Mordecai P Blaustein

..The significance of these effects is heightened by the evidence that ouabain is endogenous in mammals...

..Indeed, that is what is so fascinating and romantic about scientific research. I will describe the discovery of NCX, but will begin by explaining how I got there, and will then discuss how the discovery influenced my career path...

..These several central and peripheral mechanisms are coordinated, in part by EO, to effect and maintain the salt-induced elevation of BP...

..In sum, the reports reviewed here provide novel insight into the molecular mechanisms by which salt retention leads to hypertension...

..Thus, endogenous ouabain, and vascular alpha2 Na+ pumps and NCX1, are critical links between salt and hypertension. New pharmacological agents that act on these molecular links have potential in the clinical management of hypertension...

..In NCX1(SM-/-) mouse artery myocytes, the reduced Ca(2+) entry via NCX1 may lower cytosolic Ca(2+) concentration and thereby reduce MT and BP. The reduced LVGC activity may be the consequence of a low cytosolic Ca(2+) concentration...

..66 nM should raise resistance by approximately 35%. We conclude that dynamic constriction in response to circulating nanomolar ouabain in small arteries likely makes a major contribution to the increased vascular tone and BP in OH rats...

..These molecular and functional changes provide a mechanism for the increased peripheral vascular resistance (whole body autoregulation) that underlies the sustained hypertension...

..This may explain the augmented myogenic responses and enhanced phenylephrine-induced vasoconstriction in OH arteries (83) as well as the high blood pressure in OH rats...

..These ouabain/endogenous ouabain-modulated mechanisms underlie the whole body autoregulation associated with increased vascular resistance and elevation of BP in human, salt-sensitive hypertension...

..Enhanced expression and function of ASM NCX1 and TRPC/Orai1-containing channels in hypertension implies that these proteins are potential targets for pharmacological intervention...

..Similar methods may be useful for studying localized Ca(2+) signals in other subPM microdomains and signals associated with other organelles...

..The results indicate that Mg(2+) relaxes MT by inhibiting Ca(2+) influx through LVGCs. These data provide new information about the central role of Ca(v)1.2 LVGCs in generating and maintaining MT in mouse mesenteric small arteries...

..We conclude that in NCX1(SM-/-) myocytes, reduced Ca(2+) entry via NCX1 lowers cytosolic [Ca(2+)], thereby reducing PKC activation that lowers LVGC activation...

..Accordingly, in salt-dependent hypertension, EOLC probably increases vascular resistance and blood pressure by reducing alpha2 Na(+) pump activity and promoting Ca(2)(+) entry via NCX in myocytes...

..Amino acid substitutions in the 1-120 alpha1 and alpha2 constructs, and in full-length alpha1, revealed that Leu-27 and Ala-35 are essential for targeting/tethering the constructs to PM-S/ER junctions...

..Chronic exposure to ouabain, in vivo, leads to hypertension and DVR endothelial dysfunction, manifested as reduced [Ca(2+)](CYT) responses to both ouabain- and endothelium-dependent vasodilators...

..Based on the observed variance of the FRET data, this method should enable the detection of a difference in basal [Ca(2+)](i) of 29 nM between two groups of 12 mice with a significance of P < 0.05...

..The data suggest that Ca(2+) entry through SOCs helps maintain both myogenic tone and alpha(1)-adrenoceptor-induced tonic vasoconstriction...

..This, in turn, augments adjacent ER Ca(2+) stores and thereby amplifies Ca(2+) signaling without elevating bulk [Na(+)](cyt)...

..These include agents that compete with EO for binding to the Na+ pump and inhibitors of NCX1...

..These PM and ER components appear to be linked through the cytoskeletal spectrin network, to which they are probably tethered by Ank 2...

..Blaustein and colleagues delve into the report and discuss possible explanations for these findings, suggest alternative ones, and advocate for enrolling greater numbers of women in clinical studies...

..As a result of this organization, low-dose ouabain can selectively modulate Na+ and Ca2+ concentrations in the PLasmERosomes and jSR Ca2+ stores, and can thereby regulate Ca2+ signalling...

..The presence of these channels in freshly isolated SMC depends critically on the enzymatic dissociation conditions. This could resolve controversy about the presence of Na+ channels in arterial smooth muscle...

..Fluorescent dyes can also be introduced to visualize a variety of activities, some of which may be specific to vascular smooth muscle cells. This protocol requires about 3 h on each of 2 consecutive days to complete...

..Here we discuss recent observations on mechanisms of salt sensitivity that involve endogenous ouabain and novel pathways in the brain and discuss their possible relationship to arterial and renal function in hypertension...

..3 mutants. These findings indicate that salt-sensitive hypertension is triggered by Ca(2+) entry through NCX1 in arterial smooth muscle and suggest that NCX1 inhibitors might be useful therapeutically...

..This article presents the characteristics of selective and non-selective NCX inhibitors and their therapeutic potential as a new calcium regulator...

..Ca2+ signaling mice should provide significant advantages in the study of processive biological signaling...