Endothelin-a Receptor Blockade Attenuates the Hypertension in a Rat Model of Pregnancy-Induced Hypertension.

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 679-679
Author(s):  
Barbara T Alexander ◽  
Anna N Rinewalt ◽  
Matthew B Massey ◽  
William M Bennett ◽  
Joey P Granger
Keyword(s):  
Mean Arterial Pressure ◽  
Perfusion Pressure ◽  
Receptor Blockade ◽  
Pregnancy Induced Hypertension ◽  
Pregnant Rats ◽  
Endothelin A Receptor ◽  
Induced Hypertension ◽  
Endothelin A ◽  
Uterine Perfusion ◽  
Renal Expression

6 A rat model of pregnancy-induced hypertension (PIH) produced by chronic reductions in uterine perfusion pressure (RUPP) is associated with a significant elevation in mean arterial pressure and as previously reported by our laboratory, proteinuria and reductions in kidney function. The purpose of this study was to examine the role of endothelin in mediating the hypertension in response to chronic reductions in uterine perfusion pressure in conscious, chronically-instrumented pregnant rats. Mean arterial pressure in RUPP rats (n=7) was significantly higher (123.0 ± 0.8 vs 101.3 ± 1.5 mmHg) than control pregnant rats (n=8). Renal expression of preproendothelin was also significantly elevated (>45%, P<.05) in the medulla (44.1 ± 6.3 vs 24.0 ± 2.6 densitometric units, respectively) and in the cortex (>20%, 37.7 ± 2.4 vs 29.9 ± 2.8 densitometric units, respectively) of the RUPP animals as compared to normal pregnant animals. Chronic administration of the selective endothelin-A receptor antagonist (ABT-627, 5mg/kg/day for 10 days, n=9) markedly attenuated the increase in MAP observed in the RUPP animals (123.0 ± 0.8 mmHg in the RUPP animals vs. 103.3 ± 2.3 mmHg in RUPP animals with ET-A antagonist, P<.05). Endothelin-A receptor blockade had no significant effect on blood pressure in the normal pregnant animals (101.3 ± 1.5 mmHg in normal pregnant rats vs. 96.0 ± 0.9 mmHg in normal pregnant animals with ET-A antagonist, n=8). In summary, hypertension in the RUPP model of pregnancy-induced hypertension was associated with enhanced renal expression of preproendothelin. In addition, hypertension in the RUPP model of PIH was significantly attenuated by selective endothelin-A receptor blockade. These findings suggest that endothelin plays a major role in mediating the hypertension observed in this animal model of pregnancy-induced hypertension produced by chronic reductions in uterine perfusion pressure.

Enhanced [Ca 2+ ] I and Contractility of Renal Arterial Smooth Muscle in a Rat Model of Hypertension Produced by Reduction of Uterine Perfusion Pressure in Late Pregnancy

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 719-720
Author(s):  
Jason G Murphy ◽  
Jason N Herrington ◽  
Barbara T Alexander ◽  
Joey P Granger ◽  
Raouf A Khalil
Keyword(s):  
Smooth Muscle ◽  
Perfusion Pressure ◽  
Late Pregnancy ◽  
Cell Length ◽  
Pregnancy Induced Hypertension ◽  
Cell Contraction ◽  
Pregnant Rats ◽  
Induced Hypertension ◽  
Uterine Perfusion ◽  
Renal Vascular

P147 Reduction of uterine perfusion pressure during late pregnancy has been suggested to trigger increases in renal vascular resistance and pregnancy-induced hypertension; however, the cellular mechanisms involved are unclear. We investigated whether reduction of uterine perfusion pressure in late pregnancy is associated with increased [Ca 2+ ] i and contractility of renal arterial smooth muscle. Single smooth muscle cells were isolated from renal interlobular arteries of late pregnant Sprague-Dawley rats and a hypertensive pregnant rat model produced by chronic reduction in uterine perfusion pressure (RUPP). The cells were loaded with fura-2 and cell length and [Ca 2+ ] i were measured. In cells of pregnant rats incubated in Hank’s solution (1 mmol/L Ca 2+ ), resting [Ca 2+ ] i was 62±3 nmol/L and cell length was 69±3 μm. In RUPP rats, resting [Ca 2+ ] i (101±3 nmol/L) was significantly greater and cell length (53±2 μm) was shorter than pregnant rats. In pregnant rats, angiotensin II (AII, 10 -7 mol/L) caused transient increase in [Ca 2+ ] i to 412±25 nmol/L followed by a maintained increase to 158±15 nmol/L, and 23±2% cell contraction. In RUPP rats, the AII-induced [Ca 2+ ] i transient (434±22 nmol/L) was not significantly different from pregnant rats, but the maintained [Ca 2+ ] i was significantly elevated to 198±7 nmol/L and cell contraction was increased to 33±3%. In pregnant rats, the Ca 2+ channel agonist Bay K8644 (1 μmol/L) caused maintained increase in [Ca 2+ ] i to 292±12 nmol/L and 31% contraction that were significantly enhanced in RUPP rats. In Ca 2+ -free (2 mmol/L EGTA) Hank’s, AII- and caffeine (10 mmol/L)-induced [Ca 2+ ] i transient and cell contraction were not significantly different between pregnant and RUPP rats suggesting no difference in Ca 2+ release from intracellular stores. The enhanced basal, maintained AII- and Bay K8644-induced [Ca 2+ ] i and cell contractility in RUPP rats suggest enhanced Ca 2+ entry mechanisms of smooth muscle contraction in resistance renal arteries and may, in part, explain the increased renal vascular resistance associated with pregnancy-induced hypertension.

scholarly journals Melanocortin-4 Receptor Deficiency Attenuates Placental Ischemia-Induced Hypertension in Pregnant Rats

Hypertension ◽  
2019 ◽  
Vol 73 (1) ◽  
pp. 162-170 ◽  
Author(s):  
Frank T. Spradley ◽  
Ana C. Palei ◽  
Christopher D. Anderson ◽  
Joey P. Granger
Keyword(s):  
Blood Pressure ◽  
Nervous System ◽  
Perfusion Pressure ◽  
Wild Type ◽  
Pregnant Rats ◽  
Melanocortin 4 Receptor ◽  
Induced Hypertension ◽  
Sympathetic Nervous ◽  
Uterine Perfusion ◽  
Placental Ischemia

Preeclampsia is a pregnancy-specific disorder of new-onset hypertension linked to placental ischemia. While obesity is a major risk factor for preeclampsia, not all obese pregnant women develop pregnancy-induced hypertension or preeclampsia. Previously, we reported that placental ischemia-induced hypertension is dependent upon intact signaling of the sympathetic nervous system. Moreover, in various models of obesity, blockade of MC4R (melanocortin-4 receptor) signaling protects against the development of hypertension via suppression of the sympathetic nervous system. Less is known about this pathway during obese pregnancy. Although blockade of MC4R may lead to increased body weight during pregnancy, we tested the hypothesis that placental ischemia-induced hypertension is attenuated in obese MC4R-deficient pregnant rats. On gestational day 14, MC4R wild-type or heterozygous-deficient (MC4R-def) rats were subjected to chronic placental ischemia via the reduced uterine perfusion pressure procedure or Sham surgery then examined on gestational day 19. In Sham MC4R-def versus Sham wild-type pregnant rats, there was increased body weight, fat mass, and circulating leptin levels but they had similar fetus weights. Reduced uterine perfusion pressure reduced fetus weights in both strains. Reduced uterine perfusion pressure increased blood pressure in wild-type rats but this response was significantly attenuated in MC4R-def rats, although blood pressure was elevated in Sham MC4R-def over Sham wild-type. These data indicate that while obese MC4R-def pregnant rats have higher blood pressure during pregnancy, placental ischemia-induced hypertension is attenuated in obese MC4R-def pregnant rats. Thus, obese women with abnormal MC4R signaling may be less susceptible to the development of placental ischemia-induced hypertension.

scholarly journals Reduction of Uterine Perfusion Pressure Induced Redistribution of Endothelin Receptor Type-B Between the Intima and Media Contributes to the Pathogenesis of Pregnancy-Induced Hypertension

2017 ◽  
Vol 44 (5) ◽  
pp. 1715-1725 ◽  
Author(s):  
Yuan Sun ◽  
Xicheng Zhang ◽  
Zhaolei Chen ◽  
Miao Xu ◽  
Minghui Ou
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Perfusion Pressure ◽  
Receptor Expression ◽  
Pregnancy Induced Hypertension ◽  
Endothelin Receptor ◽  
Type B ◽  
Induced Hypertension ◽  
The Media ◽  
Uterine Perfusion

Background/Aims: Studies have shown that a change in endothelin receptor expression in the artery is related to pregnancy-induced hypertension (PIH). However, the mechanism underlying this change remains unclear. Methods: To test whether the distribution of endothelin receptor type-A (ETAR) and type-B (ETBR) plays an important role in PIH, a reduction of uterine perfusion pressure (RUPP) rat model was used to mimic some of the features of PIH; the resulting variable endothelin receptor expression was investigated in the media and intima of the aorta. Single vascular smooth muscle cells (VSMCs) were isolated from RUPP and normal pregnant (NP) rats to study the effect of ETAR and ETBR in smooth muscle cells. Results: Compared with NP rats, RUPP rats had a significant redistribution of ETBR expression in the intima and media, while there was no significant difference in ETAR expression between the two groups. ETBR upregulation in VSMCs enhanced cellular contraction and contributed to PIH. The TNF-α plasma levels in RUPP rats were two-fold higher than those of NP rats, which upregulated the expression of ETBR in VSMCS through the NF-κB pathways in RUPP rats. Conclusion: Redistribution of ETBR between the media and intima played an important role in the pathogenesis of PIH.

scholarly journals Nicotinamide ameliorates a preeclampsia-like condition in mice with reduced uterine perfusion pressure

2017 ◽  
Vol 312 (2) ◽  
pp. F366-F372 ◽  
Author(s):  
Tomofumi Fushima ◽  
Akiyo Sekimoto ◽  
Yuji Oe ◽  
Emiko Sato ◽  
Sadayoshi Ito ◽  
...  
Keyword(s):  
Perfusion Pressure ◽  
Reduce Blood Pressure ◽  
Vitamin B ◽  
Therapeutic Effects ◽  
Pregnancy Induced Hypertension ◽  
Induced Hypertension ◽  
Maternal Hypertension ◽  
Pregnant Mice ◽  
Survival And Growth ◽  
Uterine Perfusion

Preeclampsia (PE) is pregnancy-induced hypertension with proteinuria that typically develops after 20 wk of gestation. Antihypertensives currently used for PE reduce blood pressure of PE mothers but do not prevent preterm delivery and do not alleviate fetal growth restriction (FGR) associated with PE. We have recently shown that the activation of the endothelin (ET) system exacerbates PE. However, ET receptor antagonists are teratogenic and not suitable for pregnant women. The vitamin B3 nicotinamide (Nam) inhibits vasoconstriction by ET and is generally considered safe and harmless to babies. Nam also alleviates oxidative stress, which exacerbates PE and FGR. The aim of the present study was to evaluate therapeutic effects of Nam on the PE-like phenotype using a reduced uterine perfusion pressure (RUPP) model in mice that we have recently developed. We bilaterally ligated uterine vessels of pregnant mice and administered Nam or water daily by gavage. Nam improved maternal hypertension, proteinuria, and glomerular endotheliosis in RUPP mice. Moreover, Nam prolonged pregnancies and improved survival and growth of the embryos in RUPP PE mice. In conclusion, Nam alleviates the PE-like phenotype and FGR in the murine RUPP model. Nam could help treat maternal hypertension and FGR in human PE.

scholarly journals Effects of Endothelin A Receptor Blockade on Endothelial Function in Patients With Chronic Heart Failure

Circulation ◽  
2001 ◽  
Vol 103 (7) ◽  
pp. 981-986 ◽  
Author(s):  
Rudolf Berger ◽  
Brigitte Stanek ◽  
Martin Hülsmann ◽  
Bernhard Frey ◽  
Sandra Heher ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Endothelial Function ◽  
Receptor Blockade ◽  
Endothelin A Receptor ◽  
Endothelin A

scholarly journals Characterisation of cardiac health in the reduced uterine perfusion pressure model and a 3D cardiac spheroid model, of preeclampsia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Claire Richards ◽  
Kimberly Sesperez ◽  
Michael Chhor ◽  
Sahar Ghorbanpour ◽  
Claire Rennie ◽  
...  
Keyword(s):  
Perfusion Pressure ◽  
Late Onset ◽  
Cardiac Fibroblasts ◽  
Immunofluorescent Staining ◽  
Collagen Deposition ◽  
Human Coronary Artery ◽  
Pregnant Rats ◽  
Cardiac Health ◽  
Increased Risk ◽  
Uterine Perfusion

Abstract Background Preeclampsia is a dangerous cardiovascular disorder of pregnancy that leads to an increased risk of future cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health in preeclampsia are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preeclampsia and cardiovascular disease (CVD). Therefore, in this study we aimed to characterise cardiac health and FKBPL regulation in the rat reduced uterine perfusion pressure (RUPP) and a 3D cardiac spheroid model of preeclampsia. Methods The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidney, liver and placenta (n ≥ 6). Picrosirius red staining was performed to quantify collagen I and III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl, Icam1, Vcam1, Flt1 and Vegfa mRNA in hearts and/or placentae and ELISA to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion. Immunofluorescent staining was also conducted to analyse the expression of cardiac FKBPL. Cardiac spheroids were generated using human cardiac fibroblasts and human coronary artery endothelial cells and treated with patient plasma from normotensive controls, early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE); n = 3. FKBPL and CD31 expression was quantified by immunofluorescent labelling. Results The RUPP procedure induced significant increases in blood pressure (p < 0.001), collagen deposition (p < 0.001) and cardiac BNP45 (p < 0.05). It also induced a significant increase in cardiac FKBPL mRNA (p < 0.05) and protein  expression  (p < 0.01). RUPP placentae also exhibited increased collagen deposition and decreased Flt1 mRNA expression (p < 0.05). RUPP kidneys revealed an increase in average glomerular size (p < 0.05). Cardiac spheroids showed a significant increase in FKBPL expression when treated with LOPE plasma (p < 0.05) and a trend towards increased FKBPL expression following treatment with EOPE plasma (p = 0.06). Conclusions The rat RUPP model induced cardiac, renal and placental features reflective of preeclampsia. FKBPL was increased in the hearts of RUPP rats and cardiac spheroids treated with plasma from women with preeclampsia, perhaps reflective of restricted angiogenesis and inflammation in this disorder. Elucidation of these novel FKBPL mechanisms in cardiac health in preeclampsia could be key in preventing future CVD.

Impact of hyperleptinemia during placental ischemia-induced hypertension in pregnant rats

2021 ◽  
Author(s):  
Ana C. Palei ◽  
Hunter L. Martin ◽  
Barbara A. Wilson ◽  
Christopher D. Anderson ◽  
Joey P. Granger ◽  
...  
Keyword(s):  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
No Donor ◽  
Induced Hypertension ◽  
Cgmp Signaling ◽  
Uterine Perfusion ◽  
Plasma Leptin ◽  
Placental Ischemia

The prevalence of preeclampsia and obesity have increased. While obesity is a major risk factor for preeclampsia, the mechanisms linking these morbidities are poorly understood. Circulating leptin levels increase in proportion to fat mass. Infusion of this adipokine elicits hypertension in non-pregnant rats, but less is known about how hyperleptinemia impacts blood pressure during placental ischemia, an initiating event in the pathophysiology of hypertension in preeclampsia. We tested the hypothesis that hyperleptinemia during reduced uterine perfusion pressure (RUPP) exaggerates placental ischemia-induced hypertension. On gestational day (GD) 14, Sprague-Dawley rats were implanted with osmotic mini-pumps delivering recombinant rat leptin (1 mg/kg per min, i.v.) or vehicle concurrently with the RUPP procedure to induce placental ischemia or Sham. On GD 19, plasma leptin was elevated in Sham+Leptin and RUPP+Leptin. Leptin infusion did not significantly impact mean arterial pressure (MAP) in Sham. MAP was increased in RUPP+Vehicle vs. Sham+Vehicle. In contrast to our hypothesis, placental ischemia-induced hypertension was attenuated by leptin infusion. To examine potential mechanisms for attenuation of RUPP-induced hypertension during hyperleptinemia, endothelial-dependent vasorelaxation to acetylcholine was similar between Sham and RUPP; however, endothelial-independent vasorelaxation to the nitric oxide (NO)-donor, sodium nitroprusside, was increased in Sham and RUPP. These findings suggest that NO/cyclic guanosine monophosphate (cGMP) signaling was increased in the presence of hyperleptinemia. Plasma cGMP was elevated in Sham and RUPP hyperleptinemic groups compared to vehicle groups but plasma and vascular NO metabolites were reduced. These data suggest that hyperleptinemia during placental ischemia attenuates hypertension by compensatory increases in NO/cGMP signaling.

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