Physiol. Res.  52: 689-700, 2003

Gender-Specific Genetic Determinants of Blood Pressure and Organ Weight: Pharmacogenetic Approach     

T. UENO1, J. TREMBLAY1, J. KUNEŠ2,3, J. ZICHA2,3, Z. DOBEŠOVÁ2,3, Z. PAUSOVA1, A.Y. DENG1, Y. SUN1, H. J. JACOB4, P. HAMET1

1Centre de recherche, Centre hospitalier de l’Université de Montréal-Hôtel-Dieu, Montréal, Québec, Canada, 2Institute of Physiology AS CR, Prague, Czech Republic, 3Center for Experimental Research of Cardiovascular Diseases, Prague, Czech Republic, 4Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

Received May 21, 2003
Accepted July 24, 2003


Summary
A total genome scan and pharmacogenetic study were designed to search for genetic determinants of blood pressure (BP) as well as heart and kidney weights. Genome scanning was carried out in 266 F2 intercrosses from Prague hypertensive hypertriglyceridemic rats for phenotypes of organ weights, baseline BP, BP after blockade of the renin-angiotensin system (RAS) by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester. Pharmacogenetic analysis showed that, in males, BP was controlled by two loci on chromosomes 1 and 5 (Chr1, Chr5) through the SNS, and these loci showed a positive contribution for relative kidney weight (KW/BW). On the other hand, baseline BP in females was controlled by two loci on Chr3 and Chr7. The effect of these loci was not mediated by the RAS, SNS or NO system. These loci did not show any effect for KW/BW. Negatively-linked loci for KW/BW and relative heart weight (HW/BW) were identified on Chr2 in both genders. Another negatively-linked locus for KW/BW, located on Chr8 in males, affected BP through the SNS. This locus on Chr8 overlapped with a previously-reported modifier locus for polycystic kidney disease (PKD). In conclusion, this pharmacogenetic study determined two loci for BP and relative organ mass implicating sympathetic overactivity. Concordance of the identified locus for KW/BW and BP through the SNS on Chr8 with the PKD locus revealed the importance of this region for renal complications in various diseases.


Key words
Prague hypertriglyceridemic rat • Quantitative trait locus • Heart weight • Kidney weight • Hypertension • Pharmacogenetics


© 2003 by the Institute of Physiology, Czech Academy of Sciences