Calcium Antagonistic Properties Research Articles

Age-related changes in responsiveness of the rat aorta to depolarizing and receptor-mediated contractile stimuli and to calcium antagonism.

This study was undertaken to determine the relative age-dependent responsiveness of the rat aorta to depolarizing (potassium) and receptor-activating (norepinephrine) contractile stimulants, and to the calcium antagonists propyl-methylenedioxyindene (pr-MDI) and nifedipine. Pr-MDI exhibits intracellular calcium antagonistic and calcium channel blocking properties in this tissue, while nifedipine acts principally as a calcium channel blocker. Thoracic strips from young (4-6 months old) and senescent (22-23 months old) Fischer F344 rats were contracted with KCl (10-60 mmol/l) or norepinephrine (10(-9)-5 X 10(-6) mol/l). Aortae from old rats were significantly more sensitive to norepinephrine than aortae from young rats, while the reverse was observed for KCl. Pr-MDI (10(-5)-10(-4) mol/l) significantly relaxed the aortic contractions induced by norepinephrine (10(-7) mol/l, a nondepolarizing concentration producing 88% of maximum response in young and old aortae) and by KCl (50 mmol/l, a depolarizing concentration producing 96% of maximum response in young and old aortae). However, there were no age-related differences in sensitivity to the relaxant effects of pr-MDI against either stimulant. Pr-MDI was more effective in relaxing KCl-induced contractions than those induced by norepinephrine. Similar results were obtained with nifedipine (10(-10)-10(-6) mol/l). These results indicate that senescence of the rat aorta is accompanied by an enhanced responsiveness of adrenergic alpha-receptor-mediated contraction, a reduced responsiveness to depolarizing stimuli, and no change in sensitivity to calcium antagonism.

Calcium Channel Types in Cardiac Myocytes

Bisoprolol, (±)1-(4-[(2-isopropoxyethoxy)-methyl]-phenoxy)-3-isopropyl-amino-2-propanol-hemifumarate, is a new, highly selective β1-adrenoceptor blocking agent without intrinsic sympathomimetic activity and low to moderate local anaesthetic activity. As demonstrated in binding experiments, and in classical pharmacological studies using rats, guinea pigs, cats, and dogs, bisoprolol markedly differentiated between β1-adrenoceptors of the heart, or the renal juxtaglomerular apparatus, and the β2-subtype in arterial blood vessels, bronchi, liver, or skeletal muscle. Up to concentrations nearly 100-fold higher than the therapeutic plasma levels in humans, bisoprolol did not affect the functional refractory period of the heart, and was devoid of a direct suppressive effect on myocardial contractility and of calcium antagonistic properties in heart and vascular muscle. The pattern of haemodynamic effects of bisoprolol was typical of β-blockers and included decreases in blood pressure (BP), heart rate (HR), and cardiac output, concomitant with an increase in calculated total peripheral resistance. In contrast to other β-blockers, bisoprolol increased renal blood flow in anaesthetized dogs. Bisoprolol lowered BP in hypertensive dogs and rats, attenuated the development of spontaneous hypertension in rats, decreased plasma renin activity and protected the heart from the sequelae of transient ischemia. It did not block presynaptic β-adrenoceptors in blood vessels. Serum lipids and the serum lipoprotein profile remained unaltered after bisoprolol. Bisoprolol was devoid of affinity for autonomic receptors other than β-adrenoceptors or for autacoid receptors. This is probably one of the reasons why bisoprolol did not affect the function of the central nervous, respiratory, and gastrointestinal systems in an obvious way. The high β1-selectivity of bisoprolol is linked with extremely favourable pharmacokinetic properties. These include nearly complete enteral absorption and virtual absence of liver first-pass metabolism, both resulting in high bioavailability, long plasma half-life, pharmacokinetics that are linear over a wide dose range and independent of age, food intake and hydroxylator status, low plasma protein binding, and a 1: 1 ratio of hepatic metabolization to renal elimination of the unaltered substance. This sum of favourable pharmacological and pharmacokinetic properties characterize bisoprolol as an optimized β-blocker.

Calcium antagonists and beta blockers in the control of mild to moderate systemic hypertension, with particular reference to verapamil and propranolol

The antianginal and antiarrhythmic role of calcium antagonists is well established. Recent preliminary studies have indicated that, like β blockers, calcium antagonists may produce short- and long-term hypotensive effects in patients with mild to moderate essential hypertension. The pharmacologic properties of calcium antagonists provide a clear rationale for their use in the control of essential hypertension. The comparative hypotensive effects of verapamil (80 to 160 mg 3 times a day) and propranolol (40 to 120 mg 3 times a day) were evaluated over 4 weeks, preceded by a 4-week placebo phase, in a double-blind protocol in 17 patients with mild to moderate hypertension. Verapamil (n = 10) reduced the mean sitting systolic blood pressure by 10.7% (p < 0.01) and standing by 7.6% (p < 0.04). The corresponding data for propranolol (n = 7) were 4.8% (not significant) and 5% (p = 0.04). Verapamil reduced the sitting diastolic blood pressure by 10.8% (p < 0.01), propranolol by 7.5% (p = 0.01); the standing diastolic blood pressure was reduced by 10.7% with verapamil (p < 0.01) and by 8.6% (p = 0.01) with propranolol. With verapamil the mean heart rate fell from 77.60 ± 8.42 to 70.20 ± 4.85 beats/min (p = 0.03); with propranolol it fell from 76.85 ± 6.91 to 66.29 ± 4.54 beats/min (p < 0.01). Although a trend towards a slightly greater hypotensive effect was apparent with verapamil compared with propranolol, the difference was not statistically significant. It is concluded that verapamil and propranolol exert comparable hypotensive potency in patients with mild to moderate hypertension.

High β1-Selectivity and Favourable Pharmacokinetics as the Outstanding Properties of Bisoprolol

Bisoprolol, (+/-)1-(4-[(2-isopropoxyethoxy)-methyl]-phenoxy)-3-isopropyl-amino -2- propanol-hemifumarate, is a new, highly selective beta 1-adrenoceptor blocking agent without intrinsic sympathomimetic activity and low to moderate local anaesthetic activity. As demonstrated in binding experiments, and in classical pharmacological studies using rats, guinea pigs, cats, and dogs, bisoprolol markedly differentiated between beta 1-adrenoceptors of the heart, or the renal juxtaglomerular apparatus, and the beta 2-subtype in arterial blood vessels, bronchi, liver, or skeletal muscle. Up to concentrations nearly 100-fold higher than the therapeutic plasma levels in humans, bisoprolol did not affect the functional refractory period of the heart, and was devoid of a direct suppressive effect on myocardial contractility and of calcium antagonistic properties in heart and vascular muscle. The pattern of haemodynamic effects of bisoprolol was typical of beta-blockers and included decreases in blood pressure (BP), heart rate (HR), and cardiac output, concomitant with an increase in calculated total peripheral resistance. In contrast to other beta-blockers, bisoprolol increased renal blood flow in anaesthetized dogs. Bisoprolol lowered BP in hypertensive dogs and rats, attenuated the development of spontaneous hypertension in rats, decreased plasma renin activity and protected the heart from the sequelae of transient ischemia. It did not block presynaptic beta-adrenoceptors in blood vessels. Serum lipids and the serum lipoprotein profile remained unaltered after bisoprolol. Bisoprolol was devoid of affinity for autonomic receptors other than beta-adrenoceptors or for autacoid receptors. This is probably one of the reasons why bisoprolol did not affect the function of the central nervous, respiratory, and gastrointestinal systems in an obvious way. The high beta 1-selectivity of bisoprolol is linked with extremely favourable pharmacokinetic properties. These include nearly complete enteral absorption and virtual absence of liver first-pass metabolism, both resulting in high bioavailability, long plasma half-life, pharmacokinetics that are linear over a wide dose range and independent of age, food intake and hydroxylator status, low plasma protein binding, and a 1:1 ratio of hepatic metabolization to renal elimination of the unaltered substance. This sum of favourable pharmacological and pharmacokinetic properties characterize bisoprolol as an optimized beta-blocker.

Central actions of calcitonin on body temperature and intestinal motility in rats: evidence for different mediations

The effects of intracerebroventricular (i.c.v.) administration of calcitonin and PGE 2 on intestinal motility and body temperature were examined in conscious rats chronically fitted with intraparietal electrodes in the small intestine, a cannula in a cerebral lateral ventricle and a subcutaneous thermistor probe. Both calcitonin and PGE 2 restored the fasted pattern of intestinal motility in fed rats and induced an increase in body temperature. Indomethacin, an inhibitor of the cyclooxygenase with calcium antagonistic properties, and TMB-8, an intracellular calcium antagonist, blocked the effects of calcitonin on intestinal motility and body temperature. Piroxicam, an inhibitor of the cyclooxygenase which does not affect calcium uptake blocked the thermic but not the intestinal effects of calcitonin. TMB-8 but not indomethacin or piroxicam partially blocked the effects of PGE 2 on both intestinal motility and body temperature. It is concluded that the central hyperthermic effect of calcitonin is mediated through the formation and the release of prostaglandins whereas the central action of calcitonin on digestive motility results from intracerebral effects on calcium fluxes.

Potential anti-anaphylactic activity of clenbuterol, a beta-agonist with calcium antagonist properties

Clenbuterol 10(-8) to 10(-6) M inhibited antigen-induced histamine release from passively sensitized human lung tissue. This inhibition was not antagonized by propranolol, whereas the inhibitions observed with isoprenaline and fenoterol were reduced by propranolol. Clenbuterol also inhibited compound 48/80-induced histamine release and immunological histamine secretion from actively sensitized peritoneal rat mast cells. High concentrations of clenbuterol were required (10(-5) to 10(-3) M) and propranolol did not antagonize these inhibitions of histamine release. Isoprenaline and salbutamol did not modify the secretion from rat mast cells. The potential anti-anaphylactic activity of clenbuterol, might be partly related to its calcium antagonist property.

Effect of the calcium antagonist verapamil on human leucocyte sodium transport in vitro.

Sodium efflux rate constants and intracellular sodium were measured in leucocytes from healthy volunteers in the presence and absence of the calcium antagonist verapamil hydrochloride. Verapamil stimulated sodium pump activity and this effect was dependent on the presence of external calcium. Verapamil has been reported to reverse the abnormality of sodium transport seen in leucocytes from patients with essential hypertension and the present study demonstrates that sodium pump activity in leucocytes from control subjects is also stimulated by exposure to verapamil in vitro. This direct cellular effect appears to be due to the calcium antagonist properties of the drug.

Regression of Left Ventricular Hypertrophy in Hypertension

We examined the effect of three antihypertensive agents with differing modes of action on blood pressure, heart rate, plasma catecholamines, plasma renin activity, and echocardiographic left ventricular mass. Twenty-six patients were studied; nine were treated with nifedipine, a calcium antagonist, nine were treated with timolol, a nonselective beta-blocker, and eight were treated with indapamide, a diuretic with some probable calcium antagonist properties. All drugs reduced blood pressure satisfactorily; the reduction of systolic blood pressure was not significantly different among the three drugs, but timolol reduced diastolic blood pressure by a greater amount than did either indapamide or nifedipine. Left ventricular (LV) mass was reduced equally by all three drugs. However, there were markedly different effects on the other parameters measured. Heart rate was reduced to a greater extent by timolol than by the other two drugs. Plasma renin activity was reduced by timolol, unchanged by nifedipine, and increased by indapamide. There were no significant changes in either adrenaline or noradrenaline with any of the three drugs. We conclude that these data do not support the hypothesis that the sympathetic nervous system is primarily responsible for left ventricular hypertrophy, and suggest that reduction of left ventricular mass with antihypertensive agents is not the property of any one class of drug.

A comparative study on possible calcium antagonistic properties of indapamide and other drugs potentially interfering with calcium transport in isolated vascular smooth muscle

In the present study the effects of indapamide (IN) were compared with those of chlorthalidone (C) and of drugs potentially interfering with calcium transport, e.g. verapamil (V), papaverine (P), phentolamine (PH) and diazoxide (D) using isolated rabbit aorta in order to detect calcium antagonistic properties. IN and C failed to show any relaxation effect towards either noradrenaline (NA)- or high K +-precontracted aorta strips, whereas V and P reduced the K + contraction dose dependently and PH, V, P and D induced a significant relaxation of the NA contraction. Preincubation with IN or C did not affect the dose-response curve of NA-induced contractions. PH antagonized the NA contraction strongly whereas V and P shifted the dose-response curve to the right only at the highest concentration. In a Ca 2+-depleted and high K +-depolarized aorta preincubation with V was able to antagonize Ca 2+-induced contraction effectively in a dose-dependent fashion whereas P only showed partial inhibition at the highest concentration. The effects of the drugs on responses to NA in a Ca 2+-free medium were also investigated. This type of contraction is likely to be due to mobilization of internally located Ca 2+. The results demonstrate that PH was able to counteract this type of contraction effectively whereas only a high concentration of V, P and D was effective in reducing the Na contraction in Ca 2+-free medium. Both IN and C failed to affect this type of contraction. In conclusion, the present results indicate that neither IN nor C possess calcium entry and or intracellular calcium antagonistic properties under different conditions as measured in a conduit vessel of rabbits. Moreover, the results point to an additional site of calcium antagonistic action for V, P and D, especially at higher concentrations.

Ketotifen: current views on its mechanism of action and their therapeutic implications.

The mechanism of action of ketotifen in the prevention of bronchial asthma is discussed, the pathogenesis of the disease itself being taken as a starting point. The following biological effects of ketotifen may be relevant to its therapeutic activity: the inhibition of release of myotonic mediators, leukotrienes in particular, the inhibition of slow reacting substances-induced bronchoconstriction in vivo, calcium antagonistic properties, and the prevention or reversal of decreased beta-adrenoceptor sensitivity. In asthmatic patients the prevention of bronchospasm due to mediator release and a progressive reduction of bronchial hyperreactivity are the major consequences of these properties.

In vitro studies on cetamolol, a new potent cardioselective beta-adrenoceptor blocking agent with intrinsic sympathomimetic activity.

In vitro studies on the new beta-adrenoceptor antagonist, cetamolol (Betacor), have demonstrated that the compound is a potent antagonist of the chronotropic effects of isoproterenol on guinea pig atria. The pA2 value (8.05) of cetamolol was slightly lower than that of propranolol (8.44). The compound was shown to possess a moderate degree of cardioselectivity as indicated by a lower pA2 value for the antagonism of isoproterenol-induced relaxation of the isolated guinea pig trachea (pA2 = 7.67) compared with that derived from atrial experiments (pA2 = 8.05). Up to concentrations of 10(-4) M, cetamolol displayed negligible negative inotropic activity relative to propranolol in the electrically stimulated guinea pig left atrial preparation. When applied to isolated right atria from reserpinized rats, cetamolol had a positive chronotropic effect (approximately 75% of that displayed by practolol) which was antagonized by pretreatment with propranolol, thus indicating intrinsic sympathomimetic activity. Specificity experiments in a number of isolated tissues indicated that cetamolol had very little antihistaminic, anticholinergic, alpha 1-adrenergic blocking, or calcium antagonistic properties. Biochemical receptor binding studies are in general agreement with the observations from the isolated tissue experiments.

Clinical efficacy and safety of indapamide in essential hypertension

Indapamide, a new methylindoline diuretic that appears to act on the distal renal tubules, is also reported to reduce vascular smooth muscle vasopressor reactivity and possibly to have a calcium-antagonist effect. Since 1973, sixteen studies by a number of European investigators who treated 301 patients with indapamide have revealed satisfactory control in 53% of patients who mild hypertension (standing diastolic pressures <90 mm Hg) and in 43% of patients with moderate hypertension when the drug was used without other agents. Multiple American clinical trials of indapamide in hypertension have been conducted, including double-blind, placebo-controlled protocols and trials comparing indapamide with traditional diuretic agents. A cooperative, double-blind, 40-week study compared antihypertensive response to indapamide, 2.5 mg and 5 mg daily, with response to hydrochlorothiazide, 50 mg daily, in the treatment of mild to moderate hypertension. Pretreatment diastolic blood pressures averaged 101 mm Hg. At 40 weeks of treatment, indapamide, 2.5 mg daily, had produced a fall in diastolic pressure of 15 mm Hg; indapamide, 5 mg daily, a reduction of 16 mm Hg; and hydrochlorothiazide, 50 mg daily, a fall of 15 mm Hg. Seventy-five percent of patients taking 2.5 mg of indapamide daily and 88% of those taking 5 mg achieved satisfactory blood pressure reduction. Hypokalemia may occur with indapamide but is a minor problem and seldom necessitates potassium supplementation. Serum uric acid increases were observed in only a few subjects, and clinical side effects are infrequent and mild. Indapamide is a useful antihypertensive agent with good patient tolerance in mild or moderate hypertension and may offer advantages over traditional diuretics in view of its possible vasodilator and calcium-antagonist properties, once-a-day dosage, and good therapeutic effect with prolonged usage.

Conformational analysis of the calcium- antagonist gallopamil

Conformational analysis of gallopamil was performed in order to gain insight into the molecular determinant of its calcium-antagonistic property. Whereas the neutral form of gallopamil was characterized by a single, largely predominant configuration, the protonated form of the drugs yielded several conformers, some of which were characterized by a readily accessible ionized site. The capacity of gallopamil to inhibit ionophore-mediated calcium translocation in a two-phase bulk system was inversely related to the pH of the queous phase. These findings indicate that the capacity of gallopamil to interfere with the transport of cations is critically dependent on the availability of a protonated configuration of the drug.

Calcium antagonistic activity and myocardial ischemic protection by both stereoisomers of verapamil.

The effects of the optical isomers of verapamil were compared on intact and partially ischemic pig hearts as well as on vascular smooth muscle of rabbits and rats. In K+-depolarized strips of rabbit mesenteric artery, both isomers shifted calcium dose-response curves (tension development) in a qualitatively similar manner to the right, with threshold concentrations of 10–8 m (—)verapamil and 10–7 m (+)verapamil. In K+-depolarized rat aortic strips, the calcium antagonistic activity was quantified. (+)Verapamil was at least as potent as several other coronary drugs [(±)verapamil = 1]: perhexiline 0.02, prenylamine 0.05, fendiline 0.05, diltiazem 0.15, (±)verapamil 0.15, (-)verapamil 1.5. The optical isomers of D600 showed a considerably greater difference in calcium antagonistic potency (about a factor of 60) as compared to verapamil (factor of 10). In the pig heart, reversible and reproducible ischemia reactions were provoked by repeated occlusions (3 min) of a branch of the LAD followed by reperfusion for 15 min. In the tested range of 0.4–2.0 mg/kg i.V., (-I-)verapamil dose-dependently reduced ischemic ST elevations in four epicardial leads. At an intermediate dose of 1 mg/kg, (+Verapamil diminished ST-elevations by 32% (occlusion 11 min p.i.). Results not statistically different were obtained with 0.1 mg/kg (-)verapamil (28%) and 0.2 mg/kg (±)verapamil (40%). No qualitative differences between the isomers could be observed with regard to hemodynamic parameters with equieffective reduction of the ischemia reaction: slight decrease in heart rate; prolongation of PQ duration with only minimal and insignificant effect of (+)verapamil; decrease of systolic and diastolic blood pressure, left ventricular pressure, and LV dp/dt max . In contrast to optically active and racemic verapamil, nifedipine in a hypotensive dose (0.05 mg/kg i.v.) increased heart rate and diminished ischemic ST elevations only moderately (13%). The results obtained on vascular smooth muscle and ischemic pig heart clearly show that there are no remarkable qualitative differences between verapamil enantiomers. It can be concluded that (+)verapamil, by its calcium antagonistic properties, contributes to the therapeutic efficacy of the racemic drug.KeywordsOptical IsomerEpicardial LeadRacemic DrugRabbit Mesenteric ArteryHypotensive DoseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Effects of prenylamine on transmembrane action potentials as related to the change in external potassium concentrations in guinea pig papillary muscle.

We studied the effects of 4.8 muM prenylamine on transmembrane potentials in isolated guinea pig papillary muscles using a conventional microelectrode technique and compared them with those of 36.9 microM lidocaine. Prenylamine reduced Vmax at 1 Hz increasingly as the external potassium, [K]o, was increased from 2.7 to 10 mM. The reduction was also increased as the driving rate was increased from 0.25 to 5 Hz. The rate-dependent depression was less in 2.7 and 8.1 mM with 7.2 mM [Ca]o and more in 5.4 and 8.1 mM [K]o with 1.8 mM [Ca]o. Prenylamine produced a marked delay in the recovery of Vmax in premature responses inserted between constant driving stimuli at 0.25 Hz. The delay was also less in the former two, and more in the latter two media. Thus the effects of prenylamine on Vmax were more rate dependent and less [K]o-dependent than those of 36.9 microM lidocaine. At the diastolic interval of 100 ms, prenylamine depressed the overshoot, action potential duration at 0 mV level (APDo) and Vmax in premature responses more markedly than did 36.9 microM lidocaine, the differences of the effects being more significant for the first two. The results are interpreted as representing the calcium-antagonistic property of prenylamine of which lidocaine appears to be devoid.

Clinical and Pharmacological Properties of Calcium Antagonists in Essential Hypertension in Humans and Spontaneously Hypertensive Rats

The abnormal cellular contractile mechanisms causing the development of essential hypertension in humans and rats were investigated, primarily with the use of Ca2+ and Ca antagonists. Helical strips isolated from mesenteric arteries of spontaneously hypertensive rats (Aoki SHR) showed an increased Ca2+ -induced tension development in the presence of noradrenaline or a high potassium concentration. The tension development of the SHR strips was greatly inhibited by Ca antagonists. In the patients with essential hypertension, both elevated blood pressure and elevated total peripheral resistance were reduced to normal levels by Ca antagonists. The drugs increased cardiac output and stroke volume. The hypotensive effect of the drugs was due to arterial vasodilation. We concluded that there might be an abnormally high sensitivity of the cell membrane system of vascular smooth muscle to both Ca2+ and Ca antagonists in patients with essential hypertension and in SHR. Abnormalities in Ca2+ channels, Ca2+ uptake, and Ca2+ binding of the cell membrane, which cause the high sensitivity, might greatly increase the Ca2+ levels of cytosol in the muscle. The increased cytosol Ca2+ induces, in turn, either increased contraction or decreased relaxation and a decrease in the arterial lumen. Any decrease in the lumen results in peripheral resistance enhancement, which is responsible for the increase in arterial blood pressure in essential hypertension. Thus, we propose the membrane theory of essential hypertension--that membrane abnormalities lead to hypertension.

Development of diltiazem, a calcium antagonist: coronary vasodilating and antihypertensive actions.

We found that the coronary vasodilating action resides in novel 1,5-benzothiazepine derivatives. The calcium antagonistic property of diltiazem has been demonstrated in vascular and visceral smooth muscles as well as in cardiac ventricular muscle. Although the vasodilating action of diltiazem was the most potent in coronary and vertebral artery, it also dilates other peripheral arteries including renal artery. Antihypertensive action of diltiazem has been shown in several experimental models, such as SHR, renal hypertensive and DOCA/saline rats. Diuretic effect of diltiazem was observed in SHR. Following chronic administration of diltiazem to SHR, the increment of blood pressure was significantly lowered without changing body fluid. In addition, hypotensive action of diltiazem by i.c.v. was observed only at a very high dose. We assume that the vasodilating action of diltiazem is primarily involved in the mechanism responsible for its antihypertensive action.

Electrophysiological and antiarrhythmic properties of propafenon in isolated cardiac preparations.

Propafenon, a new antiarrhythmic drug, caused a 30% decrease in maximal driving frequency and a 65 ms net increase in functional refractory period of isolated guinea pig atria at a concentration as low as 0.5 microgram/ml. The spontaneous rate of isolated atria and the contractility of electrically driven ventricular strips were reduced after treatment with propafenon 1 microgram/ml. Propafenon 0.5 microgram/ml also altered action potentials of sheep Purkinje fiber. It reduced the action potential and overshoot amplitudes, decreased the maximum rate of depolarization of the action potential upstroke in a frequency-dependent fashion, shortened the action potential and effective refractory period, and depressed the membrane responsiveness. Moreover, propafenon antagonized the chronotropic and inotropic effects of isoprenaline in isolated guinea pig heart preparations; the pA2 value was about 6.4. Finally, propafenon possessed very weak calcium antagonist properties, being about 100 times less potent than verapamil in this respect. We conclude that propafenon is an antiarrhythmic drug with beta-adrenoceptor blocking and "membrane stabilizing" activities in the same range of concentrations and that it has a calcium antagonistic activity only at much higher concentrations.

Calcium and calcium-antagonistic effects on prolactin and growth hormone responses to thyrotropin-releasing hormone and L-dopa in man.

The significance of calcium for the responsiveness of human lactotrophs and somatotrophs to iv TRH and oral L-dopa was investigated in 11 young healthy women. Both TRH and L-dopa were administered on three different background infusions: 1) saline, 2) verapamil, and 3) calcium. Twenty-five micrograms of TRH raised the PRL level from 15.1 +/- 2.3 to 76.9 +/- 8.8 ng/ml in 15 min (P less than 0.001). Calcium infusion blunted this PRL response by 33 +/- 8% (P less than 0.02), whereas verapamil, known for its calcium-antagonistic properties, left in unaffected. Five hundred milligrams of L-dopa increased the GH level from 2.2 +/- 0.7 to 16.7 +/- 2.2 ng/ml in 60 min (P less than 0.002) and reduced the PRL level from 11.6 +/- 2.9 to 3.1 +/- 0.4 ng/ml in 150 min (P less than 0.05). Neither calcium nor verapamil influenced these GH and PRL responses significantly. These findings indicate that human somatotrophs may be less dependent than human lactotrophs on normocalcemia for adequate hormone secretion.

The effect of 2-n-propyl-3-dimethylamino-5,6-methylenedioxyindene on caffeine-induced contractures of skeletal muscle.

It has been previously postulated that 2-n-propyl-3-dimethylamino-5,6-methylenedioxyindene (pr-MDI) exhibits calcium antagonistic properties with an intracellular site of action. The present investigation further substantiates this hypothesis by providing evidence that pr-MDI inhibits caffeine-induced contractures (which are mediated by intracellular calcium) of the isolated rat hemidiaphragm skeletal muscle both in the presence and in the absence of extracellular calcium.