Altered Na+-K+ pump activity and plasma lipids in salt-hypertensive Dahl rats: relationship to Atp1a1 gene

Abstract

A genetic variant of the gene for the α1-isoform of Na+-K+-ATPase ( Atp1a1) was suggested to be involved in the pathogenesis of salt hypertension in Dahl rats through altered Na+:K+ coupling ratio. We studied Na+-K+ pump activity in erythrocytes of Dahl salt-sensitive (SS/Jr) rats in relation to plasma lipids and blood pressure (BP) and the linkage of polymorphic microsatellite marker D2Arb18 (located within intron 1 and exon 2 of Atp1a1 gene) with various phenotypes in 130 SS/Jr × SR/Jr F2 rats. Salt-hypertensive SS/Jr rats had higher erythrocyte Na+ content, enhanced ouabain-sensitive (OS) Na+ and Rb+ transport, and higher Na+:Rb+ coupling ratio of the Na+-K+ pump. BP of F2 hybrids correlated with erythrocyte Na+ content, OS Na+ extrusion, and OS Na+:Rb+ coupling ratio, but not with OS Rb+ uptake. In F2 hybrids there was a significant association indicating suggestive linkage ( P < 0.005, LOD score 2.5) of an intragenic marker D2Arb18 with pulse pressure but not with mean arterial pressure or any parameter of Na+-K+ pump activity (including its Na+:Rb+ coupling ratio). In contrast, plasma cholesterol, which was elevated in salt-hypertensive Dahl rats and which correlated with BP in F2 hybrids, was also positively associated with OS Na+ extrusion. The abnormal Na+:K+ stoichiometry of the Na+-K+ pump is a consequence of elevated erythrocyte Na+ content and suppressed OS Rb+:K+ exchange. In conclusion, abnormal cholesterol metabolism but not the Atp1a1 gene locus might represent an important factor for both high BP and altered Na+-K+ pump function in salt-hypertensive Dahl rats.