Biomedical subjects

Y Abiko

Publications and source records attributed to Y Abiko.

At least 127 records · Page 7Linked to original sources

PubMed1996

Effects of different magnitudes of tension-force on alkaline phosphatase activity in periodontal ligament cells.

Alkaline phosphatase (ALP) activity is involved in the process of calcification in various mineralizing tissues, and it is found at much higher levels in the periodontal ligament (PDL) than in other connective tissues. Since the PDL lies between hard tissues and functions as a cushion mitigating mechanical stress, such as occlusal and orthodontic forces, this stress may modulate ALP activity in PDL cells, which themselves may affect adjacent alveolar bone metabolism. The objective of this study was to determine the level of ALP activity and the gene expression of liver/bone/kidney (L/B/K) ALP in human PDL fibroblasts in response to cyclic tension-forces. Human PDL cells were cultured on flexible-bottomed plates and placed on a Flexercell Strain Unit. Cells were flexed at 6 cycle/min (5 sec strain, 5 sec relaxation) at 6 levels of tension-force (9%, 12%, 15%, 18%, 21%, and 24% increase in surface area) for 5 days. There was no significant difference in cell proliferation between the cells subjected to the tension-force and the controls. There was a 10% and 42% decrease, respectively, in the ALP activity in PDL cells exposed to low (9%) and high (24%) tension-forces, and these decreases were dependent on the magnitude of the tension-force. The finding of inhibited ALP activity in response to tension-force was consistent with the observation that L/B/K ALP mRNA levels were decreased in response to cyclic tension-force. These results suggest that tension-force may affect PDL metabolism, depending on the functional role of ALP.

Alkaline Phosphatase↗

PubMed1996

[A new approach to the understanding of the mechanism of ischemia/reperfusion damage in the heart and the effects of anti-ischemic drugs].

The classical understanding of the mechanism of anti-anginal or anti-ischemic drugs is an increase in blood supply to the heart and/or a decrease in oxygen consumption of the heart, maintaining energy balance in the heart between supply and demand and hence maintaining the tissue levels of high-energy phosphates. This scheme is reasonable. During reperfusion following ischemia, however, there is more serious damage to the heart, although the tissue levels of high-energy phosphates increase. This is probably because toxic substances are generated in the heart during ischemia/reperfusion. We propose that both lysophosphatidylcholine and palmitoyl-L-carnitine that accumulate in the myocardium during ischemia/reperfusion are candidates for the toxic substances that accelerate ischemia/reperfusion damage to the heart. Therefore, drugs that have anti-lysophosphatidylcholine and/or anti-palmitoyl-L-carnitine effects are promising for the treatment of ischemic heart diseases. We found that K-7259, a novel derivative of dilazep having a minimal effect on the normal heart, is a drug that attenuates the deleterious effects of both lysophosphatidylcholine and palmitoyl-L-carnitine on the heart, and therefore attenuates the ischemia/reperfusion damage.

Adrenergic beta-Antagonists↗

PubMed1996

Efonidipine, a long-acting dihydropyridine derivative, attenuates coronary vasoconstriction induced by endothelin-1 in dogs.

Effect of efonidipine, a long-acting dihydropyridine derivative, on the endothelin-1 (ET-1)-induced coronary vasoconstriction was studied in open-chest anesthetized dogs. Efonidipine (0.03 or 0.1 mg/kg) was administered i.v. 10 min before an intracoronary injection of ET-1 (30 pmol/kg). An intracoronary injection of ET-1 decreased coronary blood flow (CBF) that was measured by a flow probe. The ET-1-induced decrease in CBF was sustained for more than 30 min without significant changes in blood pressure and heart rate. Pretreatment with efonidipine attenuated the decrease in CBF induced by ET-1 significantly and dose-dependently. ET-1 also reduced coronary diameter for more than 30 min as evaluated by the coronary angiography technique. Pretreatment with efonidipine also attenuated the reduction in coronary diameter induced by ET-1 significantly and dose-dependently. These effects of efonidipine were sustained for at least 30 min after the ET-1 administration. It is concluded that efonidipine attenuates the ET-1-induced vasoconstriction, and therefore the drug would be useful for some patients with variant angina, in which ET-1 is involved in the genesis of coronary vasoconstriction.

Animals↗

PubMed1996

K-7259, a novel dilazep derivative, and d-propranolol attenuate H2O2-induced cell damage.

We studied the effects of dilazep, K-7259 (a novel derivative of dilazep) and d-propranolol on the change in cell shape and accumulation of nonesterified fatty acids (NEFA) induced by hydrogen peroxide (H2O2) in isolated rat cardiac myocytes. Myocytes were incubated in a Krebs-Ringer bicarbonate buffer containing 2 mM diethyltriamine pentaacetic acid (DETAPAC) and 2mM FeSO4 for 10 min, and then treated with 2mM H2O2 for 50 min. Before the treatment with H2O2, the percentage of the number of rod-shaped cells to that of total cells was 66 +/- 2%, and decreased to 35 +/- 3%, 25 +/- 4% and 14 +/- 2%, after 30, 40 and 50 min of the H2O2 treatment, respectively. The levels of NEFA (lauric, myristic, palmitoleic, arachidonic, linoleic, palmitic, oleic and stearic acids) increased after the treatment with H2O2. In the absence of FeSO4 and DETAPAC, however, H2O2 did not have these effects, and therefore all the experiments with drugs were performed in the presence of Fe2SO4 and DETAPAC. K-7259 (30 microM) and d-propranolol (50 microM) attenuated both the changes in cell shape and accumulation of NEFA induced by H2O2, whereas dilazep (30 or 50 microM) did not. N-(2-mercaptopropionyl)glycine (2 mM), an .OH scavenger, inhibited the H2O2-induced changes completely. These results suggest that K-7259 and d-propranolol attenuate the H2O2-induced changes in cell shape and accumulation of NEFA, probably because of their .OH-scavenging effect.

Animals↗

PubMed1996

Protective effects of dilazep and its novel derivative, K-7259, on mechanical and metabolic derangements induced by hydrogen peroxide in the isolated perfused rat heart.

The effect of dilazep, a potentiator of the adenosine-mediated effects, on the hydrogen peroxide (H2O2)-induced mechanical and metabolic derangements was studied in the isolated rat heart, and compared with that of K-7259, a dilazep derivative having less potentiating action on the adenosine-mediated effects. The heart was perfused aerobically by Langendorff's technique at a constant flow and driven electrically. H2O2 (600 microM) decreased the left ventricular developed pressure and increased the left ventricular end diastolic pressure in the heart (i.e, mechanical dysfunction), decreased the tissue ATP level and increased the tissue AMP level (i.e., metabolic change) and increased the tissue level of malondialdehyde (i.e., lipid peroxidation). These mechanical and metabolic alterations induced by H2O2 were attenuated by dilazep (1 microM), and the effect of dilazep was not modified by 8-(p-sulfophenyl)-theophylline (20 microM), a nonselective adenosine receptor antagonist. K-7259 (1 microM) also attenuated the H2O2-induced mechanical and metabolic derangements. Nevertheless, neither dilazep nor K-7259 modified the tissue malondialdehyde level, which was increased by H2O2, and the mechanical function and energy metabolism of the normal (H2O2-untreated) heart. These results suggest that both dilazep and K-7259 attenuate mechanical and metabolic derangements induced by H2O2. The protective action of dilazep and K-7259 on the H2O2-induced derangements is not due to potentiation of adenosine-mediated effects, reduction of lipid peroxidation or preservation of energy.

Animals↗

PubMed1996

Effects of 6-(3-dimethylaminopropionyl)forskolin hydrochloride on energy metabolism in dog hearts in situ.

The effect of NKH477 (6-(3-dimethylaminopropionyl)forskolin hydrochloride, CAS 138605-00-2) [formula: see text], a newly developed forskolin derivative, on mechanical function, carbohydrate metabolism and energy metabolism was examined in the dog heart, and compared with that of dobutamine. Intravenous injection of NKH477 (10 or 30 micrograms/kg) or dobutamine (1 or 3 micrograms/kg) increased the maximum rate of rise of left ventricular pressure (LVdP/dtmax), producing a positive inotropic effect. The duration of the effect of NKH477 was longer than that of dobutamine. In addition, NKH477 (10 or 30 micrograms/kg) increased heart rate (positive chronotropic effect). Nevertheless, neither NKH477 (10 or 30 micrograms/kg) nor dobutamine (1 or 3 micrograms/kg) modified the tissue levels of adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, creatine phosphate and lactate. Glycolytic flux (as expressed by the ratio of ([glucose-6-phosphate] + [fructose-6-phosphate]) / [fructose-1,6-diphosphate]) and redox state (as expressed by the ratio of [lactate] / [pyruvate]) in the myocardial cells were not influenced by NKH477 (10 or 30 micrograms/kg) or dobutamine (1 or 3 micrograms/kg). These results suggest that NKH477 produces both positive inotropic and positive chronotropic effects, while it does not interfere with the myocardial energy and carbohydrate metabolism.

Adenine Nucleotides↗

PubMed1996

Dilazep and its derivative, K-7259, attenuate mechanical derangement induced by palmitoyl-L-carnitine in the isolated, perfused rat heart.

The effect of dilazep, a potentiator of the adenosine-mediated effects, on the palmitoyl-L-carnitine (PALCAR)-induced mechanical derangement was studied in the isolated rat heart and compared with that of K-7259, a dilazep derivative having less potentiating action on the adenosine-mediated effects. The heart was perfused aerobically by the Langendorff's technique at a constant flow and driven electrically. PALCAR (5 microM) decreased the left ventricular developed pressure and increased the left ventricular end diastolic pressure in the heart (i.e., mechanical dysfunction). These mechanical alterations induced by PALCAR were attenuated by dilazep (1 microM) and K-7259 (1 microM). In contrast, adenosine (10 or 100 microM) did not attenuate the PALCAR-induced mechanical derangement. On the other hand, neither dilazep nor K-7259 modified the mechanical function of the normal (PALCAR-untreated) heart. These results suggest that dilazep and K-7259 attenuate the PALCAR-induced mechanical derangement and that the protective action of both drugs is not due to potentiation of adenosine-mediated effects.

Adenosine↗

PubMed1996

Human gingival fibroblast migration promoted by platelet-derived growth factor on titanium is correlated with release of urokinase type plasminogen activator.

The purpose of this study was to examine if the migration of human gingival fibroblasts on titanium was promoted by platelet-derived growth factor (PDGF) and whether the release of urokinase-type plasminogen activator (uPA) was correlated with it. The migration of the fibroblast on titanium was significantly promoted by PDGF in a wound healing assay (p < 0.001). The promotive effect was inhibited by aprotinin, a serine protease inhibitor used for the inhibition of uPA (p < 0.001). The conditioned medium when fibroblast migration was promoted contained a higher concentration of uPA than did that of the control. These results indicated that the promotive effect of PDGF on the migration of human gingival fibroblasts on titanium was correlated with the release of uPA from the fibroblasts.

Aprotinin↗

PubMed1995

Effect of glibenclamide on ischemic canine myocardium with glucose infusion.

Glibenclamide, an ATP-sensitive K (K ATP) channel blocker, worsens the ischemia-induced metabolic derangement in the heart through inhibition of K ATP channels. We examined whether the hypoglycemic effect of glibenclamide was involved in the worsening of myocardial energy metabolism during ischemia. Pentobarbital-anesthetized dogs were subjected to 15-min ligation of the left anterior descending coronary artery. Either vehicle (dimethyl sulfoxide, DMSO) or glibenclamide (1 mg/kg) was injected i.v. 10 min before the ligation. In half of the animals given glibenclamide, glucose was continuously infused at 3 mg/kg per min immediately after glibenclamide injection. Glibenclamide increased the serum insulin level and decreased the blood glucose level. Glucose infusion completely abolished the hypoglycemia due to glibenclamide. Glibenclamide enhanced the decrease in ATP and total adenine nucleotides and increase in tissue lactate caused by ischemia. Glucose infusion did not cancel the augmentation of ischemia-induced alterations of myocardial energy metabolism caused by glibenclamide. These results suggest that K ATP channels directly play an important role in endogenous mechanisms of myocardial protection against ischemic damage.

Animals↗

PubMed1995

Effect of Campylobacter rectus LPS on plasminogen activator-plasmin system in human gingival fibroblast cells.

The plasminogen activator (PA)-plasmin system is implicated in the degradation of the extracellular matrix in inflammation through activation of metalloproteases and prekallikrein. We examined the activation of the PA-plasmin system in human gingival fibroblast cells (Gin-1 cells) following treatment with lipopolysaccharide (LPS) from Campylobacter rectus, which is frequently detected at sites of periodontal disease. The C. rectus LPS stimulated the plasmin activity in the conditioned medium of Gin-1 cells in a time- and dose-dependent manner, and C. rectus LPS also stimulated the PA activity in the conditioned medium. The PA produced by Gin-1 cells was determined to be urokinase PA (uPA), as preincubation of Gin-1 conditioned medium with anti-uPA antiserum completely inhibited the PA activity while that with anti-tPA antiserum had no inhibitory effect. The concentration of PA inhibitor-1 (PAI-1) in the conditioned medium was decreased by the addition of C. rectus LPS. Therefore, the enhancement of plasmin activity in the conditioned medium was dependent on increased uPA activity via the decrease of the PAI-1 level of Gin-1 cells treated with C. rectus LPS. Furthermore, the conditioned medium of Gin-1 cells treated with C. rectus LPS showed significantly increased kallikrein activity, indicating the conversion of prekallikrein to kallikrein, which converts kininogen into kinin. These findings suggest that C. rectus LPS is a potent stimulator of inflammation of gingival tissue which acts through stimulation of the PA-plasmin system.

Campylobacter↗

PubMed1995

Protective effect of hypoxia on mechanical and metabolic changes induced by hydrogen peroxide in rat hearts.

The effect of hypoxia (20% O2 for 5 min) on the hydrogen peroxide (H2O2)-induced myocardial change was studied in the Langendorff rat heart, which was perfused at a constant flow rate and driven electrically. H2O2 decreased the left ventricular developed pressure, increased the left ventricular end-diastolic pressure, and decreased the myocardial ATP level. These mechanical and metabolic alterations induced by H2O2 were less prominent in the hypoxia-reoxygenated heart than in the normoxic heart (i.e., hypoxia had a protective effect on the H2O2-induced change). Both 8-phenyltheophylline (8-PT), a nonselective adenosine-receptor antagonist, and glyburide (Gly), an inhibitor of the ATP-sensitive potassium (KATP) channel, significantly reduced the protective effect of hypoxia. The adenosine A1-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DP-CPX) reduced the protective effect of hypoxia incompletely. Gly, 8-PT, and DPCPX did not affect the mechanical function and energy metabolism of the hypoxia-reoxygenated heart without H2O2. These results suggest that brief and mild hypoxia attenuates the H2O2-induced mechanical and metabolic changes and that the protective effect of hypoxia is probably mediated by activation of the adenosine receptors, which open the KATP channel.

Animals↗

PubMed1995

Inhibition of prostaglandin E2 and interleukin 1-beta production by low-power laser irradiation in stretched human periodontal ligament cells.

It is well-known that orthodontic treatment usually causes some discomfort and pain to the patients. Recently, it has been reported that low-power laser irradiation is effective in reducing the pain accompanying tooth movement. However, the mechanism of such pain relief cannot be elucidated. Since high levels of prostaglandin (PG) E2 and interleukin (IL)-1 beta are found in the periodontal ligament (PDL) during tooth movement, and both factors are involved in the induction of pain, the effects of low-power laser irradiation on PGE2 and IL-1 beta production in stretched human PDL cells were studied in vitro. The PDL cells, derived from healthy premolars extracted for orthodontic treatment, were utilized for experiments. Cells were seeded in flexible-bottomed culture plates, and the bottom of each plate was elongated (18% increase) under vacuum at 6 cycles per min for 1, 3, or 5 days. The stretched cells were irradiated with a Ga-Al-As low-power diode laser (60 mW) once a day for 3, 6, or 10 min (from 10.8 to 36.0 J) for 1, 3, or 5 days. PGE2 and IL-1 beta levels in the medium were measured by radioimmunoassay. In response to mechanical stretching, human PDL cells showed a marked elevation in PGE2 production in a time-dependent manner. IL-1 beta production was also elevated, but this remained constant. The increase in PGE2 production was significantly inhibited by laser irradiation in a dose-dependent manner. The increase in IL-1 beta production was also significantly inhibited by laser irradiation, although the inhibition was only partial.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1995

A study on dilazep: I. Mechanism of anti-ischemic action of dilazep is not coronary vasodilation but decreased cardiac mechanical function in the isolated, working rat heart.

In the isolated, perfused working rat heart, ischemia (15 min) decreased the mechanical function and the tissue levels of adenosine triphosphate and creatine phosphate and increased the levels of lactate and free fatty acids. Reperfusion (20 min) did not restore the mechanical function, but restored incompletely the levels of metabolites, with the exception of free fatty acids, which increased further during reperfusion. Dilazep was given 5 min before starting ischemia until the end of ischemia. Dilazep at 5 or 10 microM decreased the cardiac mechanical function, but did not affect coronary flow in the pre-ischemic heart. Dilazep at 5 or 10 microM accelerated the recovery of mechanical function and coronary flow during reperfusion, and it attenuated metabolic changes induced by ischemia and reperfusion. Dilazep at 1 microM neither decreased the pre-ischemic mechanical function nor restored the mechanical function during reperfusion, although it attenuated the accumulation of free fatty acids during reperfusion. These results suggest that dilazep attenuates both ischemia- and reperfusion-induced myocardial damage and that the anti-ischemic action of dilazep is not due to coronary vasodilation but probably due to an energy-sparing effect and other effects that remain to be studied.

Animals↗

PubMed1995

A study on dilazep: II. Dilazep attenuates lysophosphatidylcholine-induced mechanical and metabolic derangements in the isolated, working rat heart.

The effects of dilazep, d-propranolol and lidocaine on the mechanical and metabolic changes induced by lysophosphatidylcholine (LPC) were studied in isolated, perfused working rat heart. After a stabilization period, the heart was perfused for 5 min with LPC (10 microM) alone, LPC plus dilazep (5, 10 or 20 microM), LPC plus d-propranolol (30 or 50 microM) or LPC plus lidocaine (30 or 100 microM) and then perfused with normal Krebs-Henseleit bicarbonate (KHB) buffer for a further 20 min. Perfusion with LPC for 5 min followed by KHB for 20 min irreversibly decreased cardiac mechanical function, decreased the tissue levels of adenosine triphosphate and creatine phosphate significantly, and increased the tissue levels of lactate and free fatty acids including arachidonic acid. Dilazep or d-propranolol significantly attenuated the mechanical and metabolic changes induced by LPC, but lidocaine did not. These results indicate that the exogenous LPC causes ischemia-like changes, suggesting that LPC is one of the important factors in producing ischemia-reperfusion derangements in terms of mechanical and metabolic functions, and that both dilazep and d-propranolol can prevent the LPC-induced myocardial damage.

Animals↗

PubMed1995

Effects of photodegradation products of nifedipine: the nitroso-derivative relaxes contractions of the rat aortic strip induced by norepinephrine and other agonists.

Effects of four photodegradation products of nifedipine (nitroso-, nitro-, azoxy- and N,N'-dioxide-derivatives) were studied in the rat aortic strip suspended in the bath medium. In the CaCl2-free bath medium containing 40 mM KCl, CaCl2 (2.5 mM) induced contraction, which was relaxed by nifedipine (-log [EC50] = 8.66 M) and all the four photodegradation products (-log[EC50] = 4.15-4.82 M). The EC50 values for all these substances were not affected by denuding the vessel of endothelium. In the bath medium containing KCl (15 mM), Bay K-8644 (2 x 10(-6) M) induced contraction, which was relaxed by nifedipine (10(-9)-10(-6) M) and its four photodegradation products (3 x 10(-6)-10(-4) M). Norepinephrine (10(-7) M) induced contraction, which was relaxed by the nitroso-derivative (10(-4) M) noncompetitively (pIC50 = 4.37) but not by three other photodegradation products. Both methylene blue and hemoglobin had no effect on the relaxation produced by the nitroso-derivative. Phorbol 12-myristate 13-acetate induced contraction, which was inhibited completely by the nitroso-derivative (10(-4) M) but only by 42% by nifedipine (10(-4) M). Prostaglandin F2 alpha (3 x 10(-6) M), endothelin-1 (10(-9) M) and 5-hydroxytryptamine (10(-6) M) also induced contraction, which was relaxed effectively by the nitroso-derivative (10(-4) M) but not by any of the three other photodegradation products.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1995

Positive inotropic effect of the novel forskolin derivative 6-(3-dimethylaminopropionyl)forskolin hydrochloride.

The effect of NKH477 (6-(3-dimethylaminopropionyl)forskolin hydrochloride, CAS 138605-00-2), a novel water-soluble forskolin derivative, on the energy metabolism of the heart was examined and compared with that of dobutamine. The isolated rat heart was perfused with Krebs-Henseleit bicarbonate buffer with a gas mixture containing 95% O2 + 5% CO2 according to the Langendorff's technique. NKH477 (1 or 10 mumol/l) increased maximum rate of rise of left ventricular pressure (LVdP/dtmax) (positive inotropic action), heart rate (positive chronotropic action), and coronary flow. On the other hand, dobutamine (50 or 500 nmol/l) exhibited the positive inotropic action only. Both NKH477 (10 mumol/l) and dobutamine (500 nmol/l) increased the tissue adenosine monophosphate level, and decreased the tissue creatine phosphate level (a decrease in energy store) in the heart. Nevertheless, neither NKH477 (1 or 10 mumol/l) nor dobutamine (50 or 500 nmol/l) modified the tissue adenosine triphosphate level and the value of energy charge potential, an index of myocardial energy state. These results suggest that NKH477 produces both positive inotropic and positive chronotropic actions, while it does not disturb myocardial energy state, although it decreases the energy store.

Adrenergic beta-1 Receptor Agonists↗

PubMed1994

Effects of antiischemic drugs on veratridine-induced hypercontracture in rat cardiac myocytes.

The effects of different groups of substances (beta-adrenoceptor antagonists, Ca2+ channel blockers and vasodilators) which are known to have antiischemic properties were studied on veratridine-induced hypercontracture. Veratridine increases Na+ influx by slowing the inactivation process of the Na+ channel, thereby inducing a continuously increased Na+ entry in depolarized cells. Veratridine (6.3 x 10(-6) M) produced a change in cell shape from rod-shape to round, resulting from hypercontracture of cells. Before treatment with veratridine the proportion of rod-shaped cells was 70% and fell to 0% 5 min after the treatment with veratridine. dl-Propranolol, d-propranolol, l-penbutolol, d-penbutolol, nisoldipine, and dilazep all inhibited veratridine-induced hypercontracture dose dependently. In contrast, acebutolol, atenolol, timolol, nifedipine, diltiazem, and nitroglycerin did not inhibit the rounding of cells. Concomitantly with the rounding of cells, the [Ca2+]i was increased by veratridine. dl-Propranolol, d-propranolol and dilazep prevented the increase of [Ca2+]i induced by veratridine, whereas timolol and nitroglycerin did not. These results show that dl-propranolol, d-propranolol, l-penbutolol, d-penbutolol, nisoldipine, and dilazep possess Na+ channel blocking actions on the veratridine-modified Na+ channel, thereby preventing excessive Na+ influx and secondary Ca2+ overload.

Adrenergic beta-Antagonists↗

PubMed1994

Effects of tilisolol on ischemic myocardial metabolism in dogs.

The effects of tilisolol on ischemic myocardial energy and carbohydrate metabolism were examined, and compared with those of propranolol. Ischemia was induced by ligating the left anterior descending coronary artery for 3 or 30 min in anesthetized open-chest dogs, 5 min after saline, tilisolol (0.2 mg.kg-1, i.v.), or propranolol (1 mg.kg-1, i.v.) injection. During ischemia, the myocardial energy stores were depleted, and the levels of glycolytic intermediates were altered, associated with ST segment elevation and TQ segment depression of the epicardial electrocardiogram. Tilisolol prevented the myocardial energy depletion and alterations of carbohydrate metabolism caused by 3 min of ischemia, to the same extent as did propranolol. Even 30 min after ischemia, the prevention of these ischemic changes was sustained by tilisolol, but not by propranolol. Tilisolol briefly reduced the ST segment elevation and TQ segment depression induced by ischemia. These results suggest that the protective effects of tilisolol on the ischemic myocardium are more potent and long-lasting than those of propranolol.

Adrenergic beta-Antagonists↗