title: Changes in systemic haemodynamics, regional myocardial function and perfusion induced by alinidine in pigs with and without narrowed coronary arteries.
abstract: Intravenous administration of 0.2-6.0 mg kg-1 of alinidine, an N-allyl derivative of clonidine, exerted a pronounced bradycardic action and also decreased the maximum rate of rise in left ventricular pressure (max LVdP/dt), cardiac output, and mean arterial blood pressure in anaesthetized as well as in conscious pigs. When, in the anaesthetized animals, heart rate was kept constant by atrial pacing, no changes were observed with alinidine in maxLVdP/dt and cardiac output at doses up to 0.4 mg kg-1. At higher doses, however, there was a significant reduction in these variables, demonstrating a marked negative inotropic action of the drug at higher concentrations. In pigs with normal hearts alinidine homogeneously reduced myocardial perfusion, but no imbalance in the myocardial oxygen supply-demand relationship was noticed due to a simultaneous reduction of the metabolic needs of the myocardium. After constriction of the left anterior descending coronary artery to an extent that systolic myocardial wall thickening was reduced to 30% of its base-line value, transmural myocardial blood flow and the endocardial-epicardial (endo-epi) ratio in the affected myocardial segment had decreased from 1.42 +/- 0.15 to 0.68 +/- 0.11 ml min-1 g-1 and from 1.05 +/- 0.08 to 0.59 +/- 0.10, respectively. Though myocardial blood flow in the normal segments decreased, alinidine, in a dose (0.4-0.9 mg kg-1) that lowered heart rate by about 25%, caused a redistribution of blood flow to the ischaemic myocardium in favour of the endocardium as the endo-epi ratio increased to 1.08 +/- 0.12. Concomitantly, systolic wall thickening of the hypokinetic segment returned to 50% of its base-line value. Thus, alinidine ameliorated the imbalance between oxygen supply and demand in the post-stenotic myocardial segment, probably by prolongation of the diastolic perfusion time and a diminution in myocardial oxygen demand both through a reduction in heart rate. However, other factors, such as negative inotropy may also have partly contributed. Since treatment of pathological cardiovascular conditions with drugs with positive inotropic and vasodilatory properties is often accompanied by tachycardia, we also studied the effects alinidine in combination with the phosphodiesterase inhibitor sulmazole. Alinidine did not interfere with the positive inotropic and vasodilatory (systemic as well as coronary) properties of sulmazole, but prevented the tachycardia. These data suggest that combination of negative chronotropic drugs as alinidine with agents with a cardiovascular profile similar to sulmazole may be attractive, when unwanted tachycardia occurs.
authors.affiliation: Laboratory for Experimental Cardiology, Thoraxcenter, Rotterdam, The Netherlands.
authors.forename: P D
authors.initials: PD
authors.lastname: Verdouw
authors.forename: D J
authors.initials: DJ
authors.lastname: Duncker
authors.forename: T J
authors.initials: TJ
authors.lastname: Heere
authors.forename: P R
authors.initials: PR
authors.lastname: Saxena
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003250:Constriction; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D013552:Swine
chemical_list: D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; C022192:alinidine; C029758:sulmazole; D003000:Clonidine