Bronchodilating effect and anabolic effect of inhaled procaterol.

While the use of oral beta (2)-agonists by athletes is prohibited because of their anabolic effects, some inhaled beta (2)-agonists can be used in accordance with the World Anti-Doping Agency regulations. We examined the dose disparity between the bronchodilating effect and anabolic effect of inhaled procaterol, a selective beta (2)-agonist, to determine if the drug might be effective for athletes with asthma. Intact rats were given nebulized procaterol at 0.001, 0.01, 0.1 and 1 mg/mL by inhalation, and its inhibitory effect on carbachol-induced bronchoconstriction was evaluated. Castrated rats were given nebulized procaterol at 0.03, 0.1, 0.3 and 1 mg/mL by inhalation 3 times a day for 14 days, and anabolic markers (body weight gain, weight of the levator ani muscle and gastrocnemius muscle) were measured. At 0.01 mg/mL and higher, procaterol dose-dependently inhibited carbachol-induced bronchoconstriction with a significant effect. At doses of up to 0.3 mg/mL, there were no signs indicating an anabolic effect of procaterol. At 1 mg/mL, however, a slight but statistically significant increase in the weight of the levator ani muscle was observed with no significant changes in other anabolic markers. It was suggested that inhaled procaterol might be useful for athletes with asthma because of the big dose disparity between its bronchodilating effect and anabolic effect in rats.

Differential properties of the optical-isomers of pranidipine, a 1,4-dihydropyridine calcium channel modulator.

Pranidipine is an optically-active 1,4-dihydropyridine (DHP) voltage-dependent L-type calcium channel inhibitor. Certain enantiomeric pairs display opposite effects, i.e., inhibition and activation of the calcium channel while others exhibit the same qualitative actions. We investigated pranidipine, a new DHP, using a paradigm of vascular smooth muscle reactivity. In isolated rat aorta, depolarized with 80 mM KCl, both isomers of pranidipine caused a right-ward shift of the concentration-contraction curves for extracellular Ca2+. The apparent pA2, values of the S-isomer and R-isomer were 10.03 and 8.36, respectively, providing evidence that the calcium channel blocking action of the S-isomer was 50 times more potent than that of the R-isomer. Antihypertensive actions of these two isomers studied in pentobarbital-anaesthetized spontaneously hypertensive rats, revealed that the S-isomer, at doses of 3-30 microg/kg i.v. decreased blood pressure in a dose-dependent manner, while the R-isomer had no effect on blood pressure at those doses. We conclude that the pair of enantiomers of pranidipine qualitatively display the same Ca2+ channel blocking action and that neither isomer exhibits Bay K 8644-like activation. Pranidipine may be useful in studies on the architecture of the DHP receptor 'pocket'.

[Effects of pranidipine (OPC-13340), a novel 1,4-dihydropyridine derivative Ca-antagonist, on isolated porcine coronary contraction and acute myocardial ischemia in the pig].

Pranidipine (OPC-13340) is a novel, potent and long-acting 1,4-dihydropyridine derivative Ca-antagonist being developed for clinical use as an antihypertensive and antianginal drug. Pranidipine at concentrations of 10(-9) - 10(-6) M suppressed the contraction induced by serotonin (10(-8) - 10(-5) M) or histamine (10(-8) - 10(-4) M) in isolated porcine coronary arteries in a non-competitive and concentration-dependent manner. The potency of this effect of pranidipine was almost similar to that of nifedipine. In anesthetized open-chest pigs with coronary artery occlusion, pranidipine at a dose of 10 micrograms/kg, i.v. lowered blood pressure and increased heart rate, peak dP/dt and % segment shortening of the non-ischemic zone before occlusion. Pranidipine inhibited the ST elevation of the electrocardiogram and the increase in left ventricular end-diastolic pressure during ischemia. These results suggest that pranidipine might relieve symptoms via inhibition of coronary spasm and reduce myocardial ischemia due to reduction of both preload (left ventricular end-diastolic pressure) and afterload (blood pressure).

Effects of the new long-acting dihydropyridine calcium antagonist pranidipine on the endothelium-dependent relaxation in isolated rat aorta in vitro.

The action of methyl 3-phenyl-2 (E)-propenyl 1,4-dihydro-2,6-dimethyl- 4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (pranidipine, OPC-13340, CAS 99522-79-9) on the endothelium-dependent relaxation in the isolated aorta in vitro was examined in comparison with other calcium antagonists (nifedipine, nitrendipine, nicardipine, diltiazem and verapamil). In the isolated aortic preparation of Wistar rats, acetylcholine (10(-5) mol/l), ATP (10(-5) mol/l or histamine (10(-5)-10(-4) mol/l) caused endothelium-dependent relaxation when the strips were previously contracted with prostaglandin F2 alpha. This endothelium-dependent relaxation recovered within a few minutes, although the mechanisms of this contraction after relaxation were not clear. The pretreatment with pranidipine for 20 min extended the duration of the endothelium-dependent relaxation, however, there was no potentiation in magnitude of the relaxation. This effect on the duration of endothelium-dependent relaxation was prominent in pranidipine, namely, other calcium antagonists tested had not this action at clinical concentrations. This phenomenon was also observed when the strips were pre-contracted with norepinephrine. This action of pranidipine might be some beneficial feature for therapeutic use of the compound.

Cardiovascular effects of OPC-13340, a potent, long-acting 1,4-dihydropyridine calcium channel blocker, in dogs.

The cardiovascular effects of OPC-13340, a newly developed 1,4-dihydropyridine calcium channel blocker, were examined in several canine preparations. In conscious normotensive and DOCA-salt hypertensive dogs, OPC-13340, at doses of 10 to 30 micrograms/kg, i.v., and 0.3 to 3 mg/kg, p.o., exerted an hypotensive action in a dose-dependent manner. The hypotensive action of OPC-13340 was longer lasting and more potent than that of nicardipine and nifedipine. In conscious, normotensive instrumented dogs, OPC-13340, at doses of 1 and 3 mg/kg, p.o., dose-dependently decreased total peripheral resistance and mean blood pressure and increased heart rate, cardiac output and left ventricular contractility. In anesthetized open-chest dogs, OPC-13340, at doses of 1 to 30 micrograms/kg, i.v., increased coronary blood flow and decreased mean blood pressure, heart rate, coronary vascular resistance, arteriovenous oxygen difference and myocardial oxygen consumption. In contrast to OPC-13340, nicardipine did not change the myocardial oxygen consumption. From these results it was concluded that OPC-13340 lowered blood pressure and improved coronary circulation in dogs and that the duration of these actions was longer lasting than that of nifedipine and nicardipine. These actions of OPC-13340 may be useful in the treatment of hypertension and angina pectoris.

General pharmacological properties of the new vasodilator flosequinan.

Pharmacological effects of a new vasodilator, flosequinan (7-fluoro-1-methyl-3-(methylsulfinyl)-4(1H)-quinolone, BTS 49 465, CAS 76568-02-0) on the central nervous system, somatic nervous system, autonomic nervous system and smooth muscle, digestive system and miscellaneous organs were investigated. 1. The central nervous system: Flosequinan inhibited acetic acid-induced writhing at doses of more than 30 mg/kg p.o. and decreased body temperature and tended to decrease spontaneous movement slightly in mice at a dose of 100 mg/kg p.o. However, flosequinan had little effect on hexobarbital-induced hypnosis, reserpine-induced hypothermia and motor coordination and lacked anticonvulsant and analgesic activities in mice. Flosequinan had little effect on general behavior in rats and did not have any effect on spontaneous EEG and EEG arousal response in rabbits. 2. The somatic nervous system: Flosequinan did not cause muscle relaxation in mice and had little effect on neuromuscular transmission in cats. No local anesthetic activity was exhibited through inhibition of the corneal reflex in guinea pigs. 3. The autonomic nervous system and smooth muscle: Flosequinan produced a relaxation of the isolated trachea of guinea pigs at concentrations of more than 3 x 10(-5) mol/l, but its potency was very weak in comparison with that of isoproterenol (isoprenaline). Flosequinan inhibited spontaneous motility of the isolated uterus of pregnant rats at concentrations higher than 10(-4) mol/l and the motility of the uterus of non-pregnant rats in vivo was inhibited at 30 mg/kg i.v. Flosequinan does not seem to exert any on norepinephrine, serotonin, acetylcholine or histamine. This is supported by the fact that at concentrations of 10(-4)-3 x 10(-3) mol/l non-competitive inhibition was observed with regard of the contractions of the isolated aorta and vas deferens of rats induced by norepinephrine, the contraction of isolated rat stomach induced by serotonin, the contraction of isolated guinea-pig ileum induced by acetylcholine, histamine and barium chloride and the contraction of the isolated uterus of non-pregnant rats induced by oxytocin. However, flosequinan was more potent as a relaxant of vascular than of these other smooth muscles. The drug was slightly inhibitive at a high dose of 30 mg/kg i.v. with regard of the contraction of nictitating membrane induced by stimulation of preganglionic sympathetic nerve in cats. 4. The digestive system: Flosequinan at 100 mg/kg p.o. inhibited intestinal propulsion in mice and inhibited spontaneous motility of stomach and duodenum of rats at a dose of 30 mg/kg i.v.(ABSTRACT TRUNCATED AT 400 WORDS)

General pharmacological properties of the main metabolite of flosequinan.

The general pharmacological profile of 7-fluoro-1-methyl-3-(methylsulfonyl)- 4(1H)-quinolone BTS 53 554, CAS 76568-68-8), the main metabolite of a new vasodilator, flosequinan (BTS 49 465), was investigated. 1. The central nervous system: BTS 53 554 at the dose of 30 mg/kg i.v. caused an increase in respiratory rate and a sedation in general behavior in rats. The drug also inhibited acetic acid-induced writhing and slightly decreased normal body temperature in mice. However, the drug at the doses up to 30 mg/kg i.v. had little effect on the spontaneous movement, hexobarbital-induced hypnosis, reserpine-induced hypothermia and motor coordination in mice. The drug showed neither anticonvulsant nor analgesic actions in mice. Furthermore, it had no effect on the spontaneous EEG, sleep-wakefulness cycle and EEG arousal response in rabbits at doses up to 10 mg/kg intravenously. 2. The somatic nervous system: BTS 53 554 induced no muscle relaxation in mice and exerted no local anesthetic action in guinea pigs by corneal reflex method. In addition, it had little effect on the neuromuscular transmission in cats. 3. The autonomic nervous system and smooth muscle: BTS 53 554 showed no effect on the sympathetic ganglionic transmission in cats. In isolated smooth muscles, at doses up to 10(-3) mol/l it showed little effect on the acetylcholine- or barium chloride-induced contraction of guinea-pig ileum, norepinephrine-induced contraction of rat vas deferens or oxytocin-induced contraction of nonpregnant rat uterus. However, it inhibited non-competitively norepinephrine-induced contraction of isolated rat aorta at 10(-4) mol/l or more and serotonin-induced contraction of isolated rat fundus at 3 x 10(-4) mol/l or more. In the isolated guinea-pig ileum, the drug slightly inhibited the histamine-induced maximal contraction at 10(-3) mol/l. These results suggest BTS 53 554 had no specific effect on norepinephrine, serotonin, acetylcholine or histamine. The drug relaxed isolated guinea-pig trachea at 3 x 10(-5) mol/l or more and inhibited the spontaneous movement of isolated pregnant rat uterus at 10(-4) mol/l or more, although these actions were extremely weaker than those of isoproterenol (isoprenaline). BTS 53 554 also showed a slight inhibition of uterus movement in anesthetized rats at 30 mg/kg intravenously. 4. The digestive system: BTS 53 554 tended to inhibit the gastrointestinal propulsion in mice and showed a slight inhibition of gastric and intestinal motilities in rats at 10 mg/kg intravenously.(ABSTRACT TRUNCATED AT 400 WORDS)

Antihypertensive activity of OPC-13340, a new potent and long-acting dihydropyridine calcium antagonist, in rats.

The antihypertensive action of OPC-13340, a new dihydropyridine, was studied in rats and compared with the action of nicardipine and other dihydropyridines. OPC-13340 showed more potent and longer hypotensive action than nicardipine when administered either intravenously (i.v.) or orally in normotensive and hypertensive rats. Among 6 compounds tested, (OPC-13340, nifedipine, nitrendipine, nisoldipine, nicardipine and diltiazem), OPC-13340 was the most potent and long-acting when administered orally to spontaneously hypertensive rats (SHR). Tachycardia after administration of OPC-13340 was less or diminished earlier than that of nicardipine. Oral administration of OPC-13340 (3 mg/kg) once daily for 13 days did not cause any rebound phenomena in SHR. The compound inhibited Ca- or K-induced contractions in isolated rat aorta and shortened action potential duration in guinea pig papillary muscle, suggesting Ca channel blocking action. OPC-13340 might be useful as a drug for once-daily therapy of essential hypertension.

The role of cyclic AMP in the positive inotropic effect mediated by beta 1- and beta 2-adrenoceptors in isolated human right atrium.

The time course of the effects of isoprenaline (3 X 10(-7) mol/l) on contractile force and on the cyclic AMP level was studied in the electrically driven isolated muscle strip of the human right atrium. Isoprenaline produced a rise in cyclic AMP content (maximum increase after 60 s) preceding the increase in contractile force. The effects of isoprenaline on contractile force and on the intracellular level of cyclic AMP were enhanced in the presence of the phosphodiesterase inhibitor papaverine (10(-5) mol/l). On the other hand, the beta-adrenoceptor antagonist propranolol (10(-7) mol/l) suppressed isoprenaline-induced cyclic AMP increases, but reduced the increase in force of contraction by only 35%. In addition, both the beta 1-selective antagonist bisoprolol (3 X 10(-9)-3 X 10(-8) mol/l) and the beta 2-selective antagonist ICI 118,551 (3 X 10(-9)-3 X 10(-8) mol/l) inhibited the isoprenaline-induced cyclic AMP increase concentration-dependently; ICI 118,551 produced more pronounced inhibition than bisoprolol. It is concluded that cyclic AMP is involved in the positive inotropic action of isoprenaline evoked by beta 1- and beta 2-adrenoceptor stimulation in isolated human right atrium; however, an additional cyclic AMP independent mechanism cannot be ruled out.

Beta-2 adrenoceptor-mediated relaxation of the isolated human saphenous vein.

On isolated strips of human saphenous vein, pretreated with 5 microM phenoxybenzamine and contracted with 10 mM KCl, the beta adrenoceptor mediating the relaxant effects of isoproterenol, procaterol and norepinephrine was characterized using the selective beta-1 adrenoceptor antagonist, bisoprolol, and the selective beta-2 adrenoceptor antagonist, ICI 118,551. All three agonists produced concentration-dependent relaxations of the isolated saphenous vein with an order of potency: procaterol (pD2 value, 7.69) greater than isoproterenol (pD2 value, 7.41) much greater than norepinephrine (pD2 value, 5.30). ICI 118,551 (3 X 10(-10) to 3 X 10(-9) M) was nearly 100 times more potent than bisoprolol (10(-7) to 10(-6) M) in antagonizing the relaxant effects of isoproterenol and procaterol. The slopes of the Schild plots for the antagonistic effects of ICI 118,551 and bisoprolol against isoproterenol- and procaterol-induced relaxations were not significantly different from unity indicating interaction with a homogeneous population of beta adrenoceptors. The pA2 value for ICI 118,551 amounted to 9.11 to 9.20 and for bisoprolol to 6.50 to 6.63. In addition, the concentration-response curve for the relaxant effect of norepinephrine was significantly shifted to the right by 10(-9) M ICI 118,551, but not affected by 10(-7) M bisoprolol. These results indicate that on the isolated strips of the human saphenous vein the beta adrenoceptor mediating relaxation is of the beta-2 subtype.

Lymphocyte beta 2-adrenoceptors mirror precisely beta 2-adrenoceptor, but poorly beta 1-adrenoceptor changes in the human heart.

To study the relationship of changes in human lymphocyte beta-adrenoceptors to changes potentially occurring in solid tissues we studied 16 patients undergoing elective coronary artery bypass grafting and determined the density of lymphocyte beta 2-adrenoceptors [by (-)125I-iodocyanopindolol (ICYP) binding] in comparison to beta-adrenoceptor density and responsiveness (contractile responses to isoprenaline) in the corresponding right atria. Lymphocyte beta 2-adrenoceptor density (with a range of 278-2442 ICYP binding sites/cell) was significantly correlated with beta-adrenoceptor density in the corresponding atria (54.8-171.6 fmol ICYP bound/mg protein, r = 0.784, P less than 0.001). In these atria the levels of beta 1- and beta 2-adrenoceptors (assessed by non-linear regression analysis of competition curves of the selective beta 2-adrenoceptor antagonist ICI 188,551 with ICYP binding) were approximately .70 and 30%, respectively. Lymphocyte beta 2-adrenoceptor density, however, correlated significantly better with atrial beta 2-adrenoceptor (r = 0.8441; P less than 0.001) than beta 1-adrenoceptor (r = 0.6226, P less than 0.05) density. On 12 of the 16 atria (electrically driven with 1 Hz at 37 degrees C) isoprenaline (10(-9) to 3 X 10(-6) mol/l) caused positive inotropic effects. The maximum increase in contractile force evoked by saturating concentrations of isoprenaline (mean: 3.52 +/- 0.62 mN), however, correlated equally well with beta 1- and beta 2-adrenoceptor density in the corresponding atria (r = 0.6834 and 0.6567, respectively). These results indicate that changes in lymphocyte beta 2-adrenoceptors can be taken as a precise index of changes of beta 2-adrenoceptors in other (solid) tissues; beta 1-adrenoceptor alterations, however, are only poorly reflected in the lymphocytes.

Human beta-adrenoceptors: relation of myocardial and lymphocyte beta-adrenoceptor density.

In human right atria obtained from 21 patients during open-heart surgery, beta-adrenoceptor density [assessed by iodine-125-labeled (-)-cyanopindolol binding] and responsiveness (positive inotropic responses to isoprenaline) were linearly related to the beta-adrenoceptor density in the corresponding circulating lymphocytes. This direct relation of human myocardial and lymphocyte beta-adrenoceptor alterations, therefore, makes it possible to monitor drug- or disease-induced beta-adrenoceptor changes in tissues not easily accessible in humans.

Human myocardial beta-adrenoceptors: demonstration of both beta 1- and beta 2-adrenoceptors mediating contractile responses to beta-agonists on the isolated right atrium.

On the isolated electrically driven muscle strip of human right atrial appendages the beta-adrenoceptor subtypes mediating the positive inotropic effects of isoprenaline, dobutamine and procaterol were characterized using the beta 1-selective antagonist bisoprolol and the beta 2-selective antagonist ICI 118,551. The three agonists induced concentration-dependent increases in force of contraction with an order of potency: procaterol (pD2-value: 8.03) greater than isoprenaline (pD2-value: 7.73) greater than dobutamine (pD2-value: 5.44). In saturating concentrations all three agonists produced the same maximum of developed tension. ICI 118,551 (10(-9)--10(-7) mol/l) and bisoprolol (10(-9)--10(-7) mol/l) were nearly equipotent in antagonizing the positive inotropic effects of isoprenaline and dobutamine. However, the slopes of the Schild-plots for both antagonists against both agonists were significantly less than 1.0 indicating interaction with beta 1- and beta 2-adrenoceptors. On the other hand, ICI 118,551 (10(-10)--10(-8) mol/l) was approximately 100 times more potent than bisoprolol (10(-8)--10(-6) mol/l) in antagonizing the positive inotropic effect of the highly selective beta 2-agonist procaterol. In addition, the slopes of the Schild-plots for antagonism of ICI 118,551 and bisoprolol against procaterol were not significantly different from unity indicating interaction with a homogeneous class of beta-adrenoceptors. The pA2-value for ICI 118,551 was 9.49, for bisoprolol it amounted to 6.99.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-related inhibitory effects of the beta-adrenoceptor blocking drugs carteolol and propranolol on cardiac hypertrophy in spontaneously hypertensive rats.

The inhibitory effect of two kinds of beta-adrenoceptor blocking drugs [propranolol: 1-100 mg/kg per day; carteolol: 0.3-30 mg/kg per day] on the development of cardiac hypertrophy was studied in young spontaneously hypertensive rats (SHR: 4 weeks old). Though neither propranolol or carteolol given for 6 weeks reduced the development of hypertension in SHR, both drugs did reduce the increase in the heart weight/body weight ratio in a dose-dependent manner. This potency of carteolol was about 300 times greater than that of propranolol. The potency of carteolol with regard to the reduction in the myocardial protein/DNA ratio was about 300 times greater than that of propranolol. The beta-blocking potency, estimated from the area under the dose-response curve (beta-blocking action) of carteolol, was also 300 times greater than that of propranolol and correlated well with the extent of the structural changes in the heart. Thus, the possibility that the degree of beta-blocking potency may strongly relate to structural changes in the heart of young SHR has to be given consideration.