Increase In Coronary Flow Rate Research Articles

Cardioprotective effects of silver fir (Abies alba) extract in ischemic-reperfused isolated rat hearts

BackgroundSilver fir trunk extract (SFTE) is a complex mixture of antioxidative polyphenols (lignans and phenolic acids) from the trunks of silver fir trees (Abies alba, lignum). In our previous study, we have shown that SFTE exerts strong antioxidative and protective effects against atherogenic, diet-induced arterial wall damage.ObjectiveThe aim of the present study was to test the potential protective effects of SFTE and its compounds, two phenolic acids (p-coumaric and protocatechuic acids) in ischemia–reperfusion injury of isolated rat hearts.DesignIsolated hearts of Wistar rats aged 4–8 weeks were exposed to perfusion, ischemia, and reperfusion periods. The experiments were performed using the following five groups: control, SFTE (10 µg/L), SFTE (100 µg/L), protocatechuic acid, and p-coumaric. Aortas were isolated to measure vascular responses in the presence of Nω-Nitro-l-arginine.ResultsSFTE dose-dependently reduced ischemic-reperfusion heart damage, which was indicated as the decrease in the lactate dehydrogenase (LDH) release rate and arrhythmias duration by 80% and an increase in coronary flow rate during the reperfusion period. Two tested compounds (p-coumaric and protocatechuic acids) acted less cardioprotective, since they decreased the duration of arrhythmias only by 40 and 45%, respectively, and did not decrease LDH release rates during the reperfusion period. Only p-coumaric acid increased coronary flow rates, whereas protocatechuic acid did not.ConclusionsWe conclude that the SFTE exerted the strongest cardioprotective effect, whereas its constituents (the p-coumaric and protocatechuic acids) were less effective in inducing cardioprotection.

Reduced coronary reserve in response to short‐term ischaemia and vasoactive drugs in ex vivo hearts from diabetic mice

The aim of the present study was to compare the coronary flow (CF) reserve of ex vivo perfused hearts from type 2 diabetic (db/db) and non-diabetic (db/+) mice. The hearts were perfused in the Langendorff mode with Krebs-Henseleit bicarbonate buffer (37 degrees C, pH 7.4) containing 11 mmol L(-1) glucose as energy substrate. The coronary reserve was measured in response to three different interventions: (1) administration of nitroprusside (a nitric oxide donor), (2) administration of adenosine and (3) production of reactive hyperaemia by short-term ischaemia. Basal CF was approximately 15% lower in diabetic when compared with non-diabetic hearts (2.1 +/- 0.1 vs. 2.6 +/- 0.2 mL min(-1)). The maximum increase in CF rate in response to sodium nitroprusside and adenosine was significantly lower in diabetic (0.6 +/- 0.1 and 0.9 +/- 0.1 mL min(-1) respectively) than in non-diabetic hearts (1.2 +/- 0.1 and 1.4 +/- 0.1 mL min(-1) respectively). Also, there was a clear difference in the rate of return to basal CF following short-term ischaemia between diabetic and non-diabetic hearts. Thus, basal tone was restored 1-2 min after the peak hyperaemic response in non-diabetic hearts, whereas it took approximately 5 min in diabetic hearts. These results show that basal CF, as well as the CF reserve, is impaired in hearts from type 2 diabetic mice. As diabetic and non-diabetic hearts were exposed to the same (maximum) concentrations of NO or adenosine, it is suggested that the lower coronary reserve in type 2 diabetic hearts is, in part, because of a defect in the intracellular pathways mediating smooth muscle relaxation.

The Effect of Agmatine on Ischemic and Nonischemic Isolated Rat Heart.

OBJECTIVE: the natural polyamines play a protective role during ischemic injury. We studied the effects of agmatine on ischemic and nonischemic isolated rat hearts. METHODS: Thirty-one rats were randomly assigned to one of four experimental groups. Sixteen rats were injected with saline (group 1, n = 9; group 3, n = 7), and 15 rats were injected with 100 mg/kg of agmatine (group 2, n = 8; group 4, n = 7). Injections were given twice: 24 hours and 1 hour before the experiment. Using the modified Langendorf model, rat hearts were perfused with Krebs-Henseleit solution for 105 minutes during phase 1 of the experiment (groups 1 and 2). During phase 2, hearts were exposed to 45 minutes of global ischemia (groups 3 and 4). RESULTS: During phase 1, no statistically significant differences were observed between the agmatine and the control groups. During phase 2, agmatine caused a significant increase in left ventricular pressure (P <.003). At the end of reperfusion, P(max) was 111% +/- 10% from the baseline levels versus only 82% +/- 5% in the control group. After 20 minutes of reperfusion, dP/dt (first-time derivative of the ventricular pressure) in the agmatine group reached full recovery of 106% +/- 12% versus only 64% +/- 14% in the saline group (P =.059). Agmatine also caused a significant increase in coronary flow rate (P <.004) throughout the reperfusion period. Quantitative immunohistochemical staining disclosed reduced cell damage in the agmatine-treated hearts (P <.02) versus the control group. CONCLUSION: Agmatine injection given before induced ischemia improves hemodynamic recovery by mechanisms that may be attributed to its vasodilatory properties.

Amlodipine dynamic effects and myocardial pharmacokinetics in the isolated and perfused guinea-pig heart.

Myocardial dynamic effects and pharmacokinetics of amlodipine were studied in the isolated retrogradely perfused and spontaneously beating guinea-pig heart. Pharmacokinetic analysis of drug accumulation showed one-compartment characteristics with an half-life of 76 min. Whereas disposition exhibited two-compartment characteristics with phasic half-lives of 25 and 174 min., respectively. Myocardial drug accumulation was increased by 600 times at steady-state compared to the perfusion liquid. Dynamic effect parameters were studied during increasing amlodipine concentrations from 0.16 to 220 nM. Dynamic steady-states developed within 20 min. Coronary flow-rate increased with an Emax of 119% and an EC50 of 1.2 x 10(-8) M. Amlodipine produced inhibitory effects on contraction amplitude and velocities of contraction and relaxation. Observed Emax-values and curve-fitted EC50-values were: 97, 97 and 94% and 1.10(-8), 7.7 x 10(-9) and 2.1 x 10(-8) M, respectively. Heart frequency was not changed. Oxygen consumption increased markedly to a maximum of 44% at 3 x 10(-8) M amlodipine and then decreased to nearly initial values. The frequency-corrected QT-interval decreased to a maximal extent of 20% at the three highest concentrations. Myocardial efficiency expressed as the ratio of contraction velocity times frequency to oxygen consumption exhibited a progressive decline to about 2% of initial values. The PQ-interval was not changed and the QRS-interval showed only a small but significant decrease at the highest amlodipine concentration. No arrythmogenic effects were observed. The study demonstrated a very slow accumulation and disposition of amlodipine in the guinea-pig heart with a steady-state myocardial drug concentrating accumulation of 600 times. Marked increase in coronary flow-rate and oxygen consumption accompanied by a progressive negative inotropic effect were observed.

Effects of N-acetylcysteine in the rat heart reperfused after low-flow ischemia: Evidence for a direct scavenging of hydroxyl radicals and a nitric oxide-dependent increase in coronary flow

The capacity of N-acetylcysteine to directly scavenge hydroxyl radical produced by rat hearts reperfused after 90 min of low-flow ischemia was assessed by the hydroxylation of 4-hydroxybenzoate into 3,4-dihydroxybenzoate using a gas chromatography-mass spectrometric assay. Reperfused hearts showed a massive release of 3,4-dihydroxybenzoate, lactate dehydrogenase, and total glutathione, contained less reduced and oxidized glutathione, but maintained spontaneous beating and coronary flow rates close to preischemic values. Compared to untreated hearts: reperfused hearts treated with N-acetylcysteine from the start of ischemia (i) released four times less 3,4-dihydroxybenzoate, but similar amounts of lactate dehydrogenase or glutathione, (ii) showed a nitric oxide-dependent increase in coronary flow rate, and (iii) contained less oxidized glutathione, but similar amounts of reduced glutathione. Reperfused hearts receiving N-acetylcysteine since the last 5 min of ischemia had also a four-times lower 3,4-dihydroxybenzoate release, but their coronary flow rate response was similar to that of untreated hearts. These results indicate that N-acetylcysteine can directly scavenge hydroxyl radicals produced by reperfused ischemic hearts, although this effect is not associated with any protective effects as indicated by the lactate dehydrogenase and glutathione release and cannot explain the nitric oxide-dependent reperfusion hyperemia.

Coronary reserve in experimental myocardial hypertrophy.

Three types of dysfunction of the coronary circulation have been described in experimental models of hypertension associated with left ventricular hypertrophy: (1) reduced coronary reserve, (2) a relative decrease in perfusion of subendocardial layers, (3) a shift to the right, i.e. to higher pressures, of the circulation pressure autoregulation range. These abnormalities are also observed in hypertensive patients, although it is significant that they do not appear to be related to the extent of left ventricular hypertrophy. The exact causes of these abnormalities have yet to be elucidated. Left ventricular hypertrophy does not seem to be an essential factor, although in certain experimental models of hypertension, there does appear to be a mismatch between the development of the coronary vasculature and hypertrophy of the myocytes. The stresses in vessels due to the increase in systolic, and especially intraventricular diastolic pressure can be viewed as additional aggravating factors. The essential abnormalities are structural and/or functional alterations in arterial walls. The structural alterations are reflected by a narrowed lumen due to parietal thickening. This may result from growth of muscle fibres (hypertrophy or hyperplasia) or collagen tissue and/or remodelling of tissues with no overall change in mass. Functionally, the reduced ability of the arteries to stretch, resulting from endothelial alterations may also play a role in the abnormalities observed in hypertensive patients. In our studies, we examined the effect of the antihypertensive drug perindopril on the coronary circulation in renovascular hypertensive rat (two kidneys--1 clip). We found that this inhibitor of angiotensin converting enzyme (ACE) led to a regression of left ventricular hypertrophy with a return to normal of the coronary reserve. Other studies using either this model or the spontaneously hypertensive rate has also pointed to a beneficial action of ACE inhibitors and other antihypertensive agents on the coronary circulation with reversal of the structural alterations in arterioles. Coronary disease is the main cause of mortality in hypertensive patients. Ironically, antihypertensive therapy has yet to live up to its promise of reducing significantly either the incidence or severity of coronary disease in such patients. Specific alterations of the coronary circulation may account for the relative failure of antihypertensive drugs, despite their proven efficacy in other systems (e.g., stroke prevention). The coronary circulation is unique in certain important respects. It is tightly regulated, maintaining an almost constant flow rate over a wide range of aortic arterial pressures (40-160 mmHg). Extraction of oxygen by the myocardium is almost maximal under resting conditions, and so the circulatory reserve depends almost entirely on the capacity to increase blood flow. This reserve is quite large since there may be a 4 to 5-fold increase in coronary flow rate in response to effort. Another significant detail is that myocardial contraction may lead to an interruption of coronary flow, especially in the deep subendocardial layers, which thus tend to be perfused solely during diastole. This last factor can be seen as the Achilles heel of the coronary circulation, which may be severely limited by myocardial hypertrophy, especially in patients with hypertension.

Intracellular Catalase Inhibition Does not Predispose Rat Heart to Ischemia-Reperfusion and Hydrogen Peroxide-Induced Injuries

The objective of this study was to determine whether inhibition of intracellular catalase would decrease the tolerance of the heart to ischemia-reperfusion and hydrogen peroxide-induced injuries. Isolated bicarbonate buffer-perfused rat hearts were used in the study. Intracellular catalase was inhibited with 3-amino-1,2,4-triazole (ATZ, 1.5 g/kg body weight, two hours prior to heart perfusion). In the ischemia-reperfusion protocol, hearts were arrested with St. Thomas'II cardioplegic solution, made ischemic for 35 min at 37 degrees C, and reperfused with Krebs-Henseleit buffer for 30 min. The extent of ischemic injury was assessed using postischemic contractile recovery and lactate dehydrogenase (LDH) leakage into reperfusate. In the hydrogen peroxide infusion protocol, hearts were perfused with increasing concentrations of hydrogen peroxide (inflow rates 0.05-1.25 mumol/min). Inhibition of catalase activity (30.4 +/- 1.8 mU/mg protein in control vs 2.4 +/- 0.3 mU/mg in ATZ-treated hearts) affected neither pre-ischemic aerobic cardiac function nor post-ischemic functional recovery and LDH release in hearts subjected to 35 min cardioplegic ischemic arrest. Myocardial contents of lipid hydroperoxides were similar in control and ATZ-treated animals after 20 min aerobic perfusion, ischemia, and ischemia-reperfusion. During hydrogen peroxide perfusion, there was an increase in coronary flow rate followed by an elevation in diastolic pressure and inhibition of contractile function in comparison with control hearts. The functional parameters between control and ATZ-treated groups remained unchanged. The concentrations of myocardial lipid hydroperoxides were the same in both groups. We conclude that inhibition of myocardial catalase activity with ATZ does not predispose the rat heart to ischemia-reperfusion and hydrogen peroxide-induced injury.

Pharmacokinetics and dynamic effects of diltiazem in the isolated guinea-pig heart.

Myocardial pharmacokinetics of diltiazem showed two-compartment characteristics in the isolated, spontaneously beating guinea-pig heart. Half-times of initial and terminal drug accumulation phases were about 2.1 and 14.4 min., respectively. At 1 microgram ml-1 (2.4 microM) in the perfusion liquid the average concentration of diltiazem in the myocardium at steady state was about 16 micrograms g-1 (38.6 microM) with 17% referable to the deepest, possibly intracellular compartment. Increasing diltiazem concentrations from 13 to 889 ng ml-1 (31-2144 nM) produced a progressive increase in coronary flowrate from 100 to 174%. The computed Em- and EC50-values were 73.2% and 187 nM, respectively. Oxygen consumption decreased to 27.6% showing Em = 106% and IC50 = 1536 nM. Amplitude and velocity of myocardial contraction decreased to about 6% and 2%; Em = 101% and 104%, IC50 = 266 and 186 nM, respectively. Heart beating frequency decreased to 63% exhibiting Em = 58% and IC50 = 2015 nM. The PQ- and QRS-intervals increased to 133% and 112%, respectively. The frequency-corrected QT-interval decreased to 81.6%. Our findings demonstrate a relatively rapid and moderate accumulation of diltiazem in the guinea-pig heart accompanied by a marked increase in coronary flow, progressive and pronounced negative inotropic and chronotropic effects and a less than proportional decrease in oxygen consumption.

Ibuprofen, Pharmacokinetics and Pharmacodynamics in the Isolated Rabbit Heart

Myocardial pharmacokinetics and dynamic effects of the non-steroidal antiinflammatory drug ibuprofen were studied in isolated, spontaneously beating and retrogradely perfused rabbit hearts. Both myocardial uptake and disposition of ibuprofen showed two-compartment characteristics, which possibly reflects extracellular and intracellular binding sites. Initial and terminal kinetic half-lives were about 0.6 and 13.4 min., respectively. Vd beta was about 82 ml/g myocardial tissue. Stepwise increased ibuprofen concentrations from 30 to 160 micrograms/ml in the Krebs-Henseleit perfusion liquid produced a progressive increase in coronary flowrate up to 178%, which then decreased somewhat at higher concentrations. Preliminary observations showed a direct relaxing effect on PGF-2 alpha produced contractions in coronary vasculature. Oxygen consumption increased simultaneously to 143% at 160 micrograms/ml and then decreased. Myocardial contractility (measured by amplitude and rate of contraction) decreased progressively to about 55% at concentrations from 60-160 micrograms/ml and further to 20% at 580 micrograms/ml. Myocardial efficiency expressed as the ratio of contraction rate to oxygen consumption decreased to about 0.2. Heart beat frequency decreased simultaneously to 73%. The electrocardiographic PQ and QRS intervals increased to 143 and 139%, respectively, whereas the QT interval did not increase significantly. Asystolia occurred in some cases at ibuprofen concentrations of 580 micrograms/ml. The findings suggest that ibuprofen at therapeutic concentrations may possibly produce some coronary vasodilation accompanied by a slight negative inotropic effect. Interactions with other cardioactive drugs seem possible. The drug may cause direct cardiotoxic effects at supratherapeutic concentrations.

Substitution of amino group in C6 of adenosine affects coronary flow rate but not heart rate in the perfused rabbit heart.

Effects of adenosine derivatives modified at the C6 of adenosine (AD) on coronary flow rate and heart rate in the perfused rabbit heart were examined. The means of, the EC30 (-log mole) of AD, N6 -cyclohexyladenosine (CHA), N6 -[(R)-2, 5-dioxo-3-pyrroridinyl] adenosine (FR), inosine (IN) and 6-mercaptopurine (6MP) on increase in coronary flow rate were 10.6, 8.75, 8.12, 5.71 and 5.30, respectively. The means of the EC30 (-log mole) of AD, CHA and FR on inhibitory effect of heart rate were 7.67, 10.2 and 9.28, respectively. IN and 6MP did not affect the heart rate. The dose-response curves of AD, CHA and FR for increase in coronary flow rate were shifted to the right at the EC30 level by treatment with aminophylline (10 M). The increase in coronary flow rate by 6MP and IN was not affected by aminophylline. The dose-response curves of inhibitory effect on heart rate by AD, CHA and FR were shifted to the right at the EC30 level by aminophylline. Thus, modification of the amio group of adenosine (i.e., CHA and FR) enhanced negative chronotrope, but attenuated the coronary vasodilation. Substitution of the amino group (i.e., IN and 6MP) abolished negative chronotrope, but the coronary vasodilating effect was retained.

Influence of dietary linoleic acid on cardiac function and prostaglandin release and on the effects of isoprenaline in the isolated rat heart.

We studied the effects of dietary linoleate on cardiac function and on the effectiveness of isoprenaline in isolated rat heart preparations. Male Wistar rats were fed either a diet rich in linoleic acid (LA) (25% of digestible energy as sunflower oil, 5% lard) or an LA-deficient diet (30% hydrogenated palm kernel oil). Control rats received a standard lab chow. Under certain experimental conditions the LA-rich diet resulted in increased contractile force, coronary flow rate, and prostaglandin (PG) release (PG-like substances and PGI2) and in a reduction in heart rate. These effects were modified by the duration of the feeding period and/or the age of the animals. In isolated perfused hearts of rats fed on a diet rich in LA for a 10-week period the inotropic effects of isoprenaline were diminished, whereas the isoprenaline-induced increase in coronary flow rate was augmented. The PG-releasing effect of isoprenaline was antagonized by the LA-rich diet. Preliminary in vivo investigations support these in vitro results. The mechanisms by which dietary LA influences cardiac function and the effectiveness of isoprenaline remain unclear.

Effects of arachidonic acid and bradykinin on the coronary flow, release of PGI2 and cardiac functions in the perfused guinea-pig heart.

The contribution of prostacyclin (PGI2) to the coronary vasodilating action of arachidonic acid (AA) and bradykinin (BK) was examined in isolated perfused guinea-pig hearts. The injection of Aa (100 to 1,000 ng) and BK (1 to 100 ng) into the heart resulted in a dose-dependent increase in the total amount of coronary flow and a release of 6-keto-prostaglandin F1alpha, a stable metabolite of PGI2. Both AA and BK showed weak positive chronotropic effects. In addition, higher doses (300 and 1,000 ng) of AA caused a transient reduction in the coronary flow rate, left ventricular systolic pressure, and left ventricular dp/dt. The changes in coronary flow, release of PGI2, and all cardiodynamic parameters induced by AA were abolished by pretreatment of the preparation with diclofenac-Na. On the other hand, the BK-induced increase in coronary flow rate was only partially reduced by diclofenac-Na when the release of 6-keto-prostaglandin F1alpha was completely inhibited. It is concluded that in isolated perfused guinea-pig hearts, BK has both PGI2-independent and PGI-2-dependent coronary vasodilating actions; the latter action is less than 25%, and the coronary vasodilating action of AA is mainly mediated via PGI2.

EFFECTS OF ARACHIDONIC ACID AND BRADYKININ ON THE CORONARY FLOW, RELEASE OF PGI2 AND CARDIAC FUNCTIONS IN THE PERFUSED GUINEA-PIG HEART

The contribution of prostacyclin (PGI2) to the coronary vasodilating action of arachidonic acid (AA) and bradykinin (BK) was examined in isolated perfused guinea-pig hearts. The injection of AA (100 to 1,000 ng) and BK (1 to 100 ng) into the heart resulted in a dose-dependent increase in the total amount of coronary flow and a release of 6-keto-prostaglandin F1α, a stable metabolite of PGI2. Both AA and BK showed weak positive chronotropic effects. In addition, higher doses (300 and 1,000 ng) of AA caused a transient reduction in the coronary flow rate, left ventricular systolic pressure, and left ventricular dp/dt. The changes in coronary flow, release of PGI2, and all cardiodynamic parameters induced by AA were abolished by pretreatment of the preparation with diclofenac-Na. On the other hand, the BK-induced increase in coronary flow rate was only partially reduced by diclofenac-Na when the release of 6-keto-prostaglandin F1α was completely inhibited. It is concluded that in isolated perfused guinea-pig hearts, BK has both PGI2-independent and PGI2-dependent coronary vasodilating actions; the latter action is less than 25%, and the coronary vasodilating action of AA is mainly mediated via PGI2.

Effects of perfusion pressure on coronary flow, myocardial Ca2+-washout, and the occurrence of calcium paradox in isolated perfused rat heart ventricles.

The influence of perfusion pressure (5-8 kPa) on coronary flow and myocardial Ca2+-washout during Ca2+-free perfusion, and on the occurrence of calcium paradox after subsequent Ca2+-reperfusion, was studied in isolated, stimulated, rat heart ventricles. During the Ca2+-free perfusion period (3 min) the following changes were observed: 1. Rapid cessation of ventricular contractions. 2. A pressure-dependent increase in diastolic rest tension. 3. A pressure-dependent increase increase in coronary flow rate. 4. A pressure-dependent increase in myocardial Ca2+-washout. Upon Ca2+-reperfusion all hearts failed to recover fully and the incidence of complete loss of ventricular contractility ("complete calcium paradox") increased with increasing perfusion pressure. Furthermore, a clear relationship between coronary flow and effluent-Ca2+-concentration (during Ca2+-free perfusion) and the occurrence of calcium paradox (upon Ca2+-reperfusion) was observed. The results suggested that the processes underlying the calcium paradox mechanism are influenced by the perfusion pressure, mainly via an effect on coronary flow during the Ca2+-free perfusion phase and through this effect on the rate and extent of myocardial Ca2+-washout.

A comparison of stimulation frequency and electro-augmentation on myocardial function, extensibility, coronary flow rate, oxygen consumption and glucose metabolism.

Abstract. The effects of increased heart rate on the function and metabolism of the isolated perfused rat heart were studied. Single stimuli as well as paired and coupled stimuli were used to increase the heart rate from 80 to 200 beats/ min. Heartblock was produced in the rat heart to give a preparation with a heart rate of 80 beats/min. For measurements of mechanical activity a modified Langendorf perfusion system with a myographic force transducer was used. Results indicate that tension development was greater with paired than with single stimuli at frequency rates of 100–160 beats/ min. At higher frequency rates there was no difference between single and paired stimuli. However, paired stimuli increased the tension developed per min. (TTM) for all rates studied, whereas they reduced the time to peak height of developed tension for rates up to 160 beats/min. Relationships of length to tension at different rates of stimulation were also determined. Myocardial oxygen consumption and coronary flow rates increased with increasing heart rate, with both single and paired stimuli. Paired stimulation caused significantly greater oxygen consumption at all frequency rates, while the increase in coronary flow rate was similar with paired and single stimuli. The effects of increasing heart rate by single and paired stimuli on the metabolism of [U‐14C] glucose were studied. Glucose uptake and lactate production were significantly higher with paired than with single stimuli at a constant heart rate. Paired and single stimuli had a similar effect on the pattern of glucose metabolism with increased heart rate.The results suggest, in agreement with the suggestion made by other workers, that the potentiating effects of paired stimuli dependent on the interval‐strength relationship of the impulses and are probably related to the optimal availability of Ca++ at the contractile sites. Furthermore, the increased oxygen consumption, the limited increase in coronary flow rate and the reduced effect of paired stimulation on tension development at higher rates of stimulation make it doubtful whether this procedure can be used for therapeutic purposes in the failing heart.