ENDOTHELIN-A AND ENDOTHELIN-B RECEPTORS ARE DOWN-REGULATED IN THE HEARTS OF HYPERTENSIVE RATS

Endothelins are vasoactive peptides that have been implicated in the development and maintenance of systemic arterial hypertension. The biologic effects of endothelins result from activation of either or both of the two known endothelin receptor subtypes, A and B [ET-R(A) and ET-R(B)], which are present not only in blood vessels but also throughout the cardiovascular and central nervous systems. To investigate the potential role and regulation of myocardial endothelin receptors in hypertension, we examined the expression of ET-R(A) and ET-R(B) receptors in the hearts of normotensive and hypertensive rats. A cDNA probe for the ETR(A) receptor was obtained by polymerase chain reaction amplification of rat aortic smooth muscle cell mRNA, using degenerate primers specific for intramembrane domains III and VI of G-coupled receptors. Moderate stringency hybridization screening of a rat aortic smooth muscle cell cDNA library yielded a partial clone for the ETR(B) receptor. These two clones were used to examine expression of the ET-R(A) and ET-R(B) receptors in heart, brain, and kidney tissues from Wistar-Kyoto (normotensive), spontaneously hypertensive, salt-hypertensive sensitive, and salt-hypertensive resistant rats by Northern analysis. ET-R(A) and ET-R(B) mRNA were present in the hearts of normal rats. Spontaneously hypertensive rat hearts did not express either ET-R(A) or ET-R(B) mRNA, whereas both salt-hypertensive sensitive and resistant rats fed a high-salt diet expressed both ET-R(A) and ETR(B) receptor mRNAs. Conversely, in the brain of spontaneously hypertensive rats, mRNAs for both ET-R(A) and ET-R(B) mRNA were present. These observations argue for tissue-specific expression of ET-R(A) and ET-R(B) receptors in spontaneously hypertensive rats, and for differences in endothelin receptor regulation among different models of hypertension in the rat.