Affiliate Faculty, Medical Biotechnology Center
655 W. Baltimore St. BRB 5-007A
Education and Training
B.A. with Honors in Zoology (Cornell University, Ithaca)
M.D. (Washington University, St. Louis)
Post-doctoral (Cambridge University, UK)
With H.A. Schneiderman, D.C. Tosteson, D.E. Goldman, and A.L. Hodgkin.
Associate Professor/Professor of Physiology and Biophysics at Washington University, St. Louis (1968-1980)
Professor and Chairman, Department of Physiology at the University of Maryland School of Medicine, Baltimore (1979-2003)
Director, University of Maryland Center for Heart, Hypertension and Kidney Disease (1985-2014)
Professor of Physiology and Medicine, University of Maryland School of Medicine, Baltimore (1979-present)
Affiliate Professor, Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore (2005-present)
Song, H., Karashima, E., Hamlyn, J.M., and Blaustein, M.P. (2014) Ouabain-digoxin antagonism in rat arteries and neurones. J. Physiol. 592:941-969. PMCID: PMC3948557
Hamlyn, J.M., Linde, C.I., Gao, J., Huang, B.S., Golovina, V.A., Blaustein, M.P., Leenen, F.H.H. (2014) Neuroendocrine humoral and vascular components in the pressor pathway for brain angiotensin II: A new axis in long term blood pressure control. PLoS One PLoS One 9(10):e108916. PMCID: PMC4183521
Blaustein, M.P. (2014) Why isn’t endogenous ouabain more widely accepted? Am. J. Physiol. Heart Circ. Physiol. 307:H635-H639. PMCID: PMC4187390
Blaustein, M.P. (2018) The pump, the exchanger and the holy spirit: Origins and 40 year evolution of ideas about the ouabain-Na+ pump endocrine system. Am. J. Physiol. Cell Physiol. 314: C3-C26. PMCID: PMC5866383
Lu J., Wang, H.-W., Ahmad, M., Keshtkar-Jahromi M., Blaustein, M.P., Hamlyn, J.M., Leenen, F.H.H. (2018) Central and peripheral slow-pressor mechanisms contributing to angiotensin II-salt hypertension in rats. Cardiovasc. Res. 114: 233-245. PMCID: PMC5852508
Zhang, J., J.M. Hamlyn, E. Karashima, H. Raina, J.R.H. Mauban, M. Izuka, R. Berra-Romani, A. Zulian, W.G. Wier, and M.P. Blaustein. (2009) Low Dose Ouabain Constricts Small Arteries from Ouabain-Hypertensive Rats: Implications for Sustained Elevation of Vascular Resistance. Am. J. Physiol., Heart Circ. Physiol. 297:H1140-H1150. PMCID: PMC2755988.
Pulina, M.V., A. Zulian, R. Berra-Romani, O. Beskina, A. Mazzocco-Spezzia, S.G. Baryshnikov, I. Papparella, J.M. Hamlyn, M.P. Blausteinand V.A. Golovina. (2009) Up-regulation of Na+ and Ca2+ transporters in arterial smooth muscle from ouabain hypertensive rats. Am. J. Physiol. Heart Circ. Physiol. 298:H263-H274. PMCID: PMC2806143.
Zhang, J., C. Ren, L. Chen, M.F. Navedo, L.K. Antos, S.P. Kinsey, T. Iwamoto, K.D. Philipson, M.I. Kotlikoff, L.F. Santana, W.G. Wier, D.R. Matteson, and M.P. Blaustein. (2010) Knockout of Na+/Ca2+ exchanger in smooth muscle attenuates vasoconstriction and L-type Ca2+channel current, and lowers blood pressure. Am. J. Physiol. Heart Circ. Physiol. 298:H1472-H1483. PMCID: PMC2867439.
Zhang, J., L. Chen, H. Raina, M.P. Blaustein and W.G. Wier. (2010) In vivo assessment of artery smooth muscle [Ca2+]i and MLCK activity in FRET-based biosensor mice. Am. J. Physiol. Heart Circ. Physiol. 299:H946-H956. PMCID: PMC2944472.
Blaustein, M.P., and J.M. Hamlyn. (2010) Signaling mechanisms that link salt retention to hypertension: Endogenous ouabain, the Na+pump, the Na+/Ca2+ exchanger and TRPC proteins. Biochim. Biophys Acta, 1802:1219–1229. PMCID: PMC2909369.
Blaustein, M.P., Leenen, F.H., Chen, L., Golovina, V.A., Hamlyn, J.M., Pallone, T.L., Van Huysse, J.W., Zhang, J., and Wier, W.G. (2012) How NaCl raises blood pressure: A new paradigm for the pathogenesis of salt-dependent hypertension. Am. J. Physiol. Heart Circ. Physiol. 302: H1031-1049. This was a “featured article” and the subject of an AJP podcast. PMCID: PMC3311458
Linde, C.I., Karashima, E., Raina, H., Zulian, A., Wier, W.G., Hamlyn, J.M., Ferrari, P., Blaustein, M.P., and Golovina, V.A. (2012) Increased arterial smooth muscle Ca2+ signaling, vasoconstriction and myogenic reactivity in Milan hypertensive rats. Am. J. Physiol. Heart Circ. Physiol. 302:H611-H620. PMCID: PMC3353797
Linde, C.I., Antos, L.K., Golovina, V.A., and Blaustein, M.P. (2012) Nanomolar ouabain increases NCX1 expression and enhances Ca2+signaling in human artery myocytes: A mechanism that links salt to increased vascular resistance? Am. J. Physiol. Heart Circ. Physiol. 303: H784–H794. PMCID: PMC3469703
Song, H., Thomspon, S.M., and Blaustein, M.P. (2013) Nanomolar ouabain augments Ca2+ singaling in rate hippocampal neurones and glia. J. Physiol. 591:1671-89. PMID:23297310
Hamlyn, J.M. and Blaustein, M.P. (2013) Salt sensitivity, endogenous ouabain and hypertension. Curr Opin Nephrol Hypertens. Jan; 22(1): 51-58.
Song, H., Thompson, S.M. and Blaustein, M.P. (2013) Nanomolar ouabain augments Ca2+ signaling in rat hippocampal neurones and glia. J. Physiol. 591:1671-1689. PMCID: PMC3624845
Blaustein, M.P., J.P.Y. Kao, and D.R. Matteson. Cellular Physiology and Neurophysiology. 2nd Edition. The Mosby Physiology Monograph Series. Elsevier Mosby, Philadelphia, 337 pages (2012).
Calcium ions play essential roles in most cellular activities, including fertilization, cell division, motility and contraction, excitability and secretion. Moreover, altered Ca2+ regulation and signaling play central roles in many pathological conditions. My current research concerns the regulation of the intracellular Ca2+ concentration and its role in normal and pathological cell signaling in vascular smooth muscle, with a focus on the pathogenesis of salt-dependent hypertension.
The sarcoplasmic/endoplasmic reticulum (S/ER) accumulates and stores Ca2+ for subsequent release as "signal Ca2+". We identified a "signaling complex" region, termed the "PlasmERosome", that regulates Ca2+ storage and signaling. The PLasmERosome consists of three main elements: certain plasma membrane (PM) microdomains, the adjacent "junctional" S/ER (jS/ER), and the tiny pocket of cytosol between the PM and jS/ER. Ca2+ is regulated within this cytosolic region by specific ion channels, transporter isoforms and receptors contained in the PM microdomains. This, in turn, regulates Ca2+ storage and Ca2+ release (i.e., the Ca2+ signals) from the S/ER. We are identifying the component transporters within these complexes and determining how the complexes are organized and how they influence local and global Ca2+ concentrations and signaling. We employ a variety of molecular and cellular biological methods, including digital imaging. Several transgenic mouse lines are used to study cardiovascular parameters in intact animals, and the properties of isolated small arteries, individual myocytes, and cultured myocytes. Our findings are unraveling the molecular links between salt and hypertension.
Specific questions currently being addressed include:
How do mutations in the human alpha-2 and alpha-3 Na+ pumps explain, respectively, the manifestations of familial hemiplegic migraine and rapid onset dystonia with parkinsonism? The native alpha-2 Na+ pumps in primary cultured human and rodent arterial myocytes are being replaced (via transfection) by pumps bearing the human mutations. Digital imaging will be used to determine how cytosolic Na+ and Ca2+ concentrations and Ca2+ storage are altered in the transfected cells.
How does Na+ pump inhibition influence intracellular Ca2+ storage and cell signaling? Low dose ouabain (Na+ pump inhibitor), or knock-out of specific Na+ pump catalytic subunit isoforms, enhance Ca2+ signaling in most cells [Ref. 4, 7], and augment arterial vasoconstriction [Ref. 4]. Novel near-membrane ion-sensitive dyes such as the Na+ pump alpha subunit-conjugated Ca2+-sensitive protein, "G-CaMP" [Ref. 7] and Total Internal Reflective Fluorescence (TIRF) methods are being used to determine the Na+ and Ca2+ concentrations in the sub-PM cytoplasmic compartment between the PM and theS/ER. We are testing the hypothesis that these local ion concentration changes play a critical role in regulating Ca2+ signaling in vascular smooth muscle cells.
How does Ca2+ signaling regulate myogenic tone in small arteries? And, how does this control long-term blood pressure? Our goal is to understand how the mechanisms mentioned above operate in intact preparations. Ca2+ signaling within intact small arteries is being investigated with "real time" confocal microscopy and simultaneous diameter measurement [Refs. 1, 3, 7]. Arteries from normal rats and mice, and from transgenic mice with reduced Na+ pump activity, or reduced or increased Na/Ca exchanger activity, are being studied. Blood pressure and cardiac output are measured in intact, free-moving mice. Our findings are providing novel insight into the molecular mechanisms that link salt retention to high blood pressure [Ref. 1, 4, 5].
The biological preparations we use include: intact rats and mice, isolated small arteries,freshly isolated or cultured arterial smooth muscle cells, primary cultured neurons and glial cells, and neuronal slice cultures. Transgenic animals (e.g., those with knock-out or overexpression of specific Na+ and Ca2+ transporters) as well as normal animals are used.
The techniques we employ include: application of molecular and cell biological methods (e.g., immunoblotting, immunoprecipitation, PCR, and construction of DNAs, adenoviral vectors and anti-sense probes or silencer RNA, patch clamping, and high-resolution digital (fluorescence) microscopy. The latter is used for immunocytochemical detection of ion transporters, and for ion concentration monitoring with ion-sensitive dyes (including novel Ca2+ sensors introduced by transfection). Microscopy methods include standard wide-field and confocal fluorescence, 3-D image reconstruction, and analysis of near-membrane phenomena with lipophilic cation-sensitive indicators, targeted Ca2+-sensitive fluorescent proteins and TIRF. Hemodynamics is studied with telemetry in intact, conscious animals and with echocardiography in lightly anesthetized mice.
John M. Hamlyn, Ph.D. (Professor, Physiology)
Pedro A. Jose, M.D., Ph.D. (Professor, Medicine and Physiology)
W. Gil Wier, Ph.D. (Professor, Physiology)
Frans H.H. Leenen, M.D., Ph.D. (University of Ottawa Heart Institute, Ottawa, Ontario)