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Fifty-one pigs were fed a low-cholesterol basal diet, to which either 10% (by weight) of lard fat (group INORM, n=l), 2% cholesterol plus 8% lard fat (group II, n=33), or 2% cholesterol plus 4% lard fat plus 4% fish oil (group IIIPREVI n=H) was added. In all pigs, the left anterior descending coronary artery and the abdominal aorta were denuded at 1 month. In the first 24 hours thereafter, three animals in group II and two in group III PRE v died suddenly. After 3 months, 0.5% bile acids was added to the diet in groups II and IIIPREV After 8 months the degree of atherosclerosis was evaluated in groups I NO RM and IIIPREV and in 14 animals from group II (HIND)-At 4 months, one animal from Group II died of pneumonia. For the next 4 months (postinduction period), the remaining 15 animals from group II received the basal diet, to which either 10% lard fat (group 11,^, n=6) or 5% lard fat plus 5% fish oil (group II ro , n=9) was added. The hypercholesterolemic diet increased plasma cholesterol from 2 to 9-12 mM after 8 months. Fish oil had no major effects on plasma lipids during both induction and postinduction. Superoxide production by granulocytes in response to the membrane receptor-dependent A'-forniyl-methionyl-leucyl-phenylalanine (fMLP) gave a higher response in group II IND than in group INORM-In group IIIPREV > the response to phorbol myristate acetate (PMA) and fMLP was lowered, while in groups II TO and 11,^ the responses to PMA and fMLP were not affected. The response to serum-treated zymosan was similar in all groups. Abrasion caused increases in free cholesterol (40%) and phospholipids (46%) in the abdominal aortas of group INORM animals. Hypercholesterolemia increased both free and esterified cholesterol in the entire aorta. Fish oil prevented accumulation of free cholesterol in the nonabraded ascending aorta during induction and further accumulation of free cholesterol and phospholipids in the abdominal aorta during postinduction. In the nonabraded ascending aorta, triglycerides were significantly (almost five times) lower in group II F0 than in group II,j.. During both induction and postinduction, a large incorporation of n-3 polyunsaturated fatty acids (up to 20%) occurred in plasma and aortic cholesterol esters and phospholipids of groups II ro and IIIPREV In plasma lipids the major fatty acid was always 20: Sn-3, but in aortic lipids the incorporation of its elongated product 22: 5n-3 was generally equal to 20: 5n-3. Sudanophilia of the aorta was 0% for group I NO RM > 33% for group II )ND , 35% for group HI PREV , 9% for group IIu, and 7% for group II FO . Luminal encroachment of the coronary arteries in groups I NO RM and II IND was similar. Fish oil (group IIIPREV) had no effect on the development of coronary atherosclerosis. Despite the normocholesterolemia during the postinduction period in group II LF , coronary atherosclerosis progressed to 12% in the right coronary artery and to 18% in the left anterior descending coronary artery, while in group II F0 these values were 5% and 10%, respect...

1 The cardiovascular effects of the pyridazinone-derivatives pimobendan and its O-demethylmetabolite UD-CG 212 Cl (2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole HCI) were studied in conscious pigs, employing consecutive intravenous 10 min infusions of 10, 25, 50 and 100 pg kg-'min-' and 2, 4 and 8 pg kg-'min-' respectively. 2 Pimobendan caused dose-dependent increases in LVdPIdtmaX (up to 115%) and heart rate (up to 30%), while cardiac output was slightly elevated (up to 15%) and stroke volume decreased by 12%.Left ventricular end-diastolic pressure decreased in a dose-related manner from 8.7 ± 1.0 mmHg to 2.7 ± 1.7 mmHg. Mean arterial blood pressure was not significantly affected because systemic vascular resistance decreased dose-dependently up to 15%.3 After P-adrenoceptor blockade, the pimobendan-induced increases in heart rate and cardiac output were attenuated and the increase in LVdP/dtn,,X almost abolished. The responses of left ventricular enddiastolic and mean arterial blood pressure, systemic vascular resistance and stroke volume were not modified.4 UD-CG 212 Cl caused dose-related increases in LVdP/dt,,mx (up to 100%) and heart rate (up to 25%). Cardiac output was minimally elevated (up to 8%) as stroke volume decreased dosedependently up to 15%. As systemic vascular resistance decreased up to 12%, mean arterial blood pressure was slightly reduced (5%). Left ventricular end-diastolic blood pressure decreased dosedependently from 9.0 ± 0.8 mmHg to 3.8 ± 1.3 mmHg.5 After P-adrenoceptor blockade, the UD-CG 212 Cl-induced increases in heart rate and LVdP/dtmax were attenuated and almost abolished and amounted up to 15% and 20%, respectively. The responses of the other systemic haemodynamic parameters were not significantly modified. 6 We conclude that pimobendan and UD-CG 212 Cl are compounds with marked positive inotropic and venodilator properties in the conscious pig. The attenuation of the inotropic effects by pretreatment with propranolol strongly suggests that, in the conscious pig, the P-adrenergic system is significantly involved in the positive inotropic actions. The lack of effect of P-adrenoceptor blockade on the vasodilator responses to both compounds suggest a mechanism not related to fi-adrenergic activity. IntroductionThe pyridazinone-derivative pimobendan (UD-