15 results on '"Levi, R."'
Search Results
2. The association between discontinuing hormonal contraceptives and wives' marital satisfaction depends on husbands' facial attractiveness
- Author
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James K. McNulty, V. Michelle Russell, Andrea L. Meltzer, and Levi R. Baker
- Subjects
Adult ,Male ,Population ,Social Sciences ,Interpersonal communication ,Newlywed ,Personal Satisfaction ,Models, Psychological ,Developmental psychology ,Interpersonal relationship ,Beauty ,Young Adult ,Surveys and Questionnaires ,Contraceptive Agents, Female ,Humans ,Interpersonal Relations ,Longitudinal Studies ,Young adult ,Marriage ,education ,Spouses ,education.field_of_study ,Multidisciplinary ,Data Collection ,Physical attractiveness ,Family planning ,Face ,Marital status ,Female ,Cues ,Psychology ,Algorithms - Abstract
How are hormonal contraceptives (HCs) related to marital well-being? Some work suggests HCs suppress biological processes associated with women’s preferences for partner qualities reflective of genetic fitness, qualities that may be summarized by facial attractiveness. Given that realizing such interpersonal preferences positively predicts relationship satisfaction, any changes in women’s preferences associated with changes in their HC use may interact with partner facial attractiveness to predict women’s relationship satisfaction. We tested this possibility using two longitudinal studies of 118 newlywed couples. Trained observers objectively rated husbands’ facial attractiveness in both studies. In study 1, wives reported their marital satisfaction every 6 mo for 4 y and then reported the history of their HC use for their relationship. In study 2, wives reported whether they were using HCs when they met their husbands and then their marital satisfaction and HC use every 4 mo for up to three waves. In both studies, and in an analysis that combined the data from both studies, wives who were using HCs when they formed their relationship with their husband were less satisfied with their marriage when they discontinued HCs if their husband had a relatively less attractive face, but more satisfied if their husband had a relatively more attractive face. Beginning HCs demonstrated no consistent associations with marital satisfaction. Incongruency between HC use at relationship formation and current HC use was negatively associated with sexual satisfaction, regardless of husbands’ facial attractiveness. These findings suggest that HC use may have unintended implications for women’s close relationships.
- Published
- 2014
3. The association between discontinuing hormonal contraceptives and wives' marital satisfaction depends on husbands' facial attractiveness.
- Author
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Michelle Russell, V., McNulty, James K., Baker, Levi R., and Meltzer, Andrea L
- Subjects
MARITAL satisfaction ,MARITAL relations ,CONTRACEPTIVES ,INTERPERSONAL attraction ,SEXUAL attraction - Abstract
How are hormonal contraceptives (HCs) related to marital well-being? Some work suggests HCs suppress biological processes associated with women's preferences for partner qualities reflective of genetic fitness, qualities that may be summarized by facial attractiveness. Given that realizing such interpersonal preferences positively predicts relationship satisfaction, any changes in women's preferences associated with changes in their HC use may interact with partner facial attractiveness to predict women's relationship satisfaction. We tested this possibility using two longitudinal studies of 118 newlywed couples. Trained observers objectively rated husbands' facial attractiveness in both studies. In study 1, wives reported their marital satisfaction every 6 mo for 4 y and then reported the history of their HC use for their relationship. In study 2, wives reported whether they were using HCs when they met their husbands and then their marital satisfaction and HC use every 4 mo for up to three waves. In both studies, and in an analysis that combined the data from both studies, wives who were using HCs when they formed their relationship with their husband were less satisfied with their marriage when they discontinued HCs if their husband had a relatively less attractive face, but more satisfied if their husband had a relatively more attractive face. Beginning HCs demonstrated no consistent associations with marital satisfaction. Incongruency between HC use at relationship formation and current HC use was negatively associated with sexual satisfaction, regardless of husbands' facial attractiveness. These findings suggest that HC use may have unintended implications for women's close relationships. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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4. Nitric oxide synthase in macula densa regulates glomerular capillary pressure.
- Author
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Wilcox, C S, Welch, W J, Murad, F, Gross, S S, Taylor, G, Levi, R, and Schmidt, H H
- Abstract
Tubular-fluid reabsorption by specialized cells of the nephron at the junction of the ascending limb of the loop of Henle and the distal convoluted tubule, termed the macula densa, releases compounds causing vasoconstriction of the adjacent afferent arteriole. Activation of this tubuloglomerular feedback response reduces glomerular capillary pressure of the nephron and, hence, the glomerular filtration rate. The tubuloglomerular feedback response functions in a negative-feedback mode to relate glomerular capillary pressure to tubular-fluid delivery and reabsorption. This system has been implicated in renal autoregulation, renin release, and longterm body fluid and blood-pressure homeostasis. Here we report that arginine-derived nitric oxide, generated in the macula densa, is an additional intercellular signaling molecule that is released during tubular-fluid reabsorption and counters the vasoconstriction of the afferent arteriole. Antibody to rat cerebellar constitutive nitric oxide synthase stained rat macula densa cells specifically. Microperfusion of the macula densa segment of single nephrons with N omega-methyl-L-arginine (an inhibitor of nitric oxide synthase) or with pyocyanin (a lipid-soluble inhibitor of endothelium-derived relaxation factor) showed that generation of nitric oxide can vasodilate the afferent arteriole and increase glomerular capillary pressure; this effect was blocked by drugs that prevent tubular-fluid reabsorption. We conclude that nitric oxide synthase in macula densa cells is activated by tubular-fluid reabsorption and mediates a vasodilating component to the tubuloglomerular feedback response. These findings imply a role for arginine-derived nitric oxide in body fluid-volume and blood-pressure homeostasis, in addition to its established roles in modulation of vascular tone by the endothelium and in neurotransmission.
- Published
- 1992
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5. Heart as a target organ in 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity: decreased beta-adrenergic responsiveness and evidence of increased intracellular calcium.
- Author
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Canga, L, Levi, R, and Rifkind, A B
- Abstract
The heart has not been regarded as a major target organ of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity notwithstanding that lethal cardiac dysfunction can occur in the absence of histopathological changes. To assess possible TCDD cardiotoxicity, we studied the effect of TCDD five days after treatment (10 micrograms/kg of body weight; single dose given i.p. in corn oil) on the contractility of guinea pig right ventricular papillary muscle. Controls were treated with corn oil. TCDD treatment significantly decreased beta-adrenergic responsiveness. In papillary muscles from TCDD-treated guinea pigs, the positive inotropic effect of isoproterenol (0.03-0.3 microM) was decreased by a mean of 65% (P less than 0.001), and the enhancement in the velocity of relaxation was 60% less than in the controls (P less than 0.05). On the other hand, TCDD treatment did not alter the positive inotropic effect of lower concentrations of isoproterenol (0.1-10 nM). After TCDD, responsiveness to low-frequency stimulation (0.1 and 0.25 Hz) was enhanced, responsiveness to increases in extracellular Ca2+ concentration was attenuated, and isoproterenol-elicited aftercontractions in K+-depolarized preparations were increased in magnitude. Collectively, the latter findings suggest that in addition to decreasing beta-adrenergic responsiveness, TCDD increases the intracellular Ca2+ concentration in papillary muscle. Finally, slow Ca2+ channels were not blocked after TCDD treatment, inasmuch as isoproterenol restored contractility equally effectively in K+-depolarized TCDD-treated and control papillary muscles. Our findings indicate that TCDD causes a specific pattern of cardiac dysfunction in a mammalian species, selectively augmenting or decreasing different cardiac responses. The cardiac changes are consistent with reported membrane effects of TCDD; further, they suggest that the heart may be a major target organ for TCDD toxicity.
- Published
- 1988
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6. NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide.
- Author
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Kilbourn, R G, Gross, S S, Jubran, A, Adams, J, Griffith, O W, Levi, R, and Lodato, R F
- Abstract
Clinical assessment of the activity of tumor necrosis factor (TNF) against human cancer has been limited by a dose-dependent cardiovascular toxicity, most frequently hypotension. TNF is also thought to mediate the vascular collapse resulting from bacterial endotoxin. The present studies address the mechanism by which TNF causes hypotension and provide evidence for elevated production of nitric oxide, a potent vasodilator initially characterized as endothelium-derived relaxing factor. Nitric oxide is synthesized by several cell types, including endothelial cells and macrophages, from the guanidino nitrogen of L-arginine; the enzymatic pathway is competitively inhibited by NG-methyl-L-arginine. We found that hypotension induced in pentobarbital-anesthetized dogs by TNF (10 micrograms/kg, i.v., resulting in a fall in mean systemic arterial pressure from 124.7 +/- 7 to 62.0 +/- 22.9 mmHg; 1 mmHg = 133 Pa) was completely reversed within 2 min following administration of NG-methyl-L-arginine (4.4 mg/kg, i.v.). In contrast, NG-methyl-L-arginine failed to reverse the hypotensive response to an equivalent depressor dose of nitroglycerin, a compound that acts by forming nitric oxide by a nonenzymatic, arginine-independent mechanism. The effect of NG-methyl-L-arginine on TNF-induced hypotension was antagonized, and the hypotension restored, by administration of excess L-arginine (100 mg/kg, i.v.). Our findings suggest that excessive nitric oxide production mediates the hypotensive effect of TNF.
- Published
- 1990
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7. Identification of arginine as a precursor of endothelium-derived relaxing factor.
- Author
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Sakuma, I, Stuehr, D J, Gross, S S, Nathan, C, and Levi, R
- Abstract
Nitric oxide (NO) is a major endothelium-derived relaxing factor (EDRF) released in response to vasodilating amines, peptides, proteins, ionophores, and nucleotides. EDRF is an important regulator of smooth muscle tone and platelet aggregation and adhesion. Histamine and acetylcholine relax the intact norepinephrine-constricted guinea pig pulmonary artery by an EDRF-dependent mechanism in a medium free of amino acids. N omega-Monomethylarginine (N-MeArg; 0.25 mM) inhibited this relaxation by 64-73%. Inhibition by N-MeArg developed rapidly and was immediately and completely reversed by excess L-arginine but not by D-arginine or by citrulline. N-MeArg did not diminish relaxation induced by nitroprusside, an NO-generating agent, indicating that N-MeArg acts on endothelium rather than on smooth muscle. These observations strongly suggest that, in the intact guinea pig pulmonary artery, EDRF originates from enzymatic action on the guanido nitrogen(s) of an endogenous pool of arginine. This is strikingly similar to the origin of reactive nitrogen intermediates in activated macrophages.
- Published
- 1988
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8. Cardiac dysfunction caused by purified human C3a anaphylatoxin.
- Author
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del Balzo, U H, Levi, R, and Polley, M J
- Abstract
The purpose of this investigation was to define the cardiac effects of complement-derived C3a anaphylatoxin, in view of the possibility that cardiac dysfunction may occur as a result of complement activation. Purified human C3a was administered by intracoronary bolus injections into isolated guinea pig hearts. As a function of dose, C3a caused tachycardia, impairment of atrioventricular conduction, left ventricular contractile failure, coronary vasoconstriction, and histamine release. These effects were abolished by cleavage of the COOH-terminal arginine by carboxypeptidase B. The magnitude of C3a-induced tachycardia correlated with the amount of endogenous cardiac histamine released into the coronary effluent. Whereas the tachycardia was markedly reduced by the histamine H2 antagonist cimetidine, the contractile failure and the coronary vasoconstriction caused by C3a were antagonized by the leukotriene antagonist FPL 55712 and by the cyclooxygenase inhibitor indomethacin, respectively. This suggests that histamine, leukotrienes, and vasoactive prostanoates may mediate the various cardiac effects of C3a. Our findings indicate that C3a anaphylatoxin has marked cardiac effects at concentrations that are likely to be attained with a degree of C3 activation commonly seen in various disease states. Thus, our data are compatible with the hypothesis that generation of anaphylatoxins may induce cardiac dysfunction in clinical conditions.
- Published
- 1985
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9. Evaluation of individual and ensemble probabilistic forecasts of COVID-19 mortality in the United States.
- Author
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Cramer EY, Ray EL, Lopez VK, Bracher J, Brennen A, Castro Rivadeneira AJ, Gerding A, Gneiting T, House KH, Huang Y, Jayawardena D, Kanji AH, Khandelwal A, Le K, Mühlemann A, Niemi J, Shah A, Stark A, Wang Y, Wattanachit N, Zorn MW, Gu Y, Jain S, Bannur N, Deva A, Kulkarni M, Merugu S, Raval A, Shingi S, Tiwari A, White J, Abernethy NF, Woody S, Dahan M, Fox S, Gaither K, Lachmann M, Meyers LA, Scott JG, Tec M, Srivastava A, George GE, Cegan JC, Dettwiller ID, England WP, Farthing MW, Hunter RH, Lafferty B, Linkov I, Mayo ML, Parno MD, Rowland MA, Trump BD, Zhang-James Y, Chen S, Faraone SV, Hess J, Morley CP, Salekin A, Wang D, Corsetti SM, Baer TM, Eisenberg MC, Falb K, Huang Y, Martin ET, McCauley E, Myers RL, Schwarz T, Sheldon D, Gibson GC, Yu R, Gao L, Ma Y, Wu D, Yan X, Jin X, Wang YX, Chen Y, Guo L, Zhao Y, Gu Q, Chen J, Wang L, Xu P, Zhang W, Zou D, Biegel H, Lega J, McConnell S, Nagraj VP, Guertin SL, Hulme-Lowe C, Turner SD, Shi Y, Ban X, Walraven R, Hong QJ, Kong S, van de Walle A, Turtle JA, Ben-Nun M, Riley S, Riley P, Koyluoglu U, DesRoches D, Forli P, Hamory B, Kyriakides C, Leis H, Milliken J, Moloney M, Morgan J, Nirgudkar N, Ozcan G, Piwonka N, Ravi M, Schrader C, Shakhnovich E, Siegel D, Spatz R, Stiefeling C, Wilkinson B, Wong A, Cavany S, España G, Moore S, Oidtman R, Perkins A, Kraus D, Kraus A, Gao Z, Bian J, Cao W, Lavista Ferres J, Li C, Liu TY, Xie X, Zhang S, Zheng S, Vespignani A, Chinazzi M, Davis JT, Mu K, Pastore Y Piontti A, Xiong X, Zheng A, Baek J, Farias V, Georgescu A, Levi R, Sinha D, Wilde J, Perakis G, Bennouna MA, Nze-Ndong D, Singhvi D, Spantidakis I, Thayaparan L, Tsiourvas A, Sarker A, Jadbabaie A, Shah D, Della Penna N, Celi LA, Sundar S, Wolfinger R, Osthus D, Castro L, Fairchild G, Michaud I, Karlen D, Kinsey M, Mullany LC, Rainwater-Lovett K, Shin L, Tallaksen K, Wilson S, Lee EC, Dent J, Grantz KH, Hill AL, Kaminsky J, Kaminsky K, Keegan LT, Lauer SA, Lemaitre JC, Lessler J, Meredith HR, Perez-Saez J, Shah S, Smith CP, Truelove SA, Wills J, Marshall M, Gardner L, Nixon K, Burant JC, Wang L, Gao L, Gu Z, Kim M, Li X, Wang G, Wang Y, Yu S, Reiner RC, Barber R, Gakidou E, Hay SI, Lim S, Murray C, Pigott D, Gurung HL, Baccam P, Stage SA, Suchoski BT, Prakash BA, Adhikari B, Cui J, Rodríguez A, Tabassum A, Xie J, Keskinocak P, Asplund J, Baxter A, Oruc BE, Serban N, Arik SO, Dusenberry M, Epshteyn A, Kanal E, Le LT, Li CL, Pfister T, Sava D, Sinha R, Tsai T, Yoder N, Yoon J, Zhang L, Abbott S, Bosse NI, Funk S, Hellewell J, Meakin SR, Sherratt K, Zhou M, Kalantari R, Yamana TK, Pei S, Shaman J, Li ML, Bertsimas D, Skali Lami O, Soni S, Tazi Bouardi H, Ayer T, Adee M, Chhatwal J, Dalgic OO, Ladd MA, Linas BP, Mueller P, Xiao J, Wang Y, Wang Q, Xie S, Zeng D, Green A, Bien J, Brooks L, Hu AJ, Jahja M, McDonald D, Narasimhan B, Politsch C, Rajanala S, Rumack A, Simon N, Tibshirani RJ, Tibshirani R, Ventura V, Wasserman L, O'Dea EB, Drake JM, Pagano R, Tran QT, Ho LST, Huynh H, Walker JW, Slayton RB, Johansson MA, Biggerstaff M, and Reich NG
- Subjects
- Data Accuracy, Forecasting, Humans, Pandemics, Probability, Public Health trends, United States epidemiology, COVID-19 mortality
- Abstract
Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.
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- 2022
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10. America First populism, social volatility, and self-reported arrests.
- Author
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Levi R, Sendroiu I, and Hagan J
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Attitude, Female, Humans, Male, Middle Aged, Poverty, Self Report, United States, Young Adult, Crime statistics & numerical data, Politics, Social Change, Xenophobia
- Abstract
Despite research on the causes of populism and on the narratives of populist leaders, there is little empirical work on the relationship between populist attitudes and behavior, notably including criminal behavior. Our overarching concern is the recurrent social volatility of metaphorical populist themes that are central to impactful political messaging. Drawing on a national United States survey conducted around the 2016 election, we use multilevel models to show that the politically charged exclusionary boundaries of "America First" populism are behaviorally connected to increased odds of having been arrested. We argue that the rapid redrawing of social boundaries that make up populist attitudes is closely connected with the effects of economic and political frustrations during times of rapid social change. In the process, we develop a behavioral analysis of the social volatility of the recurrent populist movement in America., Competing Interests: The authors declare no competing interest.
- Published
- 2020
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11. The impact of unifying agricultural wholesale markets on prices and farmers' profitability.
- Author
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Levi R, Rajan M, Singhvi S, and Zheng Y
- Abstract
As a leading effort to improve the welfare of smallholder farmers, several governments have led major reforms in improving market access for these farmers through online agricultural platforms. Leveraging collaboration with the state government of Karnataka, India, this paper provides an empirical assessment on the impact of such a reform-implementation of the Unified Market Platform (UMP)-on market prices and farmers' profitability. UMP was created in 2014 to unify all trades in the agricultural wholesale markets of the state to be carried out within a single platform. By November 2019, 62.8 million metric tons of commodities valued at $21.7 billion (USD) have been traded on UMP. Employing a difference-in-differences method, we demonstrate that the impact of UMP on modal prices varies substantially across commodities. In particular, the implementation of UMP has yielded an average 5.1%, 3.6%, and 3.5% increase in the modal prices of paddy, groundnut, and maize. Furthermore, UMP has generated a greater benefit for farmers who produce higher-quality commodities. Given low profit margins of smallholder farmers (2 to 9%), the range of profit improvement is significant (36 to 159%). In contrast, UMP has no statistically significant impact on the modal prices of cotton, green gram, or tur. Using detailed market data from UMP, we analyze how features related to logistical challenges, bidding efficiency, in-market concentration, and the price discovery process differ between commodities with and without a significant price increase due to UMP. These analyses lead to several policy insights regarding the design of similar agri-platforms in developing countries., Competing Interests: Competing interest statement: M.R. is the Managing Director & CEO of Rashtriya e Market Services Private Limited.
- Published
- 2020
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12. Mast cell renin and a local renin-angiotensin system in the airway: role in bronchoconstriction.
- Author
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Veerappan A, Reid AC, Estephan R, O'Connor N, Thadani-Mulero M, Salazar-Rodriguez M, Levi R, and Silver RB
- Subjects
- Angiotensin II biosynthesis, Angiotensin II physiology, Animals, Bronchi metabolism, Bronchi physiology, Cell Degranulation physiology, Guinea Pigs, Humans, Lung enzymology, Lung metabolism, Lung physiology, Male, Mast Cells metabolism, Mast Cells physiology, Muscle Contraction physiology, Muscle, Smooth cytology, Muscle, Smooth metabolism, Muscle, Smooth physiology, Rats, Rats, Sprague-Dawley, Receptor, Angiotensin, Type 1 metabolism, Renin chemistry, Renin genetics, Renin physiology, Bronchi enzymology, Bronchoconstriction physiology, Mast Cells enzymology, Renin metabolism, Renin-Angiotensin System physiology
- Abstract
We previously reported that mast cells express renin, the rate-limiting enzyme in the renin-angiotensin cascade. We have now assessed whether mast cell renin release triggers angiotensin formation in the airway. In isolated rat bronchial rings, mast cell degranulation released enzyme with angiotensin I-forming activity blocked by the selective renin inhibitor BILA2157. Local generation of angiotensin (ANG II) from mast cell renin elicited bronchial smooth muscle contraction mediated by ANG II type 1 receptors (AT(1)R). In a guinea pig model of immediate type hypersensitivity, anaphylactic mast cell degranulation in bronchial rings resulted in ANG II-mediated constriction. As in rat bronchial rings, bronchoconstriction (BC) was inhibited by a renin inhibitor, an AT(1)R blocker, and a mast cell stabilizer. Anaphylactic release of renin, histamine, and beta-hexosaminidase from mast cells was confirmed in the effluent from isolated, perfused guinea pig lung. To relate the significance of this finding to humans, mast cells were isolated from macroscopically normal human lung waste tissue specimens. Sequence analysis of human lung mast cell RNA showed 100% homology between human lung mast cell renin and kidney renin between exons 1 and 10. Furthermore, the renin protein expressed in lung mast cells was enzymatically active. Our results demonstrate the existence of an airway renin-angiotensin system triggered by release of mast-cell renin. The data show that locally produced ANG II is a critical factor governing BC, opening the possibility for novel therapeutic targets in the management of airway disease.
- Published
- 2008
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13. Mast cells: a unique source of renin.
- Author
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Silver RB, Reid AC, Mackins CJ, Askwith T, Schaefer U, Herzlinger D, and Levi R
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- Animals, Cell Line, Female, Gene Expression, Humans, Kidney cytology, Kidney metabolism, Male, Microscopy, Confocal, Myocardium cytology, Myocardium metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Mast Cells metabolism, Renin metabolism
- Abstract
In addition to the traditional renin-angiotensin system, a great deal of evidence favors the existence of numerous independent tissue-specific renin-angiotensin systems. We report that mast cells are an additional source of renin and constitute a unique extrarenal renin-angiotensin system. We use renin-specific antibodies to demonstrate that cardiac mast cells contain renin. Extending this observation to the human mast cell line HMC-1, we show that these mast cells also express renin. The HMC-1 renin RT-PCR product is 100% homologous to Homo sapiens renin. HMC-1 cells also contain renin protein, as demonstrated both by immunoblot and immunocytochemical analyses. Renin released from HMC-1 cells is active; furthermore, HMC-1 cells are able to synthesize renin. It is known that, in the heart, mast cells are found in the interstitium in close proximity to nerves and myocytes, which both express angiotensin II receptors. Inasmuch as myocardial interstitium contains angiotensinogen and angiotensin-converting enzyme, and because we were able to detect renin only in mast cells, we postulate that the release of renin from cardiac mast cells is the pivotal event triggering local formation of angiotensin II. Because of the ubiquity of mast cells, our results represent a unique paradigm for understanding local renin-angiotensin systems, not just in the heart, but in all tissues. Our findings provide a rationale for targeting mast cells in conjunction with renin-angiotensin system inhibitors in the management of angiotensin II-related dysfunctions.
- Published
- 2004
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14. Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings.
- Author
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Silver RB, Poonwasi KS, Seyedi N, Wilson SJ, Lovenberg TW, and Levi R
- Subjects
- Animals, Calcium pharmacology, Calcium Channel Blockers pharmacology, Cell Line, Dose-Response Relationship, Drug, Guinea Pigs, Histamine Agonists pharmacology, Humans, Imidazoles pharmacology, Male, Myocardial Ischemia, Neuroblastoma metabolism, Norepinephrine metabolism, Potassium metabolism, Thiourea pharmacology, Time Factors, Transfection, Tumor Cells, Cultured, omega-Conotoxins metabolism, omega-Conotoxins pharmacology, Calcium metabolism, Exocytosis, Myocardium metabolism, Neurons metabolism, Norepinephrine pharmacology, Receptors, Histamine H3 metabolism, Thiourea analogs & derivatives
- Abstract
Activation of presynatic histamine H(3) receptors (H(3)R) down-regulates norepinephrine exocytosis from cardiac sympathetic nerve terminals, in both normal and ischemic conditions. Analogous to the effects of alpha(2)-adrenoceptors, which also act prejunctionally to inhibit norepinephrine release, H(3)R-mediated antiexocytotic effects could result from a decreased Ca(2+) influx into nerve endings. We tested this hypothesis in sympathetic nerve terminals isolated from guinea pig heart (cardiac synaptosomes) and in a model human neuronal cell line (SH-SY5Y), which we stably transfected with human H(3)R cDNA (SH-SY5Y-H(3)). We found that reducing Ca(2+) influx in response to membrane depolarization by inhibiting N-type Ca(2+) channels with omega-conotoxin (omega-CTX) greatly attenuated the exocytosis of [(3)H]norepinephrine from both SH-SY5Y and SH-SY5Y-H(3) cells, as well as the exocytosis of endogenous norepinephrine from cardiac synaptosomes. Similar to omega-CTX, activation of H(3)R with the selective H(3)R-agonist imetit also reduced both the rise in intracellular Ca(2+) concentration (Ca(i)) and norepinephrine exocytosis in response to membrane depolarization. The selective H(3)R antagonist thioperamide prevented this effect of imetit. In the parent SH-SY5Y cells lacking H(3)R, imetit affected neither the rise in Ca(i) nor [(3)H]norepinephrine exocytosis, demonstrating that the presence of H(3)R is a prerequisite for a decrease in Ca(i) in response to imetit and that H(3)R activation modulates norepinephrine exocytosis by limiting the magnitude of the increase in Ca(i). Inasmuch as excessive norepinephrine exocytosis is a leading cause of cardiac dysfunction and arrhythmias during acute myocardial ischemia, attenuation of norepinephrine release by H(3)R agonists may offer a novel therapeutic approach to this condition.
- Published
- 2002
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15. Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: a novel protective mechanism in myocardial ischemia.
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Silver RB, Mackins CJ, Smith NC, Koritchneva IL, Lefkowitz K, Lovenberg TW, and Levi R
- Subjects
- Animals, Cell Line, Myocardial Ischemia metabolism, Myocardial Ischemia prevention & control, Neurons metabolism, Receptors, Histamine H3 metabolism, Sodium-Hydrogen Exchangers metabolism
- Abstract
In myocardial ischemia, adrenergic nerves release excessive amounts of norepinephrine (NE), causing dysfunction and arrhythmias. With anoxia and the concomitant ATP depletion, vesicular storage of NE is impaired, resulting in accumulation of free NE in the axoplasm of sympathetic nerves. Intraneuronal acidosis activates the Na(+)/H(+) exchanger (NHE), leading to increased Na(+) entry in the nerve terminals. These conditions favor availability of the NE transporter to the axoplasmic side of the membrane, causing massive carrier-mediated efflux of free NE. Neuronal NHE activation is pivotal in this process; NHE inhibitors attenuate carrier-mediated NE release. We previously reported that activation of histamine H(3) receptors (H(3)R) on cardiac sympathetic nerves also reduces carrier-mediated NE release and alleviates arrhythmias. Thus, H(3)R activation may be negatively coupled to NHE. We tested this hypothesis in individual human SKNMC neuroblastoma cells stably transfected with H(3)R cDNA, loaded with the intracellular pH (pH(i)) indicator BCECF. These cells possess amiloride-sensitive NHE. NHE activity was measured as the rate of Na(+)-dependent pH(i) recovery in response to an acute acid pulse (NH(4)Cl). We found that the selective H(3)R-agonist imetit markedly diminished NHE activity, and so did the amiloride derivative EIPA. The selective H(3)R antagonist thioperamide abolished the imetit-induced NHE attenuation. Thus, our results provide a link between H(3)R and NHE, which may limit the excessive release of NE during protracted myocardial ischemia. Our previous and present findings uncover a novel mechanism of cardioprotection: NHE inhibition in cardiac adrenergic neurons as a means to prevent ischemic arrhythmias associated with carrier-mediated NE release.
- Published
- 2001
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