Vasoconstrictive peptides and prostanoids have been implicated in the pathogenesis of hypertension and vasospasm. Recently, we have shown that vasopressin (AVP) or angiotensin II (Ang II) stimulates receptor-mediated production of ET-1 and/or PGD2 in endothelium derived from capillaries and microvessels of human brain. These studies indicate that the same specific AVP or Ang II receptors can mediate both the formation of a vasoconstrictor ET-1 and vasodilator prostanoid PGD2. In view of these observations, we investigated the temporal dynamics and cellular mechanisms of ET-1 and prostanoid production induced by either AVP or Ang II in human brain endothelial cells (HBEC). This study demonstrates that both AVP and Ang II stimulated secretion of both immunoreactive ET-1 and prostanoids from HBEC by a receptor-mediated induction of phospholipase C (PLC) and phospholipase A2 (PLA2). The highest level of constitutive or AVP- or Ang II-induced ET-1 was observed after 24 hr incubation of HBEC. The temporal profile of AVP-stimulated production of prostanoids differed from that of Ang II. AVP-induced accumulation of prostaglandin D2 (PGD2) persisted for 24 hr while Ang II- stimulated PGD2 was only seen at 4 hr. Ang II stimulated PGI2 secretion maximally at 8 hr, whereas AVP did not stimulate PGI2 secretion. Dexamethasone (Dxm), indomethacin (Indo), and nordihydroguaiaretic acid (NDGA), the respective inhibitors of PLA2/cyclooxygenase II, cyclooxygenase and lipoxygenase, increased both constitutive and AVP- or Ang II-stimulated secretion of ET-1. Dxm also decreased AVP- or Ang II- stimulated production of PGD2 and prostaglandin F2alpha. The concomitantly observed stimulation of ET-1 and inhibition of prostanoid secretion by either Dxm or NDGA strongly suggest an intercommunication between these events which may play a role in regulating cerebral microvessel function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002689-09
Application #
3782352
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
1993
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code