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

A genetic variant of the gene for the alpha (1)-isoform of Na+-K+-ATPase (A tp1a1) was suggested to be involved in the pathogenesis of salt hypertensio n in Dahl rats through altered Na+:K+ coupling ratio. We studied Na+-K+ pum p activity in erythrocytes of Dahl salt-sensitive (SS/Jr) rats in relation to plasma lipids and blood pressure (BP) and the linkage of polymorphic mic rosatellite marker D2Arb18 (located within intron 1 and exon 2 of Atp1a1 ge ne) with various phenotypes in 130 SS/Jr x SR/Jr F-2 rats. Salt-hypertensiv e SS/Jr rats had higher erythrocyte Na 1 content, enhanced ouabain-sensitiv e (OS) Na+ and Rb+ transport, and higher Na+:Rb+ coupling ratio of the Na+- K+ pump. BP of F-2 hybrids correlated with erythrocyte Na+ content, OS Naextrusion, and OS Na+: Rb+ coupling ratio, but not with OS Rb+ uptake. In F -2 hybrids there was a significant association indicating suggestive linkag e (P< 0.005, LOD score 2.5) of an intragenic marker D2Arb18 with pulse pres sure but not with mean arterial pressure or any parameter of Na+-K+ pump ac tivity (including its Na+:Rb+ coupling ratio). In contrast, plasma choleste rol, which was elevated in salt-hypertensive Dahl rats and which correlated with BP in F2 hybrids, was also positively associated with OS Na+ extrusio n. 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 con clusion, abnormal cholesterol metabolism but not the Atp1a1 gene locus migh t represent an important factor for both high BP and altered Na+-K+ pump fu nction in salt-hypertensive Dahl rats.