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Aim: To assess the cytotoxic effects of cobra cardiotoxin (CTX) on rat aorta., Methods: Measure of contractility of aortic rings with or without endothelium., Results: In endothelium-intact rings, CTX 10 mumol.L-1 induced a transient relaxation followed by a sustained contraction. Removal of the endothelium or pre-incubation of the rings with NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) abolished the transient relaxation but did not affect the magnitude of the contractile response induced by CTX. CTX itself induced contraction of vascular smooth muscle but also reduced contractions induced by phenylephrine (PhE) or KCl stimulation in a concentration-dependent manner. Contraction induced by CTX was dependent on the external Ca2+ concentration. Maximal contractile response to CTX was obtained in medium containing Ca2+ 1 mmol.L-1. This response decreased with higher Ca2+ concentration and disappeared when Ca2+ 7 mmol.L-1, organic and inorganic calcium channel blockers were present in the external solution before CTX addition. In preparations with the endothelium intact and incubated with CTX, relaxation by acetylcholine (ACh) stimulation of the tension induced by PhE was decreased. Endothelium-dependent relaxation to ACh was preserved when Ca2+ 5 mmol.L-1 was added to the medium prior to CTX., Conclusion: CTX first triggers the release of NO from the endothelium which results in muscle relaxation, and then causes smooth muscle contraction, Ca2+ and Ca2+ channel blockers prevented the effect of CTX.

The aim of this study was to assess the nature of vascular hyporeactivity to vasopressor agents in rats with endotoxemia. Endotoxemia was induced in rats by bacterial endotoxin (E. Coli lipopolysaccaharide, LPS). In LPS-treated rats, the reactivity of endothelium-denuded aortic rings to phenylephrine (PE) and potassium chloride (KCl) was characterized by a decreased magnitude of contraction, a slower onset of contraction and a faster rate of relaxation when compared to the control aortic rings. Addition of L-arginine (L-arg), the substrate of nitric oxide synthase (NOS), but not D-arginine (D-arg), reduced further PE-induced contraction in rings from LPS-treated rats. Inhibition of contraction in rings of LPS-treated rats was partially antagonized by the inhibitor of NOS, N omega-nitro-L-arginine methyl ester (L-NAME). Thus, production of non-endothelial nitric oxide (NO) was in part responsible for the hyporesponsiveness to PE. Rings from LPS-treated rats also displayed hyporeactivity and decreased sensitivity to Ca2+ in depolarizing medium (60 mM K+). Hyporeactivity and hyposensitivity to Ca2+ could only be partially reversed by L-NAME. The inhibitory effects of LPS-treatment on both PE-and KCl-induced aortic responses and the reversal effects of L-NAME confirm the contention that NO formation is involved in vascular hyporesponsiveness in endotoxic shock. The partial reversal by L-NAME of the hyporesponsiveness to KCl- and PE-induced contraction, and hyposensitivity to Ca2+ in depolarized aorta suggest that factors other than the action of nonendothelial source of NO formation in vitro from L-arg also contribute to endotoxin-induced vascular hyporesponsiveness to vasopressor agents.

Thapsigargin (TSG), a putative selective Ca(++)-ATPase inhibitor, has been used to study Ca++ mobilization in many non-excitable cell types. This study aims to determine whether TSG is effective as a selective microsomal Ca++ uptake inhibitor by studying its ability to affect repletion of the phenylephrine (PE)-sensitive Ca++ pool in rat aorta and dog mesenteric artery evaluated by contractility studies. TSG caused a concentration-dependent contraction that was dependent on the concentration of extracellular Ca++. Ca++ influx promoted by TSG was found to occur mostly through L-type Ca++ channels in the dog mesenteric artery but not in the rat aorta. When arterial rings, depleted of their PE-sensitive internal store, were allowed to replete their stores in normal Krebs' solution or in the presence of elevated K+ levels, it was found that repletion was significantly enhanced in the presence of elevated K+. In TSG-treated rings, however, repletion was significantly inhibited under both conditions as indicated by the subsequent PE-induced contraction in Ca(++)-free medium. While the rate of contraction induced by elevated K+ levels was slow immediately after pool depletion in controls, it was rapid in TSG-treated arterial rings. The slow onset of K+ contraction may reflect Ca++ uptake into the pool which was absent in TSG-treated arteries. Differences in the behavior of the two arteries were noted and these may reflect differences in the size of their Ca++ store and their coupling to the extracellular space. Single cells isolated from the dog mesenteric artery were also found to shorten in response to TSG to an amount comparable with that obtained from whole tissue experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to evaluate the alpha 1-adrenoceptor properties of S.3341, a new alpha-adrenoceptor agonist. Experiments were performed by recording isometric tension of the rat portal vein. pD2 values and apparent intrinsic efficacy of alpha-adrenoceptor agonists (S.3341, norepinephrine, phenylephrine and clonidine) were assessed from cumulative concentration-response curves. Particular attention was paid to the variations in the amplitude of spontaneous contractions and the increase in the tonus of the vein induced by these agonists. The rank order of activity (pD2 values) of these agonists on the amplitude of spontaneous contractions and on the tonus was as follows: norepinephrine greater than or equal to phenylephrine greater than clonidine greater than S.3341. The activity of S.3341 on spontaneous contractions of the vein was found to be of the alpha 1-type only at concentrations higher than 10(-6)M. This concentration-dependent effect was antagonized by prazosin but not by rauwolscine. For concentrations lower than 10(-6)M, S.3341 decreased the amplitude of spontaneous contractions. This effect was not modified by prazosin or rauwolscine and was affected (decreased) after treatment of the vein with 6-hydroxydopamine (6-OHDA). S.3341 was barely able to increase the tonus of the vein, whatever the concentration used. Moreover, S.3341 was able to antagonize the increase in amplitude of spontaneous contraction and tonus of the vein induced by clonidine and phenylephrine. The effect of S.3341 on the slow inward calcium current was also tested and no effect was found, even at high concentrations. The results suggest that in the rat portal vein, S.3341 is a weak partial alpha 1-adrenoceptor agonist which exhibits a quite novel property not related to an adrenergic stimulation or a calcium entry blocking property. The mechanism of this novel effect remains to be elucidated.