Search PubMed⌕ Search

Biomedical subjects

Debra I Diz

Publications and source records attributed to Debra I Diz.

At least 19 recordsLinked to original sources
PubMed2007

Administration of the peroxisomal proliferator-activated receptor gamma agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment.

PURPOSE: We hypothesized that administration of the anti-inflammatory peroxisomal proliferator-activated receptor gamma (PPARgamma) agonist pioglitazone (Pio) to adult male rats would inhibit radiation-induced cognitive impairment. METHODS AND MATERIALS: Young adult male F344 rats received one of the following: (1) fractionated whole brain irradiation (WBI); 40 or 45 Gy gamma-rays in 4 or 4.5 weeks, respectively, two fractions per week and normal diet; (2) sham-irradiation and normal diet; (3) WBI plus Pio (120 ppm) before, during, and for 4 or 54 weeks postirradiation; (4) sham-irradiation plus Pio; or (5) WBI plus Pio starting 24h after completion of WBI. RESULTS: Administration of Pio before, during, and for 4 or 54 weeks after WBI prevented the radiation-induced cognitive impairment. Administration of Pio for 54 weeks starting after completion of fractionated WBI substantially but not significantly reduced the radiation-induced cognitive impairment. CONCLUSIONS: These findings offer the promise of improving the quality of life and increasing the therapeutic window for brain tumor patients.

Analysis of Variance↗
PubMed2007

Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction.

The aim of this study was to test the hypothesis that treatment with angiotensin-(1-7) [ANG-(1-7)] or ANG-(1-7) nonpeptide analog AVE-0991 can produce protection against diabetes-induced cardiovascular dysfunction. We examined the influence of chronic treatment (4 wk) with ANG-(1-7) (576 microg.kg(-1).day(-1) ip) or AVE-0991 (576 microg.kg(-1).day(-1) ip) on proteinuria, vascular responsiveness of isolated carotid and renal artery ring segments and mesenteric bed to vasoactive agonists, and cardiac recovery from ischemia-reperfusion in streptozotocin-treated rats (diabetes). Animals were killed 4 wk after induction of diabetes and/or treatment with ANG-(1-7) or AVE-0991. There was a significant increase in urine protein (231 +/- 2 mg/24 h) in diabetic animals compared with controls (88 +/- 6 mg/24 h). Treatment of diabetic animals with ANG-(1-7) or AVE-0991 resulted in a significant reduction in urine protein compared with vehicle-treated diabetic animals (183 +/- 16 and 149 +/- 15 mg/24 h, respectively). Treatment with ANG-(1-7) or AVE-0991 also prevented the diabetes-induced abnormal vascular responsiveness to norepinephrine, endothelin-1, angiotensin II, carbachol, and histamine in the perfused mesenteric bed and isolated carotid and renal arteries. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly better in ANG-(1-7)- or AVE-0991-treated animals. These results suggest that activation of ANG-(1-7)-mediated signal transduction could be an important therapeutic strategy to reduce cardiovascular events in diabetic patients.

Angiotensin I↗
PubMed2006

Baroreceptor reflex regulation in anesthetized transgenic rats with low glia-derived angiotensinogen.

Endogenous angiotensin (ANG) II and ANG-(1-7) act at the nucleus tractus solitarius (NTS) to differentially modulate neural control of the circulation. The role of these peptides endogenous to NTS on cardiovascular reflex function was investigated in transgenic rats with low brain angiotensinogen (Aogen) due to glial overexpression of an antisense to Aogen (ASrAOGEN) and in Sprague-Dawley (SD) rats. Arterial baroreceptor reflex sensitivity (BRS) for control of heart rate (HR) in response to increases in mean arterial pressure (MAP) was tested before and after bilateral microinjection of the angiotensin type 1 (AT(1)) receptor blocker candesartan or the ANG-(1-7) receptor blocker (d-Ala(7))-ANG-(1-7) into the NTS of urethane-chloralose-anesthetized ASrAOGEN and SD rats. Baseline MAP was higher in ASrAOGEN than in SD rats under anesthesia (P < 0.01). Injection of candesartan or (d-Ala(7))-ANG-(1-7) decreased MAP (P < 0.01) and HR (P < 0.05) in ASrAOGEN, but not SD, rats. The BRS at baseline was similar in ASrAOGEN and SD rats. Candesartan increased BRS by 41% in SD rats (P < 0.01) but was without effect in ASrAOGEN rats. In contrast, the reduction in BRS after (d-Ala(7))-ANG-(1-7) administration was comparable in SD (31%) and ASrAOGEN rats (34%). These findings indicate that the absence of glia-derived Aogen is associated with 1) an increase in MAP under anesthesia mediated via AT(1) and ANG-(1-7) receptors within the NTS, 2) the absence of an endogenous ANG II contribution to tonic inhibition of BRS, and 3) a continued contribution of endogenous ANG-(1-7) to tonic enhancement of BRS.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

Angiotensin metabolism in renal proximal tubules, urine, and serum of sheep: evidence for ACE2-dependent processing of angiotensin II.

Despite the evidence that angiotensin-converting enzyme (ACE)2 is a component of the renin-angiotensin system (RAS), the influence of ACE2 on angiotensin metabolism within the kidney is not well known, particularly in experimental models other than rats or mice. Therefore, we investigated the metabolism of the angiotensins in isolated proximal tubules, urine, and serum from sheep. Radiolabeled [(125)I]ANG I was hydrolyzed primarily to ANG II and ANG-(1-7) by ACE and neprilysin, respectively, in sheep proximal tubules. The ACE2 product ANG-(1-9) from ANG I was not detected in the absence or presence of ACE and neprilysin inhibition. In contrast, the proximal tubules contained robust ACE2 activity that converted ANG II to ANG-(1-7). Immunoblots utilizing an NH(2) terminal-directed ACE2 antibody revealed a single 120-kDa band in proximal tubule membranes. ANG-(1-7) was not a stable product in the tubule preparation and was rapidly hydrolyzed to ANG-(1-5) and ANG-(1-4) by ACE and neprilysin, respectively. Comparison of activities in the proximal tubules with nonsaturating concentrations of substrate revealed equivalent activities for ACE (ANG I to ANG II: 248 +/- 17 fmol x mg(-1) x min(-1)) and ACE2 [ANG II to ANG-(1-7): 253 +/- 11 fmol x mg(-1) x min(-1)], but lower neprilysin activity [ANG II to ANG-(1-4): 119 +/- 24 fmol x mg(-1) x min(-1); P < 0.05 vs. ACE or ACE2]. Urinary metabolism of ANG I and ANG II was similar to the proximal tubules; soluble ACE2 activity was also detectable in sheep serum. In conclusion, sheep tissues contain abundant ACE2 activity that converts ANG II to ANG-(1-7) but does not participate in the processing of ANG I into ANG-(1-9).

Angiotensin I↗
PubMed2006

Adventitial neuronal somata.

Confocal analysis of the whole-mount rat mesenteric branch arteries (MBA) revealed nucleated structures with axonal processes which immunostained for calcitonin gene-related peptide (CGRP). Immunocytochemistry ruled out the possibility that these were immune elements (macrophages and mast or dendritic cells) in close proximity with nerve fibers. To test our hypothesis that beta-CGRP is expressed in the rat MBA, we performed RT-PCR using total RNA isolated from the mesenteric artery arcade and intron spanning primers designed to amplify 188 bp of the beta-CGRP and 333 bp of alpha-CGRP cDNA. The PCR yielded an amplicon of the predicted size which was cloned into the pCR 3.1 vector. DNA sequence analysis of the insert showed 100% homology with the beta-CGRP cDNA, indicating that mRNA encoding beta-CGRP is expressed in the vessel. To learn whether neuronal cell bodies are located in the adventitia of MBA, we performed a limited collagenase digestion of isolated segments and plated the resulting cells in Ham's F12 medium with 10% horse serum on polyornithine-coated cover glasses. The medium was replaced after 48 h with Ham's F12 nutrient mixture containing N2 supplement. This resulted in a mixed population of fibroblasts, a small number of smooth muscle cells and a subset of cells that sprouted axons and immunostained positively for neuronal cell adhesion molecule and CGRP antigens. Fibroblasts and smooth muscle cells did not label with these antibodies. These data demonstrate, for the first time, that a population of adventitial neuronal somata (termed ANNIES), possibly of sensory nerve origin, is located in small mesenteric arteries.

Animals↗
PubMed2006

Differential expression of nuclear AT1 receptors and angiotensin II within the kidney of the male congenic mRen2. Lewis rat.

We established a new congenic model of hypertension, the mRen(2). Lewis rat and assessed the intracellular expression of angiotensin peptides and receptors in the kidney. The congenic strain was established from the backcross of the (mRen2)27 transgenic rat that expresses the mouse renin 2 gene onto the Lewis strain. The 20-wk-old male congenic rats were markedly hypertensive compared with the Lewis controls (systolic blood pressure: 195 +/- 2 vs. 107 +/- 2 mmHg, P < 0.01). Although plasma ANG II levels were not different between strains, circulating levels of ANG-(1-7) were 270% higher and ANG I concentrations were 40% lower in the mRen2. Lewis rats. In contrast, both cortical (CORT) and medullary (MED) ANG II concentrations were 60% higher in the mRen2. Lewis rats, whereas tissue ANG I was 66 and 84% lower in CORT and MED. For both strains, MED ANG II, ANG I, and ANG-(1-7) were significantly higher than CORT levels. Intracellular ANG II binding distinguished nuclear (NUC) and plasma membrane (PM) receptor using the ANG II radioligand 125I-sarthran. Isolated CORT nuclei exhibited a high density (Bmax >200 fmol/mg protein) and affinity for the sarthran ligand (KD<0.5 nM); the majority of these sites (>95%) were the AT1 receptor subtype. CORT ANG II receptor Bmax and KD values in nuclei were 75 and 50% lower, respectively, for the mRen2. Lewis vs. the Lewis rats. In the MED, the PM receptor density (Lewis: 50 +/- 4 vs. mRen2. Lewis: 21 +/- 5 fmol/mg protein) and affinity (Lewis: 0.31 +/- 0.1 vs. 0.69 +/- 0.1 nM) were lower in the mRen2. Lewis rats. In summary, the hypertensive mRen2. Lewis rats exhibit higher ANG II in both CORT and MED regions of the kidney. Evaluation of intracellular ANG II receptors revealed lower CORT NUC and MED PM AT1 sites in the mRen2. Lewis. The downregulation of AT1 sites in the mRen2. Lewis rats may reflect a compensatory response to dampen the elevated levels of intrarenal ANG II.

Angiotensin I↗
PubMed2005

Adenovirus-mediated small-interference RNA for in vivo silencing of angiotensin AT1a receptors in mouse brain.

Because of the lack of pharmacological approaches, molecular genetic methods have been required to differentiate between angiotensin type 1(AT1) receptor subtypes AT1a and AT1b. RNA interference is a new tool for the study of gene function, producing specific downregulation of protein expression. In this study, we used the small hairpin RNA (shRNA) cassette method to screen target sites for selectively silencing AT1a or AT1b receptor subtypes in cultured Neuro-2a cells using real-time RT-PCR. For in vivo functional studies, we used C57BL mice with arterial telemetric probes and computerized licking monitors to test the effect of adenovirus carrying the DNA sequence coding AT1a shRNA (Ad-AT1a-shRNA). Ad-AT1a-shRNA was injected into the lateral ventricle (intracerebroventricular) or the brain stem nucleus tractus solitaries/dorsal vagal nucleus (NTS/DVN) with measurement of water intake, blood pressure (BP), and heart rate (HR) for up to 20 days after injection. Tissue culture studies verified the specificity and the efficiency of the constructs. In animal studies, beta-galactosidase staining and Ang receptor binding assays showed expression of shRNA and downregulation of Ang AT1 receptors in the subfornical organ and NTS/DVN by >70%. Intracerebroventricular injection of Ad-AT1a-shRNA increased water intake with no effect on BP or HR. In contrast, microinjection of Ad-AT1a-shRNA into NTS/DVN caused a decrease in BP with no effect on HR or water intake. Results demonstrate the use of the RNA interference method in site-directed silencing of gene expression and provide a method for the in vivo study of Ang AT1 receptor function.

Adenoviridae↗
PubMed2005

Growth, metabolism, and blood pressure disturbances during aging in transgenic rats with altered brain renin-angiotensin systems.

Transgenic rats with targeted decreased glial expression of angiotensinogen (ASrAogen rats) did not show an increase in systolic pressure compared with Sprague-Dawley (SD) rats during aging (15-69 wk of age). ASrAogen animals had lower body weights throughout the study, similar to reports for animals with systemic knockout of angiotensinogen or treated long term with renin-angiotensin system (RAS) blockers. Further characterization of indexes of growth and metabolism in ASrAogen rats compared with (mRen2)27 and SD rats, which express elevated versus normal brain and tissue angiotensin II levels, respectively, revealed that serum leptin was 100-200% higher in SD and (mRen2)27 rats at 46 wk and 69 wk of age. Consistent with low serum leptin, ASrAogen rats had higher food intake (73%) compared with SD or (mRen2)27 rats. (mRen2)27 rats had higher resting insulin levels than ASrAogen rats at all ages. Insulin levels were constant during aging in ASrAogen rats, whereas an increase occurred in SD rats, leading to higher insulin levels at 46 and 69 wk of age compared with ASrAogen rats. IGF-1 was comparable among strains at all ages, but (mRen2)27 rats had longer and ASrAogen rats had shorter tail lengths versus SD rats at 15 wk of age. In conclusion, reduced expression of glial angiotensinogen blunts the age-dependent rise in insulin levels and weight gain, findings that mimic the effects of long-term systemic blockade of the RAS or systemic knockout of angiotensinogen. These data implicate glial angiotensinogen in the regulation of body metabolism as well as hormonal mechanisms regulating blood pressure.

Aging↗
PubMed2005

Impaired heart rate baroreflex in older rats: role of endogenous angiotensin-(1-7) at the nucleus tractus solitarii.

Age-related baroreflex reductions in function may originate from central neural dysregulation as well as vascular structural/functional changes. We determined the role of 2 angiotensin (Ang) peptides at the nucleus tractus solitarii in age-related baroreflex impairment. Baroreflex sensitivity control of heart rate in response to increases in blood pressure was tested in younger (3 to 5 months) and older (16 to 20 months) anesthetized male Sprague-Dawley rats before and after bilateral solitary tract injections of the Ang II type 1 (AT1) receptor antagonist candesartan (24 pmol) or the Ang-(1-7) antagonist (D-Ala7)-Ang-(1-7) (144 fmol or 24 pmol). Basal reflex sensitivity of older rats was significantly lower than younger rats. In younger rats, the reflex was facilitated by bilateral candesartan injections and attenuated by bilateral (D-Ala7)-Ang-(1-7) injections. In older rats, the reflex was facilitated by AT1 blockade; however, (D-Ala7)-Ang-(1-7) injected into the solitary tract nucleus had no effect. Neprilysin mRNA in the medulla was lower in older rats compared with younger rats, whereas angiotensin-converting enzyme (ACE), ACE2, and mas receptor mRNA levels of older rats did not differ from values of younger rats. Thus, opposing actions of endogenous Ang II and Ang-(1-7) in the solitary tract nucleus contribute to baroreflex function in response to increases in mean arterial pressure of younger rats. The attenuated counterbalancing effect of Ang-(1-7) on baroreflex function is lost in older rats, which may be attributable to diminished production of the peptide from neprilysin.

Aging↗
PubMed2005

Divergent regulation of circulating and intrarenal renin-angiotensin systems in response to long-term blockade.

BACKGROUND/AIMS: Long-term treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin (Ang) II type I (AT(1)) receptor blockers can improve kidney function and attenuate the progressive decline in kidney function associated with age. In this study in Wistar rats medicated for 22 months, we determined the effects of enalapril (10 mg/kg/day) and losartan (30 mg/kg/day) treatment, in comparison with vehicle (tap water), on renal AngII receptor density and circulating and urinary components of the renin-angiotensin system (RAS). METHODS: Kidney sections were incubated with [(125)I-sarcosine(1)-threonine(8)]AngII (0.6 nM) for Ang receptor density, and Ang peptides were determined using radioimmunoassays. RESULTS: Receptor density was approximately 50% higher in vasa recta, glomeruli, and tubulointerstitium in enalapril-treated rats and lower in vasa recta and glomeruli in losartan-treated relative to vehicle-treated rats. Losartan and enalapril treatment elevated plasma levels of AngI and Ang-(1-7) while AngII increased only in losartan-treated rats. In contrast, both treatments were associated with a reduction in urinary excretion of all three Ang peptides as compared with control rats. CONCLUSION: The reduction in urinary Ang peptides with losartan and enalapril treatment suggests that blockade of intrarenal AngII may be an important mechanism underlying the renoprotection seen with such treatments.

Aging↗
PubMed2005

Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) has emerged as a novel regulator of cardiac function and arterial pressure by converting angiotensin II (Ang II) into the vasodilator and antitrophic heptapeptide, angiotensin-(1-7) [Ang-(1-7)]. As the only known human homolog of ACE, the demonstration that ACE2 is insensitive to blockade by ACE inhibitors prompted us to define the effect of ACE inhibition on the ACE2 gene. METHODS AND RESULTS: Blood pressure, cardiac rate, and plasma and cardiac tissue levels of Ang II and Ang-(1-7), together with cardiac ACE2, neprilysin, Ang II type 1 receptor (AT1), and mas receptor mRNAs, were measured in Lewis rats 12 days after continuous administration of vehicle, lisinopril, losartan, or both drugs combined in their drinking water. Equivalent decreases in blood pressure were obtained in rats given lisinopril or losartan alone or in combination. ACE inhibitor therapy caused a 1.8-fold increase in plasma Ang-(1-7), decreased plasma Ang II, and increased cardiac ACE2 mRNA but not cardiac ACE2 activity. Losartan increased plasma levels of both Ang II and Ang-(1-7), as well as cardiac ACE2 mRNA and cardiac ACE2 activity. Combination therapy duplicated the effects found in rats medicated with lisinopril, except that cardiac ACE2 mRNA fell to values found in vehicle-treated rats. Losartan treatment but not lisinopril increased cardiac tissue levels of Ang II and Ang-(1-7), whereas none of the treatments had an effect on cardiac neprilysin mRNA. CONCLUSIONS: Selective blockade of either Ang II synthesis or activity induced increases in cardiac ACE2 gene expression and cardiac ACE2 activity, whereas the combination of losartan and lisinopril was associated with elevated cardiac ACE2 activity but not cardiac ACE2 mRNA. Although the predominant effect of ACE inhibition may result from the combined effect of reduced Ang II formation and Ang-(1-7) metabolism, the antihypertensive action of AT1 antagonists may in part be due to increased Ang II metabolism by ACE2.

Angiotensin I↗
PubMed2004

Alterations in sympathetic ganglionic transmission in response to angiotensin II in (mRen2)27 transgenic rats.

Hypertension in (mRen2)27 transgenic rats is partly dependent on activation of the sympathetic nervous system, but the role of ganglionic transmission is unknown. We assessed indices of synaptic plasticity (post-tetanic short-term potentiation [PTP] and long-term potentiation [LTP]) and sympathetic ganglionic transmission without tetany in superior cervical ganglia (SCG) of Hannover Sprague-Dawley rats (HnSD) versus (mRen2)27 rats. There were no differences in decay time constants [PTP=9 minutes; LTP=120 to 150 minutes in both (mRen2)27 and HnSD]. However, angiotensin (Ang) II increased PTP and LTP in SCG isolated from (mRen2)27 rats to a greater extent than HnSD. Candesartan (an AT1 antagonist) blocked the potentiation in both groups. Without a preceding tetanic pulse, 16-nM Ang II induced similar significant increases in ganglionic transmission of approximately 14% in both strains. Assessment of Ang II receptors by 125I-[Sar1Thr8]-Ang II binding showed that the AT1-receptor subtype predominates in the ganglia. The density of receptors in the SCG was comparable in (mRen2)27 and HnSD rats, whether measured in tissue from ganglia removed and frozen versus ganglia used in the transmission testing, suggesting that upregulation of receptors in vitro after removal of SCG did not occur. The divergence of effects of Ang II on LTP and PTP [greater in (mRen2)27 than HnSD] and nontetany ganglionic transmission (similar in both strains) may reflect different locations of receptors (pre- versus postsynaptic) or different signaling mechanisms involved in the two responses. We suggest that functional Ang II receptors in SCG mediate physiological actions of Ang II on ganglionic transmission and may play a pivotal role in hypertension.

Angiotensin II↗
PubMed2004

Central depletion of angiotensinogen is associated with elevated AT1 receptors in the SFO and PVN.

The brain renin-angiotensin system (RAS) is important in fluid balance and blood pressure regulation. In this study, we compared angiotensin (Ang) receptor density in the subfornical organ (SFO) and paraventricular nucleus (PVN) of a) brain angiotensinogen deficient rats (ASrAogen); b) those with high levels of brain Ang II [(mRen2)27]; c) Hannover Sprague Dawley (SD) rats at 48 and 68 wks of age. Since there was no difference between the two ages in any of the three strains, the data from the 48 and 68 wk time points were combined. There was a significantly higher level of AT1 receptors in the SFO and PVN of ASrAogen animals compared to both the SD and (mRen2)27 rats. This suggests that the brain RAS is important in regulating receptor density and that the differences may be explained by lower levels of the peptide locally. These higher levels of receptors suggest that the ASrAogen animals in adulthood and early aging would be more sensitive to either circulating or endogenous brain Ang II than the SD animals of similar age. In contrast, the similar receptor density in the (mRen2)27 and SD rats suggest that previous reports of reduced responses in the (mRen2)27 rats may result from differences in post receptor mechanisms such as intracellular signaling. Moreover, our data reveal that functional assessments are necessary in addition to receptor density levels to understand the consequences of long-term alterations in brain tissue peptides.

Angiotensin II↗
PubMed2003

Angiotensin-(1-7) reduces renal angiotensin II receptors through a cyclooxygenase-dependent mechanism.

In the kidney, angiotensin-(1-7) [Ang-(1-7)] exhibits diuretic and natriuretic properties associated with an increase in prostaglandin production. The prohypertensive effects of Ang II are attenuated in rats infused with Ang-(1-7), consistent with recent work showing that Ang-(1-7) downregulates AT1 receptors in Chinese hamster ovary-AT1A or vascular smooth muscle cells. To determine whether exposure to Ang-(1-7) reduces AT1 receptors in the kidney through an increase in prostaglandin production, kidney slices from Sprague-Dawley rats were incubated with 10 n -1 microM Ang-(1-7) in the presence or absence of 5 microM meclofenamate, a cyclooxygenase inhibitor. Following these treatments, the kidney slices were retrieved, frozen, and sectioned for determination of [125I]-Ang II binding using in vitro receptor autoradiography. Greater than 90% of the specific binding was competed for by losartan, indicating that the majority of binding was to the AT1 receptor. Incubation of kidney slices with 1 microM Ang-(1-7) caused a 20% reduction in [125I]-Ang II binding (n = 8) in the cortical tubulointerstitium, which was prevented when Ang-(1-7)-treated slices were incubated in the presence of 5 microM meclofenamate (1 +/- 2% increase, n = 8; p < 0.05). Incubation with 5 microM meclofenamate alone had no effect on [125I]-Ang II binding (-3 +/- 3%). The decrease in [125I]-Ang II binding with Ang-(1-7) was also blocked by the Ang-(1-7) antagonist [d-Ala7]-Ang-(1-7). Treatment with 1 microM [d-Ala7]-Ang-(1-7) alone had no effect on [125I]-Ang II binding (-3 +/- 6% of control). Pretreatment with 1 microM Ang II caused a similar reduction in [125I]-Ang II binding in the cortical tubulointerstitium. Neither Ang-(1-7) nor Ang II had any effect on [125I]-Ang II binding in the glomeruli and the area of the vasa recta of the kidney. These original findings suggest that prior exposure to Ang-(1-7) or Ang II causes a modest decrease in the number of AT1 receptors in the cortical tubulointerstitial area of the kidney. The reduction in Ang II binding by Ang-(1-7) was blocked by meclofenamate and [d-Ala7]-Ang-(1-7), suggesting that cyclooxygenase products released through activation of a novel receptor participate in this effect.

Angiotensin I↗