 and generated several excision alleles by remobilizing the P element. The mutants narrow abdomen (na) and har85 are confirmed to be allelic to har 38. Besides a decreased sensitivity to halothane, all mutant alleles of this locus cause a characteristic walking behavior in the absence of anesthetics. We have quantified this behavior using a geotaxis apparatus. Responses of the mutant alleles to different inhalational anesthetics were tested. The results strongly favor a multipathway model for the onset of anesthesia. Mosaic flies were tested for their response to halothane and checked for their abnormal walking behavior. The analysis suggests that both the behaviors are exhibited only by such mosaics as have the entire head of mutant origin. It is likely that this focus represents an element of a common pathway in the anesthetic response to several inhalational anesthetics but not all. This result is the first demonstration of regional specificity in the CNS of any animal for general anesthetic action.

Alleles↗
PubMed1997

Losartan versus gene therapy: chronic control of high blood pressure in spontaneously hypertensive rats.

Interruption of the renin-angiotensin system by pharmacological manipulations attenuates high blood pressure (BP) in the spontaneously hypertensive rat (SHR). However, these agents, such as losartan, need to be administered daily to maintain effective BP control. Therefore, we have hypothesized that a genetic intervention in the expression of angiotensin type 1 receptor (AT1R) should attenuate development of hypertension on a long-term basis in SHR. A retroviral-mediated AT1R antisense cDNA gene delivery system (LNSV-AT1R-AS) was used to test this hypothesis and to compare its BP-lowering effects with those of losartan. Introduction of LNSV-AT1R-AS into 5-day-old Wistar-Kyoto rats and SHR resulted in a robust expression of AT1R antisense (AS) within 3 days and persisted for at least 30 days. This expression was associated with a selective attenuation of high BP in SHR by 25 to 30 mm Hg. Although basal lowering of BP was exclusive to SHR, the angiotensin II (Ang II) pressor response was significantly reduced in all LNSV-AT1R-AS-treated rats. The decreased response to Ang II was associated with a similar attenuation of Ang II-induced dipsogenic responses in both strains of rats. The BP-lowering effects of LNSV-AT1R-AS treatment and losartan treatment were similar and primarily observed in SHR. However, the antihypertensive effect lasted less than 24 hours in losartan-treated SHR compared with 90 days in LNSV-AT1R-AS-treated SHR. In addition, losartan was unable to further lower BP in LNSV-AT1R-AS-treated SHR. Collectively, these results suggest that both losartan and LNSV-AT1R-AS treatment produces an antihypertensive response selectively in SHR that is mediated by interruption of AT1R function. However, a single, acute genetic treatment with LNSV-AT1R-AS can result in long-term control of high BP at a similar level of effectiveness as losartan, without altering plasma Ang II levels.

Animals↗