Addition Of Nifedipine Research Articles

Addition of Pentoxifylline plus Nifedipine to Chemotherapy in Patients with Cisplatin-Resistant Cancers of the Lung and Other Sites

Eight evaluable patients with cisplatin-resistant non-small cell lung cancer (6 patients), small cell lung cancer (1 patient), or both breast and ovarian cancer (1 patient) were entered on a study to determine whether the addition of nifedipine plus pentoxifylline to cisplatin-based chemotherapy would result in increased chemotherapy efficacy. No patient responded to treatment. Myelosuppression may have been augmented by the nifedipine and pentoxifylline (median granulocyte nadir, 0.3 x 10(9)/L). Two patients developed febrile neutropenia. Nifedipine and pentoxifylline had to be stopped in two evaluable patients due to hypotension, and three additional inevaluable patients withdrew from the study due to nifedipine-pentoxifylline toxicity before receiving their chemotherapy. There was no indication that other types of chemotherapy toxicity were increased by the addition of nifedipine and pentoxifylline. A major problem with the strategy followed in this protocol was that patients whose tumors had failed to respond to cisplatin-based regimens were often too ill to tolerate additional cisplatin, particularly when accompanied by nifedipine-associated hypotension.

All‐or‐nothing responses to carbachol in single intestinal smooth muscle cells of rat

1. Concentration-response relationships for carbachol (CCh)-induced increases in the cytosolic calcium concentration ([Ca2+]i) and membrane currents were studied by use of fura-2 microfluorimetry and nystatin-perforated whole-cell recording in single smooth muscle cells isolated from rat intestine. 2. CCh produced an initial peak rise in [Ca2+]i followed by a small sustained rise. In individual cells, the peak rise in [Ca2+]i did not increase in amplitude even with increasing concentrations of CCh, though the threshold concentration varied in different cells. The initial peak rise in [Ca2+]i, but not the sustained rise, was due to the release of stored Ca2+, because it was unchanged after removal of external Ca2+ and the addition of nifedipine (1 microM) or La3+ (1 mM). 3. CCh elicited an outward and inward current in a cell dialyzed with a pipette solution containing KCl at a holding potential of -30 mV and with one containing NaCl at -60 mV, respectively. In individual cells, the amplitude of each current was similar in cells stimulated at over the threshold concentration of CCh, but the threshold was different among cells. 4. The percentage of cells showing Ca(2+)-transient responses to CCh at given concentrations was similar to those showing current responses and contractile responses. 5. In thin muscle bundles, a concentration-dependent contraction was evoked by CCh in the absence of external Ca2+. Its threshold was similar to those of Ca(2+)-transient and current responses in single cells. 6. These results suggest that CCh-induced release of stored Ca2+ takes place in an all-or-nothing fashion in individual cells of the rat intestinal smooth muscle.

The effect of nifedipine, a calcium channel blocker, on human spermatozoal functions

In vitro addition of 0.1–100 μm of a calcium channel blocker, Nifedipine, resulted in a significant non-competitive inhibition in the uptake of Ca + +. The activity of Ca + +-dependent ATPase enzyme was also decreased. Motility of the spermatozoa was significantly arrested following incubation with different doses of the drug at 37 °C for different durations. The pattern of motility changed within two hours from rapid and linear progression to slow or sluggish linear or non-linear movement and finally to non-progressive motility or even immotility. Scanning electron microscopic studies revealed disruptive changes in the head as well as tail region and coiling of spermatozoa after Nifedipine treatment. An increase in the formation and release of malonyldialdehyde was observed following Nifedipine addition in a dose-dependent fashion. The membrane cholesterol and phospholipid contents were considerably lowered in the treated samples. The potential of such calcium channel blocking agent in the designing of male contraceptive programme is discussed.

Functional role of Ca(2+)-activated K+ channels in resting state of carotid arteries from SHR

Carotid arteries from spontaneously hypertensive rats (SHR) exhibited an active tone when exposed to a physiological salt solution; that is, the tension decreased when nifedipine was added. To determine the possible role of Ca(2+)-activated K+ (KCa) channels in the resting state of these arteries, the effects of agents that interact with these channels on tension and 86Rb efflux were compared in endothelium-denuded strips of carotid arteries from SHR and normotensive Wistar-Kyoto rats (WKY). The addition of charybdotoxin, a blocker of high-conductance KCa channels, to the resting strips produced a concentration-dependent contraction in SHR but not in WKY. In resting strips preloaded with 86Rb, the basal 86Rb efflux rate constant was significantly greater in SHR than in WKY. The addition of nifedipine to the resting strips decreased the basal 86Rb efflux rate constant only in SHR. The effect of nifedipine on tension and 86Rb efflux in 25.9 mM K(+)-contracted strips of WKY was comparable to the effect of this blocker in the resting strips of SHR. The basal 45Ca influx in resting strips of SHR was significantly increased when compared with WKY, and this increase in SHR was abolished by nifedipine. These results suggest that the transmembrane Ca2+ influx via L-type voltage-dependent Ca2+ channels was significantly increased in the resting state of carotid arteries from SHR and that the KCa channels were highly activated.

Activin A increases intracellular free calcium concentrations in rat pancreatic islets

Activin A stimulated insulin secretion in rat pancreatic islets, an effect that was attenuated by reduction of extracellular Ca 2+ and abolished by either nitrendipine or verapamil. Activin A increased intracellular the free Ca 2+ concentration, [Ca 2+] i in fura-2-loaded islets. Activin A-mediated elevation of [Ca 2+] i was abolished by the reduction of extracellular Ca 2+ or the addition of nifedipine. In addition, activin A did not increase [Ca 2+] i in the presence of diazoxide, an opener of ATP-sensitive K + channels. These results suggest that activin A increases insulin secretion by stimulating Ca 2+ entry.

Combination of nifedipine and doxazosin in essential hypertension.

Pharmacodynamic and pharmacokinetic interactions have been reported when an alpha 1-antagonist is combined with a calcium antagonist. We evaluated the clinical usefulness of the combination of nifedipine (20 mg twice daily, b.i.d.) and doxazosin (2 mg once daily, o.d.) in hypertensive patients in whom blood pressure (BP) control was suboptimal after doxazosin (group A) or nifedipine (group B) as monotherapy and investigated the underlying kinetic and dynamic interactions, including changes in vascular responsiveness to i.v. infusions of angiotensin II (ANGII) and phenylephrine (PE). The combination was well tolerated and associated with further significant reductions in BP. After 4 weeks of combined therapy, average supine BP over 8 h was 122/77 in group A and 137/80 in group B as compared with 140/86 and 150/88 mm Hg, respectively, during monotherapy + placebo. The combination attenuated both phenylephrine and ANG-induced pressor responses: e.g., the mean PD15 values (dose of agonist required to increase systolic BP by 15 mm Hg) for group A at 1.5-3 h were 3.5 micrograms/kg/min for PE and 7.5 ng/kg/min for ANGII as compared with 2.9 and 2.3, respectively, during treatment with doxazosin and placebo. There was no evidence of a significant kinetic interaction between the two drugs and, in particular, addition of nifedipine had no effect on the steady-state kinetics of doxazosin. In conclusion, doxazosin and nifedipine are an effective antihypertensive combination in patients who require treatment with more than one drug.

Comparison of the cardiovascular effects of nifedipine and nicardipine in the presence of atenolol

A placebo controlled double blind crossover study was performed in 12 healthy volunteers to compare the cardiovascular effects of single oral doses of nifedipine (5, 10 and 15 mg) and nicardipine (20 and 30 mg) in the presence of atenolol 100 mg. Haemodynamic measurements were made by transthoracic electrical bioimpedance cardiography (TEBC) 2 h following drug administration during passive tilting, graded bicycle exercise (30-150 W) and recovery from exercise. In the absence of calcium channel blockade, atenolol reduced mean blood pressure, heart rate, and cardiac index, and increased stroke volume, peripheral resistance, pre-ejection period, and ventricular ejection time, particularly during and after exercise. In comparison with atenolol alone, addition of nifedipine or nicardipine reduced peripheral resistance but did not produce significant changes in stroke volume, cardiac output, dZ/dt [max], pre-ejection period (PEP). Ventricular ejection time (VET), PEP/VET, or Heather index at any point in the experiment. Similar reductions in peripheral resistance were produced by nifedipine 10 mg and nicardipine 20 and 30 mg. These apparently equivalent doses of nifedipine and nicardipine had similar effects on stroke volume, cardiac index, PEP/VET and Heather index. Thus the increases in ventricular performance previously demonstrated in association with nifedipine and nicardipine therapy were not observed in the presence of beta-adrenoceptor blockade. Under these conditions no important differences have been observed in the cardiovascular effects of these two calcium channel blockers.

The alpha-adrenergic stimulation of atrial natriuretic factor expression in cardiac myocytes requires calcium influx, protein kinase C, and calmodulin-regulated pathways

It has been shown recently that alpha-adrenergic agonists can stimulate atrial natriuretic factor (ANF) expression in ventricular cardiac myocytes; however, little is known about the intracellular signals mediating this activation. The present study focused on the potential roles of calcium-regulated kinases and calcium influx in the alpha-adrenergic stimulation of ANF gene expression in ventricular myocardial cell cultures. Myocardial cells maintained for 48 h in serum-free medium supplemented with phenylephrine (PE) possessed up to 15-fold higher levels of ANF peptide and ANF mRNA than control cells. The removal of PE, or the addition of nifedipine, resulted in a rapid decline in ANF expression, suggesting that the sustained elevation of some intracellular messenger (e.g. calcium and/or phospholipid hydrolysis products) was required for the adrenergic response. The calcium channel agonist BAY K 8644 was capable of increasing ANF expression in a nifedipine-sensitive manner; however, unlike PE, it did not stimulate phosphoinositide hydrolysis. The protein kinase C inhibitor, H7, caused an approximate 75% reduction in PE-stimulated ANF expression, but had no effect on BAY K-stimulated expression. W7, a calcium/calmodulin inhibitor, completely blocked the effects of both PE and BAY K 8644. The addition of either H7 or W7 24 h after the PE addition resulted in a decline of ANF expression. These results indicate that alpha-adrenergic agonists augment ANF gene expression through at least two pathways, one that is H7-sensitive, perhaps involving the sustained activation of protein kinase C, and the other that is W7-sensitive, perhaps involving the sustained activation of calmodulin-regulated kinases. Further, it appears that BAY K 8644-mediated increases in ANF expression are independent of protein kinase C activation and dependent on calmodulin-regulated events.

The diverse effects of cromakalim on tension and 86Rb efflux in canine arterial smooth muscle

1. To characterize further the K+ channels opened by cromakalim in arterial smooth muscle, the effects of cromakalim on tension and 86Rb efflux were compared in endothelium-denuded strips of coronary, mesenteric and middle cerebral (MC) arteries of the dog. 2. Cromakalim relaxed strips precontracted with 20.9 mM K+. The maximum relaxation induced by cromakalim varied in the arteries used; 94% in the coronary artery, 60% in the mesenteric artery and only 38% in the MC artery. Cromakalim failed to relax arterial strips precontracted with 65.9 mM K+. 3. When the effects of cromakalim on 86Rb efflux were determined in 20.9 mM K(+)-contracted strips, cromakalim-induced relaxations were accompanied by a large increase in 86Rb efflux in the coronary artery, by a small increase in the mesenteric artery but by an apparent decrease in the MC artery. 4. When 10(-7) M nifedipine was added to 20.9 mM K(+)-contracted strips, to inactivate Ca2(+)-activated K+ (KCa) channels, cromakalim produced a greater increase (measured from the point at which cromakalim was administered) in 86Rb efflux than in the absence of nifedipine, suggesting that the effects of cromakalim on 86Rb efflux from the 20.9 mM K(+)-contracted strips may be the resultant of two opposing effects: an increased 86Rb efflux perhaps due to the opening of ATP-sensitive K+ (KATP) channels, and a decreased efflux due to the closing of KCa channels. 5. After the inactivation of Kca channels in 20.9mM K+-contracted strips, the cromakalim-induced increase in 86Rb efflux measured as area under the curve was eight times greater in the coronary artery than in the MC artery. The increase in 86Rb efflux in the mesenteric artery was intermediate between these extremes. 6. Cromakalim also increased the 86Rb efflux from 65.9 mm K+-contracted strips. This increase was not augmented by the addition of nifedipine. Under these conditions, a similar variation in efflux response (as area under the curve) for cromakalim was noted in the arteries used. 7. The relaxant responses of each artery to cromakalim were competitively antagonized by glibenclamide, a blocker of KATP channels. The cromakalim-induced increase in 86Rb efflux was also inhibited by glibenclamide. 8. These results suggest that cromakalim-opened K+ channels in the three arteries may differ in terms of their frequency of occurrence in the plasmalemma, their permeability to 86Rb and their ability to modulate tension development. On the other hand, the activities of Kca and voltage-sensitive K+ channels, estimated from the effects of nifedipine, were similar in the three arteries.

Effects of Nifedipine on Psychosis and

In an open label study, two fixed doses of nifedipine (30 mg and 60 mg daily) were added to the usual antipsychotic drug treatments of 10 patients suffering from chronic schizophrenia. While no patient experienced significant improvements, statistically significant falls in Brief Psychiatric Rating Scales scores were observed. A significant reduction in Abnormal Involuntary Movement Scale scores was observed in those patients with tardive dyskinesia. After the addition of nifedipine, four of the 10 patients showed large increases in plasma neuroleptic activity (radioreceptor assay) that decreased to baseline levels within two weeks. The possibility that this represents competitive inhibition and subsequent induction of the liver metabolism of the antipsychotic drugs is discussed. Adverse effects encountered are also discussed.

Changes in benzodiazepine receptors of rat brain after long-term treatment with the Ca 2+-antagonists nifedipine, verapamil, flunarizine and with the calmodulin antagonist trifluoperazine

1. The binding of [ 3H]flunitrazepam to benzodiazepine receptors in the cerebral cortex and hippocampus (membrane fraction P 2) was studied after 13-day oral treatment of male Wistar rats with the Ca 2+-antagonists nifedipine (20 mg/kg), verapamil (50 mg/kg), flunarizine (10 mg/kg) and with the calmodulin (CaM)-antagonist trifluoperazine (TFP) (3 mg/kg). 2. The changes in the binding characteristics of the benzodiazepine receptors in the frontal cortex were studied in vitro after the addition of nifedipine (10 -6 and 10 -5M) and verapamil (10 -6 and 10 -5M). 3. A significant decrease of the binding capacity ( B max) of [ 3H]flunitrazepam was established after in vivo treatment with the three Ca 2+-antagonists as well as after TFP, the decrease being much more pronounced in the hippocampus. 4. Changes in the affinity values ( K d) of [ 3H]flunitrazepam binding were found in neither of the groups. 5. No data for a direct interaction of nifedipine and verapamil with the brain benzodiazepine receptors were obtained in in vitro experiments.

Effect of plasma from patients with essential hypertension on vascular resistance in the isolated perfused rat kidney

1. Isolated perfused rat kidneys were used to study the effects of plasma fractions obtained by gel filtration from essential hypertensive patients (n = 40) and from normotensive subjects (n = 36) on resistance vessels. Perfusion pressure was recorded at a constant flow. 2. Plasma fractions were obtained by gel filtration and contained substances with a molecular mass in the range 1000-1500 Da. The plasma fractions from hypertensive patients used in this study had been shown to increase blood pressure after intravenous injection in rats. 3. In the isolated rat kidneys, the hypertensive fractions increased perfusion pressure by 20 +/- 17 mmHg (mean +/- SD, range 5-58 mmHg, n = 40). The analogous fractions from normotensive subjects did not change perfusion pressure significantly. 4. In Ca2(+)-free medium containing 2 mmol/l ethyleneglycol bis-(aminoethyl ether)tetra-acetate, the change in perfusion pressure induced by active plasma fractions was reduced by 95.2 +/- 6.3%. Addition of nifedipine to the perfusion medium reduced, but did not abolish, the pressure response of the kidneys. 5. In solutions containing phentolamine or saralasin, vasoconstriction was not reduced. 6. Thus in the active fractions from hypertensive plasma, a vasopressor agent with direct action on resistance vessels can be demonstrated. This substance probably acts by increasing Ca2+ influx in vascular smooth muscle cells.

The calcium homeostasis and the membrane potential of cultured muscle cells from patients with myotonic dystrophy

Using the fluorescence indicator, quin2, we compared the cytoplasmic Ca 2+ concentration ([Ca 2+] i) of cultured myotubes obtained from control subjects and myotonic dystrophy (MyD) patients. In Ca 2+-free buffer the [Ca 2+] i of the cultured MyD muscle cells was not significantly different from that of the control cells. In the presence of 1 mM external Ca 2+ the cultured MyD muscle cells showed a significantly higher [Ca 2+] i, which was due to the influx of Ca 2+ through voltage-operated nifedipine-sensitive Ca 2+ channels. In the presence of external Ca 2+, MyD myotubes did not respond to acetylcholine, whereas control myotubes showed a transient increase in [Ca 2+] i after addition of acetylcholine. This increase was inhibited by the addition of nifedipine. The difference in Ca 2+-homeostasis between cultured MyD muscle cells and control cells were not due to differences in the resting membrane potential or the inability of the MyD cells to depolarize as a response to acetylcholine. Therefore, culltured MyD muscle cells exhibit altered nifedipine-sensitive voltage-operated channels which are active under conditions in which they are normally present in the inactivie state, and which are unable to respond to depolarization cause by acetylcholine.

Potentiating Effect of Daunorubicin on Vasocontractile Responses to KCl and BAY K 8644 in Rat Aorta

The effects of daunorubicin on vasoconstraction by several agonists have been investigated on isolated aortic strips from rats. Pretreatment of the strips with daunorubicin (17.7 microM) potentiated the contractile response to low concentrations of KCl or to BAY K 8644 but not to phenylephrine or clonidine. The maximal contractile response to KCl was not affected by the pretreatment while that to BAY K 8644 was increased. The potentiated response to KCl could be eliminated by addition of nifedipine (1 microM) or use of a calcium-free solution. The maximal contractile response to BAY K 8644 was greatly increased by partial depolarization with KCl (10 mM, final concn) in the control solution but only slightly increased by the partial depolarization in the solution with daunorubicin. These results suggest that daunorubicin facilitates activation of the voltage-dependent calcium channel and increases the contractile responses to KCl and BAY K 8644 in rat aorta.

Nifedipine as an add-on drug in the management of refractory epilepsy

We report the effects of the addition of nifedipine, a calcium channel antagonist, to the antiepileptic therapy of 20 patients with severe medically refractory epilepsy. Six patients developed side effects and in two the drug had to be discontinued because of these. The commonest side effects were headaches, dizziness and lethargy. Two patients experienced deterioration in seizure control and only 2 patients showed improved seizure control. One of these patients subsequently developed tolerance at 5 months. In 16 patients there was no change.

Nisoldipine tablets once daily versus nifedipine capsules three times daily in patients with stable effort angina pectoris pretreated with atenolol

Treatment with nisoldipine (2 x 10 mg tablets once daily) and nifedipine (2 x 10 mg capsules three times daily) in patients with severe, but stable effort angina pretreated with atenolol (100 mg once daily in 19 patients and 50 mg once daily in one patient) were compared for their effects on bicycle exercise tolerance and their adverse effects in a randomized 2 x 4 week, double-blind, double-dummy crossover study. All patients had multivessel disease, 16 patients had occlusion of at least one vessel, and eight patients had a history of myocardial infarction. Two patients left the study during the initial nisoldipine period, one because of aggravation of the angina and the other because of suspected allergic reaction. Addition of nifedipine to atenolol treatment significantly improved the variables measured for severity of angina, such as time of exercise until 1 mm and 2 mm ST-segment depression, total exercise time and total workload. In contrast, no such improvement was noted after the addition of nisoldipine to atenolol. However, nisoldipine resulted in a significant prolongation of the time to the initiation of chest discomfort, the maximum heart rate, and the double product. In atenolol-treated patients with severe effort angina pectoris, nifedipine 20 mg tid improved exercise capacity, while nisoldipine 20 mg once daily did not have a similar effect.

Clinical Effects of Calcium Antagonists in Silent Ischemia

A number of studies have addressed the response to calcium antagonists, used alone or combined with other therapy, in patients with silent myocardial ischemia (SMI). Nifedipine, the first calcium antagonist to be studied, was shown to be superior to pindolol in patients with effort angina. Although both nifedipine and diltiazem significantly reduced episodes of ST depression, compared with placebo, in patients with stable effort angina, the addition of nifedipine to diltiazem removed the beneficial effect of diltiazem in another study. Studies have shown a reduced incidence of ischemic episodes during nicardipine treatment in patients with ambulatory ischemia, predominantly SMI, and rest angina due to coronary artery spasm. Other workers similarly reported that verapamil was superior to both placebo and propranolol in reducing painful and painless ischemia in patients with angina at rest. It has been demonstrated that, compared with placebo, nifedipine reduced ischemic episodes by 50% and also markedly reduced total ischemic time in totally asymptomatic men with coronary artery disease and SMI. It was suggested that the well-documented increase in SMI occurring between 0600 and 1200 h was reduced, but not eliminated, by nifedipine. Diltiazem may also attenuate the circadian variation in SMI. Nifedipine has been shown to be particularly effective in SMI when combined with a beta-blocker. This has been substantiated in a large group of patients; both drugs reduced the number of episodes of SMI when used as monotherapy, and the combination decreased the incidence by 95%. These findings collectively indicate that calcium antagonists are effective in reducing or preventing SMI.(ABSTRACT TRUNCATED AT 250 WORDS)

Presynaptic α 2-adrenoceptor and κ-opiate receptor occupancy promotes closure of neuronal (N-type) calcium channels

Synaptosomes prepared from rat cerebral cortex by homogenization in isotonic sucrose and centrifugation on four-step discontinuous percoll density gradients were loaded with the fluorescent indicator fura-2 to allow measurement of intrasynaptosomal free calcium concentrations ([Ca 2+] i). Incubation of fura-2 loaded synaptosomes with either the κ-opiate agonist U-50,488H(0.1–100 μM) or the α 2-adrenoceptor agonist clonidine (0.1–100 μM), resulted in a dose-dependent reduction in [Ca 2+] i and these changes were completely antagonised by prior inclusion of naloxone (20 μM) or idazoxan (RX781094) (2 μM) respectively. When the 1,4-dihydropyridine Ca 2+-channel blocker nifedipine (1 μM) was incubated with synaptosomes for 1 min, there was a 17.0% decrease in [Ca 2+] i and when it was combined with either U-50,488H (1 μM) or clonidine (1 μM) there was a reduction in [Ca 2+] i of 35.0 and 48.1% respectively i.e. the effects were additive. The increase in the depression of [Ca 2+] i produced by these drug combinations were antagonised by the inclusion of naloxone (20 μM) or idazoxan (2 μM) which resulted in decrease in free [Ca 2+] i of 26.5 and 14.1% respectively. These data indicate that the effects of clonidine and U-50,488H are not mediated by L-type Ca 2+ channels. When synaptosomes were treated for 1 min with a low concentration ω-conotoxin fraction GVIA from Conus geographus (ω-CgTx), (93 nM) there was a 15.7% decrease in [Ca 2+] i and when they were co-incubated with ω-CgTx (93 nM) plus either U-50,488H (1 μM) or clonidine (1 μM); the reduction in [Ca 2+] i was 11.4 and 18.3% respectively i.e. there was no apparent additive effect on the reduction in [Ca 2+] i. The decrease in [Ca 2+] i following treatment of synaptosomes with ω-CgTx (93 nM) (which is reported to block both L- and N-type Ca 2+ channels) was surprising since the value was not greater than that with nifedipine (a blocker of only L-type Ca 2+ channels). However, addition of nifedipine (0.01–10.0 μM) to synaptosomes preincubated with the low concentration of ω-CgTx (93 nM) showed an additional reduction in [Ca 2+] i which suggest that at low concentrations ω-CgTx may not be a good blocker of L-type Ca 2+ channels. This was confirmed by studies in which synaptosomes were preincubated with a higher concentration of ω-CgTx (1.0 μM): under these circumstances no further reduction in [Ca 2+] i could be detected when nifedipine was added (0.10–10.0 μM). On the basis of the observations above we conclude that U-50,488H and clonidine elicit their effects on [Ca 2+] i and hence neurotransmitter release, by closing N-type Ca 2+ channels. In addition, our studies indicate that ω-CgTx at low concentration, is a more potent blocker at N-type rather than L-type Ca 2+ channels.

Anti-ischemic effects of celiprolol in patients with exercise-induced angina pectoris

The anti-ischemic properties of the new cardioselective β-adrenoreceptor antagonist celiprolol were investigated in an open study of 12 men (mean age: 58 ± 6.6 years) with exercise-induced angina pectoris. After all previous anti-anginal medication had been withdrawn for at least 5 half-lives, the patients received placebo, single doses of nitroglycerin buccal spray, sublingual nifedipine, celiprolol alone, and then in association with nitroglycerin and nifedipine. Exercise tests were performed on a bicycle ergometer, with continuous electrocardiographic monitoring. Significantly more work was completed after treatment with celiprolol than at baseline (5280 ± 2500 versus 4005 ± 1792 kpm; P < 0.01). There were further improvements in work completed after the addition of nitroglycerin and nifedipine. Celiprolol reduced the mean resting heart rate from a baseline value of 77.1 beats/min to 69.2 beats/min ( P < 0.01). In contrast, nifedipine induced tachycardia (82.6 beats/min). At rest, all treatments significantly reduced systolic blood pressure, but only nifedipine significantly reduced diastolic blood pressure. At the completion of the exercise protocol, celiprolol reduced the maximal systolic and diastolic blood pressure ( P < 0.05) with further decreases after the addition of nifedipine. The double product was significantly decreased by celiprolol compared with control, nitroglycerin and nifedipine. There was a further improvement of the double product after the addition of nitroglycerin to celiprolol, but the further increase after addition of nifedipine was not significant. In conclusion, it is clear that celiprolol, both alone and in combination with nitroglycerin or nifedipine, can significantly increase the work capacity of patients with exercise-induced angina pectoris and significantly reduce myocardial oxygen consumption.

Further investigation of a potential calcium channel modulator isolated from rat erythrocytes

The contractile effects of a peptide isolated from rat erythrocytes were further studied in rat aortic rings. Previous data showed that preincubation of aortic tissue with the peptide had no effect on resting tension, but significantly enhanced K+ and norepinephrine (NE) induced contraction. The calcium channel antagonist verapamil noncompetitively blocked the effect of the peptide, whereas nifedipine blockage appeared to be competitive. In the present study the peptide enhanced K+, NE, and phenylephrine (PE) induced contraction in a concentration-dependent manner, with a maximum enhancement at peptide concentrations of 10(-7)-10(-6) M. At a concentration as low as 10(-9) M, the peptide significantly enhanced K(+)-induced, but not NE- or PE-induced, contraction. The magnitude of maximal enhancement was greater for K(+)-induced contraction than that for NE- or PE-induced contraction. Preincubation of the tissues with the peptide caused a leftward shift of cumulative concentration-response curves to K+ and NE. The peptide enhancement of contraction increased with increasing K+ and NE concentration. The peptide potentiated the contractile response to Ca2+ in K(+)-depolarizing medium. It also enhanced the contractile response to NE in intracellular Ca2(+)-pool-depleted tissue following the replenishment of extracellular Ca2+, but had no apparent effect on the mobilization of intracellular calcium. Addition of nifedipine caused a rightward shift of both the peptide and Bay K 8644 concentration-response curves.(ABSTRACT TRUNCATED AT 250 WORDS)