scholarly journals Improved cardiovascular autonomic modulation in transgenic rats expressing an Ang-(1-7)-producing fusion protein

2017 ◽  
Vol 95 (9) ◽  
pp. 993-998 ◽  
Author(s):  
Daniela Ravizzoni Dartora ◽  
Maria-Claudia Irigoyen ◽  
Karina Rabello Casali ◽  
Ivana C. Moraes-Silva ◽  
Mariane Bertagnolli ◽  
...  
Keyword(s):  
Heart Rate ◽  
Cardiovascular Effects ◽  
Chronic Administration ◽  
Acute Administration ◽  
Autonomic Modulation ◽  
Sprague Dawley ◽  
Transgenic Rats ◽  
Sd Rats ◽  
Sympathetic Modulation ◽  
Acute Elevation

Angiotensin-(1-7) counterbalances angiotensin II cardiovascular effects. However, it has yet to be determined how cardiovascular autonomic modulation may be affected by chronic and acute elevation of Ang-(1-7). Hemodynamics and cardiovascular autonomic profile were evaluated in male Sprague-Dawley (SD) rats and transgenic rats (TGR) overexpressing Ang-(1-7) [TGR(A1-7)3292]. Blood pressure (BP) was directly measured while cardiovascular autonomic modulation was evaluated by spectral analysis. TGR received A-779 or vehicle and SD rats received Ang-(1-7) or vehicle and were monitored for 5 h after i.v. administration. In another set of experiments with TGR, A-779 was infused for 7 days using osmotic mini pumps. Although at baseline no differences were observed, acute administration of A-779 in TGR produced a marked long-lasting increase in BP accompanied by increased BP variability (BPV) and sympathetic modulation to the vessels. Likewise, chronic administration of A-779 with osmotic mini pumps in TGR increased heart rate, sympathovagal balance, BPV, and sympathetic modulation to the vessels. Administration of Ang-(1-7) to SD rats increased heart rate variability values in 88% accompanied by 8% of vagal modulation increase and 18% of mean BP reduction. These results show that both acute and chronic alteration in the Ang-(1-7)-Mas receptor axis may lead to important changes in the autonomic control of circulation, impacting either sympathetic and (or) parasympathetic systems.

Differential Effects of Angiotensin II and Angiotensin-(1-7) at the Nucleus Tractus Solitarii of Transgenic Rats with Low Brain Angiotensinogen

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 700-700
Author(s):  
Aurea S Couto ◽  
Ovidiu Baltatu ◽  
Robson A S Santos ◽  
Detlev Ganten ◽  
Michael Bader ◽  
...  
Keyword(s):  
Heart Rate ◽  
Baroreflex Sensitivity ◽  
Renin Angiotensin System ◽  
Nucleus Tractus Solitarii ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Transgenic Rats ◽  
Baroreflex Control ◽  
Sd Rats ◽  
The Brain

P42 The potential importance of permanent alteration of the brain renin-angiotensin system on angiotensin (Ang) II and Ang-(1-7) effects at the level of the nucleus tractus solitarii (NTS) was investigated in transgenic rats with a deficit in brain angiotensinogen production TGR(ASrAOGEN) (TGR). Ang II (10 pmol), Ang-(1-7) (10 pmol) or NaCl (0.9%/ 50 nl) were microinjected into the NTS of urethane-anesthetized TGR (n=28) and Sprague-Dawley (SD, n=22) rats. Mean arterial pressure (MAP) and heart rate (HR) were measured via a femoral artery catheter and the baroreflex control of heart rate was evaluated after increases in MAP induced by phenylephrine (baroreflex bradycardia). Ang II microinjections into the NTS of the TGR induced a higher decrease in MAP and HR (-37 ± 5 mmHg and -69 ± 12.5 beats/min, respectively) in comparison with SD rats (-18 ± 1 mmHg and -51 ± 11 beats/min, respectively). In contrast, changes after Ang-(1-7) microinjections into the NTS of TGR (-6 ± 1 mmHg and -13 ± 5 beats/min) were significantly smaller than that induced in SD (-11 ± 2 mmHg and -24 ± 8 beats/min.). The baroreflex sensitivity was accentuated in TGR in comparison to SD rats (0.69 ± 0.06 vs. 0.44 ± 0.03 ms/ mmHg). Ang II microinjection into the NTS produced similar attenuation in the baroreflex bradycardia in both SD (0.28 ± 0.07 vs. 0.5 ± 0.07 ms/ mmHg, before injection) and TGR (0.44 ± 0.1 vs. 0.82 ± 0.1ms/ mmHg, before injection). Ang-(1-7) microinjection elicited a facilitation of the baroreflex bradycardia in SD (0.62 ± 0.1 vs. 0.4 ± 0.03 ms/ mmHg, before injection). However in TGR, baroreflex bradycardia after Ang-(1-7) was not different from saline microinjection. These results indicate that a permanent inhibition of angiotensinogen synthesis in the brain can lead to a functional up-regulation of Ang II receptors. However, the putative Ang-(1-7) receptors seem to be desensitized in the NTS of these transgenic rats. The alterated baroreflex sensitivity, both before and after Ang microinjection, indicates the functionally relevant decrease in brain Ang in TGR and supports differential regulatory mechanisms for the effects of the two Ang peptides.

scholarly journals Role of central AT1 and V1 receptors in cardiovascular adaptation to hemorrhage in SD and renin TGR rats

1999 ◽  
Vol 276 (6) ◽  
pp. H1918-H1926 ◽  
Author(s):  
Piotr Paczwa ◽  
Ewa Szczepańska-Sadowska ◽  
Slawomir Łoń, Ursula Ganten ◽  
Detlev Ganten
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Cardiovascular Effects ◽  
Sprague Dawley ◽  
Arterial Blood ◽  
Sd Rats ◽  
Vasopressin Receptors ◽  
In Series ◽  
Regulation Of Blood Pressure

In acute experiments, intracranially applied angiotensin II and vasopressin elicit significant cardiovascular effects. The purpose of the present study was to find out whether chronic intrabrain elevation of these peptides, occurring in the renin transgenic TGR(mRen2)27 (TGR) rats, results in an alteration of the cardiovascular control. Mean arterial blood pressure (MAP) and heart rate responses to hypovolemia were examined in hypertensive TGR and normotensive Sprague-Dawley (SD) rats under control conditions and during blockade of central AT1 or V1 receptors. Both groups received cerebroventricular infusions of either 1) cerebrospinal fluid ( series 1), 2) AT1 receptors antagonist (AT1ANT, series 2), or 3) V1 receptors antagonist (V1ANT, series 3). Blockade of AT1 and V1 receptors decreased MAP in TGR but not in SD rats. In SD rats, bleeding elicited a similar decrease of MAP in each series and a transient increase of heart rate in series 3. In TGR, hemorrhage caused bradycardia and decrease of MAP, which was greater than in SD rats. Hemorrhagic hypotension in TGR was abolished by V1ANT and bradycardia by V1ANT or AT1ANT. The results demonstrate remarkable differences in cardiovascular adjustment to hemorrhage in SD and TGR rats and provide evidence for enhanced involvement of central V1 and AT1 receptors in the regulation of blood pressure during hypovolemia in TGR. Central V1 vasopressin receptors play a crucial role in eliciting posthemorrhagic hypotension and bradycardia in this strain.

Enhanced isoproterenol-induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen

2006 ◽  
Vol 291 (5) ◽  
pp. H2371-H2376 ◽  
Author(s):  
Luciana A. Campos ◽  
Radu Iliescu ◽  
Marco Antonio Peliky Fontes ◽  
Wolfgang-Peter Schlegel ◽  
Michael Bader ◽  
...  
Keyword(s):  
Heart Rate ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Transgenic Rats ◽  
Baroreflex Control ◽  
Isolated Hearts ◽  
Sd Rats ◽  
The Brain

We have previously shown that a permanent deficiency in the brain renin-angiotensin system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the β-adrenoceptor (β-AR) agonist isoproterenol (Iso). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, Iso induced a significantly greater increase in left ventricular (LV) pressure and maximal contraction (+dP/d tmax) in the TGR than in the Sprague-Dawley (SD) rats. LV hypertrophy induced by Iso treatment was significantly higher in TGR than in SD rats (in g LV wt/100 g body wt, 0.28 ± 0.004 vs. 0.24 ± 0.004, respectively). The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of β-AR and upregulation of LV β-AR kinase-1 mRNA levels compared with those in SD rats. The decrease in the heart rate (HR) induced by the β-AR antagonist metoprolol in conscious rats was significantly attenuated in TGR compared with SD rats (−9.9 ± 1.7% vs. −18.1 ± 1.5%), whereas the effect of parasympathetic blockade by atropine on HR was similar in both strains. These results indicate that TGR are more sensitive to β-AR agonist-induced cardiac inotropic response and hypertrophy, possibly due to chronically low sympathetic outflow directed to the heart.

Alterations in Blood Pressure and Heart Rate Variabililty in Transgenic Rats with Low Brain Angiotensinogen

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 727-727
Author(s):  
Ovidiu Baltatu ◽  
Ben J Janssen ◽  
Ralph Plehm ◽  
Detlev Ganten ◽  
Michael Bader
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Baroreflex Sensitivity ◽  
Circadian Variation ◽  
Ang Ii ◽  
Transgenic Rats ◽  
Short Term ◽  
Baroreflex Control ◽  
Sd Rats ◽  
The Brain

P191 The brain renin-angiotensin system (RAS) system may play a functional role in the long-term and short-term control of blood pressure (BPV) and heart rate variability (HRV). To study this we recorded in transgenic rats TGR(ASrAOGEN) with low brain angiotensinogen levels the 24-h variation of BP and HR during basal and hypertensive conditions, induced by a low-dose s.c. infusion of angiotensin II (Ang II, 100 ng/kg/min) for 7 days. Cardiovascular parameters were monitored by telemetry. Short-term BPV and HRV were evaluated by spectral analysis and as a measure of baroreflex sensitivity the transfer gain between the pressure and heart rate variations was calculated. During the Ang II infusion, in SD but not TGR(ASrAOGEN) rats, the 24-h rhythm of BP was inverted (5.8 ± 2 vs. -0.4 ± 1.8 mm Hg/group of day-night differences of BP, p< 0.05, respectively). In contrast, in both the SD and TGR(ASrAOGEN) rats, the 24-h HR rhythms remained unaltered and paralleled those of locomotor activity. The increase of systolic BP was significantly reduced in TGR(ASrAOGEN) in comparison to SD rats as previously described, while the HR was not altered in TGR(ASrAOGEN) nor in SD rats. The spectral index of baroreflex sensitivity (FFT gain between 0.3-0.6 Hz) was significantly higher in TGR(ASrAOGEN) than SD rats during control (0.71 ± 0.1 vs. 0.35 ± 0.06, p<0.05), but not during Ang II infusion (0.6 ± 0.07 vs. 0.4 ± 0.1, p>0.05). These results demonstrate that the brain RAS plays an important role in mediating the effects of Ang II on the circadian variation of BP. Furthermore these data are consistent with the view that the brain RAS modulates baroreflex control of HR in rats, with AII having an inhibitory role.

Mechanisms of hypertension in transgenic rats expressing the mouse Ren-2 gene

1994 ◽  
Vol 266 (4) ◽  
pp. R1273-R1279 ◽  
Author(s):  
A. Moriguchi ◽  
K. B. Brosnihan ◽  
H. Kumagai ◽  
D. Ganten ◽  
C. M. Ferrario
Keyword(s):  
Mature Female ◽  
Response To Therapy ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Transgenic Rats ◽  
Contrast Administration ◽  
Systemic Injection ◽  
Endothelin 1 ◽  
Sd Rats ◽  
Insight Into

Transgenic (TG) rats carrying the mouse Ren-2 gene (Ren-2d)27 are a newly established monogenetic model in hypertension research. To gain an insight into the mechanisms of this form of hypertension we determined the effects of a 13-day therapy with losartan (10 mg/kg) or lisinopril (20 mg/kg) on the blood pressure (BP) and plasma levels of angiotensin (ANG) peptides of mature female TG hypertensive and Sprague-Dawley (SD) rats. The contribution of endothelium-derived nitric oxide (NO) to the maintenance of their hypertension and the response to therapy was evaluated by systemic injection of either NG-monomethyl-L-arginine (L-NMMA) or endothelin-1. Hypertension in TG rats was associated with decreased plasma ANG I, no differences in plasma ANG II, and plasma ANG-(1-7) near the detectable level. Lisinopril lowered BP more than losartan in both TG hypertensive and normotensive controls. In both strains, the chronic fall in BP produced by lisinopril was accompanied by significant increases in plasma ANG I and ANG-(1-7), while losartan augmented plasma ANG I and ANG II in both strains and plasma ANG-(1-7) in TG rats. Inhibition of NO synthase reversed the fall in BP produced by either lisinopril or losartan in SD controls. In contrast, administration of L-NMMA to TG rats given the same therapy did not. The transient endothelium-mediated relaxing phase of the depressor response to systemic injections of endothelin-1 was attenuated by losartan and lisinopril in TG rats. These studies indicate that hypertension in female TG rats is mediated by the RAS.(ABSTRACT TRUNCATED AT 250 WORDS)

AUTONOMIC MODULATION OF HEART RATE DURING HEMORRHAGIC SHOCK IN THE CONSCIOUS SPRAGUE DAWLEY RAT

1994 ◽  
Vol 22 (1) ◽  
pp. A166
Author(s):  
Brahm Goldstein ◽  
Martha L. Blair ◽  
Deanne M. Schmitt ◽  
Andrew Want
Keyword(s):  
Heart Rate ◽  
Hemorrhagic Shock ◽  
Autonomic Modulation ◽  
Sprague Dawley ◽  
Sprague Dawley Rat

Discriminative stimulus, subject-rated and cardiovascular effects of cocaine alone and in combination with aripiprazole in humans

2010 ◽  
Vol 25 (11) ◽  
pp. 1469-1479 ◽  
Author(s):  
Joshua A Lile ◽  
William W Stoops ◽  
Paul EA Glaser ◽  
Lon R Hays ◽  
Craig R Rush
Keyword(s):  
Heart Rate ◽  
Drug Discrimination ◽  
Discriminative Stimulus ◽  
Discrimination Task ◽  
Partial Agonist ◽  
Cardiovascular Effects ◽  
Behavioral Effects ◽  
Acute Administration ◽  
Duration Of Treatment ◽  
Stimulant Use

Aripiprazole is a dopamine D2 receptor partial agonist undergoing evaluation as a pharmacotherapy for stimulant-use disorders. Acutely administered aripiprazole attenuates the discriminative stimulus and other behavioral effects of d-amphetamine in humans; however, whether aripiprazole attenuates the effects of more commonly abused stimulants is unknown. The aim of this experiment was to assess the discriminative stimulus, subject-rated and cardiovascular effects of oral cocaine alone and following acute administration of aripiprazole in humans. Eight cocaine-dependent subjects learned to discriminate 150 mg cocaine from placebo. After acquiring the discrimination, the effects of cocaine (0, 25, 50, 100 and 200 mg) administered alone and in combination with aripiprazole (15 mg) were determined. Significant effects of cocaine were observed for the drug discrimination task, stimulant-like subject-rated effects and heart rate. Limited effects of aripiprazole were revealed. However, for most measures, fewer doses of cocaine were significantly greater than placebo when combined with aripiprazole, suggesting a reduction in the discriminative stimulus, self-reported and cardiovascular effects of cocaine. These data are consistent with previous studies that have tested acutely administered aripiprazole in combination with d-amphetamine and suggest that the ability of aripiprazole to modify stimulant effects is a function of the duration of treatment (acute vs. chronic).

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

2005 ◽  
Vol 23 (3) ◽  
pp. 311-317 ◽  
Author(s):  
Sherry O. Kasper ◽  
Christy S. Carter ◽  
Carlos M. Ferrario ◽  
Detlev Ganten ◽  
Leon F. Ferder ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Systolic Pressure ◽  
Normal Brain ◽  
Sprague Dawley ◽  
Transgenic Rats ◽  
Serum Leptin ◽  
Renin Angiotensin ◽  
Insulin Levels ◽  
Sd Rats

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.

Abstract MP04: Cardiac ACE2/Angiotensin-(1-7) in Rats Expressing Human Angiotensinogen Gene

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Jasmina Varagic ◽  
Jessica VonCannon ◽  
Sarfaraz Ahmad ◽  
Michael Bader ◽  
Carlos M Ferrario
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Tissue ◽  
Male Rats ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Transgenic Rats ◽  
Sd Rats ◽  
Agt Gene ◽  
Tissue Angiotensin

When compared to Sprague Dawley (SD) control rats, transgenic rats expressing the human angiotensinogen (AGT) gene [TGR(hAGT)L1623] exhibit hypertension associated with cardiac hypertrophy and higher cardiac tissue angiotensin (Ang) II. Whether the hypertension and cardiac hypertrophy in these rats expressing the human AGT are related to a non-canonical pathway for Ang II formation or suppression of the counter regulatory mechanism mediated by ACE2 and Ang-(1-7) has not been established. Consequently, cardiac peptides were determined by RIA in 9 [TGR(hAGT)L1623] and 11 SD male rats (17 weeks of age). ACE2 activities in homogenized heart tissues were determined by HPLC. Cardiac Ang II content was four times higher (37.05 ± 5.04 vs. 9.62 ± 0.93 fmol/mg protein; p <0.0001) while the Ang-(1-7) level increased only 1.3 times (18.02 ± 1.62 vs 13.37 ± 1.74 fmol/mg protein; p=0.06) in TGR(hAGT)L1623 rats when compared with SD rats. Although, the Ang II/Ang-(1-7) ratio was higher in transgenic rats harboring the human AGT gene (2.10 ± 0.27 vs 0.90 ± 0.19; p <0.005), ACE2 activities between these two strains of animals were not different (12.21 ± 0.76 vs. 10.80 ± 0.91 fmol/min/mg; p >0.05). Since human AGT protein is not cleaved by rat renin, our data continues to support the view that hypertension and cardiac hypertrophy in this transgenic strain are induced by activation of a non-renin mechanism rather than a primary suppression of the compensatory Ang II degrading pathway mediated by ACE2. Further studies are necessary to determine the role of enzymes affecting Ang-(1-7) metabolism in the observed inadequate balance between Ang II and Ang-(1-7).

Endorphinergic mechanism in the central cardiovascular and analgesic effects of clonidine

1987 ◽  
Vol 65 (8) ◽  
pp. 1624-1632 ◽  
Author(s):  
G. Kunos ◽  
R. Mosqueda-Garcia ◽  
J. A. Mastrianni ◽  
F. V. Abbott
Keyword(s):  
Receptor Antagonist ◽  
Arcuate Nucleus ◽  
Monosodium Glutamate ◽  
Opiate Receptors ◽  
Cardiovascular Effects ◽  
Male Rats ◽  
Sprague Dawley ◽  
Wky Rats ◽  
Sd Rats ◽  
Wistar Kyoto

In urethane-anesthetized male rats, injection of 5 nmol clonidine into the nucleus of the solitary tract (NTS) causes hypotension and bradycardia. These effects are greater in spontaneously hypertensive rats (SHR) and normotensive Sprague–Dawley (SD) rats than in normotensive Wistar–Kyoto (WKY) rats. The effects of clonidine are stereoselectively inhibited by 100 ng intra-NTS naloxone in SHR and SD but not in WKY rats. In SHR, the effects of clonidine are also inhibited by intra-NTS administration of ICI 174864 (a δ-receptor antagonist) but not by β-funaltrexamine (a μ-receptor antagonist), while in SD rats only the μ- and not the δ-antagonist was effective. Neonatal treatment of SHR with monosodium glutamate (MSG) reduced the β-endorphin content of the arcuate nucleus and the NTS, reduced the cardiovascular effects of clonidine, and abolished their naloxone sensitivity. MSG treatment of newborn WKY reduced the β-endorphin content of the arcuate nucleus but not the NTS and did not affect the responses to clonidine. Measurement of pain sensitivity by the formalin test indicated that clonidine was more potent as an analgesic in SHR and SD than in WKY rats, and its effect was inhibited by naloxone (2 mg/kg i.p.) in the former two strains but not in WKY. It is proposed that a naloxone-sensitive component of the cardiovascular effects of clonidine is due to release of a β-endorphin-like opioid from the NTS, and that this mechanism is present in SHR and SD but not in WKY rats. The opiate receptors mediating the effects of the opioid appear to be of the μ-subtype in SD rats and of the δ-subtype in SHR. The results also support a close relationship between central cardiovascular and pain regulatory mechanisms.

Sign in / Sign up

Export Citation Format

Share Document