{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T17:41:27Z","timestamp":1785778887888,"version":"3.56.0"},"reference-count":80,"publisher":"SAGE Publications","issue":"1_part_2","license":[{"start":{"date-parts":[[1989,1,1]],"date-time":"1989-01-01T00:00:00Z","timestamp":599616000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxicol Pathol"],"published-print":{"date-parts":[[1989,1]]},"abstract":"<jats:p>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. Studies to date have been largely descriptive rather than investigational. In reviewing the literature on drug induced arterial lesions, it is clear that information that might add to our understanding is frequently not available. Some measures not commonly used in toxicity trials that could improve the data base when vascular lesions are induced include: Holter monitoring; adequate blood pressure monitoring; and at necropsy coronary perfusion fixation, quantitation of the amount of intramural coronary disease, and fluorescent or hemotoxylin basic fuchsin picric acid stains to identify recent myocardial necrosis. The feasibility of including echocardiographic estimates of cardiac function during toxicity trials should be examined.<\/jats:p>","DOI":"10.1177\/019262338901700105","type":"journal-article","created":{"date-parts":[[2017,1,7]],"date-time":"2017-01-07T03:31:19Z","timestamp":1483759879000},"page":"94-108","source":"Crossref","is-referenced-by-count":33,"title":["Spontaneous and Induced Arterial Disease in the Dog: Pathology and Pathogenesis"],"prefix":"10.1177","volume":"17","author":[{"given":"D. K.","family":"Detweiler","sequence":"first","affiliation":[{"name":"School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[1989,1,1]]},"reference":[{"key":"bibr1-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1159\/000143849"},{"key":"bibr2-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/20.6.451"},{"key":"bibr3-019262338901700105","unstructured":"AlousiAAand DobreckHP(1983). Amrinone. In: New Drugs Annual: Cardiovascular Drugs, A Scriabine (ed). Raven Press, NY, pp. 259\u2013276."},{"key":"bibr5-019262338901700105","unstructured":"AlousiAA FabianRJ BakerJF, and StroshaneRM(1985). Milrinone. In: New Drugs Annual: Cardiovascular Drugs, A Scriabine (ed). Raven Press, NY, pp. 245\u2013283."},{"key":"bibr7-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.74.5.1075"},{"key":"bibr8-019262338901700105","first-page":"R231","volume":"236","author":"Ashkar E","year":"1979","journal-title":"Am. J. Physiol."},{"key":"bibr9-019262338901700105","doi-asserted-by":"crossref","unstructured":"AyersKMand JonesSR(1978). Cardiovascular system. In: Pathology of Laboratory Animals, Vol. 1, BenirschkeK. GarnerFM, and JonesTC (eds). Springer, Berlin, pp. 1\u201369.","DOI":"10.1007\/978-1-4612-9942-4_1"},{"key":"bibr11-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.41.5.648"},{"key":"bibr12-019262338901700105","unstructured":"BalazsT (1981). Cardiotoxicity of adrenergic bron-chiodilator and vasodilating antihypertensive drugs. In: Cardiac Toxicology, Vol. II, BalazsT (ed). CRC Press, Boca Raton, FL, pp. 61\u201373."},{"key":"bibr14-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1007\/BF02001345"},{"key":"bibr15-019262338901700105","unstructured":"BlumenthalHT (1967). Hemodynamic factors in the etiology of arteriosclerosis. In: Cowdry's Arteriosclerosis, BlumenthalHT (ed). Charles C Thomas, Springfield, IL, pp. 510\u2013538."},{"key":"bibr17-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1091470204"},{"key":"bibr18-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1091480206"},{"key":"bibr19-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1258\/002367784780958088"},{"key":"bibr20-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.30.1.67"},{"key":"bibr21-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/9.1.1"},{"key":"bibr22-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(77)90171-5"},{"key":"bibr23-019262338901700105","first-page":"18","volume":"20","author":"Christiansen GC","year":"1959","journal-title":"Am. J. Vet. Res."},{"key":"bibr24-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1091550308"},{"key":"bibr25-019262338901700105","unstructured":"DageRC RoebelLE GibsonJP OkerholmRA, and RolfCN(1985). Enoximone. In: New Cardiovascular Drugs, ScriabineA (ed). Raven Press, NY, pp. 63\u201379."},{"key":"bibr27-019262338901700105","unstructured":"DahmeE (1962). Blutgefaesse. Joests Handbuch der speziellen pathologischen Anatomie der Haustiere, Bd. 2. In: Zirkulations- und haematopoetische Organe, StunzeH (ed). Paul Parey, Berlin, 1970, pp. 240\u2013412. (Initially published as a fascicle in 1962.)"},{"key":"bibr29-019262338901700105","unstructured":"DetweilerDK (1984). Regulation of the heart. In: Dukes'Physiology of Domestic Animals, 10th ed. SwensonMJ (ed). Cornell Univ. Press, Ithaca, pp. 150\u2013162."},{"key":"bibr31-019262338901700105","unstructured":"DetweilerDK (1984). Regional and fetal circulations. In: Dukes\u2019 Physiology of Domestic Animals, 10th ed. SwensonMJ (ed). Cornell Univ. Press, Ithaca, pp. 192\u2013206."},{"key":"bibr33-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1968.tb45565.x"},{"key":"bibr34-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1965.tb49421.x"},{"key":"bibr35-019262338901700105","unstructured":"DetweilerDK PattersonDF BuchananJW, and KnightDH(1979). Cardiovascular system. In: Canine Medicine, 4th ed. Vol. 2, CatcottEJ (ed). Am. Vet. Publ., Santa Barbara, pp. 813\u2013949."},{"key":"bibr37-019262338901700105","unstructured":"Du CharmeDW, FreyburgerWA, GrahamBE, and CarlsonRG (1973). Pharmacological properties of minoxidil: A new hypertensive agent. J. Pharmacol. Exp. Therap. 184: 662\u2013670."},{"key":"bibr38-019262338901700105","unstructured":"FerransVS (1981). Overview of morphologic reactions of the heart to toxic injury. In: Cardiac Toxicology, Vol. III, Chap. 4, BalazsT (ed). CRC Press, Boca Raton, FL, pp. 83\u2013109."},{"key":"bibr40-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1002\/path.1700930113"},{"key":"bibr41-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(80)90360-9"},{"key":"bibr42-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.66.6.1150"},{"key":"bibr43-019262338901700105","unstructured":"GlagovS (1972). Hemodynamic risk factors: Mechanical stress, mural architecture, medial nutrition, and the vulnerability of arteries to atherosclerosis. In: The Pathogenesis of Atherosclerosis, WisslerRW and GeerJC (eds). William and Wilkins, Baltimore, pp. 164\u2013199."},{"key":"bibr45-019262338901700105","unstructured":"GlaisterJR (ed) (1986). Principles of Toxicological Pathology. Taylor and Francis, London."},{"key":"bibr46-019262338901700105","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.2460\/ajvr.1974.35.08.1115","volume":"35","author":"Gross DR","year":"1974","journal-title":"Am. J. Vet. Res."},{"key":"bibr47-019262338901700105","unstructured":"HatleLand AgelsenB(eds) (1985). Doppler Ultrasound in Cardiology, 2nd ed. Lea and Febiger, Philadelphia."},{"key":"bibr48-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1001010102"},{"key":"bibr49-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1136\/vr.102.24.519"},{"key":"bibr50-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1177\/030098588702400611"},{"key":"bibr51-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(79)90520-9"},{"key":"bibr52-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1177\/030098588101800209"},{"key":"bibr53-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1016\/0033-0620(87)90016-8"},{"key":"bibr54-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-198406060-00001"},{"key":"bibr55-019262338901700105","unstructured":"IsaacsKR (1987). Personal communication."},{"key":"bibr56-019262338901700105","unstructured":"JacksonH (1835\u20131911). Quotation cited by Strauss, M.B. (1968) Familiar Medical Quotations Little Brown, Boston, p. 502."},{"key":"bibr57-019262338901700105","unstructured":"JamesTN (ed) (1961). Anatomy of the Coronary Arteries. Hoeber NY."},{"key":"bibr58-019262338901700105","unstructured":"JamesTN (1971). Functional anatomy of the coronary vessels. In: Cardiac and Vascular Diseases, Vol. 1, ConnHLJr and HorwitzO (eds). Lea and Febiger, Philadelphia, pp. 24\u201340."},{"key":"bibr60-019262338901700105","doi-asserted-by":"crossref","unstructured":"JellinekH (ed) (1974). Arterial Lesions and Arteriosclerosis. Plenum Press, NY.","DOI":"10.1007\/978-1-4615-8711-8"},{"key":"bibr61-019262338901700105","unstructured":"JonesTCand HuntRD(eds) (1983). Veterinary Pathology, 5th ed. Lea & Febiger, Philadelphia."},{"key":"bibr62-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1136\/vr.92.14.363"},{"key":"bibr63-019262338901700105","unstructured":"KuDN ZarinsCK GiddensDP, and GlagovS(1984). Human carotid blood flow dynamics and early atherosclerosis. In: Cardiovascular System Dynamics Society. VIth Internat. Conf. and Workshop. University of PA, pp. 272\u2013275."},{"key":"bibr64-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1016\/0272-0590(85)90087-9"},{"key":"bibr65-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1965.tb18956.x"},{"key":"bibr66-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1965.tb49422.x"},{"key":"bibr67-019262338901700105","unstructured":"MesfinGMand PiperRC(1986). Coronary vascular injury in dogs treated with vasodilators. Abstract. 37th Ann. Mtg. Am. Coll. Vet. Pathol. Special Session: Cardiovascular Pathology. New Orleans, LA, Dec. 1\u20135, p. 53."},{"key":"bibr68-019262338901700105","unstructured":"MorganrothJ (1981). Ambulatory monitoring: Impact of spontaneous variability of simple and complex ventricular ectopy. In: Cardiac Arrhythmias, HarrisonDG (ed). Hall, Boston, pp. 479\u2013492."},{"key":"bibr70-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.14.3.250"},{"key":"bibr71-019262338901700105","unstructured":"MillerME (ed) (1964). Anatomy of the Dog. Saunders, Philadelphia."},{"key":"bibr72-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1115\/1.3149571"},{"key":"bibr73-019262338901700105","first-page":"333","volume":"72","author":"Nieberle K","year":"1937","journal-title":"Arch. Tierheilkunde"},{"key":"bibr74-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1016\/0015-6264(71)90237-9"},{"key":"bibr75-019262338901700105","doi-asserted-by":"crossref","unstructured":"RatcliffeHL LuginbuehlH SchnarrWR, and ChacoK(1960). Coronary arteriosclerosis in swine. J. Comp. Physiol. Physiol. 68: 385\u2013392.","DOI":"10.1037\/h0027520"},{"key":"bibr76-019262338901700105","first-page":"357","volume":"48","author":"Ratcliffe HL","year":"1967","journal-title":"Brit. J. Exp. Pathol."},{"key":"bibr77-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.46.1.138"},{"key":"bibr78-019262338901700105","unstructured":"RobinsonWFand MaxieMG(1985). The cardiovascular system. In: Pathology of Domestic Animals, 3rd ed. Vol. 3, JubbKVF, KennedyPC, and PalmerN (eds). Academic Press, New York, pp. 1\u201381."},{"key":"bibr80-019262338901700105","first-page":"201","volume":"6","author":"Ruben Z","year":"1986","journal-title":"The Toxicologist"},{"key":"bibr81-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.52.4.540"},{"key":"bibr82-019262338901700105","first-page":"117","volume":"57","author":"Salfelder K","year":"1950","journal-title":"Deutsch. Tieraerztl. Wschr."},{"key":"bibr83-019262338901700105","unstructured":"SchochM (1984). Langzeitregistrierung der Herzfrequenz und der Bewegungsaktivitaet von Hunden unter standardisierten Bedingungen. Inaug. Diss. Vet. med. Fak. Univ. Zuerich."},{"key":"bibr84-019262338901700105","doi-asserted-by":"crossref","unstructured":"SobotaJT MartinWB CarlsonRG, and FeenstraES(1980). Minoxidil: Right atrial cardiac pathology in animals and man. Circulation 62: 376\u2013387.","DOI":"10.1161\/01.CIR.62.2.376"},{"key":"bibr85-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9975(87)90031-4"},{"key":"bibr86-019262338901700105","doi-asserted-by":"crossref","unstructured":"SteffenRP WeishaarRE EvansDB, and KaplanH(1986). Imazodan (Cl-914). In: New Cardiovascular Drugs, ScriabineA (ed). Raven Press, NY, pp. 81\u2013105.","DOI":"10.1111\/j.1527-3466.1986.tb00489.x"},{"key":"bibr88-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4800(86)90068-7"},{"key":"bibr89-019262338901700105","doi-asserted-by":"crossref","unstructured":"StejskalV HaviN, and MalmforsT(1982). Necrotizing vasculitis as an immunological complication in a toxicity study. New toxicology for old. Arch. Toxicol. (Suppl.) 5: 238\u2013286.","DOI":"10.1007\/978-3-642-68511-8_49"},{"key":"bibr90-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1111\/j.1740-8261.1984.tb01910.x"},{"key":"bibr91-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4800(84)90003-0"},{"key":"bibr92-019262338901700105","first-page":"1","volume":"40","author":"Weissler AM","year":"1971","journal-title":"Mod. Concepts Cardiovasc. Dis."},{"key":"bibr93-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-197901000-00015"},{"key":"bibr94-019262338901700105","doi-asserted-by":"crossref","unstructured":"WilsonJR FalconeR FerraroN, and EglerJ(1986). Mechanism of skeletal muscle underperfusion in a dog model of low-output heart failure. Am. J. Physiol. 20: H227\u2013H235.","DOI":"10.1152\/ajpheart.1986.251.2.H227"},{"key":"bibr95-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.75.4.857"},{"key":"bibr96-019262338901700105","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.41.2.213"}],"container-title":["Toxicologic Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/019262338901700105","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/019262338901700105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T16:50:14Z","timestamp":1777654214000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/019262338901700105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1989,1]]},"references-count":80,"journal-issue":{"issue":"1_part_2","published-print":{"date-parts":[[1989,1]]}},"alternative-id":["10.1177\/019262338901700105"],"URL":"https:\/\/doi.org\/10.1177\/019262338901700105","relation":{},"ISSN":["0192-6233","1533-1601"],"issn-type":[{"value":"0192-6233","type":"print"},{"value":"1533-1601","type":"electronic"}],"subject":[],"published":{"date-parts":[[1989,1]]}}}