Development Of Systemic Hypertension Research Articles

Maladaptive Pulmonary Vascular Responses to Chronic Sustained and Chronic Intermittent Hypoxia in Rat.

Chronic sustained hypoxia (CSH), as found in individuals living at a high altitude or in patients suffering respiratory disorders, initiates physiological adaptations such as carotid body stimulation to maintain oxygen levels, but has deleterious effects such as pulmonary hypertension (PH). Obstructive sleep apnea (OSA), a respiratory disorder of increasing prevalence, is characterized by a situation of chronic intermittent hypoxia (CIH). OSA is associated with the development of systemic hypertension and cardiovascular pathologies, due to carotid body and sympathetic overactivation. There is growing evidence that CIH can also compromise the pulmonary circulation, causing pulmonary hypertension in OSA patients and animal models. The aim of this work was to compare hemodynamics, vascular contractility, and L-arginine-NO metabolism in two models of PH in rats, associated with CSH and CIH exposure. We demonstrate that whereas CSH and CIH cause several common effects such as an increased hematocrit, weight loss, and an increase in pulmonary artery pressure (PAP), compared to CIH, CSH seems to have more of an effect on the pulmonary circulation, whereas the effects of CIH are apparently more targeted on the systemic circulation. The results suggest that the endothelial dysfunction evident in pulmonary arteries with both hypoxia protocols are not due to an increase in methylated arginines in these arteries, although an increase in plasma SDMA could contribute to the apparent loss of basal NO-dependent vasodilation and, therefore, the increase in PAP that results from CIH.

Hypertension in neonates treated with intravitreal bevacizumab for retinopathy of prematurity.

To investigate if preterm neonates developed systemic hypertension after intravitreal bevacizumab for retinopathy of prematurity. Patients who received treatment between January 1, 2011 and January 31, 2019 were eligible for inclusion. Patients with pre-existing hypertension, congenital eye disease, or who were discharged within 72 h of treatment were excluded. Charts were reviewed for baseline data, co-morbidities, and the development of systemic hypertension within 4 weeks post treatment. After exclusions, 64 patients were analyzed. New-onset systemic hypertension was identified in 44 (69%) infants. There were no statistical differences in the demographic characteristics or presence of co-morbidities between the hypertensive and non-hypertensive groups. Of those who developed hypertension, the majority presented within the first week post treatment (55%). The majority of infants who received intravitreal bevacizumab developed new-onset systemic hypertension after treatment. Further studies may explore hypertension as a potential side effect of bevacizumab in the neonatal population.

MiRNAs, lncRNAs, and circular RNAs as mediators in hypertension-related vascular smooth muscle cell dysfunction.

Hypertension is a multifactorial disorder that involves complex genetic and environmental factors. Vascular smooth muscle cells (VSMCs) are important components of blood vessels, and their dysregulation has been shown to be involved in vascular remodeling during the development of systemic hypertension and pulmonary arterial hypertension (PAH) via multiple mechanisms, such as aberrant apoptosis, phenotype conversion, proliferation, and migration of VSMCs. With increasing advances in microarrays and next-generation sequencing, nonprotein-coding RNAs (ncRNAs) have attracted much attention due to their numerous functions in health and diseases. Among ncRNAs, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs are emerging as novel modulators in the biological behaviors of VSMCs, especially in systemic hypertension and PAH. Studies have recommended miRNAs, lncRNAs, and circular RNAs as predictive biomarkers and therapeutic targets for systemic hypertension and PAH. In this review, we summarize the current studies focusing on the roles of VSMC-derived miRNAs, lncRNAs and circular RNAs in the pathologies of systemic hypertension and PAH. MiRNAs, lncRNAs, and circular RNAs might serve as attractive targets for the prevention and treatment of VSMC dysfunction-linked systemic hypertension and PAH.

Effects of Neonatal Caffeine Administration on Vessel Reactivity in Adult Mice.

The effects of neonatal caffeine therapy in adults born preterm are uncertain. We studied the impact of neonatal caffeine on systemic blood pressure, vessel reactivity, and response to stress in adult mice. Mice pups were randomized to caffeine (20 mg/kg/d) or saline by intraperitoneal injection for 10 days after birth. We performed tail-cuff BP (8/12 weeks), urinary 8-hydroxydeoxyguanosine and fecal corticosterone (14 weeks), and vessel reactivity in aortic rings (16 weeks) in adult mice. No differences were noted in systolic, diastolic, and mean blood pressures between the two groups at 8 and 12 weeks of age. However, norepinephrine-induced vasoconstriction was substantially higher in aortic rings in CAF-treated male mice. More significant vasodilator responses to nitric oxide donors in aortic rings in female mice may suggest gender-specific effects of caffeine. Female mice exposed to caffeine had significantly lower body weight over-time. Caffeine-treated male mice had substantially higher fecal corticosterone and urinary 8-hydroxydeoxyguanosine at 14 weeks, suggestive of chronic stress. We conclude sex-specific vulnerability to the heightened vascular tone of the aorta in male mice following neonatal caffeine therapy. Altered vessel reactivity and chronic stress in the presence of other risk factors may predispose to the development of systemic hypertension in adults born preterm.

NADPH oxidases and HIF1 promote cardiac dysfunction and pulmonary hypertension in response to glucocorticoid excess

Cardiovascular side effects are frequent problems accompanying systemic glucocorticoid therapy, although the underlying mechanisms are not fully resolved. Reactive oxygen species (ROS) have been shown to promote various cardiovascular diseases although the link between glucocorticoid and ROS signaling has been controversial. As the family of NADPH oxidases has been identified as important source of ROS in the cardiovascular system we investigated the role of NADPH oxidases in response to the synthetic glucocorticoid dexamethasone in the cardiovascular system in vitro and in vivo in mice lacking functional NADPH oxidases due to a mutation in the gene coding for the essential NADPH oxidase subunit p22phox. We show that dexamethasone induced NADPH oxidase-dependent ROS generation, leading to vascular proliferation and angiogenesis due to activation of the transcription factor hypoxia-inducible factor-1 (HIF1). Chronic treatment of mice with low doses of dexamethasone resulted in the development of systemic hypertension, cardiac hypertrophy and left ventricular dysfunction, as well as in pulmonary hypertension and pulmonary vascular remodeling. In contrast, mice deficient in p22phox-dependent NADPH oxidases were protected against these cardiovascular side effects. Mechanistically, dexamethasone failed to upregulate HIF1α levels in these mice, while vascular HIF1α deficiency prevented pulmonary vascular remodeling. Thus, p22phox-dependent NADPH oxidases and activation of the HIF pathway are critical elements in dexamethasone-induced cardiovascular pathologies and might provide interesting targets to limit cardiovascular side effects in patients on chronic glucocorticoid therapy.

IMMUNOLOGICAL ASPECTS OF ESSENTIAL HYPERTENSION

According to modern concept of the etiopathogenesis of essential hypertension, immune cells play an important role in its development. Mediators produced by immunocompetent cells participate in the initiation and maintenance of chronic systemic inflammation and promote the development of vascular remodeling which is an important part of the pathogenesis of the disease and target organ damage. The immune mechanisms underlying blood pressure elevation include the activation of innate and adaptive immune cells. Endothelial damage triggers an inflammatory cascade, causing migration of the immune cells to the inflammatory site, mediated by chemokines and adhesion molecules. Macrophage infiltration of perivascular tissue contributes to impaired vasodilation and damage to target organs due to the production of active forms of oxygen. Angiotensin II also causes T cell infiltration of perivascular adipose tissue and adventitia and an increased production of tumor necrosis factor alpha and interferon gamma. In addition, T lymphocytes express the mineralocorticoid receptor involved in the development of systemic hypertension. An important role in the progression of hypertension belongs to interleukin-17, which is involved in blood pressure elevation and vascular remodeling. The review also contains data on the effect of gut microbiota on the regulation of blood pressure and the development of hypertension.

The relationship between systemic sclerosis and hypertension and ecocardiographıc findings

Aims: The aim of this study was to evaluate the basic demographic and clinical features of systemic sclerosis in our patient group and to determine the relationship between the duration of disease and the development of hypertension in scleroderma patients. Settings and Design: Systemic sclerosis is a rare, autoimmune disease with a limited or widespread involvement of connective tissue of different organs. In the literature, it is recommended that each center following the scleroderma population remove their patient data. Methods and Material: Patients who were followed up with the diagnosis of systemic sclerosis were included in our study. The duration of the disease, the accompanying diseases, basic demographic characteristics, inflammation markers and echocardiographic characteristics of the patients were evaluated. A total of 150 patients were included in the study (87.3% female, mean age 47.7). The duration of the disease was 5.41 years. Results: 37% of the patients had hypertension. There was a positive correlation between disease duration and hypertension (r: 0.278, p: 0.001). Echocardiographic evaluation revealed pulmonary hypertension in 10 patients. Hypertension was more prevalent in this disease group than the population with the same characteristics. As the disease duration increased, the incidence of systemic hypertension increased. Conclusions: The first of the striking findings in our study was that the rate of pulmonary hypertension due to scleroderma was found to be similar to that in other Middle Eastern societies. In the second important finding, peripheral connective tissue involvement of scleroderma was found to be important in the development of systemic hypertension.

Nrf2 Deficiency Upregulates Intrarenal Angiotensin-Converting Enzyme-2 and Angiotensin 1-7 Receptor Expression and Attenuates Hypertension and Nephropathy in Diabetic Mice

We investigated the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in renin-angiotensin system (RAS) gene expression in renal proximal tubule cells (RPTCs) and in the development of systemic hypertension and kidney injury in diabetic Akita mice. We used adult male Akita Nrf2 knockout mice and Akita mice treated with trigonelline (an Nrf2 inhibitor) or oltipraz (an Nrf2 activator). We also examined rat immortalized RPTCs (IRPTCs) stably transfected with control plasmids or plasmids containing rat angiotensinogen (Agt), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (Ace2), or angiotensin 1-7 (Ang 1-7) receptor (MasR) gene promoters. Genetic deletion of Nrf2 or pharmacological inhibition of Nrf2 in Akita mice attenuated hypertension, renal injury, tubulointerstitial fibrosis, and the urinary albumin/creatinine ratio. Furthermore, loss of Nrf2 upregulated RPTC Ace2 and MasR expression, increased urinary Ang 1-7 levels, and downregulated expression of Agt, ACE, and profibrotic genes in Akita mice. In cultured IRPTCs, Nrf2 small interfering RNA transfection or trigonelline treatment prevented high glucose stimulation of Nrf2 nuclear translocation, Agt, and ACE transcription with augmentation of Ace2 and MasR transcription, which was reversed by oltipraz. These data identify a mechanism, Nrf2-mediated stimulation of intrarenal RAS gene expression, by which chronic hyperglycemia induces hypertension and renal injury in diabetes.

Hypertension in cancer patients treated with anti-angiogenic based regimens.

New anti-cancer drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway are highly effective in the treatment of solid tumors, however concerns remain regarding their cardiovascular safety. The most common side effect of VEGF signaling pathway (VSP) inhibition is the development of systemic hypertension. We review the incidence, possible mechanisms, significance and management of hypertension in patients treated with VSP inhibitors.

B-Type Natriuretic Peptide Deletion Leads to Progressive Hypertension, Associated Organ Damage, and Reduced Survival: Novel Model for Human Hypertension.

Altered myocardial structure and function, secondary to chronically elevated blood pressure, are leading causes of heart failure and death. B-type natriuretic peptide (BNP), a guanylyl cyclase A agonist, is a cardiac hormone integral to cardiovascular regulation. Studies have demonstrated a causal relationship between reduced production or impaired BNP release and the development of human hypertension. However, the consequences of BNP insufficiency on blood pressure and hypertension-associated complications remain poorly understood. Therefore, the goal of this study was to create and characterize a novel model of BNP deficiency to investigate the effects of BNP absence on cardiac and renal structure, function, and survival. Genetic BNP deletion was generated in Dahl salt-sensitive rats. Compared with age-matched controls, BNP knockout rats demonstrated adult-onset hypertension. Increased left ventricular mass with hypertrophy and substantially augmented hypertrophy signaling pathway genes, developed in young adult knockout rats, which preceded hypertension. Prolonged hypertension led to increased cardiac stiffness, cardiac fibrosis, and thrombi formation. Significant elongation of the QT interval was detected at 9 months in knockout rats. Progressive nephropathy was also noted with proteinuria, fibrosis, and glomerular alterations in BNP knockout rats. End-organ damage contributed to a significant decline in overall survival. Systemic BNP overexpression reversed the phenotype of genetic BNP deletion. Our results demonstrate the critical role of BNP defect in the development of systemic hypertension and associated end-organ damage in adulthood.

Telemetry‐based Recording of Renal Cortex Oxygenation During Endogenous RAS Activation: Preliminary Observations

Upon feeding of the food additive indole‐3‐carbinol (I3C) the liver of Cyp1A1Ren2 transgenic rats produces high levels of renin which leads to hypertension and tissue damage in the kidney. We hypothesized that endogenous RAS activation in this model would be associated with renal hypoxia. Using a new technology that enables the telemetric recording of intra‐renal tissue oxygen pressure (PO2) in conscious, free roaming animals, we here report preliminary observations on renal cortical PO2 changes during endogenous RAS activation. 1 week after implantation of the electrodes the relative change in renal cortex PO2 during bouts of 3 days of endogenous activation of RAS by feeding an 0.3% or 0.6% I3C containing diet (n=5) were recorded. 3±2 days after start of the 0.6% I3C diet, s.c. bolus infusions of valsartan/losartan (20/30 mg/kg) were administered. During 0.3% and 0.6% I3C feeding, renal PO2 levels fell to 75±7 and 63±13% from baseline values (mean±SD), with a nadir after 25±5 hours. Exogenous blockade of the angiotensin‐II receptor increased oxygen levels within 14±3 min to 98±38% of baseline values (mean±SD). These data suggest that oxygen levels in the renal cortex decrease rapidly during the onset of endogenous RAS hyperactivation. The effect is mediated by AT1‐receptor activation and may precede the known development of systemic hypertension and renal injury in this model.

Up-regulation of Rhoa/Rho kinase pathway by translationally controlled tumor protein in vascular smooth muscle cells.

Translationally controlled tumor protein (TCTP), a repressor for Na,K-ATPase has been implicated in the development of systemic hypertension, as proved by TCTP-over-expressing transgenic (TCTP-TG) mice. Aorta of TCTP-TG exhibited hypercontractile response compared to that of non-transgenic mice (NTG) suggesting dys-regulation of signaling pathways involved in the vascular contractility by TCTP. Because dys-regulation of RhoA/Rho kinase pathway is implicated in increased vascular contractility, we examined whether TCTP induces alterations in RhoA pathway in vascular smooth muscle cells (VSMCs). We found that TCTP over-expression by adenovirus infection up-regulated RhoA pathway including the expression of RhoA, and its downstream signalings, phosphorylation of myosin phosphatase target protein (MYPT-1), and myosin light chain (MLC). Conversely, lentiviral silencing of TCTP reduced the RhoA expression and Rho kinase signalings. Using immunohistochemical and Western blotting studies on aortas from TCTP-TG confirmed the elevated expression of RhoA and increase in p-MLC (phosphorylated MLC). In contrast, down-regulation of RhoA and p-MLC were found in aortas from heterozygous mice with deleted allele of TCTP (TCTP+/−). We conclude that up-regulation of TCTP induces RhoA-mediated pathway, and that TCTP-induced RhoA plays a role in the regulation in vasculature. Modulation of TCTP may offer a therapeutic target for hypertension and in vascular contractility dysfunction.

Hypertension and obstructive sleep apnea

Obstructive sleep apnea (OSA) is increasingly being recognized as a major health burden with strong focus on the associated cardiovascular risk. Studies from the last two decades have provided strong evidence for a causal role of OSA in the development of systemic hypertension. The acute physiological changes that occur during apnea promote nocturnal hypertension and may lead to the development of sustained daytime hypertension via the pathways of sympathetic activation, inflammation, oxidative stress, and endothelial dysfunction. This review will focus on the acute hemodynamic disturbances and associated intermittent hypoxia that characterize OSA and the potential pathophysiological mechanisms responsible for the development of hypertension in OSA. In addition the epidemiology of OSA and hypertension, as well as the role of treatment of OSA, in improving blood pressure control will be examined.

Hemorheological Effects of Valsartan in L-NAME Induced Hypertension in Rats

Animal models are a useful tool, for example, in the study of hypertension, but its use requires robust knowledge and well characterized models in order to extrapolate the obtained results. Nitric oxide is an important regulator of vascular function and blood pressure. The chronic administration of nitric oxide synthase (NOS) inhibitors provides an animal experimental model of hypertension. Our study aims to investigate the hemorheological effects of (i) N  -nitro-L-arginine methyl ester (L-NAME) added daily to Sprague-Dawley rats in drinking water and (ii) valsartan, an angiotensin II AT1-receptor antagonist, administration when the Sprague-Dawley rats acquired the hypertensive state. In three experimental groups (Control, Hypertensive and Valsartan) systolic blood pressure was measured and blood samples were collected for determination of erythrocyte membrane deformability and fluidity as well as blood and plasma viscosities. L-NAME intake induces an increase in the systolic blood pressure indicating the development of systemic hypertension. Concerning the hemorheological parameters, the erythrocyte deformability is decreased in the hypertensive animal group and on contrary the erythrocyte membrane fluidity increased being both parameters values reverted after valsartan administration. Valsartan also decreases the plasma and blood viscosities values obtained in the animal group which have acquired systemic hypertension after L-NAME intake. In conclusion, the angiotensin II AT1-receptor antagonist, valsartan, restores in hypertensive Sprague-Dawley rats L- NAME- dependent their systolic blood pressure to the physiological values, as well as, normalized their hemorheological parameters values; due to the similarity effects to human essential hypertension we conclude that this can be a suitable animal model for hemorheological studies in the field of hypertension.

Do changes in the coupling between respiratory and sympathetic activities contribute to neurogenic hypertension?

1. It is well known that respiration markedly modulates the sympathetic nervous system. Interactions between pontine and medullary neurons involved in the control of sympathetic and respiratory functions are the main mechanism underlying the respiratory related oscillations in sympathetic nerve activity. 2. Recently, in rats treated with chronic intermittent hypoxia, we demonstrated that alterations in respiratory pattern may drive increased sympathetic outflow and hence the development of systemic hypertension. These experiments, performed in the in situ working heart-brain stem preparation, raise the possibility that enhanced central coupling between respiratory and sympathetic activities could be a potential mechanism underpinning the development and/or the maintenance of neurogenic hypertension. 3. In the present review, we discuss the neural basis of the enhanced entrainment between respiratory and sympathetic neurons in the brain stem that can be induced by chronic intermittent hypoxia and the possible implications of these mechanisms in the genesis of sympathetic overactivity and, consequently, hypertension.

Heightened aberrant deposition of hard-wearing elastin in conduit arteries of prehypertensive SHR is associated with increased stiffness and inward remodeling

Elastin is a major component of conduit arteries and a key determinant of vascular viscoelastic properties. Aberrant organization of elastic lamellae has been reported in resistance vessels from spontaneously hypertensive rats (SHR) before the development of hypertension. Hence, we have characterized the content and organization of elastic lamellae in conduit vessels of neonatal SHR in detail, comparing the carotid arteries from 1-wk-old SHR with those from Wistar-Kyoto (WKY) and Sprague Dawley (SD) rats. The general structure and mechanics were studied by pressure myography, and the internal elastic lamina organization was determined by confocal microscopy. Cyanide bromide-insoluble elastin scaffolds were also prepared from 1-mo-old SHR and WKY aortas to assess their weight, amino acid composition, three-dimensional lamellar organization, and mechanical characteristics. Carotid arteries from 1-wk-old SHR exhibited narrower lumen and greater intrinsic stiffness than those from their WKY and SD counterparts. These aberrations were associated with heightened elastin content and with a striking reduction in the size of the fenestrae present in the elastic lamellae. The elastin scaffolds isolated from SHR aortas also exhibited increased relative weight and stiffness, as well as the presence of peculiar trabeculae inside the fenestra that reduced their size. We suggest that the excessive and aberrant elastin deposited in SHR vessels during perinatal development alters their mechanical properties. Such abnormalities are likely to compromise vessel expansion during a critical period of growth and, at later stages, they could compromise hemodynamic function and participate in the development of systemic hypertension.

Glomerular Involvement in Adults with Sickle Cell Hemoglobinopathies

Patients with sickle cell anemia (SCA) may develop a glomerulopathy with proteinuria and progressive renal insufficiency, leading to ESRD. Albuminuria is a sensitive marker of glomerular damage in this population and precedes the development of renal insufficiency. For determination of the prevalence of glomerular damage in SCA and the clinical correlates of renal insufficiency, 300 adult patients with SCA were studied (hemoglobin SS = 184; and 116 with other sickling hemoglobinopathies: SC, SD, and S-beta thalassemia); albumin excretion rates (AER) and renal function (Cockroft-Gault formula) were determined, and clinical and hematologic evaluations were conducted. In hemoglobin SS disease, increased AER (micro- and macroalbuminuria) occurred in 68% of adult patients, and macroalbuminuria occurred in 26%. In other sickling disorders, increased AER occurs in 32% of adults, and macroalbuminuria occurs in 10%. The development of graded albuminuria was age dependent, so at 40 yr, 40% of patients with SS disease had macroalbuminuria. There were no differences in hematologic parameters (hemoglobin levels, white blood cell count, percentage of reticulocytes, platelet counts, or lactate dehydrogenase levels) between patients with normoalbuminuria and those with micro- or macroalbuminuria. By multivariate analysis, albuminuria correlated with age and serum creatinine in SS disease but not with BP or hemoglobin levels. In other sickling disorders, albuminuria tended to be associated with age but not with hemoglobin or BP levels. The diastolic BP was lower in patients with SCA than in African American control subjects, and the development of renal insufficiency, which was present in 21% of adults with SS disease, was not accompanied by significant hypertension. It is concluded that glomerular damage in adults with SCA is very common, and a majority of patients with SS disease are at risk for the development of progressive renal failure. The development of micro- and macroalbuminuria is not related to the degree of anemia, suggesting that sickle cell glomerulopathy is not solely related to hemodynamic adaptations to chronic anemia. In contrast to other glomerulopathies, the development of systemic hypertension is uncommon in SS disease with renal insufficiency.

Early gestation dexamethasone alters baroreflex and vascular responses in newborn lambs before hypertension

Exposure of the early gestation ovine fetus to exogenous glucocorticoids induces alterations in postnatal cardiovascular physiology, including hypertension. To determine whether autonomic function and systemic vascular reactivity are altered by in utero programming before the development of systemic hypertension, we examined arterial baroreflex function and in vivo hemodynamic and in vitro vascular responses to vasoactive agents in 10- to 14-day-old newborn lambs exposed to early gestation glucocorticoids. Dexamethasone (Dex, 0.28 mg.kg-1.day-1) or saline was administered to pregnant ewes by intravenous infusion over 48 h beginning at 27 days gestation (term 145 days), and lambs were allowed to deliver (n=6 in each group). Resting mean arterial blood pressure (MABP; 77+/-1 vs. 74+/-3 mmHg) and heart rate (HR; 249+/-9 vs. 226+/-21 beats/min) were similar in Dex-exposed and control animals, respectively. The arterial baroreflex curve, relating changes in HR to MABP, was significantly shifted toward higher pressure in the Dex-exposed lambs although no change in the sensitivity (gain) of the response was seen. In vivo changes in blood pressure in response to bolus doses of ANG II (20, 50, and 100 ng/kg) and phenylephrine (2, 5, and 10 microg/kg) were similar in the two groups. However, Dex lambs displayed greater decreases in MABP in response to ganglionic blockade with tetraethylammonium bromide (10 mg/kg; -30+/-3 vs. -20+/-3 mmHg, P<0.05) and greater increases in MABP after nitric oxide synthase blockade with NG-nitro-L-arginine (25 mg/kg; 23+/-3 vs. 13+/-2 mmHg, P<0.05) compared with control lambs. By in vitro wire myography, mesenteric and femoral artery microvessel contractile responses to KCl were similar, whereas responses to endothelin (in mesenteric) and norepinephrine (in femoral) were significantly attenuated in Dex lambs compared with controls. Femoral vasodilatory responses to forskolin and sodium nitroprusside were similar in the two groups (n=4). These findings suggest that resetting of the baroreflex, accompanied by increased sympathetic activity and altered nitric oxide-mediated compensatory vasodilatory function, may be important contributors to programming of hypertension.

Newborn lamb coronary artery reactivity is programmed by early gestation dexamethasone before the onset of systemic hypertension

Exposure of the early gestation ovine fetus to exogenous glucocorticoids induces organ-specific alterations in postnatal cardiovascular physiology. To determine whether early gestation corticosteroid exposure alters coronary reactivity before the development of systemic hypertension, dexamethasone (0.28 mg x kg(-1) x day(-1)) was administered to pregnant ewes by intravenous infusion over 48 h beginning at 27 days gestation (term, 145 days). Vascular responsiveness was assessed in endothelium-intact coronary arteries isolated from 1-wk-old steroid-exposed and age-matched control lambs (N = 6). Calcium imaging was performed in fura 2-loaded primary cultures of vascular smooth muscle cells (VSMC) from the harvested coronary arteries. Early gestation steroid exposure did not significantly alter mean arterial blood pressure or coronary reactivity to KCl, thromboxane A(2) mimetic U-46619, or ANG II. Steroid exposure significantly increased coronary artery vasoconstriction to acetylcholine and endothelin-1. Vasodilatation to adenosine, but not nitroprusside or forskolin, was significantly attenuated following early gestation steroid exposure. Endothelin-1 or U-46619 stimulation resulted in a comparable increase in intracellular calcium concentration ([Ca(2+)](i)) in coronary VSMC isolated from either dexamethasone-treated or control animals. However, the ANG II- or KCl-mediated increase in [Ca(2+)](i) in control VSMC was significantly attenuated in VSMC harvested from dexamethasone-treated lambs. Coronary expression of muscle voltage-gated l-type calcium channel alpha-1 subunit protein was not significantly altered by steroid exposure, whereas endothelial nitric oxide synthase expression was attenuated. These findings demonstrate that early gestation glucocorticoid exposure elicits primary alterations in coronary responsiveness before the development of systemic hypertension. Glucocorticoid-induced alterations in coronary physiology may provide a mechanistic link between an adverse intrauterine environment and later cardiovascular disease.

Fulminant hepatic failure

Abstract Analysis of the first 150 cases collected from 73 centers reporting to the Fulminant Hepatic Failure Surveillance Study showed that 80 patients had presumable viral hepatitis, of whom 62 died. Of 41 patients who had recent surgery, 36 died. In 35 patients massive liver necrosis developed less than three weeks after halothane anesthesia, and 27 (77 per cent) of these had multiple exposures to halothane. The risk from halothane is small, but this complication was present in nearly one quarter of the cases reported in our study. When the use of halothane is desired, multiple exposure should be avoided, if possible. Moreover, postoperative fever after exposure to halothane, otherwise "unexplained," is an important warning sign, and should be thoroughly investigated and taken into consideration when further exposure to this anesthetic is contemplated. The physician prescribing halothane must balance need against risk.