Benzothiazepines, diltiazem and JTV-519, exert an anxiolytic-like effect via neurosteroid biosynthesis in mice.

We investigated whether benzothiazepines could produce anxiolytic effects via allopregnanolone (ALLO) biosynthesis in mice. We compared the behavioral effects caused by benzothiazepines to those caused by carbamazepine and sodium valproate. We found that a pretreatment with finasteride (a 5 alpha-reductase inhibitor) suppressed carbamazepine-induced anxiolytic effects but not the effects of sodium valproate. Similar to carbamazepine, diltiazem and JTV-519 displayed anxiolytic effects that were suppressed by a pretreatment with finasteride. We clearly demonstrate that the benzothiazepines, diltiazem and JTV-519, exert an anxiolytic-like effect via ALLO biosynthesis in mice.

Cladribine inhibits a diltiazem-induced increase in red blood cell purine nucleotide concentrations in a zebrafish model.

Minimizing drug interactions is paramount to improving the efficacy and tolerability of cancer therapy. The zebrafish represents an innovative cancer model due to highly conserved genetics and inherent capacity for high-throughput chemical screening. This pilot study extends the utility of the zebrafish to a preclinical model for pharmacodynamics by examining the interaction of the nucleoside analogue, cladribine with the calcium channel blocker, diltiazem. Cladribine (0.7-3.5 mM) and/or diltiazem (2.4 mM), was injected intraperitoneally into adult zebrafish and red blood cell (RBC) lysates were assayed by HPLC for levels of purine nucleotides (e.g. ATP), potential biomarkers of cardiovascular health. Diltiazem increased RBC ATP concentrations, which were inhibited by co-injection of cladribine. These results suggest a novel drug interaction and highlight the feasibility of the zebrafish as an in vivo model for pharmacodynamic studies.

Clinical pharmacokinetics of thalidomide

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions in being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (Cmax) of 1-2mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUCoo) of 18mg - h/L, apparent elimination half-life of 6 hours and apparent systemic clearence of 10 L/H. Thalidomide pharmacokinetics are best described by a one-comportment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacolinetics (the 'flip-flop' phenomenon), with its elimination rate being faster than in absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The 'true' apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state Cmax (Cssmax) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accululation, with Css of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400mg. Because of the low solubility of thalidomide Cmax is less than proportional to dose, and tmax is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokonetics are not expected to change in patients with impaired liver...

The mechanism of the increasing action of TA-993, a new 1,5- benzothiazepine derivative, on limb blood flow in anesthetized dogs: selective suppression of sympathetic nerve activity.

TA-993, (-)-cis-3-acetoxy-5-(2-(dimethylamino)ethyl)-2, 3-di-hydro-8-methyl-2-(4-methylphenyl)-1,5-benzothiazepin-4(5H)one maleate, a new 1,5-benzothiazepine derivative with l-cis configuration, has a unique and selective increasing action on limb blood flow with little influence on arterial pressure besides an antiplatelet action. We studied the mechanism of increasing action of TA-993 on limb blood flow in anesthetized dogs. In a canine blood-perfused hindlimb preparation with a donor dog, TA-993 (100 microg/kg i.v.) did not increase femoral blood flow when administered to the donor dog, but did when administered to a recipient dog. TA-993 did not show the increasing action on femoral blood flow in the presence of hexamethonium or phentolamine, whereas it did in the presence of propranolol or atropine. TA-993 also showed a weak increasing effect on heart rate, which was inhibited by any one of these blockers. TA-993 (300 microg/kg i.v.) did not alter the phenylephrine (1-100 ng/kg i.a.)- or the talipexole (3-100 ng/kg i.a.)-induced increase in perfusion pressure in an autoperfused hindlimb. These results suggest that the increasing action of TA-993 on limb blood flow is mediated by the sympathetic nervous system but that the adrenergic receptors are not likely to be the central point of action of this new agent. There is a possibility that the mechanism of the increasing action on heart rate is different from that of its increasing action on limb blood flow.

Interaction between timolol eyedrops and oral nicardipine or oral diltiazem in healthy Japanese subjects.

OBJECTIVE: Timolol is widely used for the topical therapy of glaucoma. Adverse cardiovascular effects include slowing of the heart rate and weakening of myocardial contractility. We investigated pharmacodynamic interactions with respect to cardiovascular and ocular responses between timolol ophthalmic solution and either nicardipine, which does not directly inhibit cardiac conduction, or diltiazem, which does. METHODS: Two studies utilized a randomized, double-blind, Latin-square, placebo-controlled design involving four separate treatments given at least 1 week apart. Eight healthy male Japanese volunteers received a single drop of 0.5% timolol or artificial tears in each eye with or without a single oral dose of nicardipine (40 mg), and with or without a single oral dose of diltiazem (60 mg). Subjects exercised on a bicycle ergometer before and 1.5 and 3 h after dosing. At these times, heart rate and blood pressure were measured at rest and after exercise. The intraocular pressure was measured at rest. RESULTS: One drop of 0.5% timolol per eye significantly reduced the exercise-induced increase in heart rate and blood pressure, and intraocular pressure at rest. The timolol ophthalmic solution suppressed the reflex sympathetic cardiac stimulation that resulted from the primarily vasodilative action of nicardipine. No additional reduction in heart rate occurred when the ophthalmic timolol solution was administered in conjunction with diltiazem. The concomitant use of timolol and nicardipine or diltiazem did not induce an additional reduction in intraocular pressure. Oral nicardipine or diltiazem did not reduce intraocular pressure. Care should be taken when using topical timolol in patients with cardiovascular or respiratory diseases.

Use of glucagon for acute intravenous diltiazem toxicity.

Intravenous diltiazem has become a preferred medication for treating supraventricular tachyarrhythmias in hospitalized patients. We present a case of inadvertent acute overdosage, its clinical effects, and successful treatment using intravenous glucagon.

Pharmacological studies on a new antihypertensive agent, S-2150, a benzothiazepine derivative: 1. Antinecrotic and antiarrhythmic effects in reperfused rat hearts.

S-2150 is a new 1,5-benzothiazepine derivative that inhibits [3H]diltiazem and [3H]WB4101 bindings to the membrane of rat tissue. The effects of S-2150 on ischemia/ reperfusion injury were studied in anesthetized rats. S-2150 reduced the myocardial infarct size (IS) induced by 20-min coronary artery occlusion followed by reperfusion. To evaluate reperfusion-induced ventricular tachycardia and fibrillation (VT, VF), we occluded the coronary artery for 4 min and then reperfused it. The incidence of arrhythmia was blocked by S-2150, and this effect offered protection against cardiac death. Prazosin did not modify the IS or incidence of reperfusion arrhythmias, but combined treatment with a noneffective dose of diltiazem showed significant cardioprotective effects. We also compared the direct effects of S-2150 and diltiazem on cardiac function and coronary perfusion flow using isolated rat hearts. Both drugs decreased mechanical function and increased coronary flow, with S-2150 being less cardiodepressive and more vasodilatory. S-2150 is cardioprotective at doses comparable to hypotensive doses even though its cardiodepressant effect is much weaker than that of diltiazem. This effectiveness may be partly explained by its dual characteristics: blocking the Ca channel and the alpha 1-adrenoceptor.

Studies on the interactions between the angiotensin converting enzyme inhibitor enalaprilat and calcium antagonists in rats.

OBJECTIVE: To investigate the hypotheses that the synergistic hypotensive interaction between angiotensin converting enzyme (ACE) inhibitors and calcium antagonists is mediated via alpha1-adrenoceptor blockade and that in the presence of ACE inhibitors the alpha1-adrenoceptor potency of clinically used calcium antagonists may be sufficiently enhanced to add to the hypotensive effect. METHODS: The interactions between the ACE inhibitor enalaprilat and the calcium antagonists diltiazem, cinnarizine, felodipine and verapamil were studied in anesthetized rats for effects on blood pressure and in isolated perfused rat tail arteries for effects at alpha1-adrenoceptors. RESULTS: It was found that in isolated tail arteries enalaprilat had no effect on the weak alpha1-adrenoceptor antagonist actions of diltiazem, cinnarizine and felodipine. Similarly, enalaprilat did not affect the hypotensive responses to these calcium antagonists. However, enalaprilat was found to potentiate the alpha1-adrenoceptor antagonist action of verapamil, both in vitro and in vivo, as well as the hypotensive action of verapamil. CONCLUSIONS: These results support the above hypothesis in the case of verapamil only; for calcium antagonists in general the hypothesis was not supported. The results are consistent with a growing body of evidence showing that the distinction between calcium antagonists and alpha1-adrenoceptor antagonists is becoming less sharply defined.

The calcium antagonist diltiazem has antiarrhythmic effects which are mediated in the brain through endogenous opioids.

The purpose of this study was to examine the hypothesis that the calcium channel blocker, diltiazem, modulates catecholamine-induced arrhythmias through CNS mechanisms. Rats, that had catheters previously inserted into the lateral cerebral ventricle and femoral artery, received diltiazem, 10 or 50 micrograms/kg or the diluent, into the lateral cerebral ventricle (i.c.v.). Epinephrine was infused to produce arrhythmias. The onset of ventricular arrhythmias, premature ventricular complexes, occurred at a significantly (P less than 0.05) greater dose of epinephrine, after diltiazem, compared to the control group and in a dose-dependent manner, with the mean (+/- 1 SEM) dose of epinephrine being 198 +/- 5, 175 +/- 13 and 115 +/- 15 micrograms/kg in the groups treated with 50 and 10 micrograms/kg of diltiazem and the control groups, respectively. The development of fatal arrhythmias, mainly ventricular tachyarrhythmias, occurred at significantly (P less than 0.05) greater concentrations of epinephrine with diltiazem, 50 and 10 micrograms/kg, 225 +/- 5 and 183 +/- 13 micrograms/kg, respectively, compared to controls, 131 +/- 15 micrograms/kg. Endogenous opioids of the mu-type were implicated in this action of diltiazem, because the mu opioid antagonist naloxone, 1 mg/kg (i.v.), significantly (P less than 0.05) antagonized the antiarrhythmic effects of centrally administered diltiazem and the mu opioid agonist DAGO (i.c.v.), did not further enhance the suppression of epinephrine-induced arrhythmias, produced by diltiazem, 50 micrograms/kg. Atropine sulfate, which crosses the blood-brain barrier and atropine methylnitrate, which does not enter the brain, each at 1 mg/kg (i.v.), produced an equal and significant antagonism of the effect of diltiazem, 50 micrograms/kg, that was less than that of naloxone. The combination of naloxone plus atropine sulfate completely prevented the effect of diltiazem, 50 micrograms/kg, on arrhythmias. The antiarrythmic action of diltiazem could not be explained by alteration of the blood pressure or heart rate response to epinephrine. The results suggest that: (a) calcium channels on neurons in the CNS play an important role in the modulation of epinephrine-induced cardiac arrhythmias, (b) diltiazem can suppress arrhythmias through CNS mechanisms, (c) activation of the parasympathetic nervous system mediates some of the effect of diltiazem, but (d) the mechanism of action of diltiazem is modulated through endogenous opioids.

Avanços terapêuticos em cardiologia: parte 1 - Antagonistas do cálcio: estado atual em cardiologia / Therapeutic advances in cardiology: part 1 - Calcium antagonists: up-to-date state in cardiology

O cálcio representa a base celular para a excitaçäo e contraçäo da musculatura cardiovascular. Os bloqueadores do cálcio têm estruturas moleculares diferentes, com efeitos comuns, e repercussöes cardiovasculares com potências desiguais. Aumentam o fluxo coronário, diminuem a pós-carga, o consumo de oxigênio e o espasmo coronário. Têm múltiplas indicaçöes clínicas, representando um marco na estratégia terapêutica em cardiologia

Cromakalim (BRL 34915) counteracts the epileptiform activity elicited by diltiazem and verapamil in rats.

1. The effects of BRL 34915 (cromakalim), a potassium channel opener, have been tested on the epileptiform activity elicited by high dose/concentrations of some calcium antagonists in in vivo (diltiazem) and in vitro (diltiazem and verapamil) experiments in rats. 2. Diltiazem (150-300 mg kg-1, i.p.) induced behavioural and electroencephalographic (EEG) seizures that were completely prevented by cromakalim (10 nmol/10 microliters, i.c.v.). Whereas, pentobarbitone (5-10 mg kg-1, i.p.) only prevented the behavioural component of the seizures. 3. In hippocampal slices, verapamil (1.5-2.0 mM) produced, within 30-60 min of perfusion, a CA1 epileptiform bursting in 80% of the experiments. This epileptiform activity was prevented by the cromakalim concentration (50 microM) that did not affect the control CA1 synaptic transmission per se. Pentobarbitone also prevented verapamil-induced epileptiform bursting only at the concentration (100 microM) that also reduced control CA1 synaptic transmission. 4. Diltiazem (1.5 mM) produced a biphasic excitatory-depressant effect within 60 min of perfusion. A CA1 epileptiform bursting appeared in 100% of the experiments within 30 min of perfusion. These excitatory effects were followed by a depression phase, characterized by a reduction of the magnitude of CA1 excitatory postsynaptic potentials (e.p.s.ps) and population spike. 5. The diltiazem-induced epileptiform bursting was prevented by cromakalim at a concentration (50 microM) that did not affect the control CA1 synaptic transmission per se. Pentobarbitone also prevented the diltiazem-induced epileptiform bursting only at a concentration (100 microM) that also reduced the control CA1 synaptic transmission. Both cromakalim (50 microM) and pentobarbitone (100 microM) failed to affect the depressant effects of diltiazem on CA1 hippocampal area. On the contrary, high (3.3mM) calcium solutions prevented both the excitatory and the depressant effects of 1.5 mm diltiazem within 60 min.6. These data indicate an involvement of potassium currents in the epileptiform activity elicited by high doses of diltiazem and verapamil.

Antagonistic effects of epinephrine, glucagon and methylatropine but not calcium chloride against atrio-ventricular conduction disturbances produced by high doses of diltiazem, in conscious dogs.

Conscious dogs (n = 6) with chronically implanted electrocardiogram electrodes and arterial and venous catheters were infused with a large dose of diltiazem (1 mg/dog per min i.v. over 60 min) to evoke hypotension and atrioventricular disturbances (AVII and AVIII blocks) which lasted for several hours. These effects are also observed in humans after accidentally or intentionally taking overdoses of diltiazem and particularly verapamil. In the intoxicated dog, administration of methylatropine (50 micrograms/kg per min i.v. over 10 min), epinephrine (0.2 and 0.4 microgram/kg per min i.v. over 60 min) and glucagon (2 micrograms/kg/min i.v. over 15 min) but not CaCl2 (3 mg/kg/min i.v. over 15 min) abolished almost entirely the AVII and AVIII blocks produced by diltiazem and re-established a normal sinus rhythm. However, these treatments failed to normalize AV conduction, and did not modify the moderate hypotensive effects of diltiazem. These findings support available clinical observations that beta-adrenoceptors agonists, glucagon and atropine rather than calcium salts are beneficial for the successful treatment of cardiovascular toxicity associated with the intake of supratherapeutic doses of diltiazem or verapamil.

Glucagon antagonism of calcium channel blocker-induced myocardial dysfunction.

Calcium channel blockers (CCBs) may produce profound myocardial depression. Glucagon antagonized verapamil-induced hypotension and bradycardia in rats; however, glucagon's ability to antagonize other CCBs is unexplored. This study determined: a) if glucagon reverses verapamil-induced depression by a direct cardiac effect, b) if myocardial depression induced by diltiazem and nifedipine (representing different classes of CCBs) is also reversed by glucagon, and c) the glucagon concentration needed to reverse myocardial depression. Isolated rat hearts were perfused at a constant flow rate in a Langendorff preparation. Developed pressure (dP), contractility (+dP/dtmax), relaxation (-dP/dtmax), heart rate, and coronary vascular resistance were recorded. A CCB (n = 6, each blocker) was infused until greater than 50% depression of contractility was achieved. Glucagon was then simultaneously infused (perfusion concentration of 0.6-1.1 x 10(-7) M), and repeat cardiac variables were recorded. In a separate group of 36 hearts, glucagon dose response was determined. After producing a greater than 50% depression in dP/dtmax with 3 mumol of diltiazem, a single concentration of glucagon was infused simultaneously into each heart (perfusion concentrations between 10(-6) and 10(-9) M) and percent recovery of baseline function was determined. Glucagon restored baseline contractility and dP with all three CCBs. Complete reversal of diltiazem-induced myocardial depression occurs at glucagon concentrations greater than or equal to 5 x 10(-7) M. We conclude that a) glucagon directly reverses myocardial depression from three classes of CCBs at concentrations achieved in vivo, and b) glucagon may be useful in the treatment of CCB-induced myocardial toxicity.

Different interaction of bepridil and diltiazem with BAY K 8644 in the abolition of autoregulation of renal blood flow.

The effect of bepridil and diltiazem on autoregulation of renal blood flow was examined in connection with interaction of BAY K 8644 in perfused kidney of anesthetized dogs. When the perfusion pressure was changed stepwise over the range between 60 and 200 mm Hg, renal blood flow remained nearly constant between 100 and 200 mm Hg. Intra-arterial infusion of diltiazem (50 microgram/min) or bepridil (1 mg/min) increased renal blood flow at perfusion pressure above 100 mm Hg and completely inhibited renal autoregulation. Simultaneous infusion of 5 microgram/min of BAY K 8644 with diltiazem antagonized both the increase of renal blood flow and the impairment of autoregulation, whereas simultaneous infusion of BAY K 8644 (5 micrograms/min) could not block the impairment of renal autoregulation induced by bepridil. These results show that the inhibitory effect of bepridil on autoregulation of renal blood flow is due to some mechanism other than Ca channel blocking action in renal vasculature.

Differential antagonism by Bay K 8644 of vasodilator effects of nifedipine, diltiazem, nicorandil and nitroglycerin in dog femoral circulation.

1. The modification by Bay K 8644 of the vasodilator effects of nifedipine, diltiazem, nicorandil and nitroglycerin was investigated in the femoral arterial bed of anaesthetized dogs. 2. The right femoral artery was cannulated and its arterial bed was perfused with autologous blood at a constant pressure slightly higher than the mean systemic arterial blood pressure. Bay K 8644 was infused intra-arterially (i.a.) and the 4 vasodilators were injected i.a. as bolus doses. 3. The vasodilator effects of nifedipine (0.3-10 nmol), diltiazem (0.01-1 mumol), nicorandil (0.1-10 mumol) and nitroglycerin (0.3-100 nmol) were all suppressed by infusions of Bay K 8644 (3-100 nmol min-1). 4. The dose-response curve of nifedipine was shifted parallel to the right by the infusion of Bay K 8644 and the dose-ratio was the greatest of the 4 drugs. 5. The dose-response curve of diltiazem was also shifted to the right by Bay K 8644. However, the dose-ratio was far smaller than that of nifedipine. 6. The vasodilator effect of nicorandil was not antagonized as much by Bay K 8644 as that of nitroglycerin. This less effective antagonism of nicorandil by Bay K 8644 can be explained if nicorandil, which although structurally a nitrate, can in addition cause relaxation of vascular smooth muscle by hyperpolarizing the membrane which would result in Bay K 8644 being less effective.

Analysis of new imidazoline derivative-induced increase in the maximum response to norepinephrine in the rat vas deferens.

The effects of newly synthesized 5-imidazoline derivatives on the dose-response relationship to norepinephrine were investigated in the normal and denervated vasa deferentia of the rat. Three derivatives (K-3827, K-4011 and K-4300) exerted alpha-antagonistic action, the potency of which was similar to that of tolazoline. The pA2 values of these derivatives and currently known alpha-antagonists (tolazoline, phentolamine and prazosin, but not yohimbine) in the denervated tissue were slightly but significantly larger than those in the normal tissue. All imidazoline derivatives and alpha-antagonists produced an increase in the maximum response to norepinephrine in the normal vas deferens. In the denervated tissue, however, K-3827, K-4011 and alpha-antagonists caused only a rightward shift of the dose-response curve to norepinephrine, but not an increase in the maximum response, i.e., relatively pure alpha-antagonism. In contrast, the other 3 imidazoline derivatives, K-4299 and K-6342 which exhibited neither alpha-agonistic nor antagonistic action and K-4300, increased the maximum response to norepinephrine even after denervation. Their effects were nonspecific in that they also potentiated acetylcholine-induced contractions in both normal and denervated tissues. These 3 imidazoline derivatives antagonized the action of diltiazem. The effects of imidazoline derivatives and alpha-antagonists were discussed in relation to those of denervation, and the drug enhancement by 3 imidazoline derivatives was analyzed from the viewpoint of calcium movement.

Effects of verapamil and diltiazem on human platelet function.

In this study the antiplatelet properties of two calcium channel blockers, verapamil and diltiazem, were evaluated. In 20 random aspirin-abstaining donors, both diltiazem and verapamil (0.01-10 microM) reduced epinephrine-induced aggregation [46 +/- 6% (SE) inhibition] and demonstrated a dose-dependent inhibition of epinephrine-induced [14C]serotonin release (43 +/- 3% reduction). However, at equimolar concentrations, verapamil was twice as effective. Neither drug altered ADP, collagen, thrombin, or calcium ionophore-induced platelet aggregation or platelet granule secretion. Neither drug prevented formation of thromboxane B2 during secondary aggregation. Verapamil, but not diltiazem, increased the Kd of [3H]yohimbine binding from 2.03 to 46.99 nM without altering the calculated number of binding sites per platelet (124 sites/platelet). Supplemental calcium added to citrated platelet-rich plasma reversed both verapamil and diltiazem-induced inhibition of platelet aggregation. We conclude that, at the concentrations tested, both verapamil and diltiazem are specific inhibitors of epinephrine-induced platelet activation. Clearly, both agents may be acting by preventing epinephrine-induced increases in plasma membrane permeability to calcium. However, the greater potency of verapamil compared with diltiazem with only verapamil binding to alpha2-adrenergic receptors suggests that alpha-blockade represents a significant component of verapamil-induced platelet inhibition.

Inotropic effects of Ca2+ channel agonist and antagonists in neuraminidase-treated left atria of rats.

The effects of removal of sialic acid from cardiac sarcolemma on contractile functions and on inotropic responses to Ca2+ channel agonist and antagonists were investigated in rat left atria. About 64% of the total sialic acid content of the left atria was removed during a 90 min exposure to neuraminidase (2 u ml-1). The removal of sialic acid neither affected the development of twitch tension induced by stimulation at a frequency of 0.5 Hz, nor altered the interval-dependent changes in contractility such as the force-frequency relationship and post rest contractions. The positive inotropic effects produced by isoprenaline, and by an increase in extracellular Ca2+ concentration were the same in the neuraminidase-treated preparations as those in the untreated preparations. Bay K 8644, a Ca2+ channel agonist, induced an increase in contractility in the neuraminidase-treated preparations comparable to that in the untreated ones. Neuraminidase treatment significantly attenuated the negative inotropic effects of verapamil and diltiazem, whereas it had no effect on that of nifedipine. The results indicate that sialic acid removal modifies neither the basal contractile functions nor the positive inotropism which is associated with an enhancement of the slow inward Ca2+ current. However, sialic acid, which constitutes the glycocalyx of the cardiac sarcolemma, may be involved in the mechanism of the Ca2+ channel antagonistic actions of verapamil and diltiazem, but not that of nifedipine. Thus, our results provide pharmacological evidence that verapamil and diltiazem behave differently from the dihydropyridine compounds.

Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle.

Antagonism between either the dihydropyridine calcium agonist, Bay k 8644, or high external Ca2+ and the calcium antagonists, nifedipine, verapamil and diltiazem, and Mn2+ was investigated in canine isolated ventricular trabeculae. Bay k 8644 (10(-7)-10(-5)M) produced a slowly developing increase in developed tension which reached a maximum at 10(-6)M. A small decrease in the positive inotropic effect of Bay k 8644 at 10(-5)M was probably due to the negative inotropic effect of the solvent, 0.5% ethanol. Bay k 8644 (10(-7)-10(-5)M) produced a rightward parallel shift of the concentration-response curves for the negative inotropic effects of nifedipine (10(-8)-10(-5)M) and verapamil (10(-7)-3 X 10(-5)M). The slopes of the Schild plots were -0.92 for nifedipine (pA2 value = 6.58) and -0.48 for verapamil. Bay k 8644 (10(-6) and 10(-5)M) produced only a slight rightward shift of the concentration-response curves for the negative inotropic effect of diltiazem (10(-7)-3 X 10(-5)M) and did not affect the negative inotropic effect of Mn2+ (10(-4)-10(-2)M). Addition of 2.5 X 10(-3)M Ca2+ (5.05 X 10(-3)M Ca2+) to the medium produced a greater maximum positive inotropic effect than Bay k 8644. The concentration-response curves for the negative inotropic effects of nifedipine, verapamil and diltiazem obtained under these conditions were not essentially different from those under control conditions (2.55 X 10(-3)M Ca2+). 6 These results indicate that Bay k 8644, while producing a positive inotropic effect, antagonizes the negative inotropic effect of nifedipine by competing with the latter for the same site closely associated with the calcium channel. In contrast, Bay k 8644 antagonizes the negative inotropic effects of verapamil and diltiazem by interfering allosterically with the binding of these calcium antagonists to their sites of action. Bay k 8644 does not antagonize the negative inotropic effect of Mn2+. No pharmacological antagonism was observed between the three organic calcium antagonists and high external Ca2+_

[Effects of diltiazem on hemodynamics and His bundle electrogram in the anesthetized dog (author's transl)].

Effects of diltiazem, a calcium antagonist, on the cardiovascular system in the pentobarbital anesthetized dogs were investigated. Diltiazem (100 micrograms/kg and 300 micrograms/kg, i.v.) decreased blood pressure, heart rate and total peripheral resistance, while cardiac output and stroke volume were markedly increased. The max dp/dt of left ventricular pressure tended to increase with a dose of 100 micrograms/kg. Left ventricular end-diastolic pressure was slightly increased with a dose of 400 micrograms/kg. Rate pressure product was significantly reduced. Diltiazem (30 micrograms/kg and 100 micrograms/kg) increased pulmonary arterial flow together with the increase in both systolic and diastolic pulmonary arterial pressure. Diltiazem (100 micrograms/kg) increased common carotid, femoral and superior mesenteric arterial blood flow by 30 to 40%, whereas vertebral blood flow was increased by over 100%. The dose dependency in the vertebral blood flow was remarkable. Response of the vertebral artery to diltiazem was similar to that reported in the case of the coronary artery. In the His bundle electrogram, diltiazem increased the AH interval by about 10% at 100 micrograms/kg and 25% at 200 micrograms/kg, without changing the HV interval. Diltiazem-induced AH prolongation was completely depressed by epinephrine but only partially so by CaCl2. Thus, the effects of diltiazem on sinus rhythm and AV conduction in the anesthetized dog were more potent than the effects on cardiac contractility, although weaker than the effects of the vasodilating action. The vasodilator effects appear to be the primary action of diltiazem on the cardiovascular system.