Different pathways of calcium sensitization activated by receptor agonists and phorbol esters in vascular smooth muscle

Open Access
Publisher Website
Google Scholar
Abstract
1 It has been shown that receptor agonists and activators of protein kinase C, phorbol esters, increase Ca2+ sensitivity of contractile elements in vascular smooth muscle. To discover if protein kinase C is involved in the agonist-mediated Ca2+ sensitization, we examined the effects of receptor agonists in the rat isolated aorta in which protein kinase C activity had been diminished by pretreatment with phorbol 12-myristate 13-acetate for 24 h. 2 In the aorta with protein kinase C activity, a high concentration (1 μm) of 12-deoxyphorbol 13-isobutyrate induced contraction and a low concentration (100 nm) potentiated high K+-induced contraction. In addition, prostaglandin F2α induced greater contractions than high K+ at a given cytosolic Ca2+ level. The maximally effective concentrations of noradrenaline and endothelin-1 also induced greater contraction than high K+. In the aorta without protein kinase C activity, the contraction induced by 12-deoxyphorbol 13-isobutyrate and its potentiation of the high K+-induced contraction were abolished. However, prostaglandin F2α, noradrenaline and endothelin-1 still induced a greater contraction than high K+. 3 In the aorta without protein kinase C activity, noradrenaline, endothelin-1 and prostaglandin F2α, but not 12-deoxyphorbol 13-isobutyrate, induced contractions in the presence of the Ca2+ channel blocker, verapamil, or in the absence of external Ca2+, by increasing Ca2+ sensitivity. 4 In the permeabilized preparations, inhibition of protein kinase C activity abolished the effect of potentiation of the Ca2+-induced contraction by 12-deoxyphorbol 13-isobutyrate although the potentiation of the contraction by prostaglandin F2α did not change. 5 These results suggest that there are two pathways for Ca2+ sensitization in rat aorta; a protein kinase C-dependent pathway which is activated by phorbol esters, and a protein kinase C-independent pathway which is activated by receptor agonists.