Effects of ritanserin on transmembrane action potentials in canine Purkinje fibers.

Ritanserin has been reported to be a potential antiarrhythmic. We studied the cellular electrophysiologic effects of ritanserin in canine Purkinje fibers. Ritanserin produced significant depressant effects on transmembrane action potentials elicited in canine Purkinje fibers. At concentrations of 10 and 40 mg/liter, ritanserin decreased Vmax (the upstroke velocity) of action potential in a dose-dependent fashion and shortened the duration of fast response action potential. These concentrations of ritanserin also reduced the amplitude and duration of the slow response action potentials induced in Purkinje fibers treated with isoproterenol (10(-5) M) and high K+ (22 mM). These in vitro results suggest that the cellular electrophysiologic actions of ritanserin may be due to its direct actions on cardiac sodium and calcium channels, which, in turn, may account for its antiarrhythmic effects.

Synthesis, calcium-channel-blocking activity, and antihypertensive activity of 4-(diarylmethyl)-1-[3-(aryloxy)propyl]piperidines and structurally related compounds.

A series of 4-(diarylmethyl)-1-[3-(aryloxy)propyl]piperidines and structurally related compounds were synthesized as calcium-channel blockers and antihypertensive agents. Compounds were evaluated for calcium-channel-blocking activity by determining their ability to antagonize calcium-induced contractions of isolated rabbit aortic strips. The most potent compounds were those with fluoro substituents in the 3- and/or 4-positions of both rings of the diphenylmethyl group. Bis(4-fluorophenyl)acetonitrile analogue 79 was similar in potency to bis(4-fluorophenyl)methyl compound 1. The methylene analogue of 1 (78) and derivatives of 1 that contained a hydroxyl (76), carbamoyl (80), amino (81), or acetamido (82) substituent on the methyl group were less potent. In most cases, substituents on the phenoxy ring, changes in the distance between the aryloxy group and the piperidine nitrogen, and the substitution of S, N(CH3), or CH2 for the oxygen atom of the aryloxy group had only a small to moderate effect on the potency. The best compounds in this series were more potent than verapamil, diltiazem, flunarizine, and lidoflazine, but were less potent than nifedipine. Compounds were evaluated for antihypertensive activity in spontaneously hypertensive rats (SHR) at an oral dose of 30 mg/kg. Of the 55 compounds tested, only nine produced a statistically significant (p less than 0.05) reduction in blood pressure greater than 20%; all of these compounds had fluoro substituents in both rings of the diphenylmethyl group. One of the most active compounds in the SHR at 30 mg/kg was 1-[4-[3-[4-[bis(3,4-difluorophenyl)methyl]-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone (63), which produced a 35% reduction in blood pressure and was similar in activity to nifedipine. At lower doses, however, 4-[bis(4-fluorophenyl)methyl]-1-[3-(4-chlorophenoxy)propyl]piperidine (93) was one of the most effective antihypertensive agents, producing reductions in blood pressure of 17 and 11% at oral doses of 10 and 3 mg/kg, respectively; 63 was inactive at 10 mg/kg.

AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels.

In vivo and in vitro methods were used to characterize AHR-16303B, a novel compound with antagonistic action at 5-HT2 receptors and voltage-sensitive calcium channels. The 5-HT2 receptor-antagonistic properties of AHR-16303B were demonstrated by inhibition of (a) [3H]ketanserin binding to rat cerebral cortical membranes (IC50 = 165 nM); (b) 5-hydroxytryptamine (5-HT)-induced foot edema in rats (minimum effective dose, (MED) = 0.32 mg/kg orally, p.o.); (c) 5-HT-induced vasopressor responses in spontaneously hypertensive rats (SHR) (ID50 = 0.18 mg/kg intravenously (i.v.), 1.8 mg/kg p.o.), (d) 5-HT-induced antidiuresis in rats (MED = 1 mg/kg p.o.), and (e) platelet aggregation induced by 5-HT + ADP (IC50 = 1.5 mM). The calcium antagonist properties of AHR-16303B were demonstrated by inhibition of (a) [3H]nimodipine binding to voltage-sensitive calcium channels on rabbit skeletal muscle membranes (IC50 = 15 nM), (b) KCl-stimulated calcium flux into cultured PC12 cells (IC50 = 81 nM), and (c) CaCl2-induced contractions of rabbit thoracic aortic strips (pA2 = 8.84). AHR-16303B had little or no effect on binding of radioligands to dopamine2 (DA2) alpha 1, alpha 2, H1, 5-HT1 alpha, beta 2, muscarinic M1, or sigma opioid receptors; had no effect on 5-HT3 receptor-mediated vagal bradycardia; and had only minor negative inotropic, chronotropic, and dromotropic effects on isolated guinea pig atria. In conscious SHR, 30 mg/kg p.o. AHR-16303B completely prevented the vasopressor responses to i.v. 5-HT, and decreased blood pressure (BP) by 24% 3 h after dosing.

AHR-14310C: a potent, long-acting, nonsedating H1-antihistamine that prevents antigen-induced mucus formation in sensitive rats.

AHR-14310C(5-[2-[4-[bis(4-fluorophenyl)hydroxymethyl- 1-piperidinyl]ethyl]-3-methyl]-2-oxazolidinone ethanedioate, hydrochloride salt) displays potent and long-acting antihistaminic activity in guinea pigs and in dog and guinea pig models of immediate hypersensitivity. Given orally 1, 5 or 24 hr before an i.v. histamine challenge, AHR-14310C produced ED50 values of 0.76, 0.22 and 0.58 mg/kg, respectively, in protecting naive guinea pigs from the lethal effects of the histamine challenge. AHR-14310C was also effective when the histamine was administered as an aerosol (1-, 5- and 24-hr ED50 values = 0.69, 0.38 and 1.08 mg/kg, respectively). AHR-14310C also attenuated the anaphylactic responses to aerosolized antigen in sensitive guinea pigs and the skin response to antigen in naturally sensitive dogs. AHR-14310C, at doses in vastly excess of those required to block histamine-induced hypotension, did not alter the electroencephalogram of cats, as did the sedating antihistamine, diphenhydramine. AHR-14310C did not affect the autonomic responses to acetylcholine, isoproterenol, epinephrine or 1,1-dimethyl-4-phenylpiperazinium chloride in dogs. At low doses (0.316-1.0 mg/kg p.o.), AHR-14310C blocked antigen-induced tracheal mucous changes in sensitive rats. AHR-14310C has therapeutic potential in allergic individuals, particularly in asthmatics, where bronchorrhea or mucus plugging is a problem.

A dual electrophysiologic test for atrial antireentry and ventricular antifibrillatory studies. Effects of bethanidine, procainamide, and WY-48986.

We have developed a dual electrophysiologic test that allows measurement of both antireentry and antifibrillatory activities of potential antiarrhythmics in the same anesthetized dog. The reentry portion of the model was created surgically by a Y-shaped crushing around the tissue between the superior and inferior vena cava and tissue parallel to the AV groove. The pacing-induced tachycardia that results from circus movements around the tricuspid ring is very persistent in duration and regular in cycle length. The antifibrillatory activities were assessed by determination of the ventricular fibrillation threshold (VFT) using train-stimuli method. Control VFT was measured every 15-20 min in duplicate and followed by induction of atrial reentry. A drug was infused to intervene the atrial tachycardia. After the conversion of the arrhythmia (either by drug regimens or pacing), postdrug VFT was measured, again in duplicate. Bethanidine (20 mg/kg), procainamide (30 mg/kg), and WY-48986 (10 mg/kg), a Class III antiarrhythmic, were evaluated in this dual test. Bethanidine and procainamide prolonged the cycle length of atrial reentry to a greater extent than WY-48986. The atrial arrhythmias were consistently terminated by procainamide and WY-48986 whereas bethanidine converted the tachycardias in one of the five dogs studied. All three agents elevated VFT with bethanidine producing higher values than procainamide and WY-48986. In conclusion, the dual electrophysiologic testing system offers both economic and scientific advantages for the study of modes of action of antiarrhythmic agents.

Effects of AHR-12234 on cardiac transmembrane action potentials, in situ cardiac electrophysiology and experimental models for arrhythmias.

We studied the effects of AHR-12234, a new antiarrhythmic agent, on cardiac transmembrane action potentials, in situ cardiac electrophysiology and in several models for arrhythmias in the dog. AHR-12234 (5 x 10(-5)-2 x 10(-4) M) induced a dose-related and use-dependent decrease in dV/dtmax in canine Purkinje fibers and ventricular muscles. Action potential duration was shortened in Purkinje fibers but lengthened in ventricular muscle. In the anesthetized dog, AHR-12234 at a lower dose (2.64 mg/kg) increased AH intervals and effective refractory period of atrium, and AV node. At higher cumulative doses of 7.92 and 13.2 mg/kg, AHR-12234 increased the effective refractory period and conduction time in the atrium, AV node and ventricle. It also increased Purkinje system conduction time and sinus nodal recovery time. In the conscious dog model for reentrant atrial tachycardia, i.v. (effective doses: 12.3 +/- 4.2 mg/kg), or oral (20 to 60 mg/kg) administration of AHR-12234 prolonged the cycle length of the tachycardia and terminated the arrhythmia. The duration of action of oral AHR-12234 against this arrhythmia persisted for 24 hr. In the 1-day infarcted conscious dogs, AHR-12234 administered either i.v. (effective doses: 3.8 +/- 0.9 mg/kg) or orally (20 mg/kg), effectively converted the ventricular arrhythmia into sinus rhythm. AHR-12234 did not produce any adverse side effects in the above two conscious dog models. AHR-12234 was also effective in ablating ouabain-induced ventricular tachycardias in anesthetized dogs following an i.v. dose of 5 mg/kg. These results indicate that the structurally novel AHR-12234 is effective against arrhythmias due to abnormal automaticity, triggered activity and reentry.

Rocastine (AHR-11325), a rapid acting, nonsedating antihistamine.

Rocastine [AHR-11325, 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4- oxazepine-5(4H)-thione (E)-2-butenedioate)] is a rapid-acting, potent, nonsedating antihistamine. In guinea pigs challenged with a lethal dose of histamine, rocastine is as effective [based on 1 hr. oral, protective dose (PD50S)] as brompheniramine, chlorpheniramine, pyrilamine, and promethazine and superior to astemizole, diphenhydramine, terfenadine, and oxatomide. Rocastine has a faster onset of action than does terfenadine; rocastine being as effective with a 15 min pretreatment time (PD50 = 0.13 mg/kg) as it is with a 1 hr pretreatment time (PD50 = 0.12 mg/kg), while the 15 min PD50 of terfenadine (PD50 = 44.0 mg/kg) is 22 times greater than the 1 hr PD50 (PD50 = 1.93 mg/kg). Against aerosolized histamine, rocastine was 7.12 x, 2.63 x, and equipotent to pyrilamine in preventing histamine-induced prostration at pretreatment times of 1,3, and 6 hr, respectively. Rocastine protected guinea pigs from collapse induced by aerosolized antigen; rocastine was approximately 36 x more potent (based on 1 hr PD50) than diphenhydramine and as potent as oxatomide and terfenadine. Rocastine did not alter the EEG of cats at doses in vast excess (150x) of its antihistaminic dose nor did it potentiate yohimbine toxicity in mice. Further, rocastine possesses no anticholinergic, antiadrenergic, or antiserotonergic properties in vitro. Rocastine is a selective, nonsedating, H1-antagonist with a rapid onset of action.

Effect of bopindolol on renin secretion and renal excretory function in rats.

We investigated the effects of the new beta-adrenoceptor antagonist, bopindolol, on stimulated renin secretion and on renal function in conscious rats. Intravenous doses of 10, 31.6, and 100 micrograms/kg of bopindolol antagonized the rise in plasma renin activity (PRA) induced by the administration of isoproterenol (10 micrograms/kg, s.c.). Peak PRA, evident at 15 min after isoproterenol, reached 27 +/- 3 ng/ml/h with bopindolol (100 micrograms/kg) pretreatment vs. 105 +/- 7 ng/ml/h in saline controls. Antagonism by bopindolol (100 micrograms/kg, i.v.) of isoproterenol-stimulated rise in PRA persisted through 12 h. Within this dosage range, bopindolol itself had no significant effect on PRA. Significant antagonism of beta-adrenoceptor-induced hypotension resulted with 31.6 and 100 micrograms/kg of i.v. bopindolol. Orally administered bopindolol produced significant antagonism of isoproterenol-induced increase in PRA at a dose of 316 micrograms/kg; however, oral doses of 31.6-316 micrograms/kg of bopindolol failed to significantly alter furosemide-stimulated increase in PRA. Bopindolol alone had little effect on renal excretory function but caused a slight attenuation of furosemide-induced diuresis and electrolyte excretion. Plasma electrolytes and osmolarity were unaffected by bopindolol alone or in conjunction with furosemide. These results indicate that bopindolol (a) is a potent, long-acting, orally active, antagonist of beta-adrenoceptor-stimulated renin secretion in the rat, (b) is ineffective in antagonizing furosemide-induced rise in PRA, (c) does not elevate basal levels of PRA by virtue of its intrinsic sympathomimetic activity, and (d) does not cause dramatic alteration of renal excretory function at effective beta-blocking doses.

Cardiovascular and renal actions of calcium channel blocker chemical subgroups: a search for renal specificity.

The diuretic and natriuretic responses to structurally distinct classes of Ca2+ channel blockers have been compared, to determine whether any agent provoked K+-sparing natriuresis, and to assess the relation of such responses with drug effects on blood pressure. Conscious normotensive Sprague-Dawley rats received vehicle or one of the following drugs in an oral saline load (40 mL kg-1) nifedipine, nimodipine, nitrendipine, prenylamine, cinnarizine, flunarizine, diltiazem, verapamil, hydrochlorothiazide, amiloride, or hydralazine, at doses from 0.316 to 100 mg kg-1. Urine was collected for 6h. Blood pressure was monitored directly in parallel studies. Diltiazem (31.6, 100 mg kg-1) and flunarizine (100 mg.kg-1) enhanced urine and electrolyte excretion in spite of marked hypotension; diltiazem was the only drug to produce dose-related renal responses. In contrast, equihypotensive doses of hydralazine and nifedipine produced overt urine and electrolyte retention. Nitrendipine and prenylamine (0.316 mg kg-1 each) produced slight diuresis or natriuresis without altering blood pressure; higher doses had no effect. The 31.6 mg kg-1 doses of verapamil, nitrendipine, and nimodipine markedly reduced blood pressure, but neither enhanced nor limited urine and electrolyte excretion. Cinnarizine failed to produce any cardiovascular or renal effects. Diuretic responses evoked by the Ca2+ channel blockers were not class-specific, showed no tendency towards sparing K+, were generally weaker than those produced by low doses of amiloride or hydrochlorothiazide, and were dissociable from drug-induced changes in blood pressure.

Involvement of dopamine receptor subtypes in dopaminergic modulation of aldosterone secretion in rats.

The postulation that dopamine (DA) may tonically inhibit aldosterone (ALDO) secretion has arisen from the finding that metoclopramide, a non-selective DA receptor antagonist with prominent non-dopaminergic actions, stimulates ALDO secretion. Experiments were performed to determine: (a.) the ability of several non-specific and subtype-specific DA receptor antagonists to stimulate ALDO secretion, (b.) the subtype DA receptor involved in regulating ALDO secretion, and (c.) if ALDO responses were associated with changes in plasma Na+(pNa), K+(pK), or osmolality (pOsm). Blood samples were withdrawn from carotid arterial catheters in conscious, fasted male Sprague-Dawley rats before and following intra-arterial administration of lactated Ringer's placebo, furosemide (10 mg/kg), or one of several DA receptor antagonists. Furosemide stimulated ALDO, decreased pK, and left pNa and pOsm unchanged. The non-selective DA receptor antagonists metoclopramide (0.2, 0.6 mg/kg), rs-sulpiride (0.2 mg/kg), and haloperidol (0.1 mg/kg), and the DA-2 receptor antagonists domperidone (0.1 mg/kg) and s-sulpiride (0.1 mg/kg) each stimulated ALDO, and left pNa, pK, and pOsm unchanged. Conversely, the DA-1 receptor antagonists SCH 23390 (0.03, 0.1 mg/kg) and r-sulpiride (0.1 mg/kg) failed to stimulate ALDO, and left pNa, pK, and pOsm unaltered. These studies suggest that ALDO secretion in rats is modulated by a mechanism involving DA-2, but not DA-1 subtype receptors, and that the ALDO responses to DA receptor antagonism are independent of changes in pNa, pK, and pOsm.

Antagonism of cisplatin-induced emesis by metoclopramide and dazopride through enhancement of gastric motility.

The antiemetic activity, gastric motor activity, and dopamine receptor effects of metoclopramide, dazopride, and sulpiride were assessed to establish if enhancement of gastric motility or antagonism of central dopamine receptors is the predominant action for drug-induced suppression of cisplatin-induced emesis. Emesis produced in dogs by cisplatin is antagonized by metoclopramide and dazopride. The antiemetic actions of metoclopramide and dazopride are associated with their ability to enhance gastric motor activity. Dazopride, unlike metoclopramide, has minimal dopamine receptor antagonist properties. Sulpiride is a potent dopamine receptor antagonist; however, it had no effect on the stomach and was ineffective in suppressing cisplatin-induced emesis.