scholarly journals EXPRESS: Endothelial-derived eNAMPT drives EndMT and preclinical PH: Rescue by an eNAMPT-neutralizing mAb

2021 ◽  
pp. 204589402110597
Author(s):  
Mohamed Ahmed ◽  
Nahla Zaghloul ◽  
Prisca Zimmerman ◽  
Nancy G. Casanova ◽  
Xiaoguang Sun ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Unmet Need ◽  
Sprague Dawley ◽  
Mesenchymal Transition ◽  
Molecular Pattern ◽  
Sprague Dawley Rats ◽  
Sequencing Studies ◽  
Pulmonary Arterial ◽  
Nicotinamide Phosphoribosyl Transferase

Rationale: Pharmacologic interventions to halt/reverse the vascular remodeling and right ventricular (RV) dysfunction in pulmonary arterial hypertension (PAH) remains an unmet need. We previously demonstrated extracellular nicotinamide phosphoribosyl-transferase (eNAMPT) as a DAMP (damage-associated molecular pattern protein) contributing to PAH pathobiology via TLR4 ligation. We examined the role of endothe-lial cell (EC)-specific eNAMPT in experimental PH and an eNAMPT-neutralizing mAb as a therapeutic strategy to reverse established PH. Methods: Hemodynam-ic/echocardiographic measurements and tissue analyses were performed in Sprague Dawley rats exposed to 10% hypoxia/Sugen (3 weeks) followed by return to normoxia and weekly intraperitoneal delivery of the eNAMPT mAb (1 mg/kg). WT C57BL/6J mice and conditional EC-cNAMPTec-/- mice were exposed to 10% hypoxia (3 weeks). Bio-chemical and RNA sequencing studies were performed on rat PH lung tissues and human PAH PBMCs. Results: Hypoxia/Sugen-exposed rats exhibited multiple indices of severe PH (RVSP, Fulton index), including severe vascular remodeling, compared to control rats. PH severity indices and plasma levels of eNAMPT, IL-6, and TNF-a were all significantly attenuated by eNAMPT mAb neutralization. Compared to hypoxia-exposed WT mice, cNAMPTec-/- KO mice exhibited significantly reduced PH severity and evidence of EC to mesenchymal transition (EndMT). Finally, biochemical and RNAseq analyses revealed eNAMPT mAb-mediated rectification of dysregulated inflammatory signaling pathways (TLR/NF-κB, MAP kinase, Akt/mTOR) and EndMT in rat PH lung tissues and human PAH PBMCs. Conclusions: These studies underscore EC-derived eNAMPT as a key contributor to PAH pathobiology and support the eNAMPT/TLR4 inflammatory pathway as a highly druggable therapeutic target to reduce PH severity and reverse PAH.

Pulmonary vascular pressure effects by endothelin-1 in normoxia and chronic hypoxia: a longitudinal study

1996 ◽  
Vol 271 (6) ◽  
pp. H2246-H2253 ◽  
Author(s):  
S. Tjen-A-Looi ◽  
R. Ekman ◽  
J. Osborn ◽  
I. Keith
Keyword(s):  
Pulmonary Hypertension ◽  
Ventricular Hypertrophy ◽  
Pressure Effects ◽  
Blood Levels ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Calcitonin Gene ◽  
Eta Receptor ◽  
Pulmonary Arterial

The role of endothelin (ET)-1 in pulmonary arterial pressure (Ppa) homeostasis and hypoxia-induced pulmonary hypertension was examined. ET-1 was chronically infused (2 and 4 pmol.kg-1.min-1) into the pulmonary circulation of male Sprague-Dawley rats for 3, 7, and 14 days while they were exposed to normoxia or hypobaric hypoxia (inspired O2 fraction 10%). The role of endogenous ET was examined by infusion of ET antiserum (ET-AS; 0.25 and 0.5 microliter.rat-1.h-1; cross-reacting with ET-1, -2, and -3) or the ETA-receptor blocker BQ-123 (10 pmol.kg-1.min-1). ET-1 (4 pmol) increased Ppa at 3 and 7 days in normoxia and hypoxia and was ineffective at 14 days, probably from ETA-receptor downregulation. BQ-123 blunted the hypoxic Ppa rise at all times, confirming a role for ETA receptors. ET-AS (0.5 microliter) was mostly ineffective but exacerbated hypoxic Ppa at 14 days, in contrast to BQ-123, suggesting that a different ET receptor could be involved. ET-1 infusion (2 pmol) caused right ventricular hypertrophy (RVH) in normoxia and exacerbated RVH in hypoxia, whereas BQ-123 and ET-AS (0.25 microliter) reduced hypoxic RVH. In conclusion, endogenous ET-1 plays a role in hypoxia-induced pulmonary hypertension and RVH by augmenting the level of hypoxic response. ET-1 also affects hematocrit and may reduce blood levels of the vasodilator calcitonin gene-related peptide.

scholarly journals Curcumin Improves Pulmonary Hypertension Rats by Regulating Mitochondrial Function

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Jing Chen ◽  
Wen Jiang ◽  
Fei Zhu ◽  
Qiong Wang ◽  
Haiyan Yang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mitochondrial Function ◽  
Vascular Remodeling ◽  
Control Group ◽  
Sprague Dawley ◽  
Pulmonary Vascular Remodeling ◽  
Sprague Dawley Rats ◽  
Pulmonary Arterial ◽  
Toxicological Mechanism ◽  
And Function

Objective. To investigate the role of curcumin in regulating pathogenesis of pulmonary arterial smooth muscle cells (PASMCs) derived from pulmonary arterial hypertension (PAH) model. Methods. Male Sprague Dawley rats were injected with monocrotaline (MCT) to establish the PAH experimental model. The rats were divided into control group, MCT group, and curcumin group. At the end of the study, hemodynamic data were measured to determine pulmonary hypertension. Proliferation ability of PASMCs, a remodeling indicator of pulmonary artery and right ventricle, was detected. In addition, the morphology and function of mitochondria, antiglycolysis and antiproliferation pathways, and genes were also analyzed. Results. Curcumin may function by reversing MCT-mediated pulmonary vascular remodeling in rats. Curcumin effectively improved pulmonary vascular remodeling, promoted PASMC apoptosis, and protected mitochondrial function. In addition, curcumin treatment suppressed the PI3K/AKT pathway in PASMCs and regulated the expression of antiproliferative genes. Conclusion. Curcumin can improve energy metabolism and reverse the process of PAHS. However, there were side effects of curcumin in MCT-induced rats, suggesting that the dosage should be treated with caution and its toxicological mechanism should be further studied and evaluated.

The P2Y12 Receptor Antagonist Ticagrelor Ameliorates Pulmonary Hypertension

2021 ◽  
Author(s):  
nannan li ◽  
jie yin ◽  
yugen shi ◽  
li sun ◽  
qingshan zhang ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Adenosine Diphosphate ◽  
P2y12 Receptor ◽  
Sprague Dawley ◽  
Rt Pcr ◽  
Sprague Dawley Rats ◽  
Haemodynamic Changes ◽  
P2y12 Receptor Antagonist ◽  
Pulmonary Arterial ◽  
Adp Receptor

Abstract Background: Pulmonary arterial hypertension (PAH) is a disease that the pulmonary artery is abnormally elevated. P2Y12 is an adenosine diphosphate (ADP) receptor and it act as the target of thienopyridine antiplatelet drugs by controlling vascular remodeling. Inhibition of P2Y12 receptor in the process of PAH was explored in this study.Methods: The PAH model was established in Sprague-Dawley rats by single subcutaneous injection of 60 mg/kg monocrotaline (MCT). The ticagrelor solution (a selective P2Y12R inhibitor) was intraperitoneally injected into rats at a dose of 14 mg/kg from the time of MCT injection to day 28.Results: In the lung tissues of PAH rats, the marked P2Y12R was detected. Treatment with ticagrelor greatly decreased P2Y12R level and efficiently abolished the upregulation of α-SMA as demonstrated by Western blot and RT-PCR. The wall thickness and occlusion score of the pulmonary arterioles showed that blockade of P2Y12R could relieve lung remodeling caused by PAH. The haemodynamic changes at 4 weeks determined that P2Y12R inhibition affected RV pressure and right heart hypertrophy.Conclusions: P2Y12R might be involved in the pathogenesis of PAH. Blockade of P2Y12R has potential in treating PAH.

Notoginsenoside R1 Attenuates Hypoxia and Hypercapnia-Induced Vasoconstriction in Isolated Rat Pulmonary Arterial Rings by Reducing the Expression of ERK

2014 ◽  
Vol 42 (04) ◽  
pp. 799-816 ◽  
Author(s):  
Yixiao Xu ◽  
Lina Lin ◽  
Lanlan Tang ◽  
Mengxiao Zheng ◽  
Yingchun Ma ◽  
...  
Keyword(s):  
Pulmonary Arteries ◽  
Panax Notoginseng ◽  
Underlying Mechanism ◽  
Sprague Dawley ◽  
Third Order ◽  
Pulmonary Vasoconstriction ◽  
Sprague Dawley Rats ◽  
Specific Objective ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries characterized by increased vascular resistance. Pulmonary vasoconstriction has been proven to play a pivotal role in PAH. We have previously hypothesized that Panax notoginseng saponins (PNS) might attenuate hypoxia–hypercapnia-induced pulmonary vasoconstriction. The specific objective of the present study was to investigate the role of notoginsenoside R1, a main ingredient of PNS, in this process and the possible underlying mechanism. The third order pulmonary rings from the Sprague-Dawley rats were treated with different concentrations of notoginsenoside R1 (8, 40, and 100 mg/L, respectively) both before and during the conditions of hypercapnia and hypoxia. Contractile force changes in the rings were detected and the optimal concentration (8 mg/L) was selected. Furthermore, an ERK inhibitor, U0126, was applied to the rings. In addition, pulmonary arterial smooth muscle cells (PASMCs) were cultured under hypoxic and hypercapnic conditions, and notoginsenoside R1 was administered to detect the changes induced by ERK1/2. The results revealed biphasic vasoconstriction in rings under hypoxic and hypercapnic conditions. It is hypothesized that the observed attenuation of vasoconstriction and the production of vasodilation could have been induced by notoginsenoside R1. This effect was found to be significantly reinforced by U0126 (p < 0.05 or p < 0.01). ERK expression in the PASMCs under hypoxic and hypercapnic conditions was significantly activated (p < 0.05 or p < 0.01) and the observed activation was attenuated by notoginsenoside R1 (p < 0.05 or p < 0.01). Our findings strongly support the significant role of notoginsenoside R1 in the inhibition of hypoxia–hypercapnia-induced vasoconstriction by the ERK pathway.

scholarly journals eNAMPT neutralization reduces preclinical ARDS severity via rectified NFkB and Akt/mTORC2 signaling

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Tadeo Bermudez ◽  
Saad Sammani ◽  
Jin H. Song ◽  
Vivian Reyes Hernon ◽  
Carrie L. Kempf ◽  
...  
Keyword(s):  
Lung Injury ◽  
Signaling Pathway ◽  
Unmet Need ◽  
Serum Lactate ◽  
Sprague Dawley ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Molecular Pattern ◽  
Sprague Dawley Rats ◽  
Pathway Activation ◽  
Nfkb Pathway

AbstractDespite encouraging preclinical data, therapies to reduce ARDS mortality remains a globally unmet need, including during the COVID-19 pandemic. We previously identified extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a novel damage-associated molecular pattern protein (DAMP) via TLR4 ligation which regulates inflammatory cascade activation. eNAMPT is tightly linked to human ARDS by biomarker and genotyping studies in ARDS subjects. We now hypothesize that an eNAMPT-neutralizing mAb will significantly reduce the severity of ARDS lung inflammatory lung injury in diverse preclinical rat and porcine models. Sprague Dawley rats received eNAMPT mAb intravenously following exposure to intratracheal lipopolysaccharide (LPS) or to a traumatic blast (125 kPa) but prior to initiation of ventilator-induced lung injury (VILI) (4 h). Yucatan minipigs received intravenous eNAMPT mAb 2 h after initiation of septic shock and VILI (12 h). Each rat/porcine ARDS/VILI model was strongly associated with evidence of severe inflammatory lung injury with NFkB pathway activation and marked dysregulation of the Akt/mTORC2 signaling pathway. eNAMPT neutralization dramatically reduced inflammatory indices and the severity of lung injury in each rat/porcine ARDS/VILI model (~ 50% reduction) including reduction in serum lactate, and plasma levels of eNAMPT, IL-6, TNFα and Ang-2. The eNAMPT mAb further rectified NFkB pathway activation and preserved the Akt/mTORC2 signaling pathway. These results strongly support targeting the eNAMPT/TLR4 inflammatory pathway as a potential ARDS strategy to reduce inflammatory lung injury and ARDS mortality.

Abstract 17072: Acetylcholine Signaling and Endothelial to Mesenchymal Transition in Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ana Fernandez Nicolas ◽  
Alexander Vang ◽  
Thomas Mancini ◽  
Denielli da Silva Goncalves Bos ◽  
Richard T Clements ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Smooth Muscle Actin ◽  
Sprague Dawley ◽  
Mesenchymal Transition ◽  
Α7 Nachr ◽  
Pulmonary Arterial ◽  
Dual Staining

Introduction: Pulmonary arterial hypertension (PAH) is characterized by severe pulmonary vascular remodeling. Transition of endothelial cells (EC) to mesenchymal cells (EndMT) contributes to vascular remodeling; however, the role of EndMT and underlying mechanisms in PAH remain unclear. While nicotinic acetylcholine (Ach) receptor (nAChR)-mediated pathway regulates epithelial to mesenchymal transition and promotes mesenchymal cell proliferation, its role in EndMT is unknown. In this study, we investigate EndMT in PAH and delineate the mechanisms. Methods: PAH was induced in Sprague Dawley rats by SU5416 (20 mg/kg; s.c.), followed by 3 wks of hypoxia (3 wk PAH) or 3wks of hypoxia with additional 4 wks of normoxia (7 wk PAH). Rats without SU5416 and kept at normoxia served as controls. At the end of experiments, hemodynamic measurements were performed. Lung EC were then isolated and purified using CD31 antibody conjugated beads and passage 3-4 were used. EndMT was assessed by dual staining of EC markers (von Willebrand factor and Griffonia simplicifolia) and α-smooth muscle actin (α-SMA) and by the mRNA expression of EC and mesenchymal genes. Lung ACh was measured by ELISA. Results: PAH rats had elevated PA pressures at both 3 wk (PAH vs. CON in mm Hg: 77.3 vs. 24.8, p<0.05, n=4-5) and 7 wk (65.5 vs. 28.6, p<0.05, n=10-12). EndMT was evidenced in PAH (% of cells positive with both EC markers and α- SMA: 3 wks: PAH 4.2% vs. CON 1.6%, p<0.05; 7 wks: PAH 38.5% vs. CON 4.5%, p<0.05), which was associated with significantly increased expression of mesenchymal gene (CD44, PAI1, and α-SMA) and decreased expression of vascular endothelial cadherin at 7 wk. The lungs of PAH rats had higher levels of ACh (PAH vs. CON in pg/mL, 3wk: 78.7 vs. 47.3, p<0.05, n=7; 7wk: 85.1 vs. 45.6, p<0.05, n=7). A significant increase in α7 nAChR expression was found in 7wk PAH EC. In vitro , treatment with ACh markedly induced EndMT in lung EC from normal rats, which was assessed by increased dual staining of EC markers and α-SMA and increased expression of mesenchymal genes (α-SMA, PAI1, and pro-collagen 1, p<0.05 for all). Conclusions: EndMT in PAH is associated with increased lung ACh levels and α7nAChR expression in lung ECs. ACh/nAChR-mediated EndMT may contribute to the vascular remodeling in PAH.

Superoxide mediates acute renal vasoconstriction produced by angiotensin II and catecholamines by a mechanism independent of nitric oxide

2007 ◽  
Vol 292 (1) ◽  
pp. H83-H92 ◽  
Author(s):  
Armin Just ◽  
Andrea J. M. Olson ◽  
Christina L. Whitten ◽  
William J. Arendshorst
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Vascular Remodeling ◽  
Oxygen Species ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Adrenergic Agonist ◽  
Renal Vasoconstriction ◽  
Sprague Dawley Rats

NAD(P)H oxidases (NOX) and reactive oxygen species (ROS) are involved in vasoconstriction and vascular remodeling during hypertension produced by chronic angiotensin II (ANG II) infusion. These effects are thought to be mediated largely through superoxide anion (O2−) scavenging of nitric oxide (NO). Little is known about the role of ROS in acute vasoconstrictor responses to agonists. We investigated renal blood flow (RBF) reactivity to ANG II (4 ng), norepinephrine (NE, 20 ng), and α1-adrenergic agonist phenylephrine (PE, 200 ng) injected into the renal artery (ira) of anesthetized Sprague-Dawley rats. The NOX inhibitor apocynin (1–4 mg·kg−1·min−1 ira, 2 min) or the superoxide dismutase mimetic Tempol (1.5–5 mg·kg−1·min−1 ira, 2 min) rapidly increased resting RBF by 8 ± 1% ( P < 0.001) or 3 ± 1% ( P < 0.05), respectively. During NO synthase (NOS) inhibition ( Nω-nitro-l-arginine methyl ester, 25 mg/kg iv), the vasodilation tended to increase (apocynin 13 ± 4%, Tempol 10 ± 1%). During control conditions, both ANG II and NE reduced RBF by 24 ± 4%. Apocynin dose dependently reduced the constriction by up to 44% ( P < 0.05). Similarly, Tempol blocked the acute actions of ANG II and NE by up to 48–49% ( P < 0.05). In other animals, apocynin (4 mg·kg−1·min−1 ira) attenuated vasoconstriction to ANG II, NE, and PE by 46–62% ( P < 0.01). During NOS inhibition, apocynin reduced the reactivity to ANG II and NE by 60–72% ( P < 0.01), and Tempol reduced it by 58–66% ( P < 0.001). We conclude that NOX-derived ROS substantially contribute to basal RBF as well as to signaling of acute renal vasoconstrictor responses to ANG II, NE, and PE in normal rats. These effects are due to O2− rather than H2O2, occur rapidly, and are independent of scavenging of NO.

scholarly journals Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension

2021 ◽  
Vol 118 (11) ◽  
pp. e2023899118
Author(s):  
Takeshi Masaki ◽  
Makoto Okazawa ◽  
Ryotaro Asano ◽  
Tadakatsu Inagaki ◽  
Tomohiko Ishibashi ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Aryl Hydrocarbon Receptor ◽  
Vascular Lesions ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Aryl Hydrocarbon ◽  
Sprague Dawley Rats ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, often accompanied by infiltration of inflammatory cells. Aryl hydrocarbon receptor (AHR), a nuclear receptor/transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various immune cells. However, the role of AHR in the pathogenesis of PAH is largely unknown. Here, we explore the role of AHR in the pathogenesis of PAH. AHR agonistic activity in serum was significantly higher in PAH patients than in healthy volunteers and was associated with poor prognosis of PAH. Sprague–Dawley rats treated with the potent endogenous AHR agonist, 6-formylindolo[3,2-b]carbazole, in combination with hypoxia develop severe pulmonary hypertension (PH) with plexiform-like lesions, whereas Sprague–Dawley rats treated with the potent vascular endothelial growth factor receptor 2 inhibitors did not. Ahr-knockout (Ahr−/−) rats generated using the CRISPR/Cas9 system did not develop PH in the SU5416/hypoxia model. A diet containing Qing-Dai, a Chinese herbal drug, in combination with hypoxia led to development of PH in Ahr+/+ rats, but not in Ahr−/− rats. RNA-seq analysis, chromatin immunoprecipitation (ChIP)-seq analysis, immunohistochemical analysis, and bone marrow transplantation experiments show that activation of several inflammatory signaling pathways was up-regulated in endothelial cells and peripheral blood mononuclear cells, which led to infiltration of CD4+ IL-21+ T cells and MRC1+ macrophages into vascular lesions in an AHR-dependent manner. Taken together, AHR plays crucial roles in the development and progression of PAH, and the AHR-signaling pathway represents a promising therapeutic target for PAH.

scholarly journals Mild DOCA-salt hypertension: sympathetic system and role of renal nerves

2011 ◽  
Vol 300 (5) ◽  
pp. H1781-H1787 ◽  
Author(s):  
Sachin S. Kandlikar ◽  
Gregory D. Fink
Keyword(s):  
Control Period ◽  
Whole Body ◽  
Renal Nerves ◽  
Experimental Hypertension ◽  
Sympathetic Activation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Salt Hypertension ◽  
Hypertension Development

Excess sympathetic nervous system activity (SNA) is linked to human essential and experimental hypertension. To test whether sympathetic activation is associated with a model of deoxycorticosterone acetate (DOCA)-salt hypertension featuring two kidneys and a moderate elevation of blood pressure, we measured whole body norepinephrine (NE) spillover as an index of global SNA. Studies were conducted in chronically catheterized male Sprague-Dawley rats drinking water containing 1% NaCl and 0.2% KCl. After a 7-day surgical recovery and a 3-day control period, a DOCA pellet (50 mg/kg) was implanted subcutaneously in one group of rats (DOCA), while the other group underwent sham implantation (Sham). NE spillover was measured on control day 2 and days 7 and 14 after DOCA administration or sham implantation. During the control period, mean arterial pressure (MAP) was similar in Sham and DOCA rats. MAP was significantly increased in the DOCA group compared with the Sham group after DOCA administration ( day 14: Sham = 109 ± 5.3, DOCA = 128 ± 3.6 mmHg). However, plasma NE concentration, clearance, and spillover were not different in the two groups at any time. To determine whether selective sympathetic activation to the kidneys contributes to hypertension development, additional studies were performed in renal denervated (RDX) and sham-denervated (Sham-DX) rats. MAP, measured by radiotelemetry, was similar in both groups during the control and DOCA treatment periods. In conclusion, global SNA is not increased during the development of mild DOCA-salt hypertension, and fully intact renal nerves are not essential for hypertension development in this model.

Chronic intravenous administration of V1 arginine vasopressin agonist results in sustained hypertension

1994 ◽  
Vol 267 (2) ◽  
pp. H751-H756 ◽  
Author(s):  
A. W. Cowley ◽  
E. Szczepanska-Sadowska ◽  
K. Stepniakowski ◽  
D. Mattson
Keyword(s):  
Body Weight ◽  
Arginine Vasopressin ◽  
Plasma Catecholamines ◽  
Plasma Osmolality ◽  
Sprague Dawley ◽  
Prolonged Administration ◽  
Chronic Stimulation ◽  
Sustained Hypertension ◽  
Sprague Dawley Rats

Despite the well-recognized vasoconstrictor and fluid-retaining actions of vasopressin, prolonged administration of arginine vasopressin (AVP) to normal animals or humans fails to produce sustained hypertension. The present study was performed to elucidate the role of the V1 receptor in determining the ability of AVP to produce sustained hypertension. Conscious Sprague-Dawley rats with implanted catheters were infused with the selective V1 agonist, [Phe2,Ile3,Orn8]vasopressin (2 ng.kg-1.min-1), for 14 days in amounts that were acutely nonpressor. Blood pressure (MAP), heart rate (HR), body weight, and water intake (WI) were determined daily. Plasma AVP, plasma catecholamines norepinephrine and epinephrine, plasma osmolality, and electrolyte concentration were determined before and on days 1 and 7 of infusion. MAP increased significantly by 10.4 +/- 4.5 mmHg on day 1 and rose to 22 +/- 5 mmHg above control by day 14 (transient decrease on days 6-9) and then fell to control levels after the infusion was stopped. HR did not change significantly. Plasma AVP immunoreactivity increased from 2.5 +/- 0.3 to 10.9 +/- 2.1 pg/ml, whereas norepinephrine tended to fall only on day 1, with epinephrine only slightly elevated on day 7. No evidence of fluid retention was found, and rats lost sodium only on the first day of V1 agonist infusion. Body weight increased throughout the study but was unrelated to the changes of MAP. We conclude that chronic stimulation of V1 receptors results in sustained hypertension in rats.

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