Comparison of papaverine and verapamil on frequency-dependent changes in Vmax of K-depolarized ventricular tissue

The maximum upstroke velocity (Vmax) of K-depolarized guinea pig ventricular strips was used to indirectly measure frequency-dependent changes in slow inward current (Isi) caused by papaverine, verapamil, Ba2+, and isoproterenol. The effects of verapamil were studied after pretreatment with 0.8 mM Ba2+ to restore excitability of the K-depolarized tissue. Similar steady-state, frequency-dependent (0.1--4.0 Hz) changes in Vmax were observed in tissues exposed to papaverine (10(-5), Ba2+ (0.2 mM, 0.8 mM), or isoproterenol (5 x 10(-7) M). Verapamil (10(-7) M) caused a marked frequency-dependent inhibition of Vmax relative to the Ba2+-treated condition. Step increases in stimulation frequency resulted in a new steady state after only one to three depolarizations under all conditions except during exposure to verapamil. Vmax decreased exponentially after an increase in stimulation frequency during verapamil exposure, and therefore required many stimuli before a new quasi-steady-state was attained. The time constant for the recovery from inactivation of Isi determined by a paired pulse protocol was 169 +/- 16 ms for 10(-5) M papaverine, 185 +/- 14 ms for 0.8 mM Ba2+, and about 390 ms for 10(-7) M verapamil. The time required for half-recovery of Vmax after a train of 1-Hz stimuli (preceded by a rest period) was 2.5--3 s for papaverine or Ba2+ but 30--38 s for verapamil-treated preparations. The results show that papaverine is not a Ca antagonist like verapamil. The results also suggest that Ba2+ may be useful for restoring excitability in K-depolarized tissues to study the frequency-dependent changes in Vmax caused by drugs that alter Isi.     

Pilocarpine-induced relaxation of rat tail artery by a non-cholinergic mechanism and in the absence of an intact endothelium.

1. Small strips from third-order branches of rabbit mesenteric artery (approximately 150-200 microM wide) contracted in response to noradrenaline (10 microM) or 5-hydroxytryptamine (5-HT; 10 microM) in oxygenated Krebs solution containing 2.5 mM Ca2+. In a Ca(2+)-free mock intracellular solution (0 Ca2+ plus 0.2 mM EGTA), noradrenaline (10 microM) and caffeine (10 mM) induced only a single, transient contraction in artery strips, while 5-HT (10 microM) failed to induce any response. 2. In strips of mesenteric artery which had been permeabilized with Staphylococcus alpha-toxin and bathed in Ca(2+)-free mock intracellular solution, noradrenaline (10 microM), caffeine (10 mM) and D-myo-inositol (1,4,5)-trisphosphate (IP3, 100 microM), but not 5-HT (10 or 100 microM) induced a transient contraction. In contrast to the non-permeabilized strips, contractions to noradrenaline, caffeine and IP3 were restored by prior incubation (10 min) in solution containing 0.08 microM Ca2+. The contractions to noradrenaline and IP3 in permeabilized muscle strips required the presence of 100 microM guanosine 5'-triphosphate (GTP), although in the absence of Ca2+. GTP alone did not induce contraction. 3. Exposure of permeabilized mesenteric artery strips to IP3 significantly reduced the subsequent contractile responses to caffeine. Contractile responses to caffeine and IP3 were abolished by the Ca(2+)-ATPase inhibitor, thapsigargin (1 microM). 4. Ca2+ (0.1-10 microM) induced concentration-dependent contraction in permeabilized artery strips. In strips which were submaximally contracted with 0.5 microM Ca2+/100 microM GTP, the subsequent addition of 5-HT (10 microM) stimulated further contraction. The protein kinase C inhibitor, H-7 (1 microM) abolished the 5-HT/GTP-induced contraction, but did not alter the contraction to Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)     

盐酸小檗胺松弛离体兔肾动脉条作用原理的研究

盐酸小檗胺能松弛去甲肾上腺素、高钾和钙剂引起的兔肾动脉条的收缩,并使量效曲线右移,最大反应降低。它松弛肾动脉条的原理与维拉帕米相似,是通过拮抗钙而实现的。其拮抗参数pD’_2值为4.76,而维拉帕米为5.68,故可认为盐酸小檗胺为非竞争型钙拮抗剂,拮抗强度比维拉帕米弱。     

Influence of hexobendine, prenylamine and verapamil on the contractile response of isolated rabbit left atria and aortae to calcium (author's transl)

In isolated rabbit left atria driven electrically at a frequency of 30/min, the contraction was abolished by increasing external K+ concentrations from 5.4 to 22mM. Addition of isoproterenol (10(-6)M) restored the atrial contraction and the magnitude of contractions increased by raising external concentrations of Ca++ to 4.4 and 6.6. mM. Hexobendine attenuated the magnitude of contractions restored by isoproterenol and excess Ca++ in a dose-dependent manner, as did prenylamine and verapamil. Hexobendine did not significantly influence the membrane depolarization induced by excess K+ and there was no evidence of a beta-adrenergic blocking action. In helical strips of rabbit aortae exposed to Ca++-free media and depolarized by excess K+, the addition of Ca++ caused a marked contraction. Hexobendine, prenylamine and verapamil caused a dose-related attenuation of the Ca++-induced contraction. Relative potencies of the inhibition by hexobendine, prenylamine and verapamil were 1:16.5:100. Inhibitory effects of these drugs were partially antagonized by excess Ca++. Greater attenuation of the contractile response to 25 mM K+ than the response to 2 X 10(-6)M noradrenaline was observed in preparations treated with hexobendine. It may be concluded that interference with the influx of Ca++ across cell membrane in atrial muscles and aortic smooth muscles participates in the inhibition of contractility by hexobendine.     

Effects of disopyramide on the isolated rabbit aorta and pulmonary artery

1. Disopyramide (8 X 10(-5)-4 X 10(-4) M) contracted the rabbit aortic strips and this could be prevented by verapamil or by omitting Ca2+ from Krebs solution. 2. Disopyramide (1.5-6 X 10(-5) M) significantly potentiated the contractile response of the rabbit aortic strips to noradrenaline, clonidine and methoxamine but not that of potassium chloride. 3. Disopyramide (2-6 X 10(-5) M) attenuated the contractile response of the rabbit pulmonary artery to transmural electrical stimulation but potentiated response to noradrenaline. Similar results were observed with the portal vein. 4. The relaxant effect of acetylcholine, on the rabbit aortic ring precontracted with noradrenaline, was blocked by disopyramide while the relaxant effect of adenosine-5'-triphosphate (ATP) was not blocked.     

DDPH对多种介质所致豚鼠离体气管平滑肌收缩的影响

目的：研究ＤＤＰＨ对多种介质引起的豚鼠离体气管平滑肌收缩的影响。方法：离体器官平滑肌实验法。结果：不同剂量的ＤＤＰＨ可非竞争性抑制Ｈｉｓｔ，ＡＣｈ及Ｃａ＾２＋的作用，使它们的量效曲线非平行右移，最大反应变低，其ｐＤ’２值分别为４．０９，３．９５，３．９５。ＤＤＰＨ还抑制Ｋ＾＋所致气管平滑肌收缩，但作用较维拉帕米弱，它们的ＩＣ５０值分别为１１．７５和１．５８μｍｏｌ／Ｌ。结论：ＤＤＰＨ通过非竞争性Ｃ     

In vitro effects of dantrolene sodium and verapamil on noradrenaline-induced contractions of rabbit aorta and their interactions

The effects of dantrolene sodium (0.1 to 10 microM) and verapamil (0.01 to 1 microM) administered alone or together (1 microM verapamil, 0.1 to 10 microM dantrolene sodium) were investigated in isolated rabbit thoracic aorta precontracted with 0.1 microM noradrenaline (NA). Verapamil plus dantrolene sodium produced a dose-dependent inhibition of aortic strips contractions evoked by NA, and all concentrations of dantrolene sodium significantly decreased the inhibitory effect of 1 microM verapamil (p < 0.001, ANOVA). In conclusion, dantrolene sodium and verapamil inhibited 0.1 microM noradrenaline-evoked aorta contractions, and all doses of dantrolene sodium decreased the inhibitory effect of 1 microM verapamil in a dose-dependent manner.     

Ketamine-inhibition of calcium-induced contractions in depolarized rat uterus: a comparison with other calcium antagonists.

The inhibitory effect of the intravenous anaesthetic ketamine on CaCl2-induced contractions in the isolated K+-depolarized uterus of the rat in Ca2+-free medium was compared with that produced by papaverine, theophylline and the calcium entry blocker verapamil. Pre-incubation for 20 min with either ketamine (0.3 to 3 mM), papaverine (3 to 30 microM), theophylline (0.1 to 1 mM) or verapamil (3 to 30 nM) induced parallel, concentration-dependent rightward displacements of the dose-response curves to Ca2+ (0.04 to 22 mM). The antagonism was competitive, except that due to verapamil, the Schild plot for which yielded a slope which differed significantly from unity. The calculated pA2 values (+/- s.e.mean) were: ketamine 3.90 +/- 0.07; papaverine 5.55 +/- 0.05; theophylline 3.99 +/- 0.1 and verapamil 9.54 +/- 0.24. These drugs differed in their ability to relax the sustained contraction induced by Ca2+ (1 mM) in K+-depolarizing solution. Ketamine and verapamil relaxed the preparation in a concentration-dependent manner whereas theophylline and especially papaverine were less potent and induced only partial maximal relaxation. The t1/2 of the relaxant effect was significantly less for ketamine than for verapamil (5 and 22 min, respectively). Only ketamine produced a relaxation comparable to that obtained by washing the preparation with Ca2+-free solution (t1/2 = approx. 5 min). Prior exposure of the depolarized uterine strip to a low concentration of Ca2+ (0.22 mM) increased the potency of ketamine, but decreased that of papaverine and theophylline, in antagonizing Ca2+ induced contractions. In contrast, this procedure did not affect the potency of verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of subthreshold ouabain on the tone of guinea-pig aortic strips following repeated noradrenaline stimulation.

1. The effect of ouabain at a concentration (0.8 microM) that does not induce contractile response in guinea-pig aortic strips has been studied on endothelium-denuded strips repeatedly stimulated with 1 microM noradrenaline or 60 mM K+ applied for 5 min every 30 min. 2. The resting tone (i.e. the tone between one noradrenaline stimulation and the following) of the aortic strips exposed to ouabain increased progressively, whereas the control strips (no ouabain) completely relaxed on washout of the agonist. In the aortic strips stimulated by 60 mM K+, the resting tone did not increase. 3. The calcium antagonist, verapamil, did not affect the increase in tone, that was nevertheless strictly dependent on external calcium, since the contracted strips completely relaxed on calcium removal and promptly contracted again on calcium readdition. This finding indicates a mechanism independent of voltage-gated calcium channels. 4. Caffeine-induced contractions, taken as a measure of sarcoplasmic reticulum calcium content, were amplified by the presence of ouabain in aortic strips either stimulated by noradrenaline or unstimulated, with a larger increase in the former. 5. These results suggest that the repeated stimulation of guinea-pig aortic strips by noradrenaline in the presence of ouabain, by raising both intracellular Na+ and Ca2+, decreases the ouabain threshold concentration required for contraction, thus increasing the responsiveness of vascular smooth muscle to the glycoside.     

Inhibition by Cd2+ verapamil and papaverine of Ca2+-induced contractions in isolated cerebral and peripheral arteries of the dog.

1 In helically cut strips of canine cerebral arteries exposed to Ca2+-free media and depolarized by K+, the addition of Ca2+ caused biphasic (transient and sustained) contractions, while in coronary and mesenteric arteries, the additon of Ca2+ produced a sustained contraction sometimes preceded by a slight transient contraction. 2. These Ca2+-induced contractions were attenuated by Cd2+ (50 to 100 micron) in a dose-dependent manner, the attenuation being greater in cerebral than in coronary and mesenteric arteries. The inhibitory effect of Cd2+ was prevented and partially reversed by 1 mM cysteine. 3. Verapamil and papaverine were also effective in attenuating the Ca2+-induced contrations in cerebral and peripheral arteries: susceptibility to verapamil was in the order, cerebral greater than coronary greater than mesenteric, while that to papaverine was in the order, cerebral=coronary greater than mesenteric. 4. It may be concluded that the agents that interfere with trans-membrane influxes of Ca2+ cause a greater relaxation in cerebral than in peripheral arteries, as is seen with papaverine, a non-specific vasodilator.     

The effect of S-(+)-boldine on the alpha 1-adrenoceptor of the guinea-pig aorta.

1. The cardiovascular activity of S-(+)-boldine, an aporphine alkaloid structurally related to papaverine, was determined. The work includes functional studies on guinea-pig isolated aorta contracted with noradrenaline, caffeine, KCl or Ca2+, and on guinea-pig trachea contracted with acetylcholine or histamine. 2. S-(+)-boldine inhibited in a concentration-dependent manner the contractile response evoked by noradrenaline (10 microM) in guinea-pig aorta (IC50 = 1.4 +/- 0.2 microM) while the KCl depolarizing solution (60 mM)- or the Ca2+ (1 mM)-induced contractions were only partially affected by boldine up to 300 microM. In contrast, papaverine relaxed noradrenaline (NA), KCl or Ca2+ induced contractions showing similar IC50 values in all cases. S-(+)-boldine had a greater potency on the contraction elicited by NA whereas papaverine acted in a non-selective manner. 3. S-(+)-boldine was found to be an alpha 1-adrenoceptor blocking agent in guinea-pig aorta as revealed by its competitive antagonism of noradrenaline-induced vasoconstriction (pA2 = 5.64 +/- 0.08), and its potency was compared with that of prazosin (pA2 = 8.56 +/- 0.24), a known potent alpha 1-adrenoceptor antagonist. In contrast, papaverine caused rightward shifts of the NA concentration-response curves with depression of maximal response indicating that it acts as a non-competitive antagonist. 4. Contraction of guinea-pig aorta induced by caffeine (60 mM) in a Ca(2+)-containing Krebs solution was not affected by a 60 min incubation period with different doses of S-(+)-boldine (1-300 microM). Papaverine inhibited partially this caffeine-induced contraction at the maximal dose used (100 microM). 5. Inositol phosphates formation induced by noradrenaline (10 microM) in guinea-pig thoracic aorta was inhibited by S-(+)-boldine (30 microM) but not by papaverine (10 microM). 6. Contractions of guinea-pig trachea caused by acetylcholine (100 microM) or histamine (10 microM) were not modified by S-(+)-boldine (0.1-100 microM). 7. These results provide evidence that S-(+)-boldine, an aporphine alkaloid, has interesting properties as an alpha 1-adrenoceptor blocker in vascular smooth muscle, and acts as a competitive antagonist of the alpha 1-adrenoceptor present in the guinea pig aorta.     

Nature of the antiadrenergic properties of an indolizine

Inhibition by 2-ethyl-3-(4-y-di-n-butylaminopropoxybenzoyl)-indolizine hydrochloride (L 9394) and by propranolol of the positive chronotropic effect of isoproterenol on spontaneously beating rabbit right atria has been studied in vitro. Propranolol behaved like a typical competitive beta 1-adrenoceptor antagonist with a pA2 value of 8.33. L 9394 acted as a non-competitive inhibitor with a pD'2 value of about 4.98. Inhibition by L 9394 and phentolamine of the norepinephrine-induced contractions of isolated rat aortic strips has been studied likewise. Phentolamine inhibited the adrenergic alpha-adrenoceptor competitively with a pA2 value of 8.69 while L 9394 behaved like a dual inhibitor, with a competitive component (pA2 value of 6.35) and a non-competitive component (pD'2 value of about 4.72).     

Contrasting effects of verapamil and amlodipine on cardiovascular stress responses in hypertension

AIMS: To compare the effects of two long-acting calcium antagonists of different types on cardiovascular stress responses in hypertension. METHODS: One-hundred and forty-five patients with mild to moderate hypertension and a mean (+/- s.e.mean) age of 51 +/- 0.9 years received for 8 weeks the phenylalkylamine verapamil sustained release (240 mg) and the dihydropyridine amlodipine (5 mg) in a double-blind cross-over design, both after 4 weeks of placebo. Blood pressure, heart rate and plasma noradrenaline were monitored during 3 min of sustained isometric handgrip and 2 min of cold pressor. RESULTS: Blood pressure was equally reduced by both drugs. After 3 min handgrip, systolic blood pressure, heart rate and rate-pressure product were lower with verapamil compared with amlodipine. Verapamil attenuated the increases in systolic blood pressure (25 +/- 2 vs 30 +/- 2 mmHg, difference 4.6, 95% CI (1.0, 8.1), P < 0.01) and rate-pressure product (3.1 +/- 0.2 vs 3.6 +/- 0.3 x 10(3) mmHg x beats min(-1), difference 0.5, 95% CI (0.1, 0.9), P < 0.01) during handgrip compared with amlodipine. Similar results were observed during cold pressor. Plasma noradrenaline levels were lower with verapamil compared with amlodipine at rest and after both tests, but the increases in plasma noradrenaline were not significantly different. CONCLUSIONS: Verapamil is more effective in reducing blood pressure and rate-pressure product responses to stress compared with amlodipine. Although plasma noradrenaline is lower with verapamil at rest and after stress, the increase during stress is not different.     

The inhibitory action of two thrombin inhibitors (TI-189 and TI-233) on the contractile responses to 5-hydroxytryptamine and prostaglandin endoperoxide analogue (U-44069) in isolated vascular strips.

1. Two arginine derivatives that were developed as thrombin inhibitors (TI-189 and TI-233) selectively inhibited the 5-hydroxytryptamine (5-HT)-induced contraction of rabbit aortic strips in a competitive manner. The PA2 values of TI-189 and TI-233 were 5.24 +/- 0.21 and 6.23 +/- 0.32 respectively. 2. Even at 10(-4) M they had no inhibitory effect on the contractile response to noradrenaline (NA), histamine, prostaglandin E2 (PGE2), PGF2 alpha, arachidonic acid or potassium in rabbit aortic strips. 3. In dog basilar and coronary arterial strips and also in rat fundus, both agents inhibited the 5-HT response in a non-competitive manner. 4. At 10(-5) M, TI-233 but not TI-189 antagonized effects of NA and KCl in the dog basilar and coronary arteries. 5. These arginine derivatives decreased the contractile responses induced by a prostaglandin endoperoxide analogue (U-44069) in rabbit aorta and in dog basilar and coronary arteries but there was no evidence for competitive antagonism. 6. These results indicate that the arginine derivatives are competitive antagonists selective for 5-HT receptors in rabbit aorta.     

Effects of nitrendipine (BAY e 5009), nifedipine, verapamil, phentolamine, papaverine, and minoxidil on contractions of isolated rabbit aortic smooth muscle

The effects of nitrendipine, a new antihypertensive agent, have been examined using the isolated rabbit aortic strip stimulated with either noradrenaline (1.7 X 10(-8) - 1.7 X 10(-5) mol/L) or potassium (22.7-52.7 mmol/L). Nifedipine, verapamil, phentolamine, papaverine, and minoxidil were used as reference compounds. Nitrendipine and nifedipine had little effect on the contractions of the aortic strip induced by noradrenaline, but concentration-dependently inhibited contractions induced by potassium depolarisation (IC50) (3.1 X 10(-9) and 8.1 X 10(-9) mol/L, respectively). Verapamil had little effect on contractions induced by the highest concentration of noradrenaline (1.7 X 10(-5) mol/L) but inhibited contractions induced by lower concentrations of noradrenaline. Potassium-induced contractions were inhibited with an IC50 of 1.4 X 10(-7) mol/L. Phentolamine competitively inhibited noradrenaline-induced contractions, but had no effect on those induced by potassium. Papaverine inhibited both noradrenaline- and potassium-induced contractions with an IC50 of 2.5 X 10(-5) and 3 X 10(-5) mol/L, respectively. Minoxidil also inhibited both types of contractions, but only at very high concentrations (IC50 1.3 X 10(-3) and 1.8 X 10(-3) mol/L). I conclude that nitrendipine, like nifedipine, acts by inhibiting the depolarisation-induced influx of calcium ions into the vascular smooth muscle. There is no evidence for alpha-adrenoceptor-blocking activity, nor for papaverine-like vasodilator activity. Verapamil also appears to act by a calcium antagonistic action; but may, in addition, possess some alpha-adrenoceptor-blocking activity.     

Comparative effects of verapamil and D-600 on the contractile responses produced by neurotransmitters and depolarizing agents in the rat isolated seminal vesicle

1. The comparative effects of verapamil and D-600, on isometric contractions produced by noradrenaline, acetylcholine, phenylephrine, clonidine, carbachol and high potassium, were studied in rat isolated seminal vesicle. 2. The aim was to see if verapamil and D-600 differed, in their selectivity, of blocking calcium, channels, and hence inhibition of isometric contractions produced in this preparation. 3. Verapamil (1 microM) and D-600 (9.5 microM), selectively, reduced the isometric contractions, greater reductions occurred in the KCl-induced contractions (control EC50 19 +/- 1.5 mM, in verapamil 58 +/- 1.3 mM, and in D-600 37 +/- 2.0 mM, means +/- SE, n = 8, P less than 0.001, less than 0.01, respectively). 4. It was concluded that KCl-induced contractions were voltage-dependent, whereas noradrenaline operated via both voltage and receptor-mediated mechanisms. 5. The clinical relevance of these results was discussed, and it may help our current understanding of the pharmacological management of sexual dysfunction.