Analysis of the genetic basis of the endothelium-dependent impaired vasorelaxation in the stroke-prone spontaneously hypertensive rat: a candidate gene approach

Objective To investigate the role of potential candidate genes in the patho genesis of the endothelium-dependent impaired vasorelaxation that associate s and co-segregates with stroke in the stroke-prone spontaneously hypertens ive rat (SHRsp) compared with the stroke-resistant SHR (SHRsr). Design and methods An SHRsp/SHRsr F-2-intercross (n = 137; 64 males, 73 fem ales) was obtained and, at the age of 6 weeks, it was placed under a stroke permissive Japanese-style diet for 4 weeks. At the end of the treatment, t he vascular function of each rat was characterized. The maximal vasorelaxat ion to acetylcholine after maximal vasoconstriction (delta ratio) was consi dered as the quantitative phenotype, The following candidate genes were rel ated to the delta ratio: renin, angiotensinogen, angiotensin-converting enz yme, angiotensin II AT(1b) receptor, atrial natriuretic peptide, brain natr iuretic peptide, atrial natriuretic peptide GC-A receptor, kallikrein, endo thelial nitric oxide synthase, In addition, polymorphic markers located ins ide areas of the rat genome where other candidates (i.e. adrenomedullin, en dothelin, Ang II AT1 a receptor) are known to map were included. Results The endothelial vascular dysfunction of the SHRsp showed a variable distribution among SHRsp/SHRsr F-2 descendants, independently from the blo od pressure levels. A genotype/phenotype co-segregation analysis for each o f the genes tested did not show any statistically significant co-segregatio n with the vascular phenotype. Conclusion A candidate gene approach used to investigate the genetic basis of the endothelial-dependent vascular dysfunction of the SHRsp strain did n ot reveal any evidence to support the hypothesis that the genes tested play any role in the pathogenesis of the stroke-related vascular abnormality. J Hypertens 2000, 18:161-165 (C) Lippincott Williams & Wilkins.