Differential participation of protein kinase C and Rho kinase in α₁-adrenoceptor mediated contraction in rat arteries

Abstract

The major functional alpha1-adrenoceptor in the rat aorta is of the alpha1Dsubtype and that in the caudal artery is of the alpha1A subtype. In the present study, the participation of protein kinase C (PKC) and Rho kinase (RhoK) in contractile responses to stimulation of the alpha1-adrenoceptors in these two arteries was investigated. Both the PKC inhibitor Ro-318220 and the RhoK inhibitor Y-27632 significantly blocked contractile responses of the aorta to phenylephrine (PE) and the selective alpha1A-adrenoceptor agonist A61603. When used in combination, the inhibitors had an additive blocking effect. In the caudal artery, Y-27632 but not Ro-318220 inhibited contractile responses to PE and A61603, and, in combination, the antagonism produced was no greater than that by Y-27632 alone. Contractile responses to direct activation of PKC with phorbol 12,13-dibutyrate were much smaller and levels of CPI-17 (PKC-activated protein phosphatase inhibitor of 17 kDa) were much lower in the caudal artery than the aorta. The results suggest that both PKC and RhoK contribute independently to contractile responses to stimulation of alpha1D-adrenoceptors in the aorta. However, RhoK, but not PKC, participates in contractile responses to stimulation of alpha1A-adrenoceptors in the caudal artery. This difference may largely be due to differences between the two arteries in the extent to which PKC participates in contraction.

Characteristics of myogenic reactivity in isolated rat mesenteric veins

“…Additionally, we showed that reductions in NE responses in the presence of chelerythrine at 2.5 M were significantly greater than corresponding reductions with KCl responses. These findings are in agreement with a demonstrated link of PKC to activation of the adrenergic pathway in VSM, while inhibition of K ϩ -depolarized VSM would imply a more general nonspecific effect on the vessels (35). We therefore conclude that the absence of myogenic reactivity in the presence of chelerythrine at 2.5 M was not explained by the complete suppression of VSM contractility, but rather is due, in part, to the effects of PKC inhibition (53).…”

“…This highlights the important role played by calcium sensitization in myogenic reactivity of veins, which enables vessels to maintain a range of pressure-induced vascular tone without large changes in intracellular calcium (53). Although most studies suggest that PKC and RhoA/Rho kinase pathways are activated independently to cause VSM contraction, cross talk between them has been suggested (35). It is therefore conceivable that inhibition of each of these pathways, i.e., PKC or Rho kinase could produce substantial reductions in myogenic reactivity.…”

Subtypes of functional α1-adrenoceptor

“…In rat tail artery, a1-adrenoceptormediated calcium sensitisation is due mainly to the activation, via the small GTP binding protein RhoA, of Rho kinase [123], which phosphorylates and so inhibits myosin light-chain phosphatase (see [124]) (see Fig. 2).…”

Impact of α1-adrenoceptor expression on contractile properties of vascular smooth muscle cells

“…Recently, this issue has been addressed in a series of experiments on intact blood vessels. This study reported a nonparallelism between ␣ 1 -AR-mediated IP formation and smooth muscle contraction in the rat aorta (12), which is possibly a result of sensitization mediated by intracellular enzymes, such as Rho kinase and PKC (31,48). Moreover, there is convincing evidence for activation of other signaling pathways by ␣ 1 -AR.…”