Expression of an angiotensin-(1-7)-producing fusion protein in rats induced marked changes in regional vascular resistance

2007 ◽  
Vol 292 (5) ◽  
pp. H2485-H2490 ◽  
Author(s):  
Giancarla A. Botelho-Santos ◽  
Walkyria O. Sampaio ◽  
Timothy L. Reudelhuber ◽  
Michael Bader ◽  
Maria J. Campagnole-Santos ◽  
...  
Keyword(s):  
Stroke Volume ◽  
Fusion Protein ◽  
Vascular Resistance ◽  
Regional Blood Flow ◽  
Peripheral Resistance ◽  
Physiological Role ◽  
Transgenic Rat ◽  
Fat Tissue ◽  
Transgenic Rats ◽  
Hemodynamic Measurements

We have described a transgenic rat line that expresses an angiotensin-(1-7)-producing fusion protein, the TGR(A1-7)3292. In these rats, testis acts as an angiotensin-(1-7) biological pump, increasing its plasma concentration 2.5-fold. In this study, we performed hemodynamic measurements in TGR(A1-7)3292 and age-matched Hannover Sprague-Dawley (SD) control rats, using fluorescent microspheres. Urethane-anesthetized transgenic rats had similar levels of baseline blood pressure (99 ± 3 mmHg) as did SD rats (101 ± 3 mmHg). However, pronounced differences were observed in other hemodynamic measurements. TGR(A1-7)3292 rats presented a significant increase in stroke volume (0.29 ± 0.01 vs. 0.25 ± 0.01 ml in SD), increased cardiac index (24.6 ± 0.91 vs. 21.9 ± 0.65 ml·min−1·kg) and decreased total peripheral resistance (3.9 ± 0.13 vs. 4.5 ± 0.13 mmHg·ml−1·min·100 g). The increase in stroke volume in transgenic rats may be partially explained by the small decrease in heart rate (326 ± 7.0 vs. 359 ± 6.0 beats/min in SD). Strikingly, TGR(A1-7)3292 rats presented a substantial decrease in the vascular resistance in lung, spleen, kidney, adrenals, brain, testis and brown fat tissue with no significant differences in the left ventricle, mesentery, skin, gastrocnemius muscle and white fat tissue. These results corroborate and extend previous results observed after acute angiotensin-(1-7) infusion, showing that chronic increase in circulating angiotensin-(1-7) produces sustained and important changes in regional and systemic hemodynamics. Moreover, our data suggest a physiological role for angiotensin-(1-7) in the tonic control of regional blood flow.

scholarly journals Hemodynamic phenotyping of transgenic rats with ubiquitous expression of an angiotensin-(1-7)-producing fusion protein

2021 ◽  
Author(s):  
Daniele T Alves ◽  
Luiz F Mendes ◽  
Walkyria Oliveira Sampaio ◽  
Leda Maria de Castro Coimbra Campos ◽  
Maria Aparecida R Vieira ◽  
...  
Keyword(s):  
Blood Flow ◽  
Fusion Protein ◽  
Regional Blood Flow ◽  
Peripheral Resistance ◽  
Free Water ◽  
Renin Angiotensin System ◽  
Sodium Concentration ◽  
Tissue Expression ◽  
Transgenic Rat ◽  
Free Water Clearance

Activation of the angiotensin (Ang) converting enzyme 2/Ang-(1-7)/MAS receptor pathway of the renin-angiotensin system induces protective mechanisms in different diseases.  Herein, we describe the cardiovascular phenotype of a new transgenic rat line (TG7371) that expresses an Ang-(1-7)-producing fusion protein.  The transgene-specific mRNA and the corresponding protein were shown to be present in all evaluated tissues of TG7371 with the highest expression in aorta and brain.  Plasma Ang-(1-7) levels, measured by radioimmunoassay were similar to control SD rats, however high Ang-(1-7) levels were found in the hypothalamus.  TG7371 showed lower baseline mean arterial pressure, assessed in conscious or anesthetized rats by telemetry or short-term recordings, associated with increased plasma ANP and higher urinary sodium concentration.  Evaluation of regional blood flow and hemodynamic parameters with fluorescent microspheres showed a significant increase in blood flow in different tissues (kidneys, mesentery, muscle, spleen, brown fat, heart and skin), with a resulting decreased total peripheral resistance.  TG7371 rats also presented increased cardiac and global sympathetic tone, increased plasma AVP levels and decreased free water clearance.  Altogether, our data show that expression of an Ang-(1-7)-producing fusion protein induced a hypotensive phenotype due to widespread vasodilation and consequent fall in peripheral resistance.  This phenotype was associated with an increase in ANP together with an increase in AVP and sympathetic drive, which did not fully compensate the lower BP.  Here we present the hemodynamic impact of long-term increase in tissue expression of an Ang-(1-7)-fusion protein and provide a new tool to investigate this peptide in different pathophysiological conditions.

Sexual dimorphism in regional blood flow responses to vasopressin in conscious rats

1997 ◽  
Vol 273 (3) ◽  
pp. R1126-R1131 ◽  
Author(s):  
Y. X. Wang ◽  
J. T. Crofton ◽  
S. L. Bealer ◽  
L. Share
Keyword(s):  
Blood Flow ◽  
Vascular Resistance ◽  
Regional Blood Flow ◽  
Pressor Response ◽  
Peripheral Resistance ◽  
Female Rats ◽  
Sexually Dimorphic ◽  
Arterial Blood ◽  
Vasoconstrictor Response ◽  
Renal Vascular

The greater pressor response to vasopressin in male than in nonestrous female rats results from a greater increase in total peripheral resistance in males. The present study was performed to identify the vascular beds that contribute to this difference. Mean arterial blood pressure (MABP) and changes in blood flow in the mesenteric and renal arteries and terminal aorta were measured in conscious male and nonestrous female rats 3 h after surgery. Graded intravenous infusions of vasopressin induced greater increases in MABP and mesenteric vascular resistance and a greater decrease in mesenteric blood flow in males. Vasopressin also increased renal vascular resistance to a greater extent in males. Because renal blood flow remained unchanged, this difference may be due to autoregulation. The vasopressin-induced reduction in blood flow and increased resistance in the hindquarters were moderate and did not differ between sexes. Thus the greater vasoconstrictor response to vasopressin in the mesenteric vascular bed of male than nonestrous females contributed importantly to the sexually dimorphic pressor response to vasopressin in these experiments.

Expression of an angiotensin-(1–7)-producing fusion protein produces cardioprotective effects in rats

2004 ◽  
Vol 17 (3) ◽  
pp. 292-299 ◽  
Author(s):  
Robson A. S. Santos ◽  
Anderson J. Ferreira ◽  
Ana Paula Nadu ◽  
Aline N. G. Braga ◽  
Alvair Pinto de Almeida ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Cardiac Contractility ◽  
Renin Angiotensin System ◽  
Transgenic Rats ◽  
Specific Expression ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Cardioprotective Effects ◽  
Hemodynamic Measurements

Angiotensin-(1–7) [ANG-(1–7)] is a recently described heptapeptide product of the renin-angiotensin system. Because biosynthesis of ANG-(1–7) increases in animals treated with cardioprotective drugs and inactivation of the gene for angiotensin converting enzyme 2 [an enzyme involved in the biosynthesis of ANG-(1–7)] leads to the development of cardiac dysfunction, it has been suggested that ANG-(1–7) has cardioprotective properties. To directly test this possibility, we have generated transgenic rats that chronically overproduce ANG-(1–7) by using a novel fusion protein methodology. TGR(A1–7)3292 rats show testicular-specific expression of a cytomegalovirus promoter-driven transgene, resulting in a doubling of circulating ANG-(1–7) compared with nontransgenic control rats. Radiotelemetry hemodynamic measurements showed that transgenic rats presented a small but significant increase in daily and nocturnal heart rate and a slight but significant increase in daily and nocturnal cardiac contractility estimated by dP/d t measurements. Strikingly, TGR(A1–7)3292 rats were significantly more resistant than control animals to induction of cardiac hypertrophy by isoproterenol. In addition, transgenic rats showed a reduced duration of reperfusion arrhythmias and an improved postischemic function in isolated Langendorff heart preparations. These results support a cardioprotective role for circulating ANG-(1–7) and provide a novel tool for evaluating the functional role of ANG-(1–7).

Abstract MP19: Endogenous 5-hydroxytryptamine May Regulate Skeletal Muscle Vascular Resistance In Normal Healthy Rats

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Gregory D Fink
Keyword(s):  
Skeletal Muscle ◽  
Vascular Resistance ◽  
Total Peripheral Resistance ◽  
Recovery Period ◽  
Peripheral Resistance ◽  
Cardiovascular Effects ◽  
Wild Type ◽  
Sprague Dawley ◽  
Vascular Beds ◽  
Hemodynamic Measurements

Infusing low doses of 5-hydroxytryptamine (5-HT) into normal rats causes chronic (weeks to months) hypotension and a fall in total peripheral resistance. These effects are mediated by activation of 5-HT 7 receptors. Therefore, we generated 5-HT 7 receptor knockout rats (5-HT 7 KO) to explore possible cardiovascular effects of 5-HT 7 receptors under normal and pathophysiological conditions. We previously reported that healthy 5-HT 7 KO rats have normal blood pressure and total peripheral resistance at rest. This suggested that 5-HT 7 receptors plays no role in cardiovascular regulation under normal conditions. But total peripheral resistance is determined by multiple vascular beds that differ in their sensitivity to 5-HT. Others have indicated that 5-HT 7 receptors in the skeletal muscle vasculature are particularly sensitive to the effects of 5-HT. Therefore, we hypothesized that 5-HT 7 KO rats would show both reduced responsiveness to exogenous 5-HT and increased resting skeletal muscle vascular resistance. Experiments were performed in isoflurane-anesthetized, male Sprague-Dawley (SD) (n=6), 5-HT 7 wild-type (5-HT 7 WT) (n=5) and 5-HT 7 KO (n=6) rats at 7-8 months of age. Arterial pressure was measured with an aortic catheter. Blood flow to the hindquarters (mostly skeletal muscle) was measured with transit-time, ultrasound flowmetry. After 10 minutes of baseline hemodynamic measurements were obtained, 5-HT was infused iv at a rate of 25 μg/kg/min for 15 minutes, followed by a 15-minute recovery period. As expected, 5-HT 7 KO rats did not show a significant fall in hindquarter vascular resistance (HQVR) during 5-HT infusion, while SD and 5-HT 7 WT did. More importantly, HQVR at baseline was significantly (p < 0.05) higher in 5-HT 7 KO rats (16.0 ± 2.0 mmHg/ml/min) than in 5-HT 7 WT rats (10.9 ± 0.06 mmHg/ml/min) or SD rats (7.0 ± 0.03 mmHg/ml/min). These results support our hypothesis that in healthy (albeit anesthetized) rats, 5-HT 7 receptors reduce skeletal muscle vascular resistance.

Effects of PAF and BN 52021 on cardiac function and regional blood flow in conscious rats

1989 ◽  
Vol 257 (1) ◽  
pp. H25-H32 ◽  
Author(s):  
A. L. Siren ◽  
G. Feuerstein
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Blood Flow ◽  
Cardiac Output ◽  
Vascular Resistance ◽  
Regional Blood Flow ◽  
Peripheral Resistance ◽  
Low Doses ◽  
Conscious Rats ◽  
High Doses

The effect of intravenous injections (0.1–3 nmol/kg) of platelet-activating factor (PAF) on blood pressure, heart rate, cardiac output, and blood flow (hindquarter, renal, mesenteric) were studied in conscious rats. PAF decreased blood pressure and total peripheral resistance (TPR) but increased heart rate; cardiac output was reduced by the highest dose. Low doses of PAF increased blood flow and decreased vascular resistance in all vascular beds, whereas high doses reduced mesenteric blood flow in part by increasing mesenteric vascular resistance. The hypotensive and cardiac effects of PAF were blocked by intravenous infusions of the selective PAF-receptor antagonists, 15 mg/kg BN 52021 and 1 mg/kg SDZ 63–441. BN 52021 also attenuated the hindquarter and renal responses to PAF, but the mesenteric responses remained relatively unchanged. The results indicate that PAF is a potent vasodilator of mesenteric greater than hindquarter = renal vessels at low doses and a cardiac depressant at high doses. A therapeutic role for the PAF antagonists BN 52021 and SDZ 63–441 is suggested in endotoxemia, anaphylaxis, and other disease states in which increased release of PAF contributes to key hemodynamic derangements.

Exercise stroke volume relative to plasma-volume expansion

1988 ◽  
Vol 64 (1) ◽  
pp. 404-408 ◽  
Author(s):  
M. K. Hopper ◽  
A. R. Coggan ◽  
E. F. Coyle
Keyword(s):  
Stroke Volume ◽  
Plasma Volume ◽  
Volume Expansion ◽  
Peripheral Resistance ◽  
Submaximal Exercise ◽  
Upright Position ◽  
Plasma Volume Expansion ◽  
Trained Subjects ◽  
The Difference ◽  
Dextran Solution

The effects of plasma-volume (PV) expansion on stroke volume (SV) (CO2 rebreathing) during submaximal exercise were determined. Intravenous infusion of 403 +/- 21 ml of a 6% dextran solution before exercise in the upright position increased SV 11% (i.e., 130 +/- 6 to 144 +/- 5 ml; P less than 0.05) in untrained males (n = 7). Further PV expansion (i.e., 706 +/- 43 ml) did not result in a further increase in SV (i.e., 145 +/- 4 ml). SV was somewhat higher during supine compared with upright exercise when blood volume (BV) was normal (i.e., 138 +/- 8 vs. 130 +/- 6 ml; P = 0.08). PV expansion also increased SV during exercise in the supine position (i.e., 138 +/- 8 to 150 +/- 8 ml; P less than 0.05). In contrast to these observations in untrained men, PV expansion of endurance-trained men (n = 10), who were naturally PV expanded, did not increase SV during exercise in the upright or supine positions. When BV in the untrained men was increased to match that of the endurance-trained subjects, SV was observed to be 15% higher (165 +/- 7 vs. 144 +/- 5 ml; P less than 0.05), whereas mean blood pressure and total peripheral resistance were significantly lower (P less than 0.05) in the trained compared with untrained subjects during upright exercise at a similar heart rate. The present findings indicate that exercise SV in untrained men is preload dependent and that increases in exercise SV occur in response to the first 400 ml of PV expansion. It appears that approximately one-half of the difference in SV normally observed between untrained and highly endurance-trained men during upright exercise is due to a suboptimal BV in the untrained men.

RSR-13, an allosteric effector of hemoglobin, increases systemic and iliac vascular resistance in rats

1996 ◽  
Vol 271 (2) ◽  
pp. H602-H613 ◽  
Author(s):  
M. P. Kunert ◽  
J. F. Liard ◽  
D. J. Abraham
Keyword(s):  
Cardiac Output ◽  
Vascular Resistance ◽  
Total Peripheral Resistance ◽  
Peripheral Resistance ◽  
Experimental Models ◽  
Metabolic Demand ◽  
Flow Probe ◽  
Inositol Hexaphosphate ◽  
Control Value ◽  
Allosteric Effector

Tissue O2 delivery in excess of metabolic demand may be a factor in the development of high vascular resistance in experimental models of volume-expanded hypertension. This hypothesis was previously tested in rats with an exchange transfusion of red blood cells treated with inositol hexaphosphate or an intravenous infusion of RSR-4, allosteric effectors of hemoglobin. The binding of these drugs with hemoglobin effect a conformational change in the molecule, such that the affinity for O2 is reduced. However, in both preparations, the changes in vascular resistance could have been nonspecific. The present studies used intravenous infusions of RSR-13, which did not share some of the problematic characteristics of RSR-4 and inositol hexaphosphate. Conscious instrumented rats (an electromagnetic flow probe on ascending aorta or an iliac, mesenteric, or renal Doppler flow probe) were studied for 6 h after an RSR-13 infusion of 200 mg/kg in 15 min. This dose significantly increased arterial P50 (PO2 at which hemoglobin is 50% saturated) from 38 +/- 0.8 to 58 +/- 1.4 mmHg at 1 h after the start of the infusion. In the 3rd h cardiac output fell significantly from a control value of 358 +/- 33 to 243 +/- 24 ml.kg-1.min-1 and total peripheral resistance significantly increased from 0.31 +/- 0.03 to 0.43 +/- 0.04 mmHg.ml-1.kg.min. Cardiac output and P50 returned toward control over the next few hours. Neither cardiac output nor total peripheral resistance changed in the group of rats receiving vehicle alone. In a separate group of rats, iliac flow decreased significantly to 60% of control and iliac resistance increased to 160% of control. Iliac flow increased significantly in the group of rats that received vehicle only. Although the mechanism of these changes has not been established, these results suggest that a decreased O2 affinity leads to an increased total peripheral resistance and regional vascular resistance and support the hypothesis that O2 plays a role in the metabolic autoregulation of blood flow.

Long-term hemodynamic actions of atrial natriuretic factor (99-126) in conscious sheep

1988 ◽  
Vol 254 (4) ◽  
pp. H811-H815 ◽  
Author(s):  
D. G. Parkes ◽  
J. P. Coghlan ◽  
J. G. McDougall ◽  
B. A. Scoggins
Keyword(s):  
Blood Pressure ◽  
Cardiac Output ◽  
Stroke Volume ◽  
Blood Volume ◽  
Total Peripheral Resistance ◽  
Atrial Natriuretic Factor ◽  
Peripheral Resistance ◽  
Natriuretic Factor ◽  
Atrial Natriuretic

The hemodynamic and metabolic effects of long-term (5 day) infusion of human atrial natriuretic factor (ANF) were examined in conscious chronically instrumented sheep. Infusion of ANF at 20 micrograms/h, a rate below the threshold for an acute natriuretic effect, decreased blood pressure by 9 +/- 1 mmHg on day 5, associated with a fall in calculated total peripheral resistance. On day 1, ANF reduced cardiac output, stroke volume, and blood volume, effects that were associated with an increase in heart rate and calculated total peripheral resistance and a small decrease in blood pressure. On days 4 and 5 there was a small increase in urine volume and sodium excretion. On day 5 an increase in water intake and body weight was observed. No change was seen in plasma concentrations of renin, arginine vasopressin, glucose, adrenocorticotropic hormone, or protein. This study suggests that the short-term hypotensive effect of ANF results from a reduction in cardiac output associated with a fall in both stroke volume and effective blood volume. However, after 5 days of infusion, ANF lowers blood pressure via a reduction in total peripheral resistance.

Reflex effects of thoracic aorta wall stretch on regional vascular resistance

1978 ◽  
Vol 56 (3) ◽  
pp. 390-394
Author(s):  
Peter M. Szeto ◽  
Franco Lioy
Keyword(s):  
Arterial Pressure ◽  
Thoracic Aorta ◽  
Vascular Resistance ◽  
Carotid Arteries ◽  
Peripheral Resistance ◽  
Adrenergic Blockade ◽  
Vascular Responses ◽  
Regional Vascular Resistance ◽  
Vascular Beds ◽  
Intact Limb

In anesthetized, vagotomized cats with both carotid arteries occluded, a stretch of the walls of the thoracic aorta, performed without obstructing aortic flow, induced a significant reflex increase in arterial pressure (35 ± 2−26 ± 1 mmHg; systolic–diastolic). This pressure increase was accompanied by significant increases in peripheral resistance in the superior mesenteric (+30%), renal (+23%), and external iliac (+23%) vascular beds. The increase in iliac resistance observed in the skinned leg was comparable with that observed in the contralateral intact limb. All these vascular responses were drastically reduced by the administration of phenoxybenzamine. After α-adrenergic blockade no signs of reflex vasodilatation could be detected during aortic stretch in any of the vascular beds examined.

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