Cardiotoxicity of Vasodilators and Positive Inotropic/Vasodilating Drugs in Dogs: An Overview

Abstract

Standard toxicological studies in dogs using high doses of vasodilators and positive inotropic/vasodilating agents give rise to a species-specific cardiotoxicity. The reason may be the extreme sensitivity of the dog to the pharmacological effects of these drugs; exaggerated pharmacodynamic effects and prolonged disturbance of homeostasis mechanisms often are responsible for the observed organ lesions. An assessment of the toxicological relevance and the risk for patients taking the drugs at therapeutic doses cannot be made without taking into account their pathomechanisms and the pathophysiological basis of the exceptional reaction patterns occurring in dogs. A large series of vasodilating and positive inotropic agents are presented, their pharmacological properties are described, and toxicological effects in dogs are compared. In view of the poor correlation between the distinct cardiac lesions induced in dogs and a lack of comparable toxicity in humans, it appears desirable to reassess the adequacy of the standard toxicological approaches for these substances.

PD‐156707: A Selective Endothelin‐A Receptor Antagonist

“…In beagle dogs, arterial lesions (principally in coronary vessels) were seen following administration of various xenobiotics, in particular, vasodilators (minoxidil, theobromine, hydralazine, adenosine agonists, and type In-phosphodiesterase inhibitors) and adrenergic mines (isoproterenol, norepinephrine, dopamine, and dobutamine) (9,10,22,27,34,35,50,5152). The picture is confounded by the observation that similar vascular lesions are reported to occur spontaneously in beagle dogs (9,20,47), although it is of note that the lesions occurring with PD 156707 were not seen in control animals.…”

Endothelin Antagonist-Induced Coronary and Systemic Arteritis in the Beagle Dog

“…Whereas drugs may induce vascular damage through a number of mechanisms, including direct cytotoxicity, thrombosis or thromboembolism and immune-mediated reactions, many cardioactive drugs seem able to produce coronary arteritis in the dog through exaggerated or sustained effects on vasomotor tone, usually through excessive vasodilatation but also by intense vasoconstriction (14). Canine coronary arteritis has been observed following the oral or intravenous administration of a number of different pharmacologically active drugs that include sympathomimetic amines, theobromine, minoxidil, calcium channel blockers, an adenosine agonist anti-hypertensive and inotropic phosphodiesterase inhibitors (5,9,10,13,18,19,22,23,25,27). Despite the diversity of these agents, many possess a common capacity at high doses to induce vasodilatation with associated severe hypotension and reflex tachycardia.…”

Coronary and Systemic Arterial Physiology and Immunohistochemical Markers Related to Early Coronary Arterial Lesions in Beagle Dogs Given the Potassium Channel Opener, ZD6169, or the Endothelin Receptor Antagonist, ZD1611

“…Administration of numerous vasoactive substances to beagle dogs has resulted in a relatively small number of cardiac and vascular pathological changes that often show a predictable pattern related to drug class (Albassam et al 2001;Greaves 1998;Herman et al 1989;Isaacs, Joseph, and Betton 1989;Jones et al 2003) and include cardioactive drugs such as endothelin receptor antagonists (ETRAs) or potassium channel openers (KCOs: Albassam et al 2001;Dogterom, Zbinden, and Reznik 1992;Isaacs, Joseph, and Betton 1989;Jones et al 2003;Louden & Morgan, 2001;Louden et al 1998;Metz et al 1991). Cardiac pathology consequent to KCO administration is diverse and often substantial with left ventricular and papillary muscle myocardial necrosis, left ventricular subendocardial hemorrhage, right atrial epicardial hemorrhage, and bilateral, intra-and extramural coronary arterial damage being frequently seen.…”