Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Oct 15;100(8):2000–2006. doi: 10.1172/JCI119731

A pharmacogenetic approach to blood pressure in Lyon hypertensive rats. A chromosome 2 locus influences the response to a calcium antagonist.

M Vincent 1, N J Samani 1, D Gauguier 1, J R Thompson 1, G M Lathrop 1, J Sassard 1
PMCID: PMC508389  PMID: 9329963

Abstract

In a backcross population (n = 281) derived from a cross of the Lyon hypertensive rat with Lyon normotensive rat, we investigated whether genetic factors influence the acute cardiovascular responses to pharmacological modulation of the renin-angiotensin system, the sympathetic nervous system, and the voltage-sensitive L-type calcium channels. Using microsatellite markers, a quantitative trait locus was identified and mapped on rat chromosome 2 that specifically influences the systolic (peak LOD score 4.4) and diastolic (peak LOD score 4.1) blood pressure responses to administration of a dihydropyridine calcium antagonist, PY108-068. The locus accounted for 10.3 and 10.4% of the total variances in the systolic and diastolic responses to PY108-068, respectively. In marked contrast, the locus had no effect on either basal blood pressure or on the responses to acute administration of a ganglionic blocking agent, trimetaphan, or of an angiotensin II subtype 1 receptor antagonist, losartan. These findings provide strong direct support for the paradigm that genetic factors may influence the response to antihypertensive drugs and suggest that the heterogeneity seen in the responses to different antihypertensive agents in human essential hypertension may have a significant genetic determination.

Full Text

The Full Text of this article is available as a PDF (170.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Clark J. S., Jeffs B., Davidson A. O., Lee W. K., Anderson N. H., Bihoreau M. T., Brosnan M. J., Devlin A. M., Kelman A. W., Lindpaintner K. Quantitative trait loci in genetically hypertensive rats. Possible sex specificity. Hypertension. 1996 Nov;28(5):898–906. doi: 10.1161/01.hyp.28.5.898. [DOI] [PubMed] [Google Scholar]
  2. Deng A. Y., Dene H., Pravenec M., Rapp J. P. Genetic mapping of two new blood pressure quantitative trait loci in the rat by genotyping endothelin system genes. J Clin Invest. 1994 Jun;93(6):2701–2709. doi: 10.1172/JCI117284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Deng A. Y., Dene H., Rapp J. P. Mapping of a quantitative trait locus for blood pressure on rat chromosome 2. J Clin Invest. 1994 Jul;94(1):431–436. doi: 10.1172/JCI117341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dubay C., Vincent M., Samani N. J., Hilbert P., Kaiser M. A., Beressi J. P., Kotelevtsev Y., Beckmann J. S., Soubrier F., Sassard J. Genetic determinants of diastolic and pulse pressure map to different loci in Lyon hypertensive rats. Nat Genet. 1993 Apr;3(4):354–357. doi: 10.1038/ng0493-354. [DOI] [PubMed] [Google Scholar]
  5. Galli J., Li L. S., Glaser A., Ostenson C. G., Jiao H., Fakhrai-Rad H., Jacob H. J., Lander E. S., Luthman H. Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat. Nat Genet. 1996 Jan;12(1):31–37. doi: 10.1038/ng0196-31. [DOI] [PubMed] [Google Scholar]
  6. Gauguier D., Froguel P., Parent V., Bernard C., Bihoreau M. T., Portha B., James M. R., Penicaud L., Lathrop M., Ktorza A. Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nat Genet. 1996 Jan;12(1):38–43. doi: 10.1038/ng0196-38. [DOI] [PubMed] [Google Scholar]
  7. Gu L., Dene H., Deng A. Y., Hoebee B., Bihoreau M. T., James M., Rapp J. P. Genetic mapping of two blood pressure quantitative trait loci on rat chromosome 1. J Clin Invest. 1996 Feb 1;97(3):777–788. doi: 10.1172/JCI118477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gustin M. P., Cerutti C., Paultre C. Z. Heterogeneous computer network for real-time hemodynamic signal processing. Comput Biol Med. 1990;20(3):205–215. doi: 10.1016/0010-4825(90)90006-b. [DOI] [PubMed] [Google Scholar]
  9. Hilbert P., Lindpaintner K., Beckmann J. S., Serikawa T., Soubrier F., Dubay C., Cartwright P., De Gouyon B., Julier C., Takahasi S. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature. 1991 Oct 10;353(6344):521–529. doi: 10.1038/353521a0. [DOI] [PubMed] [Google Scholar]
  10. Jacob H. J., Brown D. M., Bunker R. K., Daly M. J., Dzau V. J., Goodman A., Koike G., Kren V., Kurtz T., Lernmark A. A genetic linkage map of the laboratory rat, Rattus norvegicus. Nat Genet. 1995 Jan;9(1):63–69. doi: 10.1038/ng0195-63. [DOI] [PubMed] [Google Scholar]
  11. Jacob H. J., Lindpaintner K., Lincoln S. E., Kusumi K., Bunker R. K., Mao Y. P., Ganten D., Dzau V. J., Lander E. S. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell. 1991 Oct 4;67(1):213–224. doi: 10.1016/0092-8674(91)90584-l. [DOI] [PubMed] [Google Scholar]
  12. Kurtz T. W., Simonet L., Kabra P. M., Wolfe S., Chan L., Hjelle B. L. Cosegregation of the renin allele of the spontaneously hypertensive rat with an increase in blood pressure. J Clin Invest. 1990 Apr;85(4):1328–1332. doi: 10.1172/JCI114572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lander E. S., Botstein D. Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics. 1989 Jan;121(1):185–199. doi: 10.1093/genetics/121.1.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lander E. S., Green P., Abrahamson J., Barlow A., Daly M. J., Lincoln S. E., Newberg L. A., Newburg L. MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics. 1987 Oct;1(2):174–181. doi: 10.1016/0888-7543(87)90010-3. [DOI] [PubMed] [Google Scholar]
  15. Lindner A., Hinds T. R., Davidson R. C., Vincenzi F. F. Increased cytosolic free calcium in red blood cells is associated with essential hypertension in humans. Am J Hypertens. 1993 Sep;6(9):771–779. doi: 10.1093/ajh/6.9.771. [DOI] [PubMed] [Google Scholar]
  16. Lodwick D., Kaiser M. A., Harris J., Cumin F., Vincent M., Samani N. J. Analysis of the role of angiotensinogen in spontaneous hypertension. Hypertension. 1995 Jun;25(6):1245–1251. doi: 10.1161/01.hyp.25.6.1245. [DOI] [PubMed] [Google Scholar]
  17. Materson B. J., Reda D. J., Cushman W. C., Massie B. M., Freis E. D., Kochar M. S., Hamburger R. J., Fye C., Lakshman R., Gottdiener J. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med. 1993 Apr 1;328(13):914–921. doi: 10.1056/NEJM199304013281303. [DOI] [PubMed] [Google Scholar]
  18. Medeiros I. A., Zhang B. L., Bertolino S., Sassard J. Pressure control of renal renin release in Lyon hypertensive rats. J Hypertens. 1994 Aug;12(8):871–877. [PubMed] [Google Scholar]
  19. Orlov S. N., Pokudin N. I., Postnov Y. V. Calcium transport in erythrocytes of rats with spontaneous hypertension. J Hypertens. 1988 Oct;6(10):829–837. [PubMed] [Google Scholar]
  20. Pernot F., Schleiffer R., Bergmann C., Vincent M., Sassard J., Gairard A. Dietary calcium, vascular reactivity, and genetic hypertension in the Lyon rat strain. Am J Hypertens. 1990 Nov;3(11):846–853. doi: 10.1093/ajh/3.11.846. [DOI] [PubMed] [Google Scholar]
  21. Pernot F., Schleiffer R., Vincent M., Sassard J., Gairard A. Parathyroidectomy in the Lyon hypertensive rat: cardiovascular reactivity and aortic responsiveness. J Hypertens. 1990 Dec;8(12):1111–1117. doi: 10.1097/00004872-199012000-00007. [DOI] [PubMed] [Google Scholar]
  22. Pravenec M., Gauguier D., Schott J. J., Buard J., Kren V., Bila V., Szpirer C., Szpirer J., Wang J. M., Huang H. Mapping of quantitative trait loci for blood pressure and cardiac mass in the rat by genome scanning of recombinant inbred strains. J Clin Invest. 1995 Oct;96(4):1973–1978. doi: 10.1172/JCI118244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rapp J. P., Wang S. M., Dene H. A genetic polymorphism in the renin gene of Dahl rats cosegregates with blood pressure. Science. 1989 Jan 27;243(4890):542–544. doi: 10.1126/science.2563177. [DOI] [PubMed] [Google Scholar]
  24. Rubattu S., Volpe M., Kreutz R., Ganten U., Ganten D., Lindpaintner K. Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. Nat Genet. 1996 Aug;13(4):429–434. doi: 10.1038/ng0896-429. [DOI] [PubMed] [Google Scholar]
  25. Samani N. J., Gauguier D., Vincent M., Kaiser M. A., Bihoreau M. T., Lodwick D., Wallis R., Parent V., Kimber P., Rattray F. Analysis of quantitative trait loci for blood pressure on rat chromosomes 2 and 13. Age-related differences in effect. Hypertension. 1996 Dec;28(6):1118–1122. doi: 10.1161/01.hyp.28.6.1118. [DOI] [PubMed] [Google Scholar]
  26. Samani N. J., Lodwick D., Vincent M., Dubay C., Kaiser M. A., Kelly M. P., Lo M., Harris J., Sassard J., Lathrop M. A gene differentially expressed in the kidney of the spontaneously hypertensive rat cosegregates with increased blood pressure. J Clin Invest. 1993 Aug;92(2):1099–1103. doi: 10.1172/JCI116616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Saunders E., Weir M. R., Kong B. W., Hollifield J., Gray J., Vertes V., Sowers J. R., Zemel M. B., Curry C., Schoenberger J. A comparison of the efficacy and safety of a beta-blocker, a calcium channel blocker, and a converting enzyme inhibitor in hypertensive blacks. Arch Intern Med. 1990 Aug;150(8):1707–1713. [PubMed] [Google Scholar]
  28. Serikawa T., Kuramoto T., Hilbert P., Mori M., Yamada J., Dubay C. J., Lindpainter K., Ganten D., Guénet J. L., Lathrop G. M. Rat gene mapping using PCR-analyzed microsatellites. Genetics. 1992 Jul;131(3):701–721. doi: 10.1093/genetics/131.3.701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Su D. F., Cerutti C., Barrès C., Vincent M., Sassard J. Blood pressure and baroreflex sensitivity in conscious hypertensive rats of Lyon strain. Am J Physiol. 1986 Dec;251(6 Pt 2):H1111–H1117. doi: 10.1152/ajpheart.1986.251.6.H1111. [DOI] [PubMed] [Google Scholar]
  30. Zha H., Wilder R. L., Goldmuntz E. A., Cash J. M., Crofford L. J., Mathern P., Remmers E. F. Linkage map of 10 polymorphic markers on rat chromosome 2. Cytogenet Cell Genet. 1993;63(2):117–123. doi: 10.1159/000133514. [DOI] [PubMed] [Google Scholar]
  31. Zicha J., Pernollet M. G., Kunes J., Lacour B., Vincent M., Sassard J., Devynck M. A. Alterations of cytosolic calcium in platelets and erythrocytes of Lyon hypertensive rats. Am J Hypertens. 1995 Aug;8(8):842–849. doi: 10.1016/0895-7061(95)00121-5. [DOI] [PubMed] [Google Scholar]
  32. van Hooft I. M., Grobbee D. E., Frölich M., Pols H. A., Hofman A. Alterations in calcium metabolism in young people at risk for primary hypertension. The Dutch Hypertension and Offspring Study. Hypertension. 1993 Mar;21(3):267–272. doi: 10.1161/01.hyp.21.3.267. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES