Previous studies have shown that cinnarizine is an antagonist of several vasoactive drugs including adrenaline, angiotensin and 5-hydroxytryptamine. Cinnarizine inhibits the contraction induced by adrenaline in physiological solution but not that in a calcium-free depolarizing solution. It also inhibits the contraction induced by calcium in depolarizing solution The present experiments were designed to determine whether such inhibition is due to reduction of the permeability of the vascular smooth muscle membrane to Ca++ions.

Calcium appears to act as an intracellular transmitter for excitation-contraction coupling. As far as vascular smooth muscle is concerned, there is an obvious relation between the extracellular calcium concentration and the force of the tonic tension developed in the presence of adrenaline or in an isotonic potassium chloride solution. It has been postulated (DANIEL, 1965) that smooth muscle calcium could be distributed among a labile and a sequestered pool and there are many conflicting opinions regarding the possible role of each of these pools in drug action (GODFRAIND, 1971; GODFRAIND and KABA, 1989; SOMLYO and SOMLYO, 1968). The role of these calcium pools was investigated by the analysis of rat aorta contraction in the absence and in the presence of calcium antagonists and by the study of calcium exchange in resting and stimulated preparations.

1. The Na, K, Ca and Mg content and the 45Ca uptake and loss were determined in rat aortae incubated in physiological solution or in solution containing LaCl3 instead of CaCl2. 2. Aortae washed in La‐solution contained less Ca and Na than controls in physiological solution, the K content was not modified and the Mg content was slightly decreased. 3. In 50 mM‐La solution the 45Ca diffusion space was intermediate between the values found for the [14C]sorbitol space and the [14C]inulin space, indicating that there was no Ca entry within the cell nor Ca binding at superficial sites. 45Ca loss from the tissue was directly related to the La concentration. 4. Noradrenaline increased the rate of uptake of 45Ca into the Ca fraction resistant to displacement by La. This increase was dose dependent, a response of 50% of the maximum being produced by 2 x 10(‐8) noradrenaline as for the contraction. In the presence of phentolamine, the dose‐effect curves for the action of noradrenaline on 45Ca uptake were displaced in a manner characteristic of competitive antagonism. The rhoA2 for phentolamine was 7‐8. 5. In physiological solution, the rate of loss of 45Ca, from the Ca fraction resistant to displacement by La, was increased by noradrenaline the ED50 was 2 x 10(‐8) M, and the effect was abolished by phentolamine. 6. In view of the similarity of phentolamine rhoA2 estimated by measuring noradrenaline sensitive 45Ca uptake or noradrenaline evoked contraction, it is likely that the activation of alpha‐adrenergic receptors is responsible for both effects.

1. Mesenteric arteries immersed in a depolarizing solution contract in the presence of calcium. These contractions are proportional to the calcium concentration and are reversible.2. Mesenteric arteries immersed in a calcium-free depolarizing solution contract in the presence of adrenaline. Under the experimental conditions reported here, this response develops only about one-third of the contractile tension developed in polarizing solution (modified Krebs bicarbonate).3. Cinnarizine and chlorpromazine inhibit the contractile response to calcium and induce relaxation of depolarized muscle previously contracted by calcium; cinnarizine was 4 times more potent than chlorpromazine in such activity.4. Chlorpromazine inhibits the response to adrenaline in both polarizing and calcium-free depolarizing solutions, whereas cinnarizine inhibits the response in polarizing solution but not that in calcium-free depolarizing solution.5. The significance of these results is discussed.

In 1961 Khairallah & Page reported that angiotensin has a direct and an indirect action on the guinea-pig ileum. Their results were confirmed by Robertson & Rubin (1962). The part taken by the cholinergic nerves in this effect was demonstrated using atropine or ganglioplegic drugs. Nevertheless, no evidence was given about the relative importance of these two actions. This paper deals with the demonstration that these actions may be dissociated analysing the shape of the contractile response and its modification by atropine that mainly blocks the indirect action and lidoflazine that appears to be a specific antagonist of the direct action. Lidoflazine, a potent coronary vasodilator (Schaper, Xhonneux, & Jageneau, 1965), has been tested as an angiotensin antagonist by analogy with the action of cinnarizine (Schaper, Jageneau, Xhonneux, Van Nueten, & Janssen, 1963). A preliminary communication on some of this work was made at the joint meeting of the Physiological Society and the Societ6 Belge de Physiologie et Pharmacologie in Louvain in April, 1966. METHODS Guinea-pig ileum preparation Pieces 4 to 5 cm long were cut from the terminal part of the guinea-pig ileum and suspended in a 50 ml. bath containing Tyrode solution at 37° C gassed with 95% O and 5% CO2. The composition of Tyrode solution was as follows: m-mole, NaCl 137, KCI 2.68, CaCl2 1.82, MgCl6 0.105, NaHsPO 0.417, NaHCOs 11.9, glucose 5.55.