Differential effects of verapamil and flunarizine on cardiac L-type and T-type Ca channels

Summary Whole cell experiments were used to study whether the L-type and the T-type Ca channel in guinea-pig ventricular myocytes are blocked similarly by verapamil and flunarizine. The L-type current is blocked by 5 ol/l verapamil and 5 ol/l flunarizine in a use-dependent way, and block can be relieved by hyperpolarizing pulses in a potential-dependent way. The T-type current is not affected by 10 mol/l verapamil while it is blocked by 10 ol/l flunarizine in a use-dependent way. Verapamil selectively blocks the L-type channel in contrast to flunarizine. Send offprint requests to J. Tytgat at the above address     

Action of tertiary phenylalkylamines on cardiac transient outward current from outside the cell membrane

The effects of the phenylalkylamines verapamil (V), gallopamil (G), and devapamil (D) and their corresponding quaternary derivatives on the transient outward current (I_to) were examined in rat ventricular cardiomyocytes using the whole-cell patch-clamp technique. The question was addressed, whether phenylalkylamines act on I_to from the inside or the outside or from both sides of the cell membrane. To this end, the myocytes were either superfused extracellularly or perfused intracellularly with drug-containing solutions. In addition, the effects of verapamil were investigated at different pH-values. V, G, and D (30 M each), applied extracellularly, reduced the steady state current of I_to, I_{to(150 ms)}, to 34 ± 3.3, 33 ± 6, and 30 ± 5, respectively (% of control; means ± SEM). The effects of V (30 M) on I_to were similar at various external pH-values (reduction of I_to(15o ms) by 69 ± 6 at pH 6.5, by 66 ± 4 at pH7.4, by 68 ± 8 at pH 8.5, and by 58 ± 0 at pH 9.5; % of control; means ± SEM). In contrast, the effect of 4-aminopyridine (300 M) on I_to was enhanced after alkalinisation: the peak current of I_to was reduced to 49 ± 5 at pH 7.4 and to 5 ± 2 at pH 9.2 (% of control; means ± SEM). V, G, and D (300 M) failed to produce any effect on I_to, when applied intracellularly (values of I_{to(150 ms)}: 97 ± 6, 105 ± 4, and 94 ± 4, respectively; % of control; means ± SEM). In contrast, 4-aminopyridine (3 mM) depressed the peak current of I_to to 69 ± 6% of control (mean ± SEM), when applied intracellularly. The permanently charged quaternary derivatives of the phenylalkylamines q-V, q-G, and q-D (300 M) did not significantly affect I_to, when applied extracellularly (values of I_{to(150 ms)}: 94 ± 2, 90 ± 3, and 94 ± 3, respectively; % of control; means ± SEM) but diminished I_to, when applied intracellularly (reduction of I_{to(150 ms)} to 43 ± 5, 56 ± 7, and 63 ± 4, respectively; % of control; means ± SEM). Intracellularly applied V (300 M) did not reduce I_to at pH 6.5 at which V is protonated to 99.4%. It is suggested that tertiary phenylalkylamines act on I_to by binding to a membrane site accessible from the outside, whereas their quaternary derivatives affect I_to by binding to a membrane site located at the inside of the cell membrane. In contrast, 4-aminopyridine is supposed to act on I_to from the inside of the cell membrane.     

Rate of L-type calcium channels on yohimbine-precipitated clonidine withdrawal in vivo and in vitro

Summary This study was designed to elucidate the possible participation of L-type calcium channels in the expression of clonidine-withdrawal precipitated by yohimbine in clonidine-dependent animals. Mice implanted for 5 days with osmotic minipumps containing the ₂-adrenoceptor agonist clonidine showed symptoms of a withdrawal syndrome (jerks, headshakes, defecations and weight loss) when yohimbine, an ₂-adrenoceptor antagonist, was injected. Similarly, isolated rat ilea incubated with clonidine in vitro showed a withdrawal contracture when yohimbine was added to the organ bath. The effects of L-type calcium channel blockers (verapamil and diltiazem) and the stimulant Bay K 8644 on these two different types of withdrawal responses were evaluated. A dose-dependent decrease in yohimbine-precipitated clonidine withdrawal in vivo was observed when verapamil (10–40 mg/kg, s.c. and 120 g/mouse, i.cv.) or diltiazem (5–20 mg/kg, s.c. and 160 g/mouse, i.c.v.) were administered to mice dependent on clonidine. No effect was found after Bay K 8644 (0.5–5 mg/kg, s.c. and 1–5 g/mouse) was injected under these conditions. In vitro, both verapamil (0.1–5 M) and d-cis-diltiazem (1–50 M) concentration-dependently reduced the height of the yohimbine-precipitated withdrawal contracture in rat ileum incubated with clonidine. Furthermore, the effect of diltiazem was stereospecific, as d-cis-diltiazem 10 M markedly inhibited clonidine withdrawal, whereas the same concentration of l-cis-diltiazem had no effect. In contrast, the calcium channel stimulant Bay K 8644 (0.1–1 M) increased the height of the ileum withdrawal contrature. These results confirm that yohimbine-precipitated clonidine withdrawal can be obtained both in vivo and in vitro, and suggest that the expression of these abstinence responses involves activation of L- type calcium channels. The present results, together with those of previous studies of the effects of calcium channel-acting drugs on ethanol-, opiate- and benzodiazepine-withdrawal, suggest that L-type calcium channels play an important role in the expression of the withdrawal responses to CNS depressant drugs.Correspondence to: J. M. Baeyens at the above address     

Modulation of voltage-gated K(+) channels Kv11 and Kv1 4 by forskolin

Forskolin (FSK) affects voltage-gated K(+) (Kv) currents in different cell types, but it is not known which of the various subunits form FSK-sensitive Kv channels. We compared the effect of the compound at Kv1.1 and Kv1.4 channels ectopically expressed in HEK 293 cells. Low FSK concentrations induced a phosphorylation-dependent potentiation of Kv1.1 currents. At higher concentrations, this effect was superimposed by a fast, cAMP-independent channel block. Kv1.4 currents were inhibited with lower potency by FSK but were not modified by phosphorylation. The variable effect of the compound might help to distinguish between Kv subunits expressed by native cells.     

布桂嗪合用维拉帕米的镇痛作用研究

目的研究钙拈抗药维拉帕米（Ver）对布桂嗪（AP237）镇痛作用的影响。方法应用热诱发小鼠疼痛反应模型和冰醋酸诱导小鼠扭体反应模型观察Ver合用AP237对疼痛的抑制作用。结果低剂量Ver合用AP237（40mg／kg,80mg／kg）可明显提高小鼠诱发疼痛反应的痛阈值,推迟小鼠疼痛出现的时间（与单用AP237比较,P〈0．05,与对照组比较,P〈0．01）;低剂量Ver合用AF237（20mg／kg,40mg／kg）对小鼠扭体反应次数有明显的抑制作用（与单用AP237比较,P〈0．05;与单用AP237比较,P〈0．01）。结论Ver可增强AP237的镇痛作用。     

Differential effects of L-type calcium channel blockers and stimulants on naloxone-precipitated withdrawal in mice acutely dependent on morphine

The effects of L-type calcium channel blockers and stimulants on naloxone-precipitated withdrawal in miceacutely dependent on morphine were evaluated. Verapamil (10–80 mg/kg), diltiazem (20–120 mg/kg) and nicardipine (20–160 mg/kg), when administered subcutaneously, produced a dose-dependent reduction in forepaw tremor and weight loss during the abstinence reaction; jumping was also reduced by all three drugs, although the effect was not statistically significant in the case of nicardipine. By contrast, the calcium agonist Bay K 8644 (0.5–2 mg/kg, SC) increased forepaw tremor and weight loss, although this latter effect did not reach statistical significance. The effects of the calcium channel active drugs on the rotarod test were also explored, no correlation appearing with the results observed in abstinence (except for the jumping response), which suggests that the withdrawal results are not influenced by motor incoordination or unspecific CNS depression. These findings suggest that L-type calcium channels probably play an important role in withdrawal after acute morphine dependence. Taken together with other observations in chronic models, these results show that calcium channels are similarly involved in morphine abstinence after acute and chronic dependence, in contrast to the differences in the content and uptake of neuronal calcium induced by morphine under both conditions.     

The effect of calcium load and the calcium channel blocker verapamil on gentamicin nephrotoxicity in rats

Gentamicin (GM) is used against serious and life-threatening Gram negative infections. However its use is limited by the occurrence of nephrotoxicity. Reports on the interaction between GM nephrotoxicity and calcium (Ca²⁺) or Ca blockers are conflicting. Therefore, in the present work we assessed the effect of treatment of rats with graded doses of calcium carbonate, CaCO₃ (0.25, 0.5 or 1.0 g/kg) orally, or the Ca²⁺ channel blocker verapamil (1.75, 3.5 or 7.0 mg/ kg) intramuscularly (i.m.), on the nephrotoxicity induced by concomitant i.m. treatment with GM (80 mg /kg/day for 6 days). Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically by measuring the concentrations of urea and creatinine in plasma, reduced glutathione (GSH), lipid peroxidation and superoxide dismutase (SOD) activity in kidney cortex. The results indicated that the administration of CaCO₃ produced a dose-dependent amelioration in the biochemical indices of nephrotoxicity in plasma and renal cortex, which was significant at the two higher doses used. The histological picture of the renal proximal tubules followed a similar pattern. Treatment with verapamil induced a dose-dependent potentiation in the biochemical parameters of nephrotoxicity that was significant only at the highest dose used (7 mg/kg). This dose also exacerbated the GM-induced histological necrosis. The above interactions may be clinically relevant in patients treated concurrently with these agents.     

Kinetic modulation of guinea-pig cardiac L-type calcium channels by fendiline and reversal of the effects of Bay K 8644.

1. The modulation of L-type calcium channel current (ICa) by fendiline, a diphenylalkylamine type of calcium channel blocker was investigated on guinea-pig ventricular myocytes by use of the whole-cell patch-clamp technique. 2. Fendiline-induced block of ICa is accompanied by modulation of the channel kinetics in a complex manner. The time course of ICa inactivation is significantly faster and the channel availability (f infinity) curve is shifted considerably to more negative potentials by fendiline. These findings can be interpreted qualitatively in terms of a modulated receptor. 3. When the 1,4-dihydropyridine agonist (4R, 4S)-Bay K 8644 was added in presence of 30 microM fendiline a further reduction of ICa instead of the expected stimulatory effect was observed. 4. A similar 'paradoxical' inhibition of ICa was produced by the pure agonist enantiomer (4S)-Bay K 8644. Thus this novel effect of Bay K 8644 cannot be attributed to changes in affinity of the 1,4-dihydropyridine receptor site for (4R)-Bay K 8644 during fendiline action. 5. The IC50 for fendiline was reduced to 3.0 +/- 0.1 microM (control value: 17.0 +/- 2.4 microM) and the Hill slope in its presence was increased to 1.90 +/- 0.1 (control value: 1.39 +/- 0.23) by 1 microM (4R, 4S)-Bay K 8644. 6. (4R,4S)-Bay K 8644 caused the expected stimulation of ICa in the presence of verapamil, diltiazem and nifedipine, overcoming the inhibitory effect of these calcium channel blockers. 7. The 'paradoxical' inhibitory effect of the agonist Bay K 8644 can be explained in terms of an allosteric interaction between fendiline and the dihydropyridine agonist.     

卡立泊来德与维拉帕米对大鼠缺血再灌注心肌保护作用的比较研究

目的比较Na+/H+交换抑制剂卡立泊来德(cariporide)和钙离子拮抗剂维拉帕米(verapamil)这两类药物对于心肌保护作用的差别,从而给寻找更有效的心肌保护药物提供参考。方法建立大鼠在体心肌冠状动脉左前降支(LAD)缺血再灌注损伤模型,实验大鼠随机分为5组,每组6只,即伪手术组(LAD下只穿线不结扎)、对照组(缺血再灌注组,不给药)、卡立泊来德治疗组、维拉帕米治疗组、卡立泊来德与维拉帕米合用组。结扎LAD30min后松解结扎线,开始再灌注,再灌注60min后结束实验。于再灌注前分别应用卡立泊来德和维拉帕米,从心电图ST段变化、心肌损伤标志物肌钙蛋白I及肌红蛋白定量检测和心肌超微结构改变等方面探讨比较这两类药物对于心肌保护作用的差别。结果肌红蛋白值各组间差异无统计学意义(P>0.05),肌钙蛋白I值示组间差异有统计学意义(P<0.05)。卡立泊来德组、维拉帕米组及卡立泊来德与维拉帕米合用组肌钙蛋白I值与对照组比较差异有统计学意义(P<0.05);卡立泊来德组、维拉帕米组及卡立泊来德与维拉帕米合用组之间肌钙蛋白I值两两比较差异无统计学意义(P>0.05)。心电图ST值变化趋势结果示,卡立泊来德组与对照组ST值变化趋势比较差异有统计学意义(P<0.05),维拉帕米组与对照组ST值变化趋势比较差异无统计学意义(P>0.05),卡立泊来德组与维拉帕米组ST值变化趋势比较差异无统计学意义(P>0.05)。心肌细胞超微结构电镜观察结果示卡立泊来德组、维拉帕米组及卡立泊来德与维拉帕米合用组心肌细胞结构损伤较对照组轻,但三组间差异不明显。结论卡立泊来德与维拉帕米有一定的心肌保护作用,单一应用卡立泊来德的心肌保护效果较单一应用维拉帕米无明显优势,两者合用的效果并不优于单用其一者。     

Drug interaction between oral atorvastatin and verapamil in healthy subjects: effects of atorvastatin on the pharmacokinetics of verapamil and norverapamil

Aim It has been reported that verapamil and atorvastatin are inhibitors of both P-glycoprotein (P-gp) and microsomal cytochrome P450 (CYP) 3A4, and verapamil is a substrate of both P-gp and CYP3A4. Thus, it could be expected that atorvastatin would alter the absorption and metabolism of verapamil. Methods The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared after oral administration of verapamil (60 mg) in the presence or absence of oral atorvastatin (40 mg) in 12 healthy volunteers. Results Pharmacokinetics of verapamil were significantly altered by the coadministration of atorvastatin compared with those of without atorvastatin. For example, the total area under the plasma-concentration time curve to the last measured time, 24 h, in plasma (AUC_{0−24 h}) of verapamil increased significantly by 42.8%. Thus, the relative bioavailability increased by the same magnitude with atorvastatin. Although the AUC_{0−24 h} of norverapamil was not significantly different between two groups of humans, the AUC_{0−24 h, norverapamil}/ AUC_{0−24 h, verapamil} ratio was significantly reduced (27.5% decrease) with atorvastatin. Conclusion The above data suggest that atorvastatin could inhibit the absorption of verapamil via inhibition of P-gp and/or the metabolism of verapamil by CYP3A4 in humans.     

小鼠精母细胞钙通道特性及硝苯地平的作用

目的　为了建立一个合理、客观评价药物或毒物对生殖系统影响的细胞模型 ,研究了机械分离、未经酶消化的小鼠精母细胞Ca2 + 通道特性及硝苯地平对其的作用。方法　采用全细胞膜片钳技术。结果阻断K+ 电流后 ,当钳制电位 -90mV、指令电压 -80～ +1 0mV、步阶电压 1 0mV时 ,记录到Ca2 +电流 ,二价无机阳离子对Ca2 + 电流的抑制作用Ni2 +>Cd2 + ,而L型Ca2 + 通道激动剂BayK8644对电流无任何影响。分析小鼠精母细胞上记录的Ca2 + 电流为T型Ca2 + 通道开放产生。L型Ca2 + 通道阻断剂硝苯地平对精母细胞Ca2 + 电流有明显的抑制作用 ,半数最大抑制浓度为 0 .3 9μmol·L-1,而且细胞外液冲洗恢复缓慢 ,这支持了二氢吡啶类药物可用于男性避孕。结论　机械分离、未经酶消化的小鼠精母细胞模型适合进行药理学和毒理学研究     

异型南五味子丁素和戈米辛J对豚鼠心室肌细胞L—型钙离子通道的阻断作用

目的：研究异型南五味子丁素（HD）和戈米辛J（GJ）对豚鼠心肌L－型钙离子通道的作用。方法：全细胞膜片箝记录。结果：异型南五子丁素1,10μmol／L及戈米辛J10μmol／L可抑制L－型Ca^2 电流。HD和GJ对钙电流稳态激活都无影响,但它们可改变钙电流的稳态失活,提示两种药物作用于L－型钙通道的失活态.结论：HD和GJ对豚鼠心室肌细胞L－型钙离子通道有阻断作用。     

Molecular mechanisms of interaction between the neuroprotective substance riluzole and GABAA-receptors

The antiepileptic drug riluzole is used as a therapeutic agent in amyotrophic lateral sclerosis due to its neuroprotective effects. Besides presynaptic inhibition of GABAergic and preferentially glutamatergic transmission, it also potentiates postsynaptic GABA(A)-receptor function. We investigated the postsynaptic effects of riluzole on GABA(A)-receptor channels by use of the patch-clamp technique. Recombinant alpha(1)beta(2)gamma(2s) and alpha(1)beta(2) GABA(A) receptors were expressed in HEK 293 cells by transient transfection. Pulses of GABA were applied in combination with different concentrations of riluzole to whole cell or outside-out patches with either alpha(1)beta(2)gamma(2s) or alpha(1)beta(2) GABA(A)-receptor channels. Co-application of riluzole led to a slight decrease of absolute peak current amplitudes and steady-state currents in prolonged presence of GABA at saturating concentrations. In the presence of riluzole, enhancement of current amplitudes was observed with lower concentrations of GABA at alpha(1)beta(2)gamma(2s) receptors and to a lower extent also at alpha(1)beta(2) receptors. Thus, the potentiating effect of riluzole was shown to be not abolished in the absence of the gamma2s-subunit. A further prominent effect of riluzole was a highly significant acceleration of the time course of current decay, most probably pointing to an open-channel block-like mechanism of action. As both receptor subtypes were affected similarly by the block, it could be concluded that the respective binding sites should be assumed within a region of high sequence homology like it is given for the channel-lining M2 domain of GABA(A)-receptor subunits. In conclusion, three different molecular mechanisms of interaction of the neuroprotective compound riluzole were observed at two different subtypes of GABA(A) receptor channels. The results further point to the impact of the inhibitory as well as the excitatory synaptic activity as a pharmacological target to counteract chronic excitotoxicity and reveal molecular mechanisms of action of the only one neuroprotective drug in current clinical use in patients suffering from amyotrophic lateral sclerosis.     

硫酸镁对兔跨室壁L型钙电流不均一性的影响

目的　研究硫酸镁对兔左室游离壁心内膜下心肌(Endo) ,中层心肌 (M )和心外膜下心肌 (Epi)L型钙电流(ICa,L)的影响 ,探讨硫酸镁治疗尖端扭转性室型心动过速(Tdp)时 ,减少跨室壁复极离散 (TDR)离子流基础。 方法　全细胞膜片钳技术分别记录兔心室三层心肌细胞的ICa,L。结果　细胞外液加入 1mmol·L-1硫酸镁时 ,兔Endo ,M和Epi的ICa ,L密度分别为 :(9 6± 1 1) pA/pF、(10 3± 0 9)pA/pF、(7 1± 0 7) pA/pF ,加入 2mmol·L-1硫酸镁时ICa ,L密度分别为 :(7 4± 0 6 ) pA/pF、(7 8± 0 5 )pA/pF、(6 7±0 8) pA/pF ;加入 3mmol·L-1硫酸镁时ICa ,L密度分别为(6 1± 0 4 ) pA/pF、(6 3± 0 5 ) pA/pF、(5 6± 0 4 ) pA/pF ,硫酸镁呈浓度依赖性地抑制心肌细胞的ICa ,L,并使跨室壁ICa ,L的不均一性减少。高浓度的硫酸镁使三层心肌细胞ICa,L的电流 电压曲线上移 ,对ICa ,L的动力学参数无明显影响。结论　硫酸镁呈浓度依赖性的减少跨室壁ICa ,L的不均一性。     

The effects of verapamil and diltiazem on N-, P- and Q-type calcium channels mediating dopamine release in rat striatum.

1. The putative inhibitory effects of verapamil and diltiazem on neuronal non-L-type Ca2+ channels were studied by investigating their effects on either K+- or veratridine-evoked [3H]-dopamine ([3H]-DA) release in rat striatal slices. Involvement of N-, P- and Q-type channels was identified by sensitivity of [3H]-DA release to omega-conotoxin GVIA (omega-CTx-GVIA), omega-agatoxin IVA (omega-Aga-IVA) and omega-conotoxin MVIIC (omega-CTx-MVIIC), respectively. 2. KCl (50 mM)-evoked [3H]-DA release was abolished in the absence of Ca2+, and was insensitive to dihydropyridines (up to 30 microM). It was significantly blocked by omega-CTx-GVIA (1 microM), omega-Aga-IVA (30 nM) and was confirmed to be abolished by omega-CTx-MVIIC (3 microM), indicating involvement of N-, P- and Q-type channel subtypes. 3. Verapamil and diltiazem inhibited K+-evoked [3H]-DA release in a concentration-dependent manner. The inhibitory effects of verapamil or diltiazem (each 30 microM) were fully additive to the effect of omega-CTx-GVIA (1 microM), whereas co-application with omega-Aga-IVA (30 nM) produced similar effects to those of omega-Aga-IVA alone. 4. As shown previously, veratridine-evoked [3H]-DA release in Ca2+ containing medium exclusively involves Q-type Ca2+ channels. Here, diltiazem (30 microM) did not inhibit veratridine-evoked [3H]-DA release, whereas verapamil (30 microM) partially inhibited it, indicating possible involvement of Q-type channels in verapamil-induced inhibition. However, verapamil (30 microM) inhibited this release even in the absence of extracellular Ca2+, suggesting that Na+ rather than Q-type Ca2+ channels are involved. 5. Taken together, our results suggest that verapamil can block P- and at higher concentrations possibly N- and Q-type Ca2+ channels linked to [3H]-DA release, whereas diltiazem appears to block P-type Ca2+ channels only.     

Comparison of effects of L/N-type and L-type calcium channel blockers on post-infarct cardiac remodelling in spontaneously hypertensive rats

Hypertension and coronary events are becoming more prevalent in aging societies, and myocardial infarction usually occurs in calcium channel blocker (CCB)-treated hypertensive patients. We herein compared the effects of cilnidipine, an L/N-type CCB and amlodipine, an L-type CCB, on post-infarct left ventricular (LV) remodelling in spontaneously hypertensive rats (SHRs). Male SHRs were subjected to 30 minutes of left coronary artery occlusion followed by reperfusion (MI group). The administration of cilnidipine (10 mg/kg/d; MI + Cil group) or amlodipine (10 mg/kg/d; MI + Aml group) was initiated one week before surgery and continued for five weeks. Both CCBs decreased blood pressure. Four weeks after surgery, cilnidipine, but not amlodipine, attenuated LV dilatation, fractional shortening impairments, end-diastolic pressure elevations, and tau elongation. In the non-infarct region, myocyte hypertrophy and brain natriuretic peptide (BNP) mRNA levels were similarly attenuated by both CCBs. On the other hand, interstitial fibrosis, the mRNA expression of collagen type III and transforming growth factor (TGF) β and immunohistological TGF β protein expression in the non-infarct region were reduced more in the MI + Cil group than in the MI + Aml group. Additionally, elevated angiotensin-converting enzyme activity and interstitial noradrenaline concentrations in the non-infarct region were reduced by cilnidipine. These results suggest that cilnidipine reduced cardiac noradrenaline concentrations and inhibited the renin–angiotensin system, which attenuated post-infarct remodelling more than amlodipine in hypertensive rats.     

Different effects of noradrenaline,angiotensin II and BAY K 8644 on the abolition of autoregulation of renal blood flow by verapamil

Summary To examine the role of Ca channels in autoregulation of renal blood flow in response to changes of perfusion pressure, experiments were performed with perfused kidney in anesthetized dogs using a Ca channel activator, BAY K 8644, and vasoconstrictors such as noradrenaline and angiotensin II. Control observations usually showed excellent autoregulation of renal blood flow at pressures between 120 and 200 mm Hg, the autoregulatory index being less than 0.2. Verapamil (50 g/min, i.a. infusion) obviously inhibited the renal autoregulation. Simultaneous infusion of 5 g/min of BAY K 8644 with verapamil prevented both the increase of renal blood flow and the impairment of the autoregulation caused by verapamil. Whereas simultaneous infusion of noradrenaline (1 and 3 g/min) or angiotensin 11 (0.1 and 0.3 g/min) with verapamil dose-dependently reduced renal blood flow, these drugs could not antagonize the inhibitory effect of verapamil on autoregulation. The present experiments show that Ca channels play an important role in establishing renal autoregulation, and that a mere vasoconstriction by noradrenaline and angiotensin II is distinguished from autoregulatory performance.     

Regional differences in the actions of verapamil and isosorbide dinitrate on rabbit and dog vascular smooth muscle

Summary The effects of verapamil and isosorbide dinitrate (ISDN) alone or together on mechanical responses of the rabbit coronary artery and mesenteric vein, and the dog coronary artery have been investigated. Verapamil, in concentrations exceeding 10 nM consistently inhibited and at 10 M, blocked the contraction evoked by excess concentrations of K in these tissues, but agonist-induced contraction was not modified by the presence or absence of Ca. In concentrations greater than 1 M, verapamil depolarized the membrane by inhibiting the K-conductance of the membrane. ISDN had little effect on the rabbit coronary artery in concentrations below 10 M. In contrast, in the rabbit mesenteric vein and dog coronary artery, ISDN in concentrations over 1 M inhibited the contraction evoked by excess concentrations of K or by agonists. Species differences were apparent in the actions of ISDN on vascular tissues. When verapamil and ISDN were simultaneously applied to the rabbit mesenteric vein and dog coronary artery, the K-induced contraction was markedly inhibited by an amount exceeding that produced by the sum of the contractions evoked by the individual application of both agents. An enhanced vasodilating action induced by simultaneous applications of both agents indicates a possible clinical benefit for anti-anginal treatment.     

The effects of calcium channel inhibitors on twitches and noradrenaline contractions of the rat bisected vas deferens

In the prostatic half of the rat vas deferens, responses to noradrenaline 30 microM were biphasic. Ca-deprivation reduced both phases. The initial part of the noradrenaline contraction was resistant to verapamil (IC50 74.2 microM), methoxyverapamil (IC50 approximately 100 microM) and especially nifedipine (no effect up to 14.4 microM). The late part of this response and the entire response to noradrenaline in the epididymal half were abolished by verapamil (10.2 microM), methoxyverapamil (9.6 microM) or nifedipine (1.44 microM). The first phase of the twitch to single pulse transmural stimulation was abolished by nifedipine (14.4 microM) and inhibited by methoxyverapamil (57.6-96 microM); verapamil was less potent. The second phase of the twitch was totally resistant to nifedipine (14.4 microM), but more sensitive to inhibition by verapamil or methoxyverapamil than was the first. It was concluded that the calcium channel inhibitors can distinguish between three distinct types of calcium ion channel in the rat vas deferens: (1) sensitive calcium channels mediating the noradrenaline response in the epididymal half, and the late part of the noradrenaline response in the prostatic half (2) calcium channels responsible for the first phase of the twitch, blocked by high concentrations of nifedipine (3) calcium channels mediating the second phase of the twitch and the initial response to noradrenaline in the prostatic half, unaffected by nifedipine.