Preproendothelin-1 gene polymorphism is related to a change in vascular reactivity in the human mammary artery in vitro.
A gene polymorphism of preproendothelin-1 (a G-to-T transversion that predicts a Lys/Asn change at codon 198) associated with an increased risk of hypertension has been recently described in patients carrying the T allele. No study has yet determined the impact of this polymorphism on vascular reactivity, although a functional role for endothelin-1 in the pathophysiology of hypertension has been clarified. At subthreshold concentrations, endothelin-1 and angiotensin II induce a potentiation of alpha-adrenergic-dependent vascular tone caused by an increased sensitivity of the contractile apparatus to calcium. We investigated phenylephrine-induced tone and its amplification by endothelin-1 and angiotensin II in human mammary artery rings in vitro. Contractions to phenylephrine (0.1 to 100 micromol) and endothelin-1 (0.1 to 300 nmol) were not significantly different in rings from GT/TT (n=27) and GG (n=21) patients. A subthreshold concentration of endothelin-1 (10 pmol) potentiated a phenylephrine-induced contraction (eg, 44 +/- 12% increase in tone with phenylephrine 1 micromol/L, P<0.001) that was significantly higher in the GT/TT group than in the GG group (eg, 44 +/- 12% versus 82 +/- 11%, P<0.01). A similar effect on response to phenylephrine was observed with a subthreshold concentration of angiotensin II. We also found a higher response to calcium in arteries from GT/TT patients. Endothelium-dependent or -independent relaxations were unaffected by the genotype. These data suggest that the preproendothelin-1 gene polymorphism is associated with a higher potentiating effect of endothelin-1 and angiotensin II, probably in relation with higher calcium sensitivity. These changes in vascular reactivity might help to understand the relations between this polymorphism and cardiovascular disorders.
Iglarz
Marc
M
Institut National de la Santé et de la Recherche Médicale (INSERM) U 541,IFR Circulation-Paris VII, Université Paris VII, Paris, France.
Benessiano
Joëlle
J
Philip
Ivan
I
Vuillaumier-Barrot
Sandrine
S
Lasocki
Sigismond
S
Hvass
Ulrich
U
Durand
Geneviève
G
Desmonts
Jean-Marie
JM
Lévy
Bernard I
BI
Henrion
Daniel
D
D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D000804:Angiotensin II / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology; D016232:Endothelins / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008323:Mammary Arteries / Q000187:drug effects / Q000502:physiology*; D008875:Middle Aged; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011498:Protein Precursors / Q000235:genetics*; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D009599:Nitroprusside; D010656:Phenylephrine; D000109:Acetylcholine