Mechanism of Action of Angiotensin Ii on Excitation‐contraction Coupling in the Rat Portal Vein

Abstract

1 The action of angiotensin II (At II) has been studied on the electrical and mechanical activity of the vascular smooth muscle of the rat portal vein. 2 At low concentrations (between 5 x 10l0 and 10-9 M) At II induces an acceleration of spontaneous action potential (AP) discharge without change in the resting membrane potential. The frequency and size of the associated contractions are simultaneously augmented. Under these conditions the size of the spikes is not affected, thus suggesting that At II triggers the release of Ca2+ from internal stores. 3 The increase in AP discharge rate produced by low concentrations of At II results from an acceleration of the pacemaker potential. Furthermore, in the presence of 10mM tetraethylammonium (TEA), there is an acceleration of the repolarizing phase of AP.4 Ouabain (10-3 M) inhibits the increase in rhythmic activity induced by low concentrations of At II (in the presence of 1OmM TEA), thus suggesting that the Na-K pump is directly or indirectly involved in this action of the peptide. 5 At higher concentrations, At II produces a concentration-dependent depolarization with an EC50 of 1.2 x 10-8M and a maximum of 10-7M. The associated contraction has an EC50 of 3.3 x 10-8 Mand a maximum of 3 x 10-7 M. 6 Ouabain (3 x 10-3 M) depolarizes the cell membrane. Under these conditions, At II (10-7 M) has a slight depolarizing effect, but it still produces a large tonic contraction. 7 It is concluded, that At II acts on different steps of excitation-contraction coupling, depending on the concentration. At low levels, the peptide mainly accelerates spike discharge, through a mechanism involving the Na-K pump. At higher concentrations, At II depolarizes the cell membrane. The contraction is then activated by the influx of Ca2+ due to secondary AP discharge and the release of Ca2+ from intracellular stores. Pharmacomechanical coupling has an important role in the triggering of contractions both at high and at low concentrations of At II.

An analysis of the effects of urethane on cardiovascular responsiveness to catecholamines in terms of its interference with Ca++ mobilization from both intra and extracellular pools

“…This is in line with the observation that angiotensin II-induced contractions of vascular smooth muscle are highly dependent upon the mobilization of intracellular Ca + + pools 15,18,42 Urethane exerted a negative inotropic effect on spontaneously beating guinea-pig right atria at concentrations that did not significantly affect their frequency, and at higher concentrations suppressed cardiac beat. Interference with Ca ++ availability for contraction has been proposed as the cellular mechanism(s) underlying its vasodepressant and hypotensive actions in the intact animal 1'2.…”

Angiotensin II-induced delayed stimulation of phospholipase C ?1 requires activation of both phosphatidiylinositol 3-kinase ? and tyrosine kinase in vascular myocytes

“…Myo- [2][3] anti-PLCβ2 (sc-9018), antiPI3Kβ (sc-7175), anti-PI3Kδ (sc-7176), anti-PI3Kγ (sc-7177) and goat polyclonal anti-PI3Kα antibody (sc-1331) were from Santa Cruz Biotechnology (Santa Cruz, CA). Mouse monoclonal anti-PLCγ1 (P-12220), anti-PLCδ1 (P-33820) and antiphosphotyrosine PY20 (P-11230) antibodies were from Transduction Laboratories (BD Sciences, Le Pont de Claix, France).…”

Role of Ionic Currents in the Physiological Response to Angiotensin II

“…At higher concentrations there was a dose-de pendent depolarization of the membrane po tential. Both electrical and mechanical activ ities ceased in the presence of 1 mM Mn2+, suggesting the involvement of Ca2^ in the gen eration of action potentials in this preparation [30]. Zelcer and Sperelakis [63] found that l pM A ll elicited a transient depolarization of rat aortic smooth muscle cells, through a mechanism that required extracellular Na+ and was insensitive to verapamil but blocked by l mM MnCb.…”

“…Hamon and Worcel [30] reported that in the rat portal vein. A ll concentrations between 5 x 10~10 and 10~9 M induced acceleration of mechanical activity and discharge of action potentials without a change in the resting membrane potential.…”

“…A ll stimulates contraction [16,28,30], spontaneous generation of action potentials [30,63] and increases cytosolic-free Ca2+ of vascular smooth muscle [2,21]. Hamon and Worcel [30] reported that in the rat portal vein.…”