Christian Lillie

N-Allyl-derivative of clonidine, a substance with specific bradycardic action at a cardiac site.

SummaryThe most prominant action of a new substance 2-[N-allyl-N-(2,6-dichlorophenyl)-amino]-2-imidazoline, St 567 is bradycardia. As shown by ECG recordings in anaesthetized rats and cats, the bradycardia (doses ≤0.5 mg/kg) is of the sinus type, changes in PQ- and QT-intervals were neglegible, there were no changes in the QRS-complex. The bradycardic action could be localized in the heart, as was observed in spinal rats and isolated guinea-pig atria, and is of high specificity — in the isolated atria the heart rate was decreased by much smaller concentrations (EC30=2.9 μg/ml) than contractility (EC30=155 μg/ml) and maximal driving frequency (EC30=40 μg/ml). Ratios between these 3 values were calculated and revealed a profile different from those of antiarrhythmics, so called “calcium antagonists”, and cholinergic drugs. In isolated guinea-pig atria the bradycardic effect of St 567 was not affected by phentolamine (1μg/ml) or atropine (0.05 μg/ml); the tachycardic action of isoprenaline (10−4–10−1 μg/ml) was not affected by St567 (3 μg/ml) in a way that indicates competitive antagonism. Thereby an involvement of α-adrenoceptors, muscarinic receptors of β-adrenoceptors was excluded. With 30 mg/kg St 567 no gross changes in behaviour of rats were observed, allowing a differentation from other bradycardic drugs such as harmala alkaloids and veratramine. The hitherto unknown pharmacologic pattern of St567 is discussed, its possible therapeutic use in coronary heart disease is considered.

Cardiovascular actions of N-allyl-clonidine (ST 567), a substance with specific bradycardic action☆

Abstract In anaesthetized cats and dogs the prominent action of St 567 (1 and 2.5 mg/kg i.v.) was a decrease in heart rate. This was paralleled by a decrease in cardiac output; the decrease in blood pressure was much smaller or insignificant. The increase in heart period was mainly due to a prolongation of the diastolic period, the increase in ejection time was much smaller and of shorter duration. In cats the “triple product” of heart rate × ejection time × blood pressure was decreased by St 567. Cumulative injection of the drug also decreased the contractility of the heart (dp/dt max); this effect was partly due to the decrease in spotaneous heart rate as shown by comparison with results in electrically paced hearts. No obvious changes of the ECG, limb leads, were recorded except a small increase in PQ and QT which accompanied the much greater increase in PP′ . In cats with acute occlusion of a coronary artery branch, St 567 diminished the elevation of the ST-segment of the epicardial electrogram, parallel with the bradycardic effect. St 567 decreased the heart rate of conscious dogs. The bradycardia achieved thereby was directly correlated with the heart rate before injection of St 567, independent of whether this “control value” was achieved from a spontaneous sinus rate or increased by pretreatment with atropine or hydralazine. The cardiovascular profile of St 567 indicates a decrease in myocardial oxygen demand, a desirable therapeutic measure in the treatment of ischemic heart disease.

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

SummaryThe 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-imidazoline, 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 μg/ml) to a maximally rate lowering concentration of STH 2148 (30 μg/ml) exerted no further bradycardic effect. In contrast, verapamil (0.1 μg/ml) added to either STH 2148 (30 gg/ml) or a maximally effective concentration of falipamil (30 gg/ml) resulted in a further, significant reduction of sinus rate. The results are compatible with the idea of a common mechanism of the two specific bradycardic agents, different from that of calcium channel blockers.

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

SummaryThe 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 16.2 mmol/l) the bradycardic effect of the two drugs was diminished or abolished. In contrast, the negative chronotropic effect of the reference compound verapamil (“Ca2+-antagonist”) was enhanced. These results show that the bradycardic effects of AQ-A 39 and alinidine are diminished in depolarized preparations, which makes it unlikely that in intact sinus node preparations the mechanism of action is the same as that of “Ca2+-antagonists”.

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. Saline or alinidine (5 mg/kg i.v.) was administered 15 min prior to ligation. The alinidine groups received a further 0.5 mg/kg i.v. 1 and 2 h after ligation. A large number of animals in the control groups died during the first 30 min. The animals that survived 3 h had a smaller area at risk than those dying prematurely and about 100% of the area at risk became infarcted. All animals in the two alinidine groups survived the first 30 min. All these animals survived with a larger area at risk than the control groups. The area of infarction in relation to the area at risk was significantly smaller than in the control groups. The cardioprotective effects of alinidine may be explained by a reduction in heart rate and a slight reduction in blood pressure.

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[[α-(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 β-adrenoceptor stimulation. Spontaneous electrical activity in sinoatrial node preparations was increased by perfusion with isoprenaline (0.1 μg/ml); addition of alinidine (3 μg/ ml), AQ-A 39 (3 μg/ml), or propranolol (0.03–0.3 μg/ml) reduced sinus rate to the control values. The same concentrations of these drugs were tested in electrically driven (1 Hz) left atria. The positive inotropic effect of isoprenaline was not affected by alinidine and AQ-A 39; however, it was markedly reduced or abolished by propranolol. The experiments, therefore, demonstrated the bradycardic specificity of alinidine and AQ-A 39 under conditions of β-adrenoceptor stimulation. A cumulative concentration-response curve for the positive chrono-tropic effect of isoprenaline was established in spontaneously beating atria. AQ-A 39, 1 and 10 μg/ml, reduced the control sinus rate but did not affect the following concentration-response curve of isoprenaline. A similar result was published earlier for alinidine and excludes an interaction of both drugs with isoprenaline on a possible subgroup of selective β-adrenoceptors in the sinoatrial node.

Effects of peripheral α1- and α2-adrenoceptor agonists on baroreceptor responsiveness in conscious dogs

Baroreceptor responsiveness was investigated in conscious dogs following increasing doses (i.v.) of the selective α-adrenoceptor agonists methoxamine (α1) and oxymetazoline (α2), in the presence and absence of β-adrenoceptor blockade. The study was repeated in another group of dogs with background afferent baroreceptor nerve activity reduced by continuous infusion of sodium nitroprusside. Both agonists dose dependently increased mean arterial pressure and reflexly decreased heart rate. In dogs pretreated with a β-adrenoceptor antagonist a correlation between increase in mean arterial pressure (increase up to 70 mmHg) and increase in heart period (baroreceptor responsiveness) indicated no difference in the regression lines between methoxamine and oxymetazoline for both the normotensive and the sodium nitroprusside groups. However, in the dogs not pretreated with a β-adrenoceptor antagonist the slope of the regression line for oxymetazoline was steeper than that for methoxamine (P < 0.01) in the normotensive group. In the sodium nitroprusside group the regression line for oxymetazoline was situated significantly to the left of the methoxamine line (P < 0.05). It is suggested that this greater bradycardic response to the α2-adrenoceptor agonist oxymetazoline was caused by suppression of the cardiac sympathetic component (presynaptic modulation of noradrenaline release) in addition to the vagal activation and the sympathetic withdrawal component of the reflex. This indicates that drugs with α2-adrenoceptor agonistic activity influence a reflex physiological situation under conditions of low sympathetic nerve activity.