Spontaneous and induced arterial disease in the dog: pathology and pathogenesis

The spontaneous arterial diseases of the dog relevant to safety assessment studies of drugs are the extramural coronary arteritis of Hartman, intramural coronary arteriosclerosis (with amyloid deposition) occurring in older dogs with cardiac disability, intramural arteriosclerosis without amyloid deposition in the left ventricle of dogs with congenital subaortic stenosis or in the right ventricle in dogs with severe pulmonic stenosis, and necrotizing polyarteritis (nodosa). Experimentally induced lesions include right atrial necrosis and arteritis produced by minoxidil and theobromine, extramural coronary arteritis produced by positive inotropic/vasodilator drugs, intramural coronary arteriosclerosis associated with decreased peripheral resistance and tachycardia induced by hypotensive drugs (including antihypertensive and positive inotropic/vasodilator agents), and intramural arteriosclerosis associated with rapid ventricular pacing. The pathogenesis of none of these lesions is known. The left ventricular subendocardial and papillary muscle intramural coronary arterial lesions are associated with hyperdynamic activity and, in the case of drugs and subaortic stenosis, the possibility of lowered perfusion pressure and tachycardia. This has led to the supposition that these are ischemic lesions, but the evidence available either does not support or refutes that conclusion since subendocardial coronary flow and perfusion pressure are adequate with pacing tachycardia and in toxicity trials. Necrotizing polyarteritis appears to be an immune mediated disease that may appear in genetically prone beagles when they are placed under the stresses of experimental manipulation and/or a new environment. Since the right atrial minoxidil lesion can also be produced by theobromine in dogs and minoxidil can cause a left atrial lesion in swine, it is neither species nor drug specific. Its cause, however, escapes us. There appears to be little in common between the extramural coronary artery Hartman lesion and that caused by positive inotropic/vasodilator drugs. Left ventricular subendocardial and papillary muscle intramural coronary arterial lesions induced by ventricular pacing at 250 beats/min for 2 months are generally similar to those seen in toxicity trials with peripheral vasodilator drugs that induce tachycardia in electrocardiograms exceeding 200 beats/min, although in acute pacing experiments subendocardial perfusion is adequate at these heart rates. Coronary artery autoregulation may be compromised or so destabilized by the drugs that episodes of underperfusion can account for these lesions.(ABSTRACT TRUNCATED AT 400 WORDS)