Modulation by the Endothelium of the Inhibitory Effects of Pinacidil and Nimodipine on Endothelin‐Induced Contraction in Cerebral Arteries

Abstract

Abstract:The effects of pinacidil and nimodipine on endothelin-I-induced contractions in isolated cerebral arteries with and without endothelium were compared. The sensitivity to endothelin-1 was increased (0.5 log units) in the rabbit basilar artery after removal of the endothelium. The nitric oxide synthase inhibitor Nw-nitro-L-arginine (0.1 mM) also increased the sensitivity to endothelin-1 (0.6 log units) in basilar arteries with endothelium, whereas Nw-nitro-D-arginine (0.1 mM) and indomethacin (3 pM) had no effect, indicating that withdrawal of endothelium-derived nitric oxide may account for the enhancement of the endothelin-1 -induced contraction after endothelial denudation. Pinacidil (1 pM) shifted the concentration-response curve for endothelin-1 to the right without affecting the maximal response in arteries without endothelium, but had no effect on the endothelin-1-induced contraction in vessels with endothelium. Nimodipine (1 FM) reduced the maximal endothelin-1-induced contraction by approximately 50% in both the presence and absence of endothelium, whereas the sensitivity to endothelin-1 was reduced only in vessels without endothelium. Incubation in "calcium-free" medium reduced the maximal endothelin-I-induced contraction by 69% and 80% in vessels with and without endothelium, respectively. In human pial arteries with endothelium, pinacidil did not affect the endothelin-linduced contraction, whereas nimodipine and exposure to "calcium-free" solution reduced the maximal response by 3 1% and 74%, respectively. The results show that, in the rabbit, pinacidil and to a lesser extent nimodipine preferentially act on cerebral arteries with disrupted endothelium, indicating that vasoactive factors liberated from the endothelium may modify the effect of a vasodilator.

Mechanisms underlying diabetes enhancement of endothelin-1-induced contraction in rabbit basilar artery

“…These results are in accordance with results of previous work performed with cerebral arteries of non-diabetic animals (Salom et al, 1991;Petersson et al, 1997). In arteries from diabetic rabbits, endothelium denudation also displaced to the left the concentration -response curve for endothelin-1, without significant changes in the maximal contraction, suggesting a lower modulatory role of endothelium in the diabetic state.…”

Neuroinflammation in the rat – CNS cells and their role in the regulation of immune reactions

“…Class Ib molecules are also important for the interaction with NK cells (reviewed in 89). This interaction is generally thought to suppress NK cell activation, but this is not a rule as class Ib molecules have been demonstrated to mediate alloreactions with activation of NK cells in the rat (90,91). Interestingly, results supporting a role for expression of MHC class I in the nervous system other than solely pertaining to immune functions have recently emerged.…”