Magnesium deficiency produces spasms of coronary arteries: relationship to etiology of sudden death ischemic heart disease.

Isolated coronary arteries from dogs were incubated in Krebs-Ringer bicarbonate isolation and exposed to normal, high, and low concentrations of magnesium in the medium. Sudden withdrawal of magnesium from the medium increased whereas high concentrations of magnesium decreased the basal tension of the arteries. The absence of magnesium in the medium significantly potentiated the contractile responses of both small and large coronary arteries to norepinephrine, acetylcholine, serotonin, angiotensin, and potassium. These data support the hypothesis that magnesium deficiency, associated with sudden death ischemic heart disease, produces coronary arterial spasm.

Pentobarbital sodium inhibits calcium uptake in vascular smooth muscle.

This report demonstrates that the commonly used anesthetic agent, pentobarbital sodium, in concentrations of 1 . 10(-4) to 2 . 10(-3) M inhibits calcium (Ca2+) uptake in both rat aortic and portal venous smooth muscle. The data indicate that total exchangeable Ca2+ in portal vein is reduced by about 15% in 1 . 10(-4) M pentobarbital sodium, while the intracellular exchangeable Ca2+ is reduced by 24%. On the other hand, in aortic smooth muscle, while 5--20 . 10(-4) M pentobarbital sodium reduces total exchangeable Ca2+ by about 15%, intracellular Ca2+ is reduced by 22% in 5 . 10(-4) M pentobarbital sodium and by 38% in 2 . 10(-3) M pentobarbital sodium. The present studies thus reveal that concentrations of pentobarbital sodium known to be present during induction of surgical anesthesia can exert significant inhibitory effects on exchangeability and transmembrane movement of Ca2+ in at least two different types of blood vessels.

Tris(hydroxymethyl)aminomethane inhibits calcium uptake in vascular smooth muscle.

This report demonstrates that the commonly used buffering agent Tris(hydroxymethyl)aminomethane (Tris) in concentrations of 5 and 30 mM inhibits calcium (Ca2+) uptake in both rat aortic and portal venous smooth muscle. The data indicates that total exchangeable Ca2+ in portal vein is reduced by about 35% in 5 or 30 mM Tris, while the intracellular exchangeable Ca2+ is not significantly altered. On the other hand, in aortic smooth muscle, while 30 mM Tris reduces total exchangeable Ca2+ by about 20%, intracellular Ca2+ is reduced by 44% in 5 mM Tris and by 55% in 30 mM Tris. The present studies, thus, reveal that Tris exerts significant inhibitory effects on exchangeability and transmembrane movement of Ca2+ in at least two different types of smooth muscle.

Tolerance and beta-adrenergic blocking activity of flestolol, a short-acting beta blocker.

The tolerance and beta-adrenergic blocking activity of flestolol, a short-acting beta-blocker, was investigated in 30 subjects. Flestolol infused intravenously at doses up to 100 micrograms/kg/min was found to be well tolerated. A dose-dependent attenuation of isoproterenol-induced tachycardia and increase in systolic blood pressure occurred with flestolol at doses ranging from 0.5 to 15.0 micrograms/kg/min. The average percent reduction in isoproterenol-induced tachycardia (beta-blockade) at each dose of flestolol, 0.5, 2.5, 5.0, 15.0, and 50.0 micrograms/kg/min, was 15.1%, 45.9%, 67.0%, 85.9%, and 90.3%, respectively. The onset of beta-blockade occurred within 30 minutes. After the end of flestolol infusion there was a marked reduction in beta-blockade within 6 minutes, with complete recovery from beta-blockade within 30 to 45 minutes. There was a statistically significant (P less than 0.01) positive correlation between flestolol dosage and its blood levels (r = 0.91) as well as between the flestolol-induced beta-blockade and its dosage (r = 0.62).

Pharmacodynamics and pharmacokinetics of DMP 728, a platelet GPIIb/IIIa antagonist, in healthy subjects.

DMP 728 showed a dose-dependent inhibition of platelet aggregation at doses of 0.05 to 0.9 mg per subject, with a maximal inhibition (> 90%) of platelet aggregation at doses of 0.9 mg per subject and higher. Minimal changes in bleeding time from baseline were observed at doses up to 0.6 mg per subject. At the 0.9 mg/subject dose level, bleeding time was prolonged by approximately twofold to threefold above the baseline. At higher doses (1.5 mg/subject to 3.9 mg/subject), bleeding time prolongation was > 30 minutes during the infusion. In all dose groups, bleeding times returned to the control value within 8 hours after cessation of the infusion. Maximum plasma concentration and area under the curve of DMP 728 increased linearly and proportionally to the dose. No clinical changes in vital signs, 12-lead electrocardiograms, physical examinations, coagulation tests, or stool hemoccult tests were observed at any of the doses. In conclusion, DMP 728 is a potent antiplatelet agent and well tolerated at doses ranging from 0.05 to 3.0 mg/subject.

Pharmacokinetics and safety of a phenytoin prodrug given i.v. or i.m. in patients.

ACC-9653, a prodrug of phenytoin synthesized to be water soluble, is converted to phenytoin by phosphatases. In this study, 43 patients received ACC-9653 IV or IM. Side effects were transient and minor. The conversion half-lives of ACC-9653 after intravenous and intramuscular administration averaged 8.4 and 32.7 minutes, respectively. Peak phenytoin concentrations occurred 42 minutes after IV and 151 minutes after IM administration.

Intravenous nicardipine for the treatment of severe hypertension.

PURPOSE: Severe hypertension responds to treatment with nifedipine given orally or sublingually. Nicardipine hydrochloride, a water soluble dihydropyridine analogue similar to nifedipine, has less of a negative ionotropic effect and produces less reflex tachycardia than nifedipine. Our purpose was to assess the antihypertensive efficacy and safety of intravenous nicardipine in a group of patients with severe hypertension (defined as a supine diastolic blood pressure of more than 120 mm Hg). PATIENTS AND METHODS: Eighteen patients with severe hypertension received treatment with intravenous nicardipine. Nicardipine titration was performed using doses of 4 to 15 mg/hour to achieve therapeutic goal (diastolic blood pressure 95 mm Hg or less or decrease in diastolic blood pressure of more than 25 mm Hg). After this therapeutic end-point was reached, patients received maintainance therapy with nicardipine for varying lengths of time: one hour (Group I), six hours (Group II), or 24 hours. When blood pressure control was lost, patients in Groups I and II entered a second maintenance period lasting a maximum of 24 hours. Onset and offset of action of nicardipine at various infusion rates and times of infusion were measured. RESULTS: Onset time to achieve therapeutic response was rapid at 15 mg/hour (0.31 +/- 0.13 hours) when compared with lower doses (1.11 +/- 0.36 hours at 4 mg/hour; 0.54 +/- 0.09 hours at 5 mg/hour; 0.52 +/- 0.09 hours at 7 to 7.5 mg/hour). Those who showed a therapeutic response received maintenance infusions with nicardipine for one (n = 7), six (n = 6), or 24 (n = 5) hours. Sustained blood pressure control at a constant rate of nicardipine infusion was seen in all patients during the maintenance period. After discontinuation of nicardipine, the time for offset of action (increase in diastolic blood pressure of 10 mm Hg or more) was independent of duration of infusion. Decreases in both systolic and diastolic pressures correlated well with plasma nicardipine levels. Heart rate increased by about 10 beats/minute, but this increase did not correlate with plasma nicardipine levels. Side effects were minimal, consisting of headache and flushing. In seven patients, local phlebitis developed at the site of infusion. This occurred after at least 14 hours of infusion at a single site, and the incidence can probably be reduced by shortening the infusion time at a single site. CONCLUSION: Nicardipine appears to be a safe and effective drug for intravenous use in the treatment of severe hypertension.

Comparative efficacy and tolerance of esmolol to propranolol for control of supraventricular tachyarrhythmia.

This multicenter, double-blind, randomized, parallel study compared the effectiveness and tolerance of intravenous esmolol with intravenous propranolol in patients with supraventricular tachyarrhythmia (heart rate [HR] greater than 120 beats/min). Efficacy was evaluated in 53 patients receiving esmolol and in 57 patients receiving propranolol. Patients randomized to esmolol received infusions of various doses of esmolol ranging from 50 to 300 micrograms/kg/min (each dose infused for 5 minutes) over a 30-minute titration period with intermittent placebo boluses of propranolol. Those randomized for propranolol received 1 mg/min for the first 3 minutes, and then another 3 mg from minutes 5 to 8 with continuous placebo esmolol infusion during the 30-minute titration period. A therapeutic response, defined by 20% or greater reduction in HR, HR less than 100 beats/min or conversion to normal sinus rhythm, was achieved in 72% of patients on esmolol compared with 69% of patients on propranolol (difference not significant). The therapeutic response was maintained in 67% of patients on esmolol and 58% of patients on propranolol (difference not significant) during a 4-hour maintenance period. Conversion to normal sinus rhythm occurred in 14% of esmolol patients and 16% of propranolol patients during titration and 10% of esmolol and 8% of propranolol patients during maintenance. After discontinuation of study drugs, a more rapid reversal of the reduction in HR was observed in esmolol patients compared with those patients receiving propranolol. Adverse reactions were seen in 29 (45%) patients on esmolol and 11 (18%) patients on propranolol. The principle adverse reaction was hypotension, which was predominantly asymptomatic and found in 23 patients receiving esmolol and 4 receiving propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Withdrawal of magnesium enhances coronary arterial spasms produced by vasoactive agents.

1 The influence of external magnesium ions ([Mg2+]o) on the sensitivity (i.e. EC50) and contractility (maximum response) of isolated large and small coronary arteries of the dog, obtained from different regions of the myocardium, to vasoactive agents was studied. 2 Removal of [Mg2+]o from the physiological salt solution enhanced, while elevation in [Mg2+]o to 4.8 mM, lowered the contractile sensitivity to three different agents, 5-hydroxytryptamine (5-HT), angiotensin II and KCl. 3 Contractility, of both large and small coronary arteries, to 5-HT and angiotensin II was potentiated and depressed, respectively, by withdrawal and elevation of [Mg2+]o; maximum responses to KCl were not altered by 0 or 4.8 mM [Mg2+]o. 4 Cumulative concentration-contractile effect curves to CaCl2 were shifted leftward on removal of [Mg2+]o; elevation of [Mg2+]o to 4.8 mM shifted the CaCl2 concentration-effect curves to the right. Maximal contractile responses to CaCl2 were enhanced by removal of, and reduced by elevation of, [Mg2+]o. 5 The calcium channel blocking agent, verapamil (10(-6)M), inhibited completely contractile responses to KCl; contractile responses elicited by angiotensin II and 5-HT were attenuated by verapamil. 6 A variety of pharmacological antagonists (phentolamine, propranolol, methysergide, atropine, diphenhydramine), as well as use of a prostaglandin cyclo-oxygenase inhibitor, did not modify the altered contractile responses evoked by angiotensin II or KCl in different concentrations of Mg2+. 7 These results suggest: (1) [Mg2+]o may exert considerably greater influence on receptor-operated rather than membrane-potential sensitive channels involved in Ca2+ transport in coronary arterial smooth muscle; (2) Mg2+ interferes with the affinity (binding) of certain agonists (5-HT and angiotensin II) for their respective receptors in coronary vascular muscle; and (3) a functional pool of Ca2+ which is resistant to Ca2+-depletion, but accessible to activation by 5-HT and angiotensin II is present in canine coronary arterial smooth muscle.

Adverse effects of artificial buffers on contractile responses of arterial and venous smooth muscle.

1 In vitro studies were undertaken on rat aortic strips and portal vein segments in order to determine whether or not several commonly used artificial buffers, i.e., tris(hydroxymethyl) aminomethane (Tris), N-2-hydroxyethylpiperazine-N'-2-ethanesulphonic acid (HEPES), morpholine propanesulphonic acid (MOPS), N,N bis(2-hydroxyethyl) glycine (BICINE) and 1,4-piperazinediethanesulphonic acid (PIPES), can exert direct actions on vascular smooth muscle. 2 All artificial buffers used in 5 mM concentrations were found to inhibit development of spontaneous mechanical activity. 3 Tris, HEPES, MOPS, BICINE and PIPES markedly attenuated contractions induced by adrenaline, angiotensin and KCl. The fast phase components of the agonist-induced contractions were either obliterated or reduced in the presence of the artificial buffers. The sustained slow phase components were greatly reduced and retarded by the artificial buffers. 4 The relative order of artificial buffer potency (i.e., from 100% to 14% inhibition) seems to depend upon the agonist and type of smooth muscle. 5 All of these inhibitory effects were reversible, since normal contractile responses and spontaneous mechanical activity could be obtained by simply reincubating the smooth muscles in Krebs-Ringer bicarbonate buffer. 6 A variety of pharmacological antagonists failed to mimic or affect the inhibitory effects of Tris, HEPES, MOPS, PIPES and BICINE. 7 These data show that five of the most commonly used artificial buffers, to study muscles in vitro, exert adverse effects on contractility of arterial and venous smooth muscle.

Flestolol: an ultra-short-acting beta-adrenergic blocking agent.

Flestolol (ACC-9089) is a nonselective, competitive, ultra-short-acting beta-adrenergic blocking agent, without any intrinsic sympathomimetic activity. Flestolol is metabolized by plasma esterases and has an elimination half-life of approximately 6.5 minutes. This agent was well tolerated in healthy volunteers at doses up to 100 micrograms/kg/min. In long-term infusion studies, flestolol was well tolerated at the effective beta-blocking dose (5 micrograms/kg/min) for up to seven days. Flestolol blood concentrations increased linearly with increasing dose and good correlation exists between blood concentrations of flestolol and beta-adrenergic blockade. Flestolol produced a dose-dependent attenuation of isoproterenol-induced tachycardia. Electrophysiologic and hemodynamic effects of flestolol are similar to those of other beta blockers. In contrast with other beta blockers, flestolol-induced effects reverse rapidly (within 30 minutes) following discontinuation because of its short half-life. Flestolol effectively reduced heart rate in patients with supraventricular tachyarrhythmia. In patients with unstable angina, flestolol infusion was found to be safe and effective in controlling chest pain. It is concluded that flestolol is a potent, well-tolerated, ultra-short-acting beta-adrenergic blocking agent. Use of flestolol in the critical care setting is currently undergoing investigation.

Clinical experience with esmolol, a short-acting beta-adrenergic blocker in cardiac arrhythmias and myocardial ischemia.

The efficacy and safety of esmolol, an ultra-short-acting beta-adrenergic blocking agent (elimination half-life, 9 min), was investigated in 358 patients with supraventricular tachyarrhythmias (SVTs) in three multicenter studies (placebo-controlled, propranolol-controlled, and open-label baseline-controlled) and in 19 patients with myocardial ischemia (acute myocardial infarction or unstable angina) in a single-center, open-label study. Esmolol was infused intravenously in doses ranging from 25 micrograms/kg/min to 300 micrograms/kg/min. In SVT studies, efficacy was judged by one or more of the following: a reduction of at least 15% to 20% from the average baseline heart rate, heart rate less than 100 beats/min, or conversion to normal sinus rhythm (NSR). Results revealed that esmolol was superior to placebo and equal to propranolol in controlling heart rate in SVT patients. Conversion to NSR was comparable in patients treated with esmolol (14%) and in those treated with propranolol (16%). The majority of patients achieved therapeutic response at esmolol doses of 200 micrograms/kg/min or less. Among esmolol-treated patients, recovery from beta blockade (i.e., heart rate approaching baseline levels) was achieved within ten minutes after discontinuation of infusion, indicating a brief duration of action of esmolol. In contrast, beta blockade persisted 4.5 hours after discontinuation of propranolol. In patients with myocardial ischemia, esmolol effectively reduced heart rate and blood pressure, thereby decreasing rate-pressure product. The most frequent adverse effect in patients treated with esmolol was hypotension. No clinically significant laboratory abnormalities were reported in esmolol-treated patients. Esmolol was well tolerated in patients infused for durations of up to 24 hours and in patients with conditions for which treatment with beta blockers is inappropriate. These results suggest that esmolol effectively and rapidly controls the heart rate in patients with SVT and in patients with acute myocardial ischemia. Furthermore, because of its short half-life, esmolol offers excellent benefits as compared with the currently available beta-adrenergic blockers in the treatment of critically ill patients. Esmolol was well tolerated by patients for whom beta blockers in general would be unsuitable.

Pharmacokinetics and pharmacodynamics of flestolol, a new short-acting, beta-adrenergic receptor antagonist.

The pharmacokinetics and pharmacodynamics of flestolol, a new short-acting, beta-adrenergic receptor antagonist, were examined in nine healthy subjects after a constant intravenous infusion of 5 micrograms/kg/min for 72 hours. Flestolol blood levels were determined by high-performance liquid chromatography. In all subjects, flestolol blood concentration attained steady state 30 minutes after initiation of infusion. The mean +/- standard deviation steady-state concentration of flestolol was 31.1 +/- 12.0 ng/mL. The elimination half-life averaged 7.2 minutes. The mean +/- standard deviation total body clearance was 181 +/- 66 mL/min/kg. The apparent volume of distribution and the area under the curve averaged 1.89 L/kg and 2.23 micrograms-hr/mL, respectively. Flestolol did not cause any significant change (P greater than .05) in the heart rate or systolic or diastolic blood pressure from the baseline. Flestolol significantly (P less than .05) attenuated the isoproterenol-induced increase in heart rate and systolic blood pressure and decrease in diastolic blood pressure in comparison with baseline. The average maximum reduction in isoproterenol tachycardia was in the range of 63% to 79% during flestolol infusion. There was a rapid recovery from beta blockade after termination of flestolol infusion; the recovery averaged 96% 20 minutes after the infusion was stopped. We conclude that flestolol exhibits a very short half-life and is cleared mainly by extrahepatic routes. It is an effective beta blocker and possesses a short duration of action.

Esmolol-digoxin drug interaction.

An open-label baseline-controlled study was conducted in 11 healthy male subjects to study the possible interaction between the cardioselective, short-acting beta blocker esmolol and digoxin when administered concurrently under steady-state conditions. Steady-state concentration, elimination half-life, and the total body clearance of esmolol were not changed significantly (P greater than .05) by digoxin. Digoxin peak concentration and the time to reach the peak concentration were not affected by esmolol. However, the digoxin AUC during the six-hour esmolol infusion increased from 2.60 +/- 0.59 to 2.88 +/- 0.75 ng.hr/mL (P less than .05). There were no clinically significant changes in the heart rate and blood pressure during this drug interaction study. The PR intervals were similar between digoxin monotherapy and esmolol plus digoxin combined treatment. Although digoxin did not influence the kinetics of esmolol, the small increase seen in digoxin serum concentration during the combination therapy warrants that caution be exercised during concurrent administration of esmolol and digoxin to patients.

Hemodynamic effects of esmolol, an ultrashort-acting beta blocker.

The hemodynamic effects of esmolol were evaluated in 12 male patients at rest (mean age, 51 +/- 10 years) undergoing routine cardiac catheterization. Hemodynamic measurements were obtained during baseline (prior to esmolol), at steady state (during an intravenous infusion of esmolol 300 micrograms/kg/min), and at 30 minutes after stopping esmolol (postinfusion). Esmolol produced hemodynamic effects similar to the effects of other beta blockers. Significant reductions in rate-pressure product (mean decrease, 15%), cardiac index (mean decrease, 17%), stroke volume index (mean decrease, 13%), left ventricular stroke work index (mean decrease, 20%), and left ventricular ejection fraction (mean decrease, 18%) were observed. In contrast to other beta blockers, all hemodynamic effects of esmolol had returned to baseline values within 30 minutes after the infusion stopped. One patient exhibited hypotension during the esmolol infusion; this episode resolved without sequelae after discontinuation of esmolol. In summary, the effects of esmolol at rest on hemodynamic parameters and left ventricular function are similar to other beta-adrenergic blocking agents. Due to its ultrashort half-life, esmolol can be administered safely in critically ill patients whose disease status makes treatment with currently available beta blockers risky.

Efficacy of esmolol in the treatment and transfer of patients with supraventricular tachyarrhythmias to alternate oral antiarrhythmic agents.

The efficacy and safety of esmolol, a titratable intravenous beta-adrenergic blocking agent with a short elimination half-life (t 1/2 = 9.0 min) was evaluated in a multicenter open-label study for the treatment of supraventricular tachyarrhythmias (heart rate greater than 100 bpm). The study also investigated the feasibility of transferring patients from esmolol to alternate oral antiarrhythmic agents without loss of therapeutic response. Of the 113 patients studied, 95 (84%) achieved therapeutic response (reduction in heart rate of 15% or more or conversion to sinus rhythm). Most of these patients (93%) achieved the therapeutic response at esmolol doses of 200 micrograms/kg/min or lower. Transfer from esmolol to an oral antiarrhythmic agent(s) was studied in 76 patients. Alternate antiarrhythmic agents used in this study were digoxin (N = 25), propranolol (N = 21), verapamil (N = 10), metoprolol (N = 11), quinidine (N = 2), and a combination of two antiarrhythmic agents (N = 7). Sixty-seven (88%) patients were successfully transferred to oral antiarrhythmic agents without loss of the therapeutic response obtained with esmolol. The most frequent adverse effect observed during the study was hypotension, which resolved quickly (16 +/- 14 min) either by decreasing the dose or by discontinuation of esmolol infusion. This study supports previous observations concerning the safety and efficacy of esmolol in the treatment of supraventricular tachyarrhythmias. Furthermore, it demonstrates that the majority of patients successfully treated with esmolol can be safely and effectively transferred to oral therapy with alternate antiarrhythmic agents.

Safety, tolerance and pharmacokinetics of intravenous doses of the phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin: a new prodrug of phenytoin.

A new prodrug of phenytoin, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin (ACC-9653), was administered intravenously over 30 minutes to four different groups of volunteers at doses of 150, 300, 600, and 1200 mg. The prodrug and phenytoin were measured in plasma samples, collected at specified times, by specific high performance liquid chromatography (HPLC) assays. The prodrug, after achieving a maximum concentration at the end of the 30-minute infusion (Cmax 20, 36, 75, 129 micrograms/mL) declined rapidly with a half-life (t1/2) of about 8 minutes. The area under the plasma concentration-time curve (10, 19, 43, 77 mg.hr/L) was proportional to dose whereas the total clearance, 14 L/hr, was independent of dose. The volume of distribution of the prodrug, a polar, water-soluble molecule was about 2.6 L, indicating that most of the dose remained in the plasma. The concentration of phenytoin reached 90% of its maximum about 12 minutes after the end of the infusion of ACC-9653. At the dose of 1200 mg of prodrug, the average peak concentration of phenytoin was about 17 micrograms/mL, near the upper limit of the therapeutic range. Adverse reactions (lightheadedness, nystagmus, incoordination) were minor and attributed to phenytoin. No significant abnormalities in ECG, Holter monitoring, or EEG were noted after the infusion of ACC-9653.

Hemodynamic effects of flestolol, a titratable short-acting intravenous beta-adrenergic receptor blocker.

The hemodynamic effects of flestolol were evaluated in 30 patients undergoing routine cardiac catheterization. Hemodynamic measurements were obtained during baseline (prior to flestolol), at steady state during IV flestolol infusion (1, 5, and 10 micrograms/kg/min) and at 20 to 30 minutes after discontinuation (postinfusion). Flestolol-induced hemodynamic changes were similar to those induced by other beta blockers without intrinsic sympathomimetic activity. Significant dose-dependent reduction in heart rate, rate pressure product, and increase in peripheral vascular resistance were seen. Flestolol produced clinically insignificant decrease in myocardial contractility as shown by slight decrease in LVdp/dt, CI, and LVEF. Hemodynamic data from patients with paced heart rate, further confirms a direct mild cardiac depressant effect of flestolol, a finding common to other beta blockers. Consistent with the short elimination half-life of flestolol (t1/2 = 6.5 minutes), most of the hemodynamic changes rapidly returned to preinfusion level within 20 to 30 minutes following its discontinuation. Thus flestolol, with its unique pharmacokinetic profile and titrability, may be beneficial in the treatment of critically ill patients.

Interactions of magnesium and verapamil on tone and contractility of vascular smooth muscle.

Previous studies on isolated blood vessels indicate that (1) withdrawal of magnesium ([Mg2+]0) induces calcium-dependent contractile responses, and (2) Mg2+]0 and verapamil (VE) inhibit calcium influx across the cell membrane. The present study, using isolated rat aortic strips and portal veins, was designed to assess the interactions of [Mg2+]0 and VE on increases in active tension and contractility induced by withdrawal of [Mg2+]0.[Mg2+]0 was found to: (1) enhance VE-induced inhibition of portal vein amplitude, and (2) antagonize VE-induced enhanced frequency of spontaneous phasic contractions in portal veins. Both [Mg2+]0 and VE could prevent and reverse the increases in active tension developed in aortic smooth muscle upon removal of [Mg2+]0.[Mg2+]0 markedly potentiated the inhibitory effect of verapamil on calcium-induced contractions of K+-depolarized aorta but not in K+-depolarized portal vein. This synergistic effect in aortal could be due to the influence of Mg and VE at the membrane and/or the influence of Mg at intracellular sites resulting in decreased levels of functional (activator) cytoplasmic Ca2+. On the other hand, the lack of synergism in portal vein could indicate that both of these agents might be inactivating the same membrane channels involved in calcium influx.

Morphine-induced supersensitivity to acetylcholine in skeletal muscle and its mechanism of action.

The effect of in vitro morphine pretreatment (250 micron) on the sensitivity of skeletal muscle to acetylcholine (ACh) was investigated using the isolated rectus abdominis muscle of frog. Morphine (15 to 120 min) significantly increased the sensitivity of the tissue to ACh. This increase in the sensitivity was found to be greatest after 120 min. Morphine significantly increased the sensitivity of the tissue to carbachol only after 120 min. In the presence of physostigmine, morphine did not cause further augmentation of responses to ACh. Potassium chloride-induced contractile responses were not influenced by morphine. In the presence of morphine, maximum contractile responses to ACh were significantly decreased. Highly calcium (1.62 mM) in the medium decreased the magnitude of the morphine-induced supersentivity to ACh at 120 min and antagonised the decrease in maximum contractile responses to ACh. These results suggest that morphine is causing supersensitivity by both its anticholinesterase activity and its inhibitory action on presynaptic nerve terminals.