Abstract
Possible links have been investigated between activation of protein kinase C (PKC) and endothelin (ET) production by small blood vessels. Perfusion pressures were recorded from rat isolated mesenteric artery, with or without the small intestine attached, before and after addition to the perfusate of either ET-1, ET-3 or the PKC activator 12-deoxyphorbol 13-phenylacetate (DOPPA). Rises in perfusion pressure in response to ET-1 (10−8 M)or DOPPA (10−6 M) were reduced significantly by pre-treatment with either the ETA receptor antagonist PD151242 (10−6 M) or the PKC inhibitor Ro 31-8220 (10−6 M). ET-3 (10−8 M) had a significant, albeit small, effect only when the gut was still attached to the mesentery. Inthis latter preparation ET-1 and DOPPA increased the permeability of villi microvessels to colloidal carbon in the perfusate. This effect of DOPPA was reduced by pre-treatment with either PD151242 or Ro 31-8220, but the effects of ET-1 were reduced significantly only by Ro 31-8220. ET-3 (10−8 M) was without effect. The results suggest a possible bi-directional link between ETA receptors and PKC in the intestinal vasculature.
Highlights
Endothelin (ET) isolated from porcine and from human endothelial cells (ECs) was shown to consist of three distinct isopeptides, ET-1, ET-2 and ET-3
The present work was undertaken to seek evidence regarding the possible involvement of ET in this experimental situation, since phorbol esters are well known to activate PKC9,1 and one such has been shown to up-regulate the mRNA for preproendothelin-1 in cultured ECs. 11,12 Phorbol esters have been shown to increase the permeability to injected colloidal carbon of microvessels in rat small intestinal villi in vitro.[7], the effects of ET-1, ET-3 and 12-deoxyphorbol 13-phenylacetate (DOPPA) on perfusion pressure in rat mesenteric arterioles and on the permeability of microvessels to colloidal carbon in rat villi have been compared
ETa receptors have a higher affinity for ET-1 and ET2 than for ET-3, whereas ETB receptors have a similar affinity for all three isopeptides
Summary
Endothelin (ET) isolated from porcine and from human endothelial cells (ECs) was shown to consist of three distinct isopeptides, ET-1, ET-2 and ET-3. It has been suggested recently that the release of ETs, or other vasoconstrictor substances, may be responsible for the slowly developing vasoconstriction elicited by phorbol esters in rat isolated mesenteric arterioles. The present work was undertaken to seek evidence regarding the possible involvement of ET in this experimental situation, since phorbol esters are well known to activate PKC9,1 and one such has been shown to up-regulate the mRNA for preproendothelin-1 in cultured ECs. 11,12 Phorbol esters have been shown to increase the permeability to injected colloidal carbon of microvessels in rat small intestinal villi in vitro.[7], the effects of ET-1, ET-3 and 12-deoxyphorbol 13-phenylacetate (DOPPA) on perfusion pressure in rat mesenteric arterioles and on the permeability of microvessels to colloidal carbon in rat villi have been compared. The effects of pre-treatment with PD151242, an ETA receptor antagonist,[14] and Ro
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