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Exposure of bovine adrenal medullary chromaffin cells to Ba(2+) ions (in the absence of Ca(2+) ions) caused their death, measured as lactate dehydrogenase (LDH) release. The concentration of Ba(2+) required to damage the cells by about 65% ranged between 1 and 10 mM (no Ca(2+) added); the required exposure time was rather brief (15 min-4 h). The simultaneous presence of Ca(2+), Mg(2+) or Zn(2+) together with Ba(2+) (2 mM, 4 h) afforded cyprotection (60-80%). Individual selective blockers of Ca(2+) channel subtypes afforded no protection. However, combined nifedipine (3 microM) plus omega-conotoxin MVIIC (3 microM) offered full protection. Substantial protection was also seen with the "wide-spectrum" Ca(2+) channel blockers penfluridol (0.3 microM), lubeluzole (3 microM), dotarizine (3 microM), flunarizine (3 microM), and mibefradil (3 microM). This protection was due to blockade of Ba(2+) entry through Ca(2+) channels because dotarizine (10 microM) inhibited the increase in cytosolic [Ba(2+)] seen in fura-2-loaded chromaffin cells. Once Ba(2+) accumulated in the cytosol, it was not extruded by the Na(+)/Ca(2+) exchanger, as shown by the prolonged and sustained elevation of the fura-2 signal. This contrasts with the fast dissipation of the fura-2 signal generated by [Ca(2+)](i) elevation. Thus, Ba(2+) overload can cause cell death by mechanisms similar to those reported for Ca(2+) overload and might be used as a novel and convenient tool to search for new cytoprotective compounds.

1. The effect of diazepam was examined in the nerve skin preparation of the toad Caudiverbera caudiverbera. 2. Nerve stimulation was followed immediately by a transient increase in short-circuit current (SCC) and in the potential difference (PD), which consisted of a rapid and then a slow component. 3. Diazepam concentrations from 5.0 x 10(-5)M to 5.1 x 10(-4)M caused a dose-dependent block of both components to a 30% of their control values and also reduced the stimulatory responses to noradrenaline in this preparation. 4. Diazepam antagonized the potassium blocking effect of barium. 5. These results, based on electrophysiological and pharmacological evidence, are consistent with a calcium and sodium blocking effect of diazepam on the nerve skin junction of C. caudiverbera.

1. The crude aqueous/alcoholic extract (CE) of Mandevilla illustris (Apocynaceae) rhizomes was analysed against contractile response elicited by bradykinin (BK), lysyl-bradykinin (L-BK), oxytocin(Ot), acetylcholine (Ach), angiotensin II (AII) and barium chloride (BaCl2) in the isolated uterus of the rat. 2. The CE of this plant (0.5-2.0 mg/ml) caused a parallel and concentration-related rightward displacement of BK and L-BK contractile responses. Schild plot revealed a linear relationship (r close to one) and yielded nominal PA2 values of 3.6 and 3.2 respectively, but the slopes were significantly different from unity. 3. However, the anti-BK action of the CE of M. illustris was not selective to kinin action, since in the same range concentration the CE also affected uterine contractile responses induced by Ot, Ach, AII and BaCl2.

An index for comparing the inhibitory effects of vasodilators was developed to gain insight into their mechanism of action on vascular smooth muscle. Rat aortic strips were bathed in Krebs bicarbonate solution and were initially contracted to a stable tension by either phenylephrine or barium chloride. A vasodilator was then added and the remaining tension was noted; this was repeated for cumulative concentrations of vasodilator. At each concentration of vasodilator, the percent reduction in phenylephrine-induced tension (Phe) was compared to the percent reduction in barium-induced tension (Ba) and was expressed as a ratio (Phe/Ba). This ratio clearly separated verapamil and nifedipine (ratio less than 1), which block calcium influx, from papaverine (ratio = 1) which promotes calcium sequestration regardless of the source of calcium, and from dantrolene (ratio greater than 1) which interferes with intracellular calcium mobilization. This index provides a method for comparing the action of those agents presently classified as non-receptor specific vasodilators which act directly on vascular smooth muscle.

Dicyclomine inhibition of acetylcholine-induced and barium chloride-induced isotonic contractions of the smooth muscle from three segments of the lower urinary tract (bladder body, bladder base, and proximal urethra) of the guinea pig and the rabbit was studied in vitro. In the guinea pig dicyclomine caused competitive inhibition of acetylcholine-induced contraction of the bladder body (1 x 10(-7) M to 1 x 10(-5) M) and the bladder base (1 x 10(-6) M, 1 X 10(-5) M) and was less potent than atropine and propantheline. In the rabbit significant blockade of acetylcholine-induced contractions occurred at dicyclomine concentrations of 5 x 10(-6) M to 3 x 10(-5) M in the bladder body and at 1 x 10(-5) M and 3 x 10(-5) M in the bladder base. In both species dicyclomine inhibitory effects were most marked in the bladder body, moderate in the bladder base, and minimal in the proximal urethra. Dicyclomine failed to cause inhibition of the barium chloride-induced contractions in the guinea pig vesicourethral smooth muscle. In rabbits, however, significant antagonism P less than 0.01) of barium chloride-induced muscle contraction was observed with dicyclomine at concentration 1 x 10(-5) M in both bladder body and the bladder base. The clinical implication of such properties of dicyclomine are discussed.

The anticholinergic and antispasmodic activity of atropine, propantheline, imipramine, and flavoxate were judged by each drug's ability to inhibit bethanechol chloride and barium chloride-induced canine detrusor contractions. In this in vitro model, atropine and propantheline are pure anticholinergic agents. Imipramine significantly decreases both bethanechol and barium-induced contractions, while flavoxate only minimally inhibits the response to either stimulant.

The ability of imipramine, oxybutynin, and flavoxate to antagonize carbamylcholine and barium chloride (BaCl2)-induced contractions of rabbit detrusor, and to block impulse conduction in desheathed frog sciatic nerves has been assessed in vitro. Impiramine exerts noncompetitive carbamylcholine and BaCl2 blockade by 10(-5) M and a local anesthetic effect equipotent with that of tetracaine. Oxybutynin exerts a strong competitive antagonism of carbamylcholine by 10(-8) M, a noncompetitive antagonism of BaCl2 equivalent to that of imipramine, and moderate local anesthetic activity. Flavoxate, under these experimental conditions exerts little anticholinergic, antispasmodis, or local anesthetic activity. Imipramine and oxybutynin thus demonstrate a number of smooth muscle effects by which their therapeutic actions may be exerted. The mechanisms of action of flavoxate remain obscure.