Correlation between vascular responsivensss and expression of novel transcripts of the ETA-receptor in human vascular tissue.
Alternatively spliced endothelin (ET-1) receptor transcripts have been identified, but their significance to the functional effects of ET-1 has not been established. We have investigated the presence and influence of alternatively spliced ET(A) receptor transcripts on ET-1 mediated contraction of segments of human saphenous vein. The expression of ET(A) receptor transcripts was examined with quantitative reverse transcription-polymerase chain reaction (qPCR) studies, while the response of veins to ET-1 was tested with in vitro organ bath techniques. The expression of four different transcripts for the ET(A) receptor, in which either exon 3 is spliced out (Delta3), exon 4 is spliced out (Delta4), both 3 and 4 spliced out (Delta3,4) and when both exons 2 and 4 (Delta2,4) are spliced out were identified. Functional studies showed that a lack of efficacy and potency of ET-1 is associated with a significantly lower expression of the Delta3,4 transcript. ET(A) receptor antagonism was insurmountable in samples that had lower levels of the Delta3,4 transcript, while samples from patients with higher expression of the Delta3,4 showed surmountable antagonism with BQ123. These results suggest that there is a genetic basis for the variability between individuals for the contractile effect of ET-1 at ET(A) receptors.
Chester
Adrian H
AH
Imperial College London, Heart Science Centre, Harefield Hospital, Harefield, Middlesex, UB9 6JH, United Kingdom. a.chester@imperial.ac.uk
Azam
Robina
R
Felkin
Leanne E
LE
George
Robert
R
Brand
Nigel
N
D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction; D009924:Organ Culture Techniques / Q000379:methods; D010456:Peptides, Cyclic / Q000494:pharmacology; D016133:Polymerase Chain Reaction / Q000379:methods; D044022:Receptor, Endothelin A / Q000235:genetics* / Q000378:metabolism; D012501:Saphenous Vein / Q000187:drug effects / Q000502:physiology*
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; C072247:cyclo(Trp-Asp-Pro-Val-Leu)