lu-302872 and Hypertension

Angiotensin II and endothelin-1 (ET) are two hormones involved in cardiovascular diseases and well known for their capacity to induce free radical generation in vascular and cardiac tissues. In addition to its prooxidative effect, angiotensin II can increase the synthesis of ET-1 in vascular smooth muscle cells (VSMC). Our objective was to determine whether the ET-1 synthesis in VSMC is involved in angiotensin II-induced superoxide anion production in rats. Our results show that treatments of isolated VSMC with angiotensin II and ET increased superoxide. However, this increase occurred in a bimodal fashion for angiotensin II with a fast transient production (10 min) and a late sustained production (6 h), while ET-1 induced superoxide formation after a delay of 6 h. LU302872 and BQ-123, a nonselective and a selective ETA receptor antagonists, respectively, prevented angiotensin II-induced superoxide anion production only during the late phase. In contrast, BQ-3020, a selective ETB receptor antagonist, had no effect. In vivo, LU302872 reduced the aortic superoxide production induced by angiotensin II administered for 12 days. In conclusion, our results suggest that the superoxide generation induced by chronic angiotensin II infusion may be mediated by ET-1 acting on ETA receptors in VSMC in vitro. Furthermore, this effect appears to contribute to the excess superoxide production during the chronic activation of the renin-angiotensin system in vivo.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Cells, Cultured; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; In Vitro Techniques; Male; Muscle, Smooth, Vascular; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; NADPH Oxidase 4; NADPH Oxidases; Peptides, Cyclic; Propionates; Pyrimidines; Rats; Rats, Sprague-Dawley; Superoxides

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

Topics: Angiotensin II; Animals; Coronary Circulation; Desoxycorticosterone; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Heart; Hypertension; In Vitro Techniques; Male; Nephrectomy; Oligopeptides; Propionates; Pyrimidines; Rats; Rats, Sprague-Dawley; Signal Transduction; Sodium Chloride; Vasoconstriction; Vasoconstrictor Agents; Vasopressins