Contribution of endogenous endothelin in the enhanced coronary constriction in DOCA-salt hypertensive rats.
OBJECTIVE
The present study was performed to evaluate the hypersensitivity to vasoconstrictors in coronaries from uninephrectomized hypertensive rats (HTR), after a 2-week deoxycorticosterone acetate (DOCA)-salt treatment, in comparison with uninephrectomized age-matched normotensive rats (NTR).


METHODS
Coronary resistance was recorded from isolated Langendorff hearts perfused at a constant flow rate.


RESULTS
Cumulative dose-response curves to vasopressin, angiotensin II and endothelin in HTR showed an enhanced maximal response, in comparison with NTR (P< 0.05). In contrast, the sensitivity to U-46619, a thromboxane-mimetic agonist, was reduced in HTR in comparison with NTR (P< 0.05). In the presence of ET(A)/ET(B)-receptor antagonists, LU-302 872 (10 micromol/l) and PD-142 893 (0.1-1 micromol/l), cumulative dose-response curves to vasopressin and angiotensin II showed a reduced maximal response in HTR compared with NTR (P< 0.05). LU-302 872 did not change the responsiveness to U-46619 in both groups. Perfusion of hearts from NTR with a subpressor concentration of endothelin-1 (10 pmol/l) potentiated the responsiveness to vasopressin and angiotensin II, but not that of U-46619 (P< 0.05). Hypertension did not alter the dose-response curves obtained with phorbol 12-myristate 13-acetate, an activator of protein kinase C, Bay K 8644, a L-type calcium-channel activator, and KCl. Measurement of endothelin release by radioimmunoassay in the coronary effluent, before and during dose-response curves to vasopressin, angiotensin II and U-46619, showed no significant increase by the vasoconstrictors, although basal endogenous endothelin was increased in HTR (P< 0.05).


CONCLUSIONS
Two-week DOCA-salt hypertension is associated with enhanced coronary vasoconstrictor effects of endothelin, vasopressin and angiotensin II. An increased basal release of endogenous endothelin in coronaries from HTR, along with an enhanced responsiveness of the coronary smooth muscle to endothelin, may contribute to the potentiated response to vasoconstrictors. L-type calcium-channels and protein kinase C are not involved in this increased coronary reactivity to vasoconstrictors in HTR.
Millette
Esther
E
Groupe de recherche sur le système nerveux autonome, Faculté de pharmacie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Quebec, Canada, H3C 3J7.
de Champlain
Jacques
J
Lamontagne
Daniel
D
D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D003326:Coronary Circulation; D003900:Desoxycorticosterone; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000008:administration & dosage / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009392:Nephrectomy / Q000379:methods; D009842:Oligopeptides / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D012965:Sodium Chloride; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000008:administration & dosage; D014667:Vasopressins / Q000008:administration & dosage
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; C113044:LU 224332; D009842:Oligopeptides; D011422:Propionates; D011743:Pyrimidines; D014662:Vasoconstrictor Agents; D014667:Vasopressins; D000804:Angiotensin II; C076213:PD 142893; D003900:Desoxycorticosterone; D012965:Sodium Chloride