Minoxidil and other potent vasodilators cause coronary arterial injury, right atrial hemorrhagic lesions, and subendocardial necrosis in dogs, This paper discusses the pathogenesis of coronary arterial and right atrial lesions associated with minoxidil in the dog, Acute coronary vascular injury characterized by segmental medial hemorrhage and necrosis and perivascular inflammation occurred only during the first few days of treatment, after which tolerance to further acute injury developed, At 30 d or more of treatment, coronary vascular injury was characterized by perivascular fibrosis rarely attended by medial distortion or hyperplasia and subintimal thickening, changes consistent with responses to previous injury, Right atrial hemorrhagic lesions, unlike coronary vascular injury, often became progressively more extensive with continued treatment. At 3 d, atrial hemorrhage and inflammation were confined to the subepicardium ofthe right atrium, evidently around affected subepicardial branches of the right coronary artery, At 30 d, fibrovascular proliferative right atrial lesions (granulation tissue with evidence of continual hemorrhage) extended from the epicardium to the myocardium, with eventual replacement ofthe atrial wall by mature connective tissue at I yr of treatment. Minoxidil-induced cardiovascular lesions were not prevented by treatment with a l3-blocker (propranolol), or an a-blocker (dibenzylene), or by sympathetic neural activity suppression (surgical sympathectomy or constant carotid sinus nerve stimulation), suggesting that the sympathetic response to the pharmacologic activity of minoxidil was not responsible for the induction of the cardiovascular lesions. Minoxidil-related vascular lesions were confined to the most pharmacologically responsive segment of the arterial system, the coronary arteries, suggesting that medial injury may have been associated with tensile changes in the arterial wall.

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Abstract. Precursor lesions of spontaneous nephroblastoma (NB) in rats are here characterized for the first time, with a description of the progression of the tumor in prenatal, postnatal, and adult Sprague-Dawley rats (Upj:TUC[SD]spf.nb), which are genetically predisposed to the tumor. NB in the rat starts as a focal or multifocal interstitial accumulation of intensely basophilic immature (blastema) cells, invariably located in the deep renal cortex. Precursor lesions of NB (designated intralobar nephroblastematosis) and the early tumor do not overtly disrupt the overall structural organization and integrity of the kidney. However, with increasing size and neoplastic transformation, these lesions trap, compress, and displace/replace the existing renal tubules. Nephroblastematous foci occurred in one or both kidneys in tumor-bearing or non-tumor-bearing kidneys and in young and old rats. Like the precursor lesions, the early tumors in rats as young as 6 weeks of age were located in the inner cortex. Well-developed NB was comprised of blastema cells arranged in dense sheets or in ductular structures surrounded by mantles of blastema cells supported by varying amounts of fibromatous stroma. The stroma in one rat was hemangiosarcomatous (triphasic Wilms' tumor). Tumor cells were slightly pleomorphic and had varying amounts of granular cytoplasm with sparse organelles and showed junctional complexes and basal laminae whose frequency apparently depended upon whether the blastema cell tended to differentiate to epithelial or mesenchymal cells. NB in the rat was morphologically similar to immature preand postnatal kidneys, regardless of whether it occurred in young or old rats. The deep cortical location and interstitial infiltrative characteristics of precursor lesions of NB in the rat were analogous to intralobar nephrogenic rests, a variant of the precursor to Wilms' tumor in children.Key words: Intralobar nephroblastematosis; kidney; light microscopy; nephroblastoma; precursor; SpragueDawley rats; ultrastructure.Spontaneous nephroblastoma (NB), a common solid primary renal tumor in children, 11 occurs rarely in young adult rats, with an incidence of 0-0.4%. 8,12,17,19 Recently, a 14% incidence of NB was reported in a subline of Sprague-Dawley rat (Upj:TUC[SD]spf.nb) genetically predisposed to the tumor. 25 Although the progression of NB has been briefly described in a chemically induced tumor in the rat, 13 the evolution of the spontaneous tumor in animals has not been fully characterized because most of the published works are single case reports of tumors that were usually large and pseudoencapsulated and/or had displaced a substantial portion of the kidney at the time of evaluation. Precursor lesions of NB in children have been described under a variety of names, including persistent nodular blastoma, incipient Wilms' tumor, in situ nephroblastoma, Wilms' tumorelet, tubular adenoma, nephroblastic dysplasia, sclerosing hamartoma, and nephroblastomatosis. 22 A classification of precursor of NB in children has been...

Groups of 5 male beagle dogs were treated orally with hydralazine tablets in gelatin capsules at a dose of 12 or 24 mdkg twice a day (6 hours apart) for 2 consecutive days. Five male dogs treated with empty gelatin capsules served as untreated controls. Clinical findings and heart rate changes during treatment and terminal body weight, hematology, and blood chemistry changes were evaluated. The heart, liver, kidneys, spleen, and thymus of each animal were examined microscopically. Dogs in the 12 mdkg group ate less than control group. Dogs treated with 24 mdkg did not eat and vomited. Heart rates in both ofthe treated groups increased by 60 to 80% within 2 hours of treatment and remained high during the entire treatment period. Significant ' hematologic change was confined to a slight increase in platelet number of dogs treated with 24 mg/kg. Serum glucose was increased in the hydralazine treated dogs. Conjugated serum bilirubin was increased and serum potassium, chloride and phosphorus were decreased in the 24 mg/kg group. Blood urea nitrogen and serum chloride were slightly increased in dogs treated with 12 mglkg. Treatment-related pathologic alterations were confined to the heart. Two dogs from each of the hydralazine groups experienced acute localized hemorrhage into the epicardium and subepicardium of the right atrium. The media of the muscular branches of the coronary arteries, especially the left coronary artery, was hemorrhagic in 3 dogs from the 24 mg/kg group.Medial necrosis, when seen, tended to be proportional to the severity of medial hemorrhages. There was no necrosis in the papillary muscles of the heart. These acute cardiovascular alterations in dogs treated with hydralazine for 2 days-believed to be related to exaggerated pharmacologic effects of the drug-were similar to the lesions seen in dogs treated with minoxidil for 2 to 3 days.

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