Specific bradycardic agents. 1. Chemistry, pharmacology, and structure-activity relationships of substituted benzazepinones, a-new class of compounds exerting antiischemic properties.

Structural modification of the calcium-antagonist verapamil (1) by replacement of the lipophilic alpha-isopropylacetonitrile moiety by various heterocyclic ring systems has led to a new class of cardiovascular compounds which are characterized by a specific bradycardic activity. These agents reduce heart rate without binding to classical calcium channels or beta-adrenoceptors, interacting instead specifically with structures at the sino atrial node. Therefore they have also been termed sinus node inhibitors.

Effects of alinidine on survival and infarct size in rats with coronary artery occlusion.

Ligation of the left anterior descending coronary artery was performed in open-chest anaesthetized rats. One group had coronary occlusion for 3 h while ligation lasted for 30 min in a second group and was followed by a 150-min reperfusion period. The area at risk and area of infarction were determined immediately after premature death or 3 h after the ligature was set, by means of Evans blue and triphenyltetrazoliumchloride staining and subsequent photometric quantification.

The dopamine autoreceptor agonist, B-HT 920, preferentially reduces brain dopamine release in vivo: biochemical indices of brain dopamine, noradrenaline and serotonin in ventriculocisternal perfusates in the cat.

B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine), a candidate for selective dopamine (DA) autoreceptor agonist activity, was tested for its interactions with biochemical parameters of brain dopaminergic, noradrenergic and serotoninergic systems as measured in ventriculocisternal perfusates of chloralose-anaesthetized cats. DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA) and 5-hydroxyindolic acid (5-HIAA) were measured in samples of 30 min collection periods by high-pressure liquid chromatography with electrochemical detection. B-HT 920, in the dose range of 0.

Specific bradycardic agents--a novel pharmacological class?

Data have been reviewed and presented which suggest that substances from two different chemical groups, congeners of alinidine and falipamil, respectively, can be described as representatives of a novel and distinct pharmacological class: specific bradycardic agents (SBAs). They are characterized by a slowing of the sinus rate within physiological limits as the prominent cardiovascular effect. Involvement of alpha-adrenoceptors, beta-adrenoceptors and cholinergic receptors as mediators of the bradycardic effects have been excluded.

The dopamine autoreceptor agonist B-HT 920 inhibits in vivo dopamine release into the cerebroventricular system of cats.

In anesthetized cats the dopamine autoreceptor agonist B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine), 1 mg/kg i.v., greatly decreased the amount of dopamine in cerebroventricular perfusates.

Investigations differentiating the mechanism of specific bradycardic agents from that of calcium channel blockers.

The effects of two "specific bradycardic agents", falipamil (AQ-A 39) and the alinidine-congener STH 2148 (2-[N-(cyclopropylmethyl)-N-(2,6-dibromophenyl)amino]-2-imidazolin e), on the spontaneous electrical discharge rate of intact guinea-pig sinus node preparations were investigated in comparison to that of the "calcium channel blocker" verapamil. Addition of falipamil (10 micrograms/ml) to a maximally rate lowering concentration of STH 2148 (30 micrograms/ml) exerted no further bradycardic effect. In contrast, verapamil (0.

The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment.

B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at alpha 2-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2-20 mg/kg s.

Investigations into the bradycardic effects of UL-FS 49 (1,3,4,5-tetrahydro-7,8-dimethoxy-3-[3-[[2-(3,4-dimethoxyphenyl)ethyl] methylimino]propyl]-2H-3-benzazepin-2-on-hydrochloride) in isolated guinea pig atria.

The new bradycardic agent UL-FS 49 (1,3,4,5-tetrahydro-7,8-dimethoxy-3-[3-[[2-(3,4-dimethoxyphenyl]ethyl] methylimino]propyl]-2H-3-benzazepin-2-on-hydrochloride) was investigated in isolated guinea pig atria. In spontaneously beating preparations UL-FS 49, (0.03 and 0.

Antifibrillatory properties of alinidine after coronary artery occlusion in rats.

Ligation of the left anterior descending coronary artery was performed in open-chest anaesthetized rats and mortality as well as changes in ECG were evaluated for 30 min thereafter. Saline or drugs were administered 15 min prior to ligation. In the control group, following a 4 min lag period ventricular arrhythmias as single ectopic beats, ventricular tachycardia and ventricular fibrillation (VF) appeared, reaching a maximum between 10 and 20 min and disappearing after 30 min.

Possible function of alpha 1-adrenoceptors in the CNS in anaesthetized and conscious animals.

The influence of St 587 (2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine), a selective alpha 1-adrenoceptor agonist which easily penetrates the blood-brain barrier, was tested on behavior and cardiovascular functions, respectively. The substance (up to 10 mg/kg subcutaneously (s.c.

Investigations into the bradycardic action of indoramin.

Indoramin is a selective alpha 1-antagonist which reduces blood pressure without reflex tachycardia and can cause a bradycardia. The direct bradycardic effect of indoramin was investigated in various isolated cardiac preparations as well as in the intact cat. In isolated guinea-pig atria indoramin reduced spontaneous atrial rate in concentrations similar to those that reduced maximal driving frequency but smaller than those reducing contractility (EC30 = 0.

Alpha 2-adrenoceptor blocking properties of the alpha 1-selective agonist 2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine (St 587).

The selective alpha 1-adrenoceptor agonist 2-(2-chloro-5-trifluoromethylphenylimino)imidazolidine (St 587) was tested with respect to putative alpha 2-adrenoceptor blocking properties. In these studies 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine (B-HT 920) was used as a selective alpha 2-adrenoceptor agonist. At peripheral presynaptic sites St 587 (1 mg/kg i.

Decrease in bradycardic effect of AQ-A 39 and alinidine in guinea-pig sinoatrial node depolarized by high external K+-concentration.

The effects of the two "specific bradycardic agents" AQ-A 39 and alinidine on the spontaneous electrical discharge rate of intact guinea-pig sinus node preparations were investigated. At high external K+-concentrations (10.8 and 16.

B-HT 958--an antagonist at alpha 2-adrenoceptors and an agonist at dopamine autoreceptors in the brain.

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]az epine), a compound chemically related to clonidine-like drugs of the azepine type, was described previously as a mixed agonist-antagonist at peripheral alpha 2-adrenoceptor sites. In the present experiments the actions of B-HT 958 on brain noradrenergic and dopaminergic mechanisms were examined using behavioural, pharmacological and biochemical methods. (i) In the dog, intracisternally injected B-HT 958 (300 micrograms/kg) abolished the reflex bradycardia facilitated by the alpha 2-agonist B-HT 920 (10 micrograms/kg i.

Cardiovascular characterization of UL-FS 49, 1,3,4,5-tetrahydro-7,8-dimethoxy-3-[3-][2-(3,4-dimethoxyphenyl)ethyl] methylimino]propyl]-2H-3-benzazepin-2-on hydrochloride, a new "specific bradycardic agent".

UL-FS 49, a chemical congener of AQ-A 39 with structural similarities to verapamil, decreased the rate of spontaneously beating guinea-pig atria at much lower concentrations (effective concentration 30%, EC30 = 0.030 microgram/ml) than it decreased the contractility (2.5 Hz; EC30 = 108 micrograms/ml) and maximal driving frequency (EC30 = 11 micrograms/ml) in electrically driven atria.

Effects of peripheral alpha 1- and alpha 2-adrenoceptor agonists on baroreceptor responsiveness in conscious dogs.

Baroreceptor responsiveness was investigated in conscious dogs following increasing doses (i.v.) of the selective alpha-adrenoceptor agonists methoxamine (alpha 1) and oxymetazoline (alpha 2), in the presence and absence of beta-adrenoceptor blockade.

Facilitation of the Bezold-Jarisch reflex by central stimulation of alpha 2 adrenoceptors in dogs.

The Bezold-Jarisch reflex characterized by hypotension and bradycardia was elicited in anaesthetized artificially respired dogs (pretreated with a beta-adrenoceptor antagonist ) using capsaicin 10 micrograms/kg (i.v.).

Cardiovascular effects of B-HT 958, an alpha-adrenoceptor agonist with a high pre/postsynaptic activity ratio.

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]az epine), chemically related to clonidine-like drugs of the azepine type, was described previously as a partial alpha 2-adrenoceptor agonist which acted presynaptically mainly as agonist and postsynaptically as antagonist. Following i.v.

New concepts on alpha-adrenoceptors in pharmacology.

Alpha-adrenoceptors have been classified on a morphological basis as pre- and postsynaptic and on a pharmacological basis as alpha 1- and alpha 2-subtypes. Alpha 1 as well as alpha 2-receptors might be present at pre- as well as postsynaptic sites (fig. 1).

Actions of alinidine and AQ-A 39 on rate and contractility of guinea pig atria during beta-adrenoceptor stimulation.

We studied two new agents, alinidine (St 567, 2-[N-allyl-N-(2,6-dichlorophenyl)-amino]-2-imidazoline) and AQ-A 39 (5,6-dimethoxy-2-[3[[alpha-(3,4-dimethoxy)-phenylethyl] methylamino]propyl]phthalimidine), in isolated guinea pig atria with respect to their specificity to decrease heart rate but not contractility during beta-adrenoceptor stimulation. Spontaneous electrical activity in sinoatrial node preparations was increased by perfusion with isoprenaline (0.1 micrograms/ml); addition of alinidine (3 micrograms/ml), AQ-A 39 (3 micrograms/ml), or propranolol (0.

alpha 1/alpha 2 Selectivity ratio in a series of agonists and their relation to pre/postsynaptic activity ratios.

beta-Blocked pithed rats were used to obtained dose-response curves (blood-pressure increase) for 13 various alpha-adrenoceptor agonists of clinical and theoretical interest, in the absence and in the presence of the selective antagonists rauwolscine (alpha 2) and prazosin (alpha 1). Antagonist doses which shifted the dose-response curves for an agonist 10-fold to the right along the abscissa were then calculated (D10rauwolscine = D10R; D10prazosin = D10P). The ratio D10R/D10P is considered to be a quantitative estimation of an agonist's alpha 1/alpha 2 selectivity ratio.