Central effects of endothelin and its antagonists on sympathetic and cardiovascular regulation in SHR-SP

Intracerebroventricular injections of endothelin-1 (ET-1) are reported to c ause dose-related increases in sympathetic nerve activity and blood pressur e in anesthetized normotensive rats. These studies were performed to determ ine the following: which endothelin receptor, A or B, is involved in mediat ing sympathetic and cardiovascular effects of ET-1 injected centrally; whet her central endothelin tonically participates in blood pressure regulation in normotensive rats; and whether the altered endothelin system in the cent ral nervous system contributes to blood pressure elevation in hypertensive rats. ET-1, ET-A antagonist (BQ-123), or ET-B antagonist (RES-701-1) was in jected into the lateral cerebral ventricle (i.c.v.) of urethane-anesthetize d normotensive Wistar and Wistar-Kyoto (WKY) rats, spontaneously hypertensi ve rats (SHRs), and stroke-prone SHRs (SHR-SPs). In Wistar rats, i.c.v. inj ections of ET-1 (1, 5, 10 pmol) consistently increased sympathetic nerve ac tivity, thereby elevating blood pressure in a dose-related manner. The pres ser responses induced by i.c.v. ET-1 were abolished after intravenous pretr eatment with phentolamine. Neither ET-A nor ET-B antagonist, when injected centrally, altered basal levels of sympathetic nerve activity, heart rate, or blood pressure in Wistar rats. However, sympathetic activation and press er responses induced by i.c.v. injection of endothelin were completely abol ished after i.c.v. pretreatment with ET-A antagonist but were unaffected af ter pretreatment with ET-B antagonist. Although i.c.v. injections of ET-1 i ncreased sympathetic nerve activity and blood pressure in WKY rats, SHRs, a nd SHR-SPs, the magnitudes of these responses did not differ among these th ree groups. In contrast, i.c.v, injections of ET-A antagonist decreased sym pathetic nerve activity, blood pressure, and heart rate only in SHR-SPs, bu t not in WKY rats and SHRs. In addition, the depressor effects of i.c.v. ET -A antagonist in SHR-SPs were ascertained while these rats were awake. In s ummary, i.c.v. injections of ET-1 increased sympathetic nerve activity and blood pressure via ET-A receptors but not via ET-B receptors. Central ET mi ght tonically activate sympathetic nerve activity to thereby contribute to blood pressure elevation in SHR-SPs, but not in WKY rats and SHRs.