Pathologic changes in blood vessels following administration of an inotropic vasodilator (ICI 153,110) to the rat.
ICI 153,110 is an inotropic vasodilator compound intended for the treatment of congestive heart failure. It was administered to rats at dose levels of 5, 10, and 250 mg/kg/day for up to 6 months as part of its preclinical development program. Detailed clinical investigations were conducted during the course of the study and histopathological examination took place after 28 days and 182 days of treatment as well as 42 days following cessation of dosing. Changes were identified in blood vessels in the greater proportion of animals from the high dose group, although some of the changes were also observed at lower dose levels. Vascular tissues from a variety of sites were affected, particularly those of the mesentery, splanchnum, heart, testis, and the pampiniform plexus. Early changes characteristic of acute injury such as arterial medial necrosis and inflammation occurred, which were distinguishable from those following chronic administration of the compound where there was a pronounced arterial and venous wall thickening and accompanying plexiform vasculopathy. The essential components contributing to the thickening were a smooth muscle hypertrophy and hyperplasia of the media. At the end of the period following withdrawal of dosing, vascular thickening was still present and arteritis showed an increased incidence relative to that seen at termination of the main test. Systemic hypertension was not detected during these studies. Vasodilation occurring at or near normal blood pressure, resulting in breakdown of vascular autoregulation and excessive critical wall tension, may have been the cause of the pathological changes. Our findings indicate that medial necrosis is an early component in a sequence of adaptive, destructive, and reparative changes not only following a chemically induced perturbation of the hemodynamic status in arteries and veins but also following a shift back to the "normal state" on withdrawal of compound.
Westwood
F R
FR
Safety of Medicines Department, ICI Pharmaceuticals, Mereside, Macclesfield, Cheshire, United Kingdom.
Iswaran
T J
TJ
Greaves
P
P
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001167:Arteritis / Q000139:chemically induced; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology; D001831:Body Temperature / Q000187:drug effects; D002316:Cardiotonic Agents / Q000009:adverse effects*; D004095:Dihydropyridines / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004719:Endomyocardial Fibrosis / Q000139:chemically induced; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006965:Hyperplasia / Q000139:chemically induced; D006984:Hypertrophy / Q000139:chemically induced; D008297:Male; D008642:Mesenteric Veins / Q000187:drug effects; D008643:Mesentery / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009205:Myocarditis / Q000139:chemically induced; D009206:Myocardium / Q000473:pathology; D010493:Pericarditis / Q000139:chemically induced; D011724:Pyridazines / Q000009:adverse effects*; D011897:Random Allocation; D051381:Rats; D013997:Time Factors; D014665:Vasodilator Agents / Q000009:adverse effects*
D002316:Cardiotonic Agents; D004095:Dihydropyridines; D011724:Pyridazines; D014665:Vasodilator Agents; C064747:ICI 153110