An analysis of the B-adrenergic action of oxyfedrine

1-3-methoxy-ω-(1-hydroxy-1-phenylisopropylamino)-propiophenone hydrochloride (oxyfedrine) (10^?8–10^?6 g/ml) produces a positive inotropic effect on electrically driven guinea-pig left atria which is prevented by propranolol; higher concentrations depress contractile force. Oxyfedrine (10^?8–10^?6 g/ml) effectively antagonizes the action of isoprenaline but not that of theophylline ethylenediamine. Oxyfedrine (10^?5 g/ml)-induced relaxation of the guinea-pig tracheal chain is not reversed by repeated washing but is antagonized by propranolol (10^?7 g/ml). The relaxed tracheal chain contracts when an additional dose of oxyfedrine (10^?5 g/ml) or quinidine (10^?5 g/ml) was administered. The oxyfedrine-induced contraction is relaxed by papaverine (5 × 10^?6 g/ml), theophylline ethylene-diamine (10^?5 g/ml) or adenosine (5 × 10^?5 g/ml) but not by isoprenaline (2 × 10^?8 g/ml) or adrenaline (10^?7 g/ml) nor is it prevented by dibenamine (10^?5 g/ml), methysergide (10^?6 g/ml), atropine (10^?5 g/ml) or tripelennamine (10^?7 g/ml). These observations suggest that oxyfedrine interacts with the ß-adrenergic receptor, inducing at adequate concentrations, stimulation and blockade to catecholamines simultaneously; in this interaction, higher concentrations of oxyfedrine produces a direct depression (quinidine-like) of cardiac muscle and a contraction of tracheal muscle.     

An in vitro study of the effects of calcium on the cardiovascular actions of thiopentone,Althesin and ketamine in the rat

The actions of three intravenous anaesthetics, Althesin, thiopentone and ketamine have been compared on the rat isolated atria and portal vein. Although the three anaesthetics had grossly similar actions on the two preparations, i.e. depression of atrial rate and depression of the amplitude of myogenic activity in the portal vein, there were enough differences to suggest that they produced their effects by different mechanisms. These differences were particularly obvious in interactions with noradrenaline and the effects of changes in calcium ion concentration on the concentration effect relationships for the agents on the atria and portal vein. Generally Althesin was unaffected by changes in calcium ion concentration, whilst ketamine and thiopentone were affected, but in qualitatively different ways.     

The inhibitory action of oestradiol-17-beta and progesterone on venous smooth muscle.

1 The in vitro action of oestradiol-17-beta (0.1, 1.0 and 10.0 mug/ml) and progesterone (0.1, 1.0 and 10.0 mug/ml) on the spontaneous activity of the portal veins in female rats at different stages of gestation was studied. 2 Progesterone caused the spontaneous mechanical activity in the rat portal vein to decrease in amplitude and increase in frequency. This action was dose-dependent and the sensitivity of the tissue decreased throughout pregnancy. 3 Oestradiol-17-beta had a biphasic effect on spontaneous mechanical activity in the rat portal vein. At 0.1 mug/ml the vessel was stimulated while a similar effect to progesterone occurred with higher concentrations. The tissue was more sensitive to oestradiol at 7 days of gestation than at either the 10-14 or 17-21 day periods of gestation. 4 These effects of oestradiol and progesterone were still seen after blockade of the beta-adrenoceptors. 5 Hydrocortisone (10 mug/ml) had no inhibitory effect on the spontaneous mechanical activity of the vein. 6 The veins from the 17-21 days pregnant animals showed a smaller amplitude of contraction than comparable non-pregnant females.     

An in vitro study of the effects of calcium on the cardiovascular actions of thiopentone, althesin and ketamine in the rat.

The actions of three intravenous anaesthetics, Althesin, thiopentone and ketamine have been compared on the rat isolated atria and portal vein. Although the three anaesthetics had grossly similar actions on the two preparations. i.e. depression of atrial rate and depression of the amplitude of myogenic activity in the portal vein, there were enough differences to suggest that they produced their effects by different mechanisms. These differences were particularly obvious in interactions with noradrenaline and the effects of changes in calcium ion concentration on the concentration effect relationships for the agents on the atria and portal vein. Generally Althesin was unaffected by changes, but in qualitatively different ways.     

An investigation of the long duration of action of oxyfedrine

The long-lasting sympathomimetic effects of oxyfedrine on the rat perfused heart, rat uterus and guinea-pig trachealis can be prevented or terminated by propranolol. Reserpine pretreatment did not affect the early peak cardiac responses or the responses of the other two tissues but abolished the late phase of its cardiac action. Oxyfedrine caused partial depletion of cardiac noradrenaline. A high concentration was needed to affect the uptake of ³H-noradrenaline by the rat uterus. ¹⁴C-oxyfedrine was taken up by tissues — this uptake was unaffected by cocaine, desipramine, metanephrine or phenoxybenzamine; it was reduced by cooling and increased by reserpine pretreatment. The chloroform-aqueous phase partition of oxyfedrine indicated high lipid solubility and its tissue uptake was attributed to this property. In the rat uterus the slow efflux of active drug molecules could account for its long duration of action.     

Comparative effects of glyceryl trinitrate on venous and arterial smooth muscle in vitro; relevance to antianginal activity.

1. A quantitative in vitro study has been made of the actions of glyceryl trinitrate and sodium nitrite on vascular smooth muscle (dog femoral artery and saphenous vein; rat portal vein); these have been compared with the actions of papaverine, isoprenaline, salbutamol, pentaerythritol tetranitrate and trimetazidine. 2. Glyceryl trinitrate was more active on the saphenous vein than on the femoral artery in inhibiting noradrenaline and potassium-induced tone. 3. Unlike glyceryl trinitrate, sodium nitrite and isoprenaline, papaverine and diazoxide inhibited noradrenaline-induced contractions of venous and arterial smooth muscle to the same extent. 4. The selective dilator effects of glyceryl trinitrate on venous smooth muscle may explain its action in alleviating the pain of angina pectoris. It is suggested that the use of these three vascular smooth muscle preparations (arterial, and veins with and without spontaneous myogenic activity) is a useful initial screening procedure for prospective antianginal drugs acting by venodilatation.     

Inhibitory innervation of cat sphincter of Oddi.

1 Electrical stimulation with trains of 0.1-0.2 ms pulses of the cat isolated sphincter of Oddi inhibited the spontaneous contractile activity and lowered base-line tension considerably. A contraction usually followed the period of stimulation. 2 These inhibitory effects were prevented by tetrodotoxin 0.1-0.5 mug/ml but were not reduced by hexamethonilm, morphine, or blockade of alpha- or beta-adrenoreceptors of cholinoceptors with phenoxy-benzamine propranolol or atropine, respectively. 3 Adenosine-5'-triphosphate (ATP) and adenosine-5'-diphosphate (ADP) inhibited the spontaneous sphincter activity and caused relaxation thus mimicking the effects of the C-terminal octapeptide of cholecystokinin (C8-CCK), isoprenaline and prostaglandin E1 and E2. 4 ATP alone (greater than 100 mug/ml) or ATP (greater than 10 mug/ml) plus dipyridamole (1 mug/ml), relaxed the sphincter to the same degrees as did the field stimulation. 5 In sphincter maximally contracted by acetylcholine, the effect of stimulation was more marked than that recorded in uncontracted preparations. 6 The present findings suggest that the sphincter of Oddi receives inhibitory nerves that are neither cholinergic nor adrenergic.     

Effects of (+/-)- (+)- and (-)-metoprolol, (+/-)- (+)- and (-)-pindolol, (+/-)-mepindolol and (+/-)-bopindolol on the rat left atria and portal vein.

1. The effects of (+/-)- (+)- and (-)-metoprolol, (+/-)- (+)- and (-)-pindolol, (+/-)-mepindolol and (+/-)-bopindolol on the beta 1-adrenoceptor mediated responses of the rat left atria and the beta 2-adrenoceptor mediated responses of the rat portal vein to isoprenaline have been determined. 2. Racemic and (-)-metoprolol were selective beta 1-adrenoceptor antagonists. (+)-Metoprolol was devoid of beta-adrenoceptor antagonistic activity. 3. Racemic and (-)-pindolol were potent and (+)-pindolol was a modest beta-adrenoceptor antagonist. 4. (+/-)-Mepindolol and (+/-)-bopindolol were apparently competitive antagonists of the isoprenaline beta 1-adrenoceptor mediated responses of the rat left atria but non-competitive antagonists of the isoprenaline beta 2-adrenoceptor mediated responses of the rat portal vein. 5. It is suggested that (+/-)-mepindolol and (+/-)-bopindolol are slowly dissociating beta-adrenoceptor antagonists and the non-competitive antagonism can only be detected on tissues with modest receptor reserves for maximum responses to isoprenaline.     

In vitro inhibition of intestinal motility by phenylethanolaminotetralines: evidence of atypical beta-adrenoceptors in rat colon

1. The new compounds phenylethanolaminotetralines (PEAT), unlike the reference beta-adrenoceptor agonists isoprenaline (Iso), ritodrine (Ri) and salbutamol (Sal), produced half-maximal inhibition of spontaneous motility of rat isolated proximal colon at substantially lower concentrations (EC50 2.7-30 nM) than those inducing beta 2-adrenoceptor-mediated responses (relaxation of guinea-pig isolated trachea and rat uterus) and had virtually no chronotropic action (EC50 greater than 3 x 10(5) M) on the guinea-pig isolated atrium (a beta 1-adrenoceptor-mediated response). 2. The nonselective beta-adrenoceptor antagonists alprenolol and propranolol prevented the inhibition of rat colon motility by the PEAT with low and different potencies (pA2 values around 7.5 and 6.5 respectively). Conversely alprenolol and propranolol had a higher and similar potency (pA2 values around 9.0) in preventing typical beta 1 or beta 2-responses (increase in atrial frequency by Iso or tracheal relaxation by Ri or Sal). 3. The selective beta-adrenoceptor antagonists CGP 20712A (beta 1) and ICI 118,551 (beta 2) either alone or in combination, did not prevent rat colon motility inhibition by the representative PEAT SR 58611A, which was also fully resistant to alpha-adrenoceptor, acetylcholine, dopamine, histamine, opioid and 5-hydroxytryptamine antagonists. 4. These results indicate that the PEAT are a new class of beta-adrenoceptor agonists and suggest that their preferential intestinal action may be accounted for by selectivity for atypical beta-adrenoceptors, abundant in the rat colon and distinct from the currently recognized beta 1 and beta 2 subtypes.     

Classification of the beta-adrenoceptor subtype in the rat portal vein: effect of altered thyroid hormone levels.

The potencies of the beta 1-adrenoceptor agonist, noradrenaline, and the beta 2-adrenoceptor agonist, fenoterol, at beta-adrenoceptors in portal vein were examined using preparations isolated from control, methimazole-treated or l-thyroxine-treated rats. Tissues were preincubated with phenoxybenzamine (1 mumol/l) to block alpha-adrenoceptors and neuronal and extraneuronal uptake. Fenoterol was approximately 400 times more potent than noradrenaline (-log IC50 7.85 vs. 5.26) in inhibiting the spontaneous contractions of the portal vein. The beta 2-adrenoceptor antagonist, ICI 118,551, was approximately 3000 fold more potent than the beta 1-adrenoceptor antagonist, atenolol, in blocking the effects of fenoterol (pA2 9.32 and 5.88 respectively) and 400 times more potent in antagonising noradrenaline (pA2 8.96 vs. 6.23). Treatment of rats with methimazole led to decreased myogenic tone, and treatment with thyroxine to increased tone. beta-Adrenoceptor binding densities and the relative potencies of the agonists and antagonists used were unaffected by methimazole treatment. Thyroxine administration was also without effect on the relative potencies of these compounds. Our data indicate that although the portal vein is a target tissue for thyroxine, as indicated by its influence on myogenic tone, the beta-adrenoceptor population in this preparation, confirmed to be of the beta 2-subtype, is unaffected.     

The effect of catecholamine infusions on myocardial blood flow, metabolic heat production and on general haemodynamics, before and after alprenolol (H56/28), in anaesthetized cats

1. In cats anaesthetized with pentobarbitone sodium, infusions of adrenaline, noradrenaline (0.5 mug/kg per min) and isoprenaline (0.25 mug/kg per min) increased myocardial blood flow, myocardial heat production, left ventricular systolic and end-diastolic pressures, left ventricular +ve and -ve dp/dt max, and calculated cardiac output, effort and oxygen consumption. These effects (apart from the effect of noradrenaline on left ventricular systolic pressure) were markedly reduced by previous administration of alprenolol (0.5 or 1.0 mg/kg).2. Infusions of adrenaline and noradrenaline increased arterial diastolic blood pressure and isoprenaline reduced it. After alprenolol the effects of adrenaline and noradrenaline were potentiated and that of isoprenaline abolished; in some experiments isoprenaline increased arterial diastolic pressure after alprenolol. Alprenolol did not influence the increases in arterial systolic pressure which followed the administration of adrenaline and noradrenaline.3. Isoprenaline-induced tachycardia was markedly reduced and adrenaline tachycardia was converted to bradycardia after alprenolol. The bradycardia which occurred during noradrenaline infusions was unaffected.4. After blockade by alprenolol, recovery of the effects of isoprenaline on left ventricular dp/dt and on heart rate occurred more quickly than recovery of the effects on arterial diastolic pressure. This suggests that alprenolol has a greater affinity for beta(2)- than for beta(1)-adrenoceptors.5. Intravenous administration of acetylcholine decreased arterial blood pressure, left ventricular pressure and +ve and -ve dp/dt max. During recovery from these effects there was a marked increase in +ve dp/dt max. which was absent after the administration of alprenolol (0.5 mg/kg). Because this dose of alprenolol is thus able to block the effects of reflex sympathetic cardiac nerve stimulation but does not completely antagonize the effects of exogenous adrenaline on dp/dt, it is suggested that alprenolol may have some adrenergic neurone blocking activity.6. Increases in liver and myocardial blood flow and heat production produced by noradrenaline, adrenaline and isoprenaline were reduced after alprenolol.7. Isoprenaline reduced air-way resistance and this effect was abolished by alprenolol; increases in air-way resistance produced by adrenaline and nor-adrenaline were augmented. All three amines inhibited intestinal smooth muscle contractions in vivo. Only the effect of isoprenaline was reduced by alprenolol.     

Relaxant actions of khellin on vascular smooth muscle

To clarify the mechanism of the vasodilatory action of khellin on calcium, we have investigated its relaxant action on base line and on K+ and noradrenaline-induced contractile tensions in rat aorta smooth muscle and on spontaneous contractile activity of rat portal vein. Khellin relaxed both of these preparations with a similar potency, which suggests a non-specific inhibition of calcium flux, without any difference related to the specific calcium channels. We have also studied the capacity of khellin to interfere with the loading and release mechanisms of caffeine and noradrenaline-sensitive calcium stores in Ca-free medium. Khellin's Ca2+ loading reduction may be related with its capacity to inhibit calcium influx. Khellin applied during Ca2+ release also caused relaxation. We propose that this drug may enhance calcium extrusion or sequestration rather than the calcium release mechanism. These actions on calcium influx and intracellular mobilization can contribute to its vasorelaxant action.     

Centrally acting drugs alter in vitro β-endorphin processing in the rat

Strychnine (10^?5-3×10^?4M) increased the amplitude and duration of the spontaneous electrical and mechanical activity of the rat isolated portal vein. Similar effects were seen with tetraethylammonium and 4-aminopyridine. This stimulant action of strychnine was unaffected by tetrodotoxin (3×10^?7M) or prazosin (5×10^?8M) but was significantly reduced by verapamil (3×10^?8M). On the isolated aorta, only inhibitory actions of strychnine were observed, yet tetraethylammonium and 4-aminopyridine had excitatory actions. It is suggested that the stimulant actions of strychnine on the portal vein are likely to be due to a reduction in potassium conductance and/or an increase in calcium conductance of the smooth muscle cell membrane.     

Tachyphylaxis to beta-adrenoceptor agonists in human bronchial smooth muscle: studies in vitro.

In studies on human isolated peripheral airway smooth muscle; 1 A concentration dependent beta-adrenoceptor tachyphylaxis was observed to isoprenaline. 2 Cross desensitization to other beta-adrenoceptor agonists was demonstrated. 3 The desensitization was reversible with time. Hydrocortisone appeared to accelerate the recovery from the desensitized state. Low concentration isoprenaline (10(-9) mol l-1) prevented recovery whereas cyclohexamide 1.8 x 10(-4) mol l-1 had no noticeable effect on recovery. Continued occupancy of the receptor appears to prevent recovery. The recovery from the desensitized state does not apparently require synthesis of new proteins. 4 Bronchial wall cyclic AMP response to isoprenaline was attenuated after isoprenaline induced desensitization whereas total phosphodiesterase activity of bronchial wall was not altered by desensitization. Thus by exclusion the adenylate cyclase receptor complex may be altered in human peripheral airway smooth muscle beta-adrenoceptor tachyphylaxis.     

Comparison of the effects of the K(+)-channel openers cromakalim and minoxidil sulphate on vascular smooth muscle.

1 The actions of the potassium channel openers, cromakalim and minoxidil sulphate, were compared in a range of isolated blood vessel preparations. 2 Cromakalim and minoxidil sulphate inhibited spontaneous mechanical activity of the guinea-pig portal vein and relaxed the noradrenaline precontracted rat aorta with similar potency. In contrast, minoxidil sulphate was less potent than cromakalim in inhibiting spontaneous activity in the rat portal vein and was essentially inactive in the noradrenaline precontracted rat mesenteric artery and rabbit aorta. 3 Minoxidil sulphate did not antagonize the effects of cromakalim in the rabbit aorta indicating it was not acting as a partial 'agonist'. 4 Charybdotoxin, noxiustoxin and rubidium failed to discriminate between cromakalim and minoxidil sulphate indicating that the apparently selective effects of minoxidil sulphate were not mediated by either Ca(2+)-activated potassium channels, delayed rectifiers or rubidium impermeable potassium channels. 5 Glibenclamide antagonized the effects of cromakalim in an apparently competitive manner whereas the effects of minoxidil sulphate were antagonized in a non-competitive manner. The involvement of subtypes of ATP-sensitive potassium channels is discussed.     

Studies on the blood pressure of beta-adrenoceptor blocking drugs, particularly in relation to the mechanism of the pressor action induced by beta-adrenoceptor blocking drugs in rats (author's transl)

Several investigators have confirmed that beta-adrenoceptor blocking drugs produced a sustained pressor action in anesthetized rats. However, the mechanism of the pressor action has not been sufficiently explored. The following studies were done to further investigate the mechanism. (a) effects of pindolol, carteolol, propranolol, alprenolol, practolol and acebutolol (0.015-0.3 mumole/kg i.v.) on blood pressure of anesthetised rats, b) effects of these drugs on the positive chronotropic action and vasodilation induced by isoprenaline (0.1 microgram/kg i.v.) in anesthetized rats, c) effects of these drugs on the increase in heart rate and contractile force of isolated rat and guinea pig atria induced by isoprenaline, d) effects of these drugs on the relaxation of isolated guinea pig trachea induced by isoprenaline. From these experiments, the magnitude of the pressor action of beta-adrenoceptor blocking drugs in anesthetized rats was found to be more closely related to the magnitudes of inhibition produced by beta-adrenoceptor blocking drugs on isoprenaline-induced relaxation of isolated guinea pig trachea and on isoprenaline-induced vasodilation in anesthetized rats than to those on isoprenaline-induced positive chronotropic and inotropic actions of isolated atria.     

The effect of some alpha-adrenoceptor antagonists on spontaneous myogenic activity in the rat portal vein and the putative involvement of ATP-sensitive K+ channels.

In the present study we showed that the alpha-adrenoceptor antagonists phentolamine, yohimbine, prazosin, corynanthine and idazoxan, when cumulatively applied in high concentrations (1-100 mumol/l), can increase spontaneous myogenic activity in the rat portal vein. 5-Methyl-urapidil and rauwolscine were ineffective in this respect. Pretreatment with phenoxybenzamine in a concentration of 1 mumol/l (20 min), which results in alkylation of all functional alpha-adrenoceptors in the rat portal vein, was unable to antagonize the increase in spontaneous myogenic activity elicited by phentolamine. Antazoline (1-100 mumol/l), a H1 antagonist and 2-substituted imidazoline which is devoid of alpha-adrenoceptor blocking properties, exhibited similar effects on spontaneous myogenic activity as its structurally closely related analogue phentolamine. Since phentolamine is reported to interact with ATP-sensitive K+ channels we investigated the role of K+ channels in more detail. The K+ channel openers cromakalim and diazoxide elicited a decrease in spontaneous myogenic activity. Glibenclamide (0.3-3 mumol/l), a selective blocker of ATP-sensitive K+ channels in cardiac and pancreatic tissues, and phentolamine (1-10 mumol/l) shifted the concentration-response curves of cromakalim and diazoxide concentration dependently to the right. Yohimbine showed only a modest effect in the highest concentration (100 mumol/l) applied. E-4031 (0.01-0.3 mumol/l), a sotalol derivative and one of the most selective blockers of the delayed rectifier current (Ik) in cardiac tissue, was a potent contractile agent when added to the rat portal vein in the same way as the alpha-adrenoceptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stimulation of bicarbonate secretion by atypical beta-receptor agonists in rat cecum in vitro.

This study examined the effects of beta-adrenoceptor agonists on bicarbonate secretion by the rat cecum in vitro. Isoprenaline, the beta 2-selective agonist salbutamol and the 'atypical' beta-agonist SR58611A stimulated bicarbonate secretion in a concentration related manner. Another atypical agonist, BRL 37344, also stimulated. Responses to isoprenaline were antagonised by alprenolol and propranolol (both 20 microM) but not the selective antagonists practolol (10 microM) or ICI 1185511 (1 microM). Responses to SR 58611A were only antagonised by alprenolol. Replacement of Cl- by NO3- on the mucosal surface reduced basal secretion and abolished the response to isoprenaline. Exposure to a single concentration of atypical agonist resulted in desensitisation to a second application and to isoprenaline. There was no evidence of desensitisation with isoprenaline or salbutamol. The results show that beta-adrenoceptor agonists stimulated bicarbonate secretion in contrast to the previously described inhibitory effect of cholinergic drugs in this tissue. Stimulation was mediated by beta-adrenoreceptors, which had properties consistent with the atypical receptors described in gut smooth muscle and in adipose tissue. Both adrenergic and cholinergic drugs may act on the same mechanism of secretion which may involve an exchange of HCO3- for mucosal Cl-.     

Lack of effect of atrial natriuretic factor on the tone induced in rat portal vein by platelet-activating factor

The spontaneous myogenic activity of the isolated rat portal vein was inhibited by atrial natriuretic factor or by sodium nitroprusside. These compounds were not effective on the tone induced by PAF-acether or carbachol. 8-Bromo cyclic GMP and dibutyryl cyclic AMP inhibited myogenic activity and reduced the agonist-induced contractions. Only dibutyryl-cyclic AMP significantly inhibited the PAF-acether-induced contractile responses. These results indicate that the tone induced by PAF-acether can be used to discriminate between drugs which selectively increase cyclic nucleotide levels.     

A comparison of the effects of the calcium entry blockers, verapamil, diltiazem and flunarizine against contractions of the rat isolated aorta and portal vein.

1. The actions of the chemically distinct calcium entry blockers, verapamil (Ver), diltiazem (Dlz) and flunarizine (Flu) have been compared in rat isolated aorta and portal vein. 2. KCl-induced contractions of the rat aorta depend exclusively upon extracellular Ca2+, whereas, those induced by noradrenaline (NA) rely upon Ca2+ from intra- and extracellular sources. The NA-induced contraction was pharmacologically dissected under Ca2+-free conditions revealing a contraction dependent upon intracellular Ca2+ (EGTA-resistant response) or a low concentration of prazosin which left a contraction which was mediated by extracellular Ca2+ (prazosin-resistant response). 3. The portal vein produced spontaneous rhythmic contractions and a sustained contraction to NA and KCl; however, all responses appeared to depend exclusively upon extracellular Ca2+. 4. In the aorta, contractions which might be expected to depend upon Ca2+-entry through voltage-operated channels (KCl-induced contraction) showed similar sensitivities to Ver, Dlz and Flu whereas, marked differences in the sensitivity to these agents was noted against contractions which appear to depend upon Ca2+-entry through receptor-operated channels (prazosin-resistant response). Only Dlz reduced contractions mediated by intracellular Ca2+ (EGTA-resistant response). 5. In the portal vein, Ver and Dlz caused similar pronounced reductions of spontaneous and NA of KCl-induced contractions. In contrast, these contractions of the portal vein were unaffected by Flu except at a concentration of 10 microM. However, contractions induced by addition of Ca2+ (0-14 mM) to previously depolarized portal veins could be reduced by Flu (100 nM-10 microM). 6. The present study indicates that in the rat aorta, contractions mediated by intracellular Ca2+ and depolarization or receptor-activated Ca2+ entry can be pharmacologically dissected and that these processes show different sensitivities to calcium entry blockade. Of the agents tested, Ver displays the properties most commonly associated with an ideal calcium entry blocker. Ca2+-activation mechanisms in the portal vein differ from those in the aorta resulting in a different spectrum of selectivity of the calcium entry blockers studied.