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

Kobinger, W.; Lillie, Christian; Pichler, Ludwig

doi:10.1007/bf00507111

Cited by 74 publications

(29 citation statements)

References 10 publications

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“…6,40 The present data are in line with previous reports that indicated that certain derivatives of clonidine, including N-allyl-clonidine (alinidine), act as specific bradycardic agents. 41 In conclusion, clonidine can directly inhibit cardiac HCN pacemaker channels and elicit a strong bradycardic effect. This finding may be of great relevance for other neuronal effects of clonidine and other ligands with imidazoline structure, because HCN channels are ubiquitously expressed in the nervous system.…”

Section: Discussionmentioning

confidence: 89%

Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine

et al. 2007

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Background-Inhibition of cardiac sympathetic tone represents an important strategy for treatment of cardiovascular disease, including arrhythmia, coronary heart disease, and chronic heart failure. Activation of presynaptic ␣ 2 -adrenoceptors is the most widely accepted mechanism of action of the antisympathetic drug clonidine; however, other target proteins have been postulated to contribute to the in vivo actions of clonidine. Methods and Results-To test whether clonidine elicits pharmacological effects independent of ␣ 2 -adrenoceptors, we have generated mice with a targeted deletion of all 3 ␣ 2 -adrenoceptor subtypes (␣ 2ABC Ϫ/Ϫ ). ␣ 2ABC Ϫ/Ϫ mice were completely unresponsive to the analgesic and hypnotic effects of clonidine; however, clonidine significantly lowered heart rate in ␣ 2ABC Ϫ/Ϫ mice by up to 150 bpm. Clonidine-induced bradycardia in conscious ␣ 2ABC Ϫ/Ϫ mice was 32.3% (10 g/kg) and 26.6% (100 g/kg) of the effect in wild-type mice. A similar bradycardic effect of clonidine was observed in isolated spontaneously beating right atria from ␣ 2ABC -knockout and wild-type mice. Clonidine inhibited the native pacemaker current (I f ) in isolated sinoatrial node pacemaker cells and the I f -generating hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 and HCN4 channels in transfected HEK293 cells. As a consequence of blocking I f , clonidine reduced the slope of the diastolic depolarization and the frequency of pacemaker potentials in sinoatrial node cells from wild-type and ␣ 2ABC -knockout mice. Conclusions-Direct inhibition of cardiac HCN pacemaker channels contributes to the bradycardic effects of clonidine gene-targeted mice in vivo, and thus, clonidine-like drugs represent novel structures for future HCN channel inhibitors.

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Section: Discussionmentioning

confidence: 89%

Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine

et al. 2007

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“…Alinidine may act directly on the sinus node to restrict the flow of current through anion selective channels, thus slowing diastolic depolarisation and causing bradycardia (Millar & Vaughan-Williams, 1981). Alinidine does not inhibit an isoprenaline tachycardia in animals (Kobinger et al, 1979a) or man (Harron et al, 1981), but reduces an exercise tachycardia in man in a dosedependent manner. The effect of alinidine 80 mg on an exercise tachycardia is equivalent to propranolol 40 mg (Harron etal., 1981).…”

Section: Introductionmentioning

confidence: 82%

Cardiovascular effects of alinidine and propranolol alone and in combination with hydralazine in normal man.

Nicholls¹,

Harron²,

Shanks³

1983

Brit J Clinical Pharma

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1 The effect of single oral doses of alinidine 80 mg, propranolol 40 mg, hydralazine 50 mg, alinidine 80 mg combined with hydralazine 50 mg, propranolol 40 mg combined with hydralazine 50 mg, and placebo on arterial pressure and heart rate was studied in five normal volunteers in the supine and standing positions and during exercise. Observations were made before and at 1, 2, 3, 4 and 6 h after drug administration. 2 Alinidine 80 mg and propranolol 40 mg significantly reduced heart rate in the supine position, and on exercise. The reductions in supine heart rate produced by alinidine and propranolol were not significantly different, but the maximum effect of alinidine on exercise heart rate was observed later than that of propranolol. Propranolol reduced heart rate in the standing position at all time intervals after drug administration, but alinidine reduced standing heart rate only at 6 h (P < 0.01 when compared to placebo). 3 Hydralazine 50 mg increased supine heart rate by 8-10 beats min-' when compared to the pre-treatment value. These increases were significant (P < 0.05) when compared to the pre-treatment value, but not when compared to placebo. Hydralazine increased standing heart rate from 71.4 + 6.5 to 90.0 + 7.0 beats min-' (P < 0.05 when compared to placebo), but had no effect on exercise heart rate. The small increase in supine heart rate following hydralazine therapy was reduced by alinidine and propranolol, but only propranolol reduced the significant increase in standing heart rate produced by hydralazine. 4 Hydralazine reduced diastolic arterial pressure in the supine position at 2 and 4 h after drug administration (P < 0.05 when compared to placebo), but had no effect on systolic or diastolic arterial pressure in the standing position or on exercise. 5 Propranolol produced small reductions in systolic arterial pressure in the standing position, which were not significant when compared to placebo; diastolic pressure was unchanged. Propranolol reduced systolic pressure during exercise at 2, 4 and 6 h after drug administration (P < 0.05 when compared to placebo); diastolic pressure was unchanged. The effects of hydralazine and propranolol combined on arterial pressure in the standing position were similar to those observed after propranolol alone, but combined therapy produced a greater reduction in exercise systolic pressure, although these differences were not significant. 6 Alinidine reduced systolic arterial pressure in the supine position at 3, 4 and 6 h after drug administration (P < 0.01) and diastolic pressure at 2 and 4 h (P < 0.05 when compared to placebo). Alinidine reduced systolic arterial pressure in the standing position at 3, 4 and 6 h after drug administration (P < 0.05) and diastolic pressure at 2 h (P < 0.01) and 6 h (P < 0.05 when compared to placebo). During exercise, alinidine produced a small reduction in systolic arterial pressure which was not significant, and a reduction in diastolic pressure at 1 h (P < 0.05 when compared to placebo). The effects of hydralazine and alini...

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“…Atropine (10-6 M) did not affect alinidine-induced vasodilation in this study. Alinidine is a derivative of clonidine (Kobinger et al 1979). Clonidine dilated the isolated and perfused dog coronary artery mediating via histamine 112-receptors (Nakane and Chiba 1986b).…”

Section: Resultsmentioning

confidence: 99%

“…These results suggest that alinidine has a weak anti-muscarinic effect on the endothelium-dependent vasodilation of the dog coronary artery. --alinidine ; acetylcholine ; muscarinic receptor ; dog coronary artery ; endothelium Alinidine has a bradycardic effect on the sinus node automaticity (Kobinger et al 1979). Alinidine acts as an anti-muscarinic agent in the isolated and blood-perfused dog right atrium (Ogiwara et al 1987).…”

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confidence: 99%

Anti-Muscarinic Effect of Alinidine on Acetylcholine-Induced Vasodilation in Isolated and Perfused Dog Coronary Arteries.

Nakane

Furukawa

Chiba

1991

Tohoku J. Exp. Med.

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The effect of alinidine, a bradycardic agent, on the vasodilator responses to acetylcholine was examined in isolated and perfused dog coronary arteries. Single injections of acetylcholine (10-12-10-6 mol) and carbachol (10-10-10-6 mol) produced dosedependent vasodilations. The endothelial removal by a bolus injection of saponin (1 mg) inhibited those vasodilations. Alinidine (10-6 M) shifted the dose-response curves of acetylcholine and carbachol to the right, but it did not affect those for isosorbide dinitrate, isoproterenol and adenosine. The rank order of potency of muscarinic antagonists for inhibiting the a~,etylcholine-induced vasodilation was 4-DAMP > atropine > AF-DX 116 > pirenzepine > alinidine. Alinidine was approximately 100 times less potent than atropine. Single injection of alinidine (10-8-10-6 mol) dilated the dog coronary artery in a dose-related manner. The vasodilation was not affected by the pretreatment with phentolamine (10-6 M), pindolol (10-6 M), atropine (10-6 M), chlorpheniramine (10-6 M), cimetidine (10-6 M) or methysergide (10-6 M). These results suggest that alinidine has a weak anti-muscarinic effect on the endothelium-dependent vasodilation of the dog coronary artery. --alinidine ; acetylcholine ; muscarinic receptor ; dog coronary artery ; endothelium Alinidine has a bradycardic effect on the sinus node automaticity (Kobinger et al. 1979). Alinidine acts as an anti-muscarinic agent in the isolated and blood-perfused dog right atrium (Ogiwara et al. 1987). Brunner and Kukovetz (1988) indicated that alinidine behaves as a very weak agonist in the binding studies of guinea-pig atrial and ventricular muscarinic receptors. There have been only a few studies which are confirmed whether , alinidine has anti-muscarinic effects on other tissues or not. Furchgott and Zawadzki (1980) indicated that acetylcholine (ACh) releases the relaxing factor(s) from the vascular endothelium by stimulating muscarinic

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

Cited by 74 publications

References 10 publications

Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine

Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine

Cardiovascular effects of alinidine and propranolol alone and in combination with hydralazine in normal man.

Anti-Muscarinic Effect of Alinidine on Acetylcholine-Induced Vasodilation in Isolated and Perfused Dog Coronary Arteries.

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