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

JOSEF ZICHA¹, CERVANTES D. NEGRIN², ZDENA DOBEOVÁ¹, FIONA CARR², MARTINA VOKURKOVÁ¹, MARTIN W. MCBRIDE¹, JAROSLAV KUNE¹ and ANNA F. DOMINICZAK²

¹ Institute of Physiology, Academy of Sciences of the Czech Republic, Center for Experimental Research of Cardiovascular Diseases, CZ-142 20 Prague, Czech Republic
² Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow G11 6NT, United Kingdom

A genetic variant of the gene for the ₁-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 x 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.

F₂ hybrids; erythrocyte ion transport; erythrocyte sodium content; plasma cholesterol; rat chromosome 2; ₁-Na⁺-K⁺-ATPase gene

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