bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Effect of Slow‐Pressor Angiotensin II on Contractile Responses to Norepinephrine in Arteries with and without Sympathetic Innervation
Authors: Kopf Phillip G , Johnson Alan Kim , Phelps Laura E , Schupbach Chad D , Peuler Jacob D 
Published: November 2023

There is evidence that chronically elevated circulating angiotensin II alters the function of the systemic vasculature. In the present study we examined the effect of two weeks of in vivo infusion of a slow‐pressor dose of angiotensin II on vascular responsiveness to exogenous angiotensin II and norepinephrine applied in vitro. As target vessels, we chose to isolate 1) the thoracic aorta, which in the rat is essentially free of sympathetic innervation, 2) a third order mesenteric resistance artery, which like all resistance vessels is densely innervated, and 3) the most proximal portion of the caudal artery, which is densely innervated, but functions in a thermo‐regulatory mode rather than as a resistance vessel. At the completion of the infusion there were no changes in contractile responses to angiotensin II itself in any of the three arterial tissue preparations (intact rings). However, we found that contractile responses to norepinephrine were significantly increased in aortic, but not in mesenteric or caudal arterial rings. For aorta, these increases were accompanied by a significant decrease in the half‐maximally effective concentration of norepinephrine from 48 ± 5 to 31 ± 5 nanomolar in vehicle versus angiotensin II treated rats (n =10 each). Therefore, we propose that long‐term systemic administration of a slow‐pressor dose of angiotensin II can potentially increase expression of alpha‐adrenergic receptors in arterial smooth muscle to increase responsiveness to norepinephrine. However, because it is likely that angiotensin II is acting through central mechanisms to increase arterial vascular sympathetic nerve activity, increased receptor expression may be prevented in densely innervated arterial vessels. Accordingly, our results suggest that angiotensin II‐induced hypertension, at least up to 2 weeks, may not involve increased responsiveness of resistance vessels to either angiotensin II itself or sympathetic nerve activity.Support or Funding InformationUniversity of Iowa and Midwestern University
Genetic Interference with Endothelial PPARg Alters Vascular Responses to Select Renin Angiotensin System (RAS) Peptides
Authors: De Silva Travice , Hu Chunyan , Kinzenbaw Dale , Modrick Mary , Sigmund Curt , Faraci Frank 
Published: November 2023

Pharmacological activation of the nuclear receptor peroxisome proliferator‐activated receptor‐gamma (PPARg) protects the vasculature. Much less is known regarding the impact of PPARg under physiological conditions, when driven by endogenous ligands. Recently, we found that endothelial PPARg protects against angiotensin II (Ang II)‐induced vascular dysfunction. Here, we explored that concept further examining whether effects were sex‐dependent along with underlying mechanisms. We studied transgenic mice expressing a human dominant negative mutation in PPARg driven by the endothelial specific vascular cadherin promoter (E‐V290M), using age‐matched, non‐transgenic (non‐Tg) littermates as controls. Acetylcholine (an endothelium‐dependent agonist) produced similar relaxation of carotid arteries from non‐Tg and E‐V290M mice. In contrast, incubation of isolated carotid arteries with Ang II (1 nM) overnight reduced responses to acetylcholine by about 50% in male and female E‐V290M mice but not non‐Tg controls (P<0.05). Endothelial dysfunction in E‐V290M mice was restored to normal by inhibitors of superoxide (tempol), NADPH oxidase (VAS‐2870), Rho kinase (ROCK 1 and ROCK2, Y‐27632), ROCK2 (SLX‐2119), NF‐kB (NEMO‐binding domain peptide), or IL‐6 (neutralizing antibody). Responses in non‐Tg mice were not affected by these inhibitors. We next hypothesized that in addition to vascular effects of Ang II, PPARg may influence components of the angiotensin 1‐7 (Ang 1‐7) arm of the RAS. In the basilar artery, vasodilation to Ang 1‐7 was reduced in E‐V290M mice by more than 50% under baseline conditions (while responses to acetylcholine were minimally affected), an effect that was reversed by Y‐27632. Thus, effects of Ang II on vascular function are augmented by interference with endothelial PPARg through mechanisms that are sex‐independent but involve interrelated oxidant‐inflammatory signaling and Rho kinase (ROCK2). The study provides the first evidence that endothelial PPARg interacts with components of the Ang 1‐7 arm of the RAS. These cell‐specific roles for PPARg have implications for vascular pathophysiology and therapeutic approaches for vascular disease.Support or Funding InformationThis work was supported by the NIH, the Department of Veterans Affairs, and the Fondation Leducq.
Microbial Metabolite, Butyrate, Increases Blood Pressure in Rodent Models of Hypertension
Authors: Yang Tao , Magee Kacy , Malphurs Wendi , Vickroy Thomas , Zubcevic Jasenka 
Published: November 2023

IntroductionThe emerging link between gut dysbiosis and hypertension is characterized by a significant reduction in butyrate‐producing bacteria in the spontaneously hypertensive rat (SHR) compared with the Wistar Kyoto (WKY) control. Butyrate, a major end product of dietary fiber fermentation by gut microbiota, reportedly produces beneficial effects in multiple dysbiosis‐related diseases. However, butyrate has also been linked with activation of the sympathetic drive, elevated heart rate and release of norepinephrine. Considering the established link between sympathetic drive and hypertension, we investigated the role of butyrate in blood pressure (BP) control in hypertension.MethodsMale SHR (5 wo) were placed on either the fiber‐rich (butyrolytic) diet (SHR‐BD) or control diet (SHR‐CD) for 13 weeks ad libitum. Fecal/cecal butyrate levels were determined using high performance liquid chromatography (HPLC) throughout the study. Following this, fecal matter transplant (FMT) from both groups was performed separately to male WKY recipients (7 wo) with antibiotic‐depleted endogenous gut bacteria, to create two groups: WKY FMT‐BD and WKY FMT‐CD. Five weeks following FMT, both groups were infused with a subpressor dose of angiotensin II (Ang II; 50ng/kg/min) for three weeks. Separate male SHR (9 wo) were administered with daily injections of either saline or butyrate (500mg/kg/day I.P.) for four weeks. BPs were measured in all groups using tailcuff or telemetry throughout the study.ResultsElevated cecal butyrate in SHR‐BD (by 2 fold vs. SHR‐CD; P<0.001) was associated with significantly higher SBP (SHR‐CD: 183.3mmHg vs SHR‐BD: 206.6 mmHg; P<0.01). FMT from SHR‐CD and SHR‐BD caused a similar BP increase in the WKY recipients (ΔSBP=11.5 mmHg, P<0.001), However, a subsequent administration of subpressor Ang II further elevated SBP in the WKY FMT‐BD group only (by 7.7 mmHg vs. WKY FMT‐CD; P=0.06). Finally, chronic IP injection of butyrate in the SHR resulted in significant SBP increase compared to saline‐injected SHR (ΔSBP=14.5 mmHg, P<0.05).ConclusionSHR gut microbiota is pro‐hypertensive in the WKY. Moreover, subpressor Ang II exacerbates this hypertension in the presence of excess butyrate. Thus, elevated butyrate may interact with Ang II in the pathophysiology of hypertension, indicating the disadvantageous role of butyrate in the context of hypertension.Support or Funding Information1. American Heart Association 2. College of Veterinary Medicine, University of Florida
17‐Hydroxyprogesterone caproate improves fetal growth restriction possibly by reducing inflammation and placental cytolytic NK cells in response to placental ischemia during pregnancy
Authors: Amaral Lorena Machado , Elfarra Jamil , Cornelius Denise C , Cunningham Mark W , LaMarca Babbette 
Published: November 2023

Preeclampsia (PE), new onset hypertension, is characterized by elevated tumor necrosis factor (TNF‐α), anti‐angiogenic factor soluble fms‐like tyrosine kinase (sFlt‐1), natural killer (NK) cells, oxidative stress and placental ischemia predicted with increased uterine artery resistance (UARI). These contributing factors are likely contributors to the decreased fetal weight during PE pregnancies. Cytolytic NK are an important arm of the immune system killing tumors and infected cells by perforin‐granzyme‐mediated cytolysis which have been shown to be increased in PE women compared to normal pregnancy. Currently, there is no effective treatment for PE except for early delivery, making PE the leading cause for premature births worldwide. Administration of 17‐hydroxyprogesterone caproate (17‐OHPC) is approved for cessation of preterm labor in pregnancies not complicated by PE. The objective of this study was determine whether early administration of 17‐OHPC could improve pregnancy outcomes in response to placental ischemia. To do so, 17‐OHPC (3.32mg/kg) was administered intraperitoneally on gestation day 15 to reduced uterine perfusion pressure (RUPP) rats. UARI was measured using Doppler ultrasound and carotid catheters were inserted on day 18. Blood pressure (MAP), nitric oxide (NO), placental cytolytic NK cells and perforin‐grazyme levels were measured on GD 19. MAP in normal pregnant (NP) rats (n=12) was 94 ± 2, 126 ± 2 in RUPP (n=27) and 111±1 mmHg in RUPP+17‐OHPC (n=15), p<0.05. Pup weight was 2.3±0.09 in NP, 1.9± 0.04 in RUPP rats, which improved to 2.1±0.06 grams in RUPP+17‐OHPC p<0.05. UARI was 0.6±0.01 in NP (n=3), 0.8±0.03 in RUPP rats (n=4), which improved to 0.6±0.04 in RUPP+17‐OHPC (n=5), p<0.05. Total number of placental NK cells was 8.6 ± 3.1 in NP (n=3), 20.2 ±2.4 in RUPP rats (n=6), which decreased to 1.6 ± 0.54 % in RUPP+17‐OHPC (n=5), p<0.05. Activated placental NK cells was 3.8 ± 2.2 in NP (n=3), 11.9±2.01 in RUPP (n=6), which improved to 0.4 ± 0.2 % in RUPP+17‐OHPC (n=5), p<0.05. Perforin‐granzymes were 0.04±0.001, 0.004±0.001 in RUPP (n=4), which improved to 0.02±0.003, 0.0008±0.0001 pg/ug protein in RUPP+17‐OHPC (n=6), p <0.05. Plasma NOx was 22.9±1.6 in NP (n=9), 10.82±2.3 in RUPP rats (n=13) which improved to 25.5±5.2 μM in RUPP+17‐OHPC (n=5), p<0.05. Administration of 17‐OHPC improves UARI, NO bioavailability, activated cytolytic NK cells, perforin‐grazymes, pup weight, and hypertension in response to placental ischemia indicating the potential benefit of 17‐OHPC to improve NK cell modulated pathogenicity and pregnancy outcomes associated with PE.Support or Funding InformationNIH grants RO1HD067541‐06, T32HL105324
Leptin Role in Regulating Ovariectomized Induced Hypertension
Authors: Barnes Maria J. , Hackman Sophia M 
Published: November 2023

Hypertension is less prevalent in pre‐menopausal women compared to males of a similar age. Once women become menopausal, the incidence of hypertension increases significantly when compared to men. Though it has been established that estrogen plays a protective role against the development of hypertension in pre‐menopausal women, it is not clear what the underlying mechanisms might be. Most menopausal women experience a significant increase in body weight in the form of adipose tissue. Increases in adiposity is accompanied by increased levels of the “satiety hormone”, leptin, that also have cardiovascular regulatory properties. Thus, utilizing a menopausal rat model, we sought to test the hypothesis that leptin plays a role in increasing blood pressure and heart rate. Ovariectomized (OVX) adult female rats (i.e., 4‐week post‐surgery) were used in these experiments. OVX rats weighed more, had higher leptin and lower estrogen levels when compared to control females. Blood pressure and heart rate were significantly higher in OVX rats as well. When leptin was administered intracerebroventricularly into the control animals we observed a small decrease in blood pressure. However, administering the same dose in OVX rats resulted in an increase in blood pressure and heart rate. Taken together, these data suggest that estrogen dampens leptin's influence on blood pressure homeostasis and with the loss of estrogen, the influence of leptin on cardiovascular function is not inhibited.Support or Funding InformationIowa Osteopathic Educational Research Foundation
Endothelial Cell Dysfunction is Associated with the Development of Hypertension and Cardiac Hypertrophy in Npr1 Gene‐disrupted Mice
Authors: Das Subhankar , Krazit Stephen T , Pandey Kailash N 
Published: November 2023

Cardiac hypertrophy is a major predictor of progressive heart disease and an adverse prognosis. Atrial and brain natriuretic peptides (ANP and BNP) bind to guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA) and exert the beneficial effects against hypertension and cardiac hypertrophy. The objective of the present study was to examine the effect of Npr1 (coding for NPRA) gene‐disruption on the process of endothelial cell dysfunction in the development of hypertension and cardiac hypertrophy. We used six‐month old mice having different copies of Npr1 gene (0‐copy, 1‐copy, and 2‐copy). The blood pressure and echocardiographic measurements were performed in each group. Blood was collected by direct cardiac puncture and cardiac tissues were harvested immediately and snap frozen in liquid nitrogen. The 0‐copy (Npr1−/−) mice showed 35–45 mmHg higher systolic blood pressure (SBP) as compared to 2‐copy (Npr1+/+) mice. Echocardiographic measurements of Npr1 gene‐disrupted 1‐copy (Npr1+/−) and 0‐copy mice showed significant increased LVEDD (27% in 0‐copy and 10% in 1‐copy mice), intraventricular septal wall thickness (IVSTDD, 30% in 0‐copy and 15% in 1‐copy mice), and reduced fractional shortening by 24% in 0‐copy and 12% in 1‐copy mice as compared with control mice. There was also a significant increase in plasma levels of plasminogen activator inhibitor‐1 (PAI‐1; 2.2‐fold), soluble intracellular adhesion molecule (sICAM; 1.8‐fold), soluble vascular cell adhesion molecule (sVCAM; 25%), E‐selectin (4‐fold) in Npr1 gene‐disrupted (0‐copy) animals as compared with wild‐type mice. Cardiac collagen content was significantly increased by 3‐fold in 0‐copy mice as compared to control mice and was confirmed by histological study with Masson's trichrome staining of cardiac tissues. In the present study, increased plasma levels of sICAM, sVCAM, PAI‐1 and E‐selectin suggest the involvement of endothelial cell dysfunction in producing cardiac hypertrophy in Npr1 null mutant mice. Our results implicate that ANP/NPRA signaling exerts an inhibitory effect on the agents, which cause endothelial dysfunction in the heart leading to cardiac hypertrophy and cardiac remodeling.Support or Funding InformationThis work was supported by NIH grants (HL057531 and HL062147) and by an Institutional Development Award (IDeA) from the NIGMS.
Sex Differences in Sympathetic Neuronal Control of Mesenteric Arteries from Obese Dahl SS Hypertensive Rats
Authors: Gebremedhin Kibrom , Galligan James , Xu Hui 
Published: November 2023

Obesity‐associated hypertension is a risk factor for stroke, type 2 diabetes and kidney failure. Hypertension is less common in premenopausal women than in age‐matched men possibly due estrogen induced vasodilation in women. Sympathetic nerve activity increases in obesity‐related hypertension via the elevated norepinephrine (NE) and ATP release and increased constriction in resistance mesenteric arteries (MA). We hypothesized that the causes of obesity‐related hypertension differ between male and female Dahl salt‐sensitive (ss) rats. Rats were fed control and high fat (HF) diet beginning at 3 weeks of age. Body weight and mean arterial pressure (MAP) were measured until they were sacrificed at 24–26 weeks. Males (450 g) gained more weight than females (300 g) irrespective of diet and all HF fed rats became hypertensive (MAP>140 mmHg). The estrus cycle stage in female rats was determined cytologically by vaginal lavage before euthanasia. Mesenteric arteries (Inner diameter; male=275–350 μm, female=245–315 μm) were harvested and mounted on a pressure (60 mmHg) myograph and inner diameter was measured continuously. MA contractile responses to electrical field stimulation (30 stimuli at 0.2–30Hz) and drug applications were measured. MA neurogenic constriction was greater in HF‐fed male (n=9) compared to HF‐fed female arteries (n=3). Neurogenic constriction was similar in control animals while HF‐fed males had greater constriction than females. Neurogenic constriction did not vary with the estrus cycle in female rats regardless of diet. Neurogenic constrictions were blocked by combined application of prazosin (0.1 μM, α1‐adrenergic receptor antagonist) and PPADS (10 μM, P2X‐purinergic receptor antagonist) as well as suramin (100μM, P2X and P2Y‐purinergic receptor antagonist) in arteries from male and female rats. PPADS/Suramin inhibited ATP‐induced MA contraction. Constrictions caused by exogenous NE and ATP were similar in MA from HF‐fed male and female rats. Immunostaining for tyrosine hydroxylase (NE marker) and vesicular nucleotide transporter (ATP marker) revealed greater nerve distribution in HF‐fed MA from male and female rats. NE HPLC shows similar levels in male and female MA; however females have greater NE level in the perivascular fat. Our data indicate that the mechanisms of neurogenic vasoconstriction differ in MA from obese male and female rats. Differences in neurotransmission and/or nerve fiber distribution in obese male and in female rats might explain the sex differences in hypertension prevalence between human males and females.Support or Funding InformationNIH PPG: P01HL070687
Evaluation of Cardiac Autonomic Balance and Sympathetic Vasomotor Activation to Different Targets in a Model of Hypertension Induced by Nitric Oxide Synthase Blockade
Authors: Zambrano Lysien Ivania , Pontes Roberto B , Oliveira Tales L , Garcia Michelle L , Nishi Erika E , Campos Ruy R , Bergamaschi Cassia T 
Published: November 2023

High blood pressure is a global public health problem. Several factors are involved in the generation and maintenance of hypertension, such as increased sympathetic nerve activity (SNA), although controversies have been reported. Our aims were to evaluate cardiac autonomic balance and sympathetic activation of the renal (rSNA) and the splanchnic nerve (sSNA), in animals with hypertension induced by nitric oxide synthase blockade (L‐NAME). Wistar rats were treated with L‐NAME (20mg/kg/day, once a day, for 8 days). L‐NAME treated group presented increased blood pressure (152 ± 02 mmHg, n=17), compared with control group (101±01 mmHg, n= 15).Plasma nitric oxide (NO) measurement presented a significantly reduction in L‐NAME (6.8 ±0.4 pg/L n=15), compared to CTL group (9.9 ± 1.2 pg/L n=06), both rSNA (147 ± 10spikes/s, n=16) and sSNA (137 ± 13 spike/s n=14) were higher in L‐NAME treated group, compared with control group (114 ± 5, n=10 and 74 ± 13spikes/s, n=09, respectively). The spectral analysis of the pulse interval (PI) demonstrated that the L‐NAME group presented increased low frequency component (LF) (19.75±1.75, n=07 vs CTL: 6.75±1,10, n=07), reduced high frequency component (HF) (81.29 ± 1.80 n=07 vs CTL: 92.50±1.20, n=07) leading to a sympatho‐vagal imbalance (LF/HF) (0.24 ± 0.02, n=07 vs CTL: 0.08 ± 0.01, n=07).Taken altogether, our data show that the hypertension induced by nitric oxide synthase blockade is characterized by cardiac autonomic imbalance and sympathoexcitation to more than one territory and that can be involved in the generation and/or maintenance of high blood pressure.Support or Funding InformationCAPES, CNPq, UNAH.
Physiological changes in intracranial pressure affect arterial pressure
Authors: Guild Sarah‐Jane , Saxena Utkarsh Anand , Malpas Simon , McBryde Fiona , Ramchandra Rohit 
Published: November 2023

A number of cardiovascular diseases are characterised by increased levels of sympathetic nerve activity. However, the driving force behind this increase remains unclear. Studies have suggested that, in some of these diseases, reduced cerebral perfusion may cause a sympathetically mediated increase in arterial pressure in an effort to rectify the reduced cerebral perfusion e.g. Selfish Brain Hypothesis (Paton et al 2009). The objective of this research was to determine a) if physiological increases in intracranial pressure (ICP) will cause a reflex increase in arterial blood pressure to maintain cerebral perfusion pressure and b) if the response is driven by increased sympathetic nerve activity.Using an instrumented conscious sheep model, we measured intracranial pressure (subdural) and arterial pressure (carotid) using solid‐state Millar catheters. Saline was infused into the lateral ventricle through an intracerebroventricular catheter to increase intracranial pressure in a ramp‐like fashion. The ICP ramp was repeated after 2 hours of ganglionic blocker hexamethonium.The ramp increase in ICP led to a reflex linear increase in arterial pressure even when ICP remained within normal physiological levels (0–20 mmHg) (n=6, p<0.01). For example: a 10 mmHg increase in ICP lead to a 6.5 ± 1.4mmHg (n=6) increase in arterial pressure. Ganglionic blockade significantly reduced or abolished this increase in arterial pressure, suggesting mediation by increased sympathetic nerve activity. This is supported by preliminary direct renal sympathetic nerve recordings.We believe that this increase in arterial pressure is via an active control mechanism to try to correct reduced cerebral perfusion caused by the increased intracranial pressure. We speculate that alterations in this response may lead to increased sympathetic nerve activity and worsen prognosis in cardiovascular disease.Our preliminary data indicate that this response is active at physiological levels of intracranial pressure and not just at extreme levels where other reflexes such as the Cushing's response would be active. We propose that this response is an important novel addition to other known mechanisms protecting the brain from under‐perfusion.Support or Funding InformationSupported by the Health Research Council of New Zealand