Aspects on the treatment of experimentally induced coronary artery disease

In this thesis some therapeutic aspects of experimentally induced coronary artery disease are being highlighted. In chapter 2 the effects of the Ca2 • antagonist diltiazem on the progression of coronary and aortic atherosclerosis in pigs is being studied. So far, studies on the anti-atherosclerotic effects of this drug (Ginsburg et al., 1983; Naito et al., 1984; Sugano et al., 1986; Dicciani et al., 1987; Sugano et al., 1988) have only been performed in the hypercholesterolemic rabbit and in only one study (Ginsburg et al., 1983) also the effect on coronary atherosclerosis was investigated. However, hypercholesterolemic rabbits develop atherosclerosis in the small intramyocardial branches rather than in the large epicardial coronary arteries, as observed in man and in swine. Furthermore, in these studies the doses used were so high that they would never be tolerated by man. Besides a medicamentous regimen, dietary intervention may also present a possible way of dealing with atherosclerosis. In chapter 3 the regression of porcine atherosclerotic lesions and the effects of dietary flsh oil on this process have been investigated. Myocardial ischemia has been mimicked in anesthetized pigs by creating a concentric stenosis by inflating a balloon placed around the vesseL Several therapeutic approaches have been explored (chapters 4, 6, 8 and 10). The effect of a low dose of the Ca2+ antagonist nisoldipine (chapter 4) and L-propionylcarnitine (chapter 6) on ischemic and postischemic blood flow and function have been investigated. Furthermore, an attempt has been made to predict long term outcome of stunned myocardium by means of two markers for long term recovery: the post systolic wall thickening (Takayama et al., 1988) and Ca2+ uptake and phospholamban phosphorylation of the sarcoplasmic reticulum (Schoutsen et al., 1989). The reflex-mediated tachycardia, as observed in conscious (Duncker et al., 1987a), but also in anesthetized animals (Duncker et al., 1986) may, in myocardial ischemia, render a potential detrimental effect of vasodilators such as the Ca 2+ -antagonists. In chapter 5 the cardiovascular profile of the newly developed Ca2+-antagonists elgodipine has been surveyed. In chapter 7 the global and regional cardiovascular effects of nicorandil were investigated while in chapter 8 the drug was tested for its anti-ischemic potential. As indicated, nicorandil is a compound with nitrate-like actions, but it has also been shown that the cardiac effects and possibly in part the vasodilating property, are mediated by K+ channel activation. In chapter 9 we investigated the cardiovascular effects of a selective K+ channel activator for comparison with those of nicorandil. Despite new developments, B-adrenoceptor-antagonists remain important for the treatment of myocardial ischemia. In this respect the cardioselective type of £adrenergic antagonists are of particular interest. One such drug is bisoprolol (Harting et al., 1986), a compound that has been shown to exert pronounced cardiovascular actions at doses considerably lower than required to inhibit the isoproterenol-induced increases in heart rate and contractility (Duncker et al., 1987b ). In chapter 10 its effects on contractile function and myocardial flow in ischemic porcine myocardium are described

Evaluating the Precision of Estimation of an Inequality Constrained Ridge Regression Estimator by the Bootstrap Methods

markdownabstractAbstract The effects of nisoldipine (0.1 μg/kg/min; n = 9) or its solvent (n = 9) were studied in pigs, in which left anterior descending coronary artery (LADCA) blood flow in both groups was reduced to 20% of baseline for 60 min and reperfused for 2 hr. Infusions were started at 30 min of ischaemia and lasted throughout reperfusion. In both groups, flow reduction abolished regional contractile function and caused similar decreases in the level of creatine phosphate (CP; by 70%) and the energy charge (from 0.91 to 0.69), mean arterial blood pressure (by 25%), LVdP/dtmax (by 30%) and cardiac output (by 30%). During ischaemia LADCA blood flow slightly increased (from 14 ± 8 to 24 ± 6mL/min/ 100 g; P < 0.05) in the nisoldipine-treated animals, resulting in an increase in CP to 91 ± 24% of baseline and preventing further decreases in energy charge, as observed in the solvent-treated animals. After 2 hr of reperfusion in neither group return of contractile function of the post-ischaemic myocardium was observed. Post-ischaemic blood flow in the nisoldipine-treated pigs increased from 24 ± 6 mL/min/100 g to 76 ± 14 mL/min/100 g and from 19 ± 6 mL/min/100 g to 41 ± 6 mL/min/100 g in the solvent-treated animals (P < 0.05) after 2 hr of reperfusion. Myocardial work was significantly higher in the nisoldipinetreated animals (111 ± 15 mmHg.L/min as compared to 69 ± 14 mmHg.L/min in the solvent-treated pigs after 2 hr of ischaemia). The energy charge of the post-ischaemic myocardium was similar for both groups (0.84 ± 0.02 for the nisoldipine-treated and 0.83 ± 0.03 for the solvent-treated animals). The rate of sarcoplasmic reticular Ca2+ uptake of the non-ischaemic segment of the nisoldipine-treated animals was 61% higher (P < 0.05) than that of the solvent-treated animals. In the post-ischaemic myocardium similar rates of Ca2+ uptake were found in both groups, but the activities were markedly lower as compared to the non-ischaemic myocardium. It is concluded that nisoldipine increases blood flow during reperfusion, which may have been caused by coronary vasodilatation. However, attenuation of the “no-reflow” phenomenon also contributed, since more rapid rephosphorylation of ADP leading to an increase in CP during ischaemia may have preserved jeopardized cells. Moreover, nisoldipine increases the sarcoplasmic reticular Ca2+ pump activity independent of ischaemia, which may have contributed in reducing the Ca2+ overload. Abbreviation

Mechanical efficiency of stunned myocardium is modulated by increased afterload dependency

Oxygen consumption (MVO2) of stunned myocardium is relatively high compared to, and poorly correlated with, systolic contractile function. The aim of this study was to investigate whether an increased afterload dependency, induced by the decreased contractility of the stunned myocardium, contributes to the large variability in the mechanical efficiency data. Methods: In 13 anaesthetised open thorax pigs undergoing two cycles of 10 min occlusion of left anterior descending coronary artery and 30 min reperfusion, segment shortening, the slope of end systolic pressure segment length relationship (Ees), external work (EW, derived from the area inside the left ventricular pressure segment length loop), the efficiency of energy conversion (EET, = Embedded Image × 100%, where PLA = total pressure-segment length area), mechanical efficiency (Embedded Image), and their dependency on left ventricular end systolic pressure (Pes) were determined before and after induction of stunning, and during subsequent inotropic stimulation with dobutamine (1 and 3 μg·kg−1·min−1 over 15 min). Results: The stunning protocol not only caused significant decreases in segment shortening, external work, energy conversion efficiency, and Embedded Image but also increased the afterload dependency of these variab Before stunning an increase in Pes from 100 to 160 mm Hg decreased segment shortening from 18(SEM 1)% to 14(2)% (P > 0.05) and increased external work from 206(18) to 254(32) mm Hg·mm (P < 0.05). After induction of stunning the same increase in Pes caused a decrease in segment shortening from 9.5(1.8)% to −4.6(2.1)% (P < 0.05) and in external work from 149(21) to −11(10) mm Hg·mm (P < 0.05). The afterload dependency of the PLA was not altered by stunning, but the afterload dependency of energy conversion efficiency increased, since efficiency decreased from 67(3)% to 59(5)% as Pes was increased from 100 to 160 mm Hg before stunning, but from 57(5) to −7(5)% after induction of stunning (P < 0.05). Furthermore, the same increase in Pes resulted in an 8% decrease of Embedded Image before stunning and 107% after inducti stunning. Infusion of dobutamine not only restored segment shortening, external work, energy conversion efficiency, and Embedded Image of the stunned myocardium, but also attenuated their afterload dependency to levels. Conclusions: Myocardial stunning increases the afterload dependency of segment shortening, external work, energy conversion efficiency, and mechanical efficiency, which can be attenuated by inotropic stimulation with dobutamine. However, the decrease in left ventricular end systolic pressure, which accompanies the induction of stunning, counteracts the decrease in these variables. These two mechanisms can explain most of the reported scatter in mechanical efficiency

Angiotensin production by the heart: a quantitative study in pigs with the use of radiolabeled angiotensin infusions

BACKGROUND: Beneficial effects of ACE inhibitors on the heart may be mediated by decreased cardiac angiotensin II (Ang II) production. METHODS AND RESULTS: To determine whether cardiac Ang I and Ang II are produced in situ or derived from the circulation, we infused 125I-labeled Ang I or II into pigs (25 to 30 kg) and measured 125I-Ang I and II as well

The relative contributions of myocardial wall thickness and ischemia to ultrasonic myocardial integrated backscatter during experimental ischemia

Abstract The purpose of this study was to assess the empirical relationship between myocardial integrated backscatter (IB) and myocardial wall thickness (WT) in normal myocardium. A second object was to estimate the additional contribution to acute ischemic integrated backscatter levels given this relationship. Myocardial IB measurements and simultaneous myocardial WT measurements were made in 16 open-chested pigs with intact coronary circulation (normal myocardium) and 10 min after the flow in the left anterior descending coronary artery had been reduced to 20% of its baseline value (ischemic myocardium). Measurements were made 50 times during one cardiac cycle and averaged over 10 cardiac cycles. IB and WT measurements were normalized with respect to the nonischemic end-diastolic values. The relationship between IB and WT in normal myocardium was estimated in every individual pig by simple linear regression. Estimates of IB during ischemia were calculated on the basis of this relationship and the ischemic WT measurements. Differences of the estimator and the actual measurement made during ischemia depict the actual contribution of the state of acute ischemia, without the influence of WT. The slope of the relationship between IB and WT during normal myocardial contraction ranged from −0.16 to 0.03 dB/% (mean = −0.036 dB/%, SD = 0.06 dB/%). The additional contribution of ischemia ranged from −3.84 to 5.56 dB (mean = 0.31 dB, SD = 2.72 dB). It was concluded that the average contribution of ischemia to IB measurements is insignificant if the IB dependency on WT is removed from the data and that the higher level of ischemic IB measurements can be explained by the decrease in wall thickness during ischemia and not by the ischemia itself