J.M. Hartog

Cardiovascular profile of pimobendan, a benzimidazole-pyridazinone derivative with vasodilating and inotropic properties

Intravenous infusions of 0.01-0.1 mg X kg-1 X min-1 of pimobendan, a benzimidazole-pyridazinone derivative in pigs with normal coronary circulation caused dose-dependent changes in heart rate (10-35%), left ventricular systolic pressure (-5 to -45%), left ventricular filling pressure (-20 to -40%) but had only a minor effect on the maximum rate of rise of left ventricular pressure (max LVdP/dt; 10-20%). The decrease in mean arterial blood pressure was primarily due to systemic vasodilation; peripheral resistance and cardiac output decreased by up to 40 and 14%, respectively. Vasodilation occurred in several vascular beds, but was particularly pronounced in the adrenals, stomach, small intestine and myocardium. Although the increase in myocardial blood flow favoured the epicardium, vascular conductance in both the endo- and epicardial layers was significantly increased. Myocardial O2 consumption (MVO2) was not affected despite the increase in heart rate. Bolus injections of 0.1-0.5 mg X kg-1 pimobendan produced similar changes in all haemodynamic variables, except max LVdP/dt which now increased by 30-70%. As in the infusion experiments, cardiac output tended to decrease due to a pronounced reduction in ventricular preload probably as a result of venodilation and the consequent reduction in cardiac filling. However, in animals where max LVdP/dt and cardiac output were reduced and pre- and/or after-load were increased by partial occlusion of the left anterior descending coronary artery, pimobendan clearly increased both max LVdP/dt and cardiac output. Pretreatment with propranolol did not modify any of the cardiovascular responses to pimobendan, thereby excluding the involvement of a beta-adrenoceptor mechanism. Pimobendan is thus a compound with vasodilator and positive inotropic properties that improves cardiac output in animals with severe myocardial ischaemia. The finding that the mild tachycardia caused by pimobendan was not accompanied by an increase in MVO2 warrants investigation to evaluate its usefulness in the treatment of heart failure.

Dietary fatty acids and myocardial function

It is widely recognized that dietary polyunsaturated fatty acids (PUFAs) and cholesterol can profoundly influence the development of atherosclerotic plaques in coronary vessels, which may lead to myocardial infarction. The possibility that dietary fatty acids may also directly influence cardiac function has received less attention. We therefore reviewed the evidence of the effects of dietary fatty acids, in particular n-3 and n-6 PUFAs, on myocardial phospholipid fatty acid composition and cardiovascular performance. Heart organelles appear to incorporate uncommon fatty acids like 22:1 and trans- 18:1. Diets enriched with 22:1 induce myocardial lipidosis. N-9, n-6 and n-3 families compete among membrane C20 and C22 acids. Several studies have dealt with the relation between diet-induced changes of cardiac membrane (sarcolemma, sarcoplasmic reticulum and mitochondria) phospholipids and membrane function. In view of the variety of diets used and of the membrane functions studied, the results do not permit equivocal interpretation. Several investigators have reported an altered stress response of the heart due to a change of PUFAs in the diet. In rats fed with a low 18:2n-6/18:3n-3 ratio combined with relatively low amounts of saturated fatty acids, a high incidence of myocardial lesions has been observed. Pigs are less sensitive but more susceptible to the development of vitamin E deficiency, when the dietary PUFA content is high. Increased contractility and coronary flow rate have been reported for Langendorff-perfused hearts of rats fed 18:2n-6-rich diets. The effects on coronary flow rate are possibly related to alterations in eicosanoid synthesis, which may also contribute to the reduction by n-6 or n-3 PUFAs in infarct size, magnitude of recovery of function and suppression of reperfusion arrhythmias following release of a coronary artery ligation. On the other hand, increased peroxidation of membrane lipids, due to their high content of n-3 PUFA, may be deleterious.

Lipid peroxidation in normoxic and ischaemic-reperfused hearts of fish oil and lard fat fed pigs

The in situ and in vitro rate of lipid peroxidation of hearts were determined in two groups of pigs which had been fed diets which differed only in fatty acid composition for 8 weeks. During the dietary period venous plasma levels of malondialdehyde and lipofuscin were not higher in pigs receiving the highly unsaturated fatty acid-containing mackerel oil than those receiving lard fat. Malondialdehyde was produced in the coronary system of the mackerel oil fed animals. After the heart was subjected to a sequence of short periods of ischaemia (5 min) and reperfusion (10 min), myocardial malondialdehyde production in the mackerel oil fed pigs did not increase. Contribution of prostaglandin synthesis products to myocardial malondialdehyde formation is probably of minor importance. Recovery of regional heart function after the ischaemic periods was similar for both dietary groups. In the phospholipids of sarcolemmal preparations isolated from the left ventricle of mackerel oil fed animals 18:2 n-6 and 20:4 n-6 were partially replaced by 20:5 n-3 and 22:6 n-3. Ischaemia-reperfusion did not alter sarcolemmal fatty acid composition and Ca2+ pumping ATPase activity. Sarcolemmal membrane from mackerel oil fed pigs exposed in vitro to a free radical generating system showed a higher malondialdehyde production than that from lard fat fed pigs. Thus, in spite of the increased susceptibility of heart membranes to free radical generated peroxidation in mackerel oil fed animals, recovery of left ventricular function was similar following multiple short-term periods of ischaemia.

The effects of nisoldipine (Bay K 5552) on cardiovascular performance and regional blood flow in pentobarbital ‐ anaesthetized pigs with or without β‐adrenoceptor blockade

1 The effects of the 1,4‐dihydropyridine derivative nisoldipine, infused intravenously (i.v.) at 3 different rates (0.25, 0.5 and 1.0 μg kg−1 min−1), were studied in anaesthetized pigs on cardiovascular performance with or without β‐adrenoceptor blockade produced by propranolol. 2 Nisoldipine caused dose‐dependent decreases in arterial blood pressure (30%), systemic vascular resistance (30%) and left ventricular filling pressure (15%), but raised heart rate (25%) and LV dP/dt max (20%). Cardiac output was not significantly affected. 3 Transmural myocardial blood flow and vascular conductances increased dose‐dependently after nisoldipine. The elevation in blood flow to the left ventricle favoured epicardial layers. Endocardial blood flow showed small increases as the changes in conductance of the endocardial layer more than compensated for the loss in perfusion pressure. The endo‐epi blood flow ratio decreased from 1.16 ± 0.05 to 0.70 ±0.01. Myocardial O2‐consumption was unaltered as the decrease in arterial‐coronary venous O2‐content difference (30%) was balanced by the increase in transmural blood flow. 4 Nisoldipine increased blood flow to skeletal muscle (500%), stomach (50%) and adrenals (25%), but decreased that to the liver (50%), spleen (25%) and kidneys (25%). No changes were noticed in the small intestine, skin and brain. In spite of differential effects on blood flow, vascular conductance in all organs and tissues, with the exception of the liver, increased. 5 After β‐adrenoceptor blockade the responses of mean arterial blood pressure, cardiac output and systemic vascular resistance to nisoldipine remained virtually unchanged, but the elevations in heart rate and LV dP/dt max were abolished, as was the decrease in left ventricular filling pressure. 6 A higher dose of nisoldipine was required after β‐adrenoceptor blockade to elicit significant vasodilatation in the epi‐ and endocardial layers. However, the reduction in endo‐epi blood flow ratio by nisoldipine was not affected by propranolol. Myocardial O2‐consumption tended to decrease as the diminution in the arterial‐coronary venous O2‐content difference (30%) slightly exceeded the increase of left ventricular blood flow (30%). 7 Except for the brain and liver, effects of nisoldipine on regional vascular conductances were attenuated after β‐adrenoceptor blockade.

The influence of fish oil diet and norepinephrine treatment on fatty acid composition of rat heart phospholipids and the positional fatty acid distribution in phosphatidylethanolamine.

SummaryThe effect of chronic norepinephrine (NE) administration with increasing dosage from 1–4 mg/kg over a period of 2 weeks was studied on cardiac phospholipids and their fatty acid distribution in rats. Animals were fed a control diet or a 10% cod liver oil (CLO)-enriched diet. The relative distribution of various polyunsaturated fatty acids esterified to the 1- and 2-position of the phosphatidylethanolamine fraction was estimated. NE stress during control feeding significantly reduced the total phospholipid content in rat heart. No differences in the phospholipid class distribution were found. However, CLO feeding as well as chronic NE administration resulted in a decrease of ω 3 fatty fatty acids, mainly C 18:2 ω 6 and C 20:4 ω 6, which was compensated with an increase in ω 3 fatty acids, mainly C 20:5 ω 3 and C 22:6 ω 3. The changes in fatty acid composition qualitatively agree with those reported by Gudbjarnason et al. (23), except that the mortality in our NE-treated control or CLO-fed groups was considerably lower. It can probably be attributed to a different mode of NE administration. On the other hand, at the end of the CLO feeding period in rats treated with NE or not, comparing with control fed rats without NE treatment, the incidence rate of ST segment elevation in electrocardiogram (ECG) recorded under light diethylether-induced anesthesia was higher. Independent of whether the fatty acid composition of myocardial phospholipids was dietary or pharmacologically manipulated, most of the polyunsaturated fatty acids were found at the 2-position of the phosphatidylethanolamine molecules. The polyunsaturated fatty acids account for 45–50% of the fatty acyl residues and preferentially occupy the 2-position, where they can exchange for each other.

Systemic haemodynamic actions of pimobendan (UD-CG 115 BS) and its O-demethylmetabolite UD-CG 212 Cl in the conscious pig

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 HCl) were studied in conscious pigs, employing consecutive intravenous 10 min infusions of 10, 25, 50 and 100 μg kg−1 min−1 and 2, 4 and 8 μg kg−1 min−1 respectively. 2 Pimobendan caused dose‐dependent increases in LV dP/dtmax (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 β‐adrenoceptor blockade, the pimobendan‐induced increases in heart rate and cardiac output were attenuated and the increase in LVdP/dtmax almost abolished. The responses of left ventricular end‐diastolic 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/dtmax (up to 100%) and heart rate (up to 25%). Cardiac output was minimally elevated (up to 8%) as stroke volume decreased dose‐dependently 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 dose‐dependently from 9.0 ± 0.8 mmHg to 3.8 ± 1.3 mmHg. 5 After β‐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 β‐adrenergic system is significantly involved in the positive inotropic actions. The lack of effect of β‐adrenoceptor blockade on the vasodilator responses to both compounds suggest a mechanism not related to β‐adrenergic activity.

The effects of dietary mackerel oil on the recovery of cardiac function after acute ischaemic events in the pig.

To investigate the effects of fish oil nutrition on cardiac haemodynamics and the biochemical response to ischaemia-reperfusion, young pigs (5 weeks old) were fed a 9% lard fat diet or a mixed diet of 4.5% mackerel oil and 4.5% lard fat for 16 weeks. In the mackerel oil fed pigs plasma cholesterol and triglyceride levels decreased by 22% and 58% (both p less than 0.05), respectively, while levels in the animals which received only lard fat did not change. The n-6 fatty acids present in cardiac and platelet membrane phospholipids underwent a partial replacement by n-3 fatty acids in the mackerel oil fed pigs. Under anaesthesia, multiple coronary artery occlusions (5 min) were interrupted by 10 min of reperfusion. The extent of recovery of cardiac function and reduction of adenine nucleotide levels were similar for both dietary groups. The incidence of reperfusion arrhythmias was significantly lower and the reactive hyperaemic responses were of longer duration in the mackerel oil fed animals. These effects cannot be explained by diet-induced alterations in thromboxane B2/6-keto-PGF1 alpha ratio, although a marked reduction in absolute levels of both prostaglandins was seen in the mackerel oil fed pigs (p less than 0.05). In conclusion, dietary fish oil caused changes in membrane fatty acid composition and plasma prostaglandin levels, although these did not affect alterations of cardiac performance during and after short periods of ischaemia.

Effects of diets supplemented with lard fat or mackerel oil on plasma lipoprotein lipid concentrations and lipoprotein lipase activities in domestic swine

Levels of plasma lipoproteins and lipoprotein lipase activities in post-heparin serum were measured in 24-h fasted pigs which were fed a diet containing either 21 energy % mackerel oil or 21 energy % lard fat for 8 weeks. Lipoprotein fractionation was performed separately by density gradient ultracentrifugation and agarose gel chromatography. After 8 weeks levels of plasma triacylglycerol (-62%) and cholesterol (-55%) were lower in the mackerel oil than in the lard fat-fed animals. The triacylglycerol decline was exclusively due to the VLDL fraction, while cholesterol was reduced in all lipoprotein fractions (VLDL, IDL, LDL and HDL). Lipoprotein lipase activity in post-heparin serum, taken 6 h after a meal, was 31% decreased in mackerel oil-fed animals. The results support the hypothesis that regular intake of fish oil reduces VLDL secretion.

Does platelet aggregation play a role in the reduction in localized intimal proliferation in normolipidemic pigs with fixed coronary artery stenosis fed dietary fish oil

In order to investigate the effect of fish oil on intimal proliferation of coronary arteries with a fixed stenosis normolipidemic piglets received a basic diet to which either 9% (w/w) lard (L, n = 8) or 4.5% (w/w) lard and 4.5% (w/w) mackerel oil (ML, n = 8) was added for 4 months. Stenosis was applied by implanting a 4.0 X 2.0 mm (i.d.) Teflon constrictor around the left anterior descending coronary artery (LADCA) (o.d. 2.7 +/- 0.1 mm). During the dietary period ADP-induced platelet aggregation in whole blood was higher in L than in ML. Partial replacement of 20:4 n - 6 by 20:5 n - 3 fatty acids in the platelet membranes of ML may have altered platelet aggregation by changes in eicosanoid synthesis. The plasma cholesterol and triglyceride levels did not change in L, but decreased in ML. At the end of the 4-month dietary period the animals were again anesthetized and regional myocardial perfusion (radioactive labelled microspheres) and systolic segment length shortening (SLS) were measured while the hearts were paced at 160 pulses/min. Perfusion and SLS of non-LADCA nourished segment were similar for L and ML. However, transmural flow to the LADCA perfused myocardium was impaired in both groups, but the deficiency in endocardial perfusion was considerably larger in L than in ML, resulting in a larger loss of SLS in the former. Remote (2-3 cm from the site of the constrictor) luminal encroachment was minimal (less than 2%) in both groups, but at the site of the constrictor there was significant encroachment in both groups which was higher in L (62 +/- 7%) than in ML (11 +/- 4%). It is thought that in these normolipidemic pigs the reduction in platelet aggregation may play a role in the smaller intimal proliferation of the fish oil-fed animals.

Systemic and regional hemodynamic, antiarrhythmic and antiischemic effects of bevantolol in anesthetized pigs

In doses of 0.5 to 3.0 mg/kg bevantolol caused dose-dependent decreases in cardiac output (10% to 35%), primarily due to negative chronotropic actions, as heart rate decreased by 10% to 25%. Stroke volume decreased after the highest dose (15%), due to a negative inotropic action (maximum left ventricular dP/dt decreased by 40%) and a mild vasoconstriction in systemic vascular beds. Decreases in perfusion of the heart, kidneys, liver, spleen, stomach, muscles and adrenals were similar to those in cardiac output. However, blood flow to the brain and small intestine was not significantly affected. Bevantolol (0.5 or 1.5 mg/kg IV) gave full protection against ventricular fibrillation during the first period (10 minutes) of proximal left anterior descending (LAD) coronary artery occlusion in the highest dose. After the third and last reperfusion period, 70% of these animals survived, while only 8% of the untreated and 15% of the animals treated with the lower dose survived. After permanent ligation of the LAD coronary artery at midpoint, bevantolol prevented ventricular fibrillation during the first phase of early ventricular arrhythmias but was unable to prevent it during the second phase of early arrhythmias. Administration of bevantolol (1.5 mg/kg) to animals in which the LAD coronary artery blood flow was reduced to 35% of baseline did not improve transmural myocardial blood flow to the ischemic zone. However, the drug caused a redistribution in favor of the endocardial layers. The changes in flow were accompanied by a narrowing of the arterial-coronary venous differences in pH and pCO2.(ABSTRACT TRUNCATED AT 250 WORDS)