Decrease In Aortic Flow Research Articles

Overexpression of endothelial β3 -adrenergic receptor induces diastolic dysfunction in rats.

AimsDiastolic dysfunction is common in cardiovascular diseases, particularly in the case of heart failure with preserved ejection fraction. The challenge is to develop adequate animal models to envision human therapies in the future. It has been hypothesized that this diastolic dysfunction is linked to alterations in the nitric oxide (•NO) pathway. To investigate this issue further, we investigated the cardiac functions of a transgenic rat model (Tgβ3) that overexpresses the human β3‐adrenoceptor (hβ3‐AR) in the endothelium with the underlying rationale that the •NO pathway should be stimulated in the endothelium.Methods and resultsTransgenic rats (Tgβ3) that express hβ3‐AR under the control of intercellular adhesion molecule 2 promoter were developed for a specific expression in endothelial cells. Transcriptomic analyses were performed on left ventricular tissue from 45‐week‐old rats. Among all altered genes, we focus on •NO synthase expression and endothelial function with arterial reactivity and evaluation of •NO and O2 •− production. Cardiac function was characterized by echocardiography, invasive haemodynamic studies, and working heart studies. Transcriptome analyses illustrate that several key genes are regulated by the hβ3‐AR overexpression. Overexpression of hβ3‐AR leads to a reduction of Nos3 mRNA expression (−72%; P < 0.05) associated with a decrease in protein expression (−19%; P < 0.05). Concentration‐dependent vasodilation to isoproterenol was significantly reduced in Tgβ3 aorta (−10%; P < 0.05), while •NO and O2 •− production was increased. In the same time, Tgβ3 rats display progressively increasing diastolic dysfunction with age, as shown by an increase in the E/A filing ratio [1.15 ± 0.01 (wild type, WT) vs. 1.33 ± 0.04 (Tgβ3); P < 0.05] and in left ventricular end‐diastolic pressure [5.57 ± 1.23 mmHg (WT) vs. 11.68 ± 1.11 mmHg (Tgβ3); P < 0.05]. In isolated working hearts, diastolic stress using increasing preload levels led to a 20% decrease in aortic flow [55.4 ± 1.9 mL/min (WT) vs. 45.8 ± 2.5 mL/min (Tgβ3); P < 0.05].ConclusionsThe Tgβ3 rat model displays the expected increase in •NO production upon ageing and develops diastolic dysfunction. These findings provide a further link between endothelial and cardiac dysfunction. This rat model should be valuable for future preclinical evaluation of candidate drugs aimed at correcting diastolic dysfunction.

Hypercholesterolemia increases myocardial oxidative and nitrosative stress thereby leading to cardiac dysfunction in apoB-100 transgenic mice

We have previously shown that cholesterol diet-induced hyperlipidemia (marked hypertriglyceridemia and moderate hypercholesterolemia) increases cardiac formation of peroxynitrite and results in a moderate cardiac dysfunction in rats. Here our aim was to further clarify the mechanism of hyperlipidemia-induced nitrosative stress in a transgenic mouse model and to test if high cholesterol or high triglyceride is responsible for the hyperlipidemia-induced cardiac dysfunction. To determine the effect of cholesterol-enriched diet on cardiac performance and oxidative/nitrosative stress, wildtype and human apoB100 transgenic mice were fed a 2% cholesterol-enriched or a normal diet for 18 weeks. Serum cholesterol and LDL-cholesterol levels were significantly elevated only in the cholesterol-fed apoB100 transgenic mice, while serum triglycerides were increased in the transgenic mice fed a normal diet. Cholesterol-enriched diet significantly increased cardiac superoxide generation and NADPH oxidase expression and activity in apoB100 mice but not in wildtypes. Cardiac NO content and NO synthase activity did not change in either group. As assessed in isolated working hearts, aortic flow was significantly decreased only in apoB100 transgenic mice fed a cholesterol-enriched diet. The peroxynitrite decomposition catalyst FeTPPS attenuated the decrease in aortic flow in cholesterol-fed apoB100 mice. Immunohistochemistry showed elevated nitrotyrosine in the hearts of apoB100 mice fed the cholesterol-enriched diet. We conclude that hypercholesterolemia but not hypertriglyceridemia leads to increased formation of superoxide and peroxynitrite, and thereby results in cardiac dysfunction in hearts of human apoB100 transgenic mice.

Right heart bypass for left circumflex coronary artery bypass grafting.

Displacement of the heart to expose the left circumflex artery (LCX) causes hemodynamic disturbance during off-pump coronary artery bypass grafting (CABG). We applied right heart bypass (RHB) using a heparin-coated centrifugal pump without an oxygenator in an attempt to stabilize the hemodynamics. Five mongrel dogs (15.5-20 kg) were used. Hemodynamic parameters were continuously monitored at a fixed rate of 80 beats/min. The LCX was exposed with the use of an Octopus Tissue Stabilizer. After baseline data were obtained, each dog was placed in the Trendelenburg position. Finally, RHB was established with different pump flows. LCX exposure caused a significant decrease in aortic flow (to 33.1% +/- 13.1% of the baseline value) and arterial mean pressure (to 68.3% +/- 8.5%) (P < 0.001). Trendelenburg positioning caused these values to recover to 57.1% +/- 6.7% and 72.5% +/- 7.7%, respectively. RHB with 50% flow significantly improved the hemodynamic values, although 100% flow significantly increased LAP by 134.8% +/- 19.7% (P < 0.01). Tilting of the canine heart to expose the LCX caused significant deterioration of the hemodynamic values. Trendelenburg positioning was moderately effective, and RHB very effective, in improving the hemodynamics. In a limited number of cases, an appropriate flow of RHB may provide safe hemodynamic assistance during off-pump CABG of the LCX.

Correlation Between Function and Proto-oncogene Expression in Isolated Working Rat Hearts Under Various Overload Conditions

In isolated perfused working rat hearts we have studied the effects of norepinephrine (NE) and of pressure as well as volume overload alone, and in combination on heart function and expression of the proto-oncogenes c-fosand c-myc.This preparation was functionally stable over the observation period of 120 min. NE (3×10−8m) induced an immediate and sustained increase in aortic and coronary flow as well as in cardiac output. Volume overload was established by increasing left atrial filling pressure (preload) from 8–16 cm H2O and resulted in a marked increase in aortic flow and cardiac output which subsided somewhat over time. Pressure overload was created by elevation of afterload from 80–100 cm H2O and induced a decrease in aortic flow and a slight increase in coronary flow. Using specific cDNA clones, the mRNAs of c-fosand c-mycwere measured by Northern blots and quantified with densitometry. In all three conditions, c-fosmRNA was increased first, after 30 min. It was more pronounced and of longer duration in the NE-stimulated hearts. The increase in c-myc-mRNA occurred after 60 or 90 min. After 120 min, all signals were normal, although heart function was still altered in a manner specific for the respective intervention. Combination of NE with preload and afterload elevation as well as combination of preload and afterload elevation led first to an increase in cardiac output which was followed by a decline to various degrees. In all these combinations, the c-fosmRNA signal appeared earlier, after 15 min, and persisted for a longer period of time compared with the effect of a single stimulus. The c-mycmRNA was increased later, after 30 or 60 min. This increase persisted throughout the entire observation period, showing a further progressive rise. These results show that stimuli which cause cardiac hypertrophyin vivoinduce a transient and sequential increase in proto-oncogene expression in the isolated working rat heart. Combination of two hypertrophy-inducing stimuli elicit an earlier, more pronounced and longer-lasting expression of the proto-oncogenes c-fosand c-myc, while functional parameters deteriorate.

Effect of glutamate-aspartate reperfusion on postischemic neonatal myocardium

Objective: We postulated that l-glutamate– and l-aspartate–enriched perfusate would improve functional recovery of postischemic neonatal rabbit hearts. Methods: Isolated working neonatal rabbit hearts were perfused with Krebs-Henseleit buffer and then subjected to 1 hour of hypothermic cardioplegic arrest with St. Thomas' Hospital solution. Hearts were then reperfused with l-glutamate– and l-aspartate–enriched (20 mmol/L) Krebs-Henseleit buffer (AA-enriched Krebs-Henseleit buffer). Hearts reperfused with Krebs-Henseleit buffer alone acted as controls (experiment A). Another group of hearts underwent a similar protocol but were reperfused with the AA-enriched Krebs-Henseleit buffer with correction of the sodium content (experiment B). Results: Hearts reperfused with AA-enriched Krebs-Henseleit buffer showed a significant decrease in aortic flow at both 15 ( p = 0.04) and 30 ( p = 0.025) minutes compared with controls. Arrhythmias were frequent. Sodium content of the AA-enriched Krebs-Henseleit buffer was 174 ± 0.5 mmol/L. In experiment B, hearts reperfused with the AA-enriched Krebs-Henseleit buffer with correction of the sodium content exhibited no difference in aortic flow and cardiac output at either 15 or 30 minutes ( p = 0.95 and 0.5 and 0.48 and 0.78, respectively) compared with controls. No arrhythmias were observed. The sodium content of the AA-enriched Krebs-Henseleit buffer was 146 ± 0.7 mmol/L. Conclusions: A beneficial effect on functional recovery of neonatal hearts reperfused with AA-enriched Krebs-Henseleit buffer was not demonstrated. (J Thorac Cardiovasc Surg 1997;113:462-66)

Hemodynamic Mechanisms of Neurogenic Pulmonary Edema

Acute lung injury has been reported in man and animals with intracranial disorders, head trauma or cerebral compression. Early studies in our laboratory demonstrated that pulmonary hemorrhagic edema (PHE) of acute and fulminating type occurred accompanying severe hypertension and bradycardia (Cushing responses) in animals following cerebral compression (CC) or intracranial hypertension (ICH). The lung pathology was prevented by spinal transection and sympathoadrenergic blocking agents, but was not affected by decerebration, adrenalectomy, vagotomy and atropine. The effects of central sympathetic activation due to ICH on the systemic and pulmonary resistance and capacitance vessels were studied in dogs with a total heart bypass preparation. ICH caused an increase in vascular resistance with a reduction in the vascular capacity of the systemic and pulmonary circulation. The relative importance of hemodynamic changes was further analyzed with the measurement of aortic and pulmonary flows and the use of right and left heart bypass. The overall pattern of imbalance in the right and left cardiac output was characterized by an immediate fall in aortic flow accompanying a slower decline in pulmonary arterial flow. In rats with a right heart bypass, ICH produced severe pulmonary venous hypertension and PHE. In the left heart-bypassed rats, ICH induced systemic hypertension, whereas no significant changes occurred in the lungs. Our studies reveal that: (1) ICH elicits vasoconstriction of the systemic and pulmonary resistance and capacitance vessels and (2) the major cause of volume and pressure loading in the pulmonary circulation is acute left ventricular failure resulting in a dramatic decrease in aortic flow.

Converting Enzyme Inhibition by Enalapril in Experimental Heart Failure

We analyzed the effect of enalapril (0.1 mg/kg p.o. twice daily) on plasma electrolytes, urea, and creatinine in low cardiac output failure. In 14 male dogs implanted with chronic instrumentation, tachycardia was induced by ventricular pacing (265 impulses/min., 10-14 days). In 7 untreated dogs, pacing progressively lowered aortic flow by 44% and induced hyponatremia and elevations of plasma urea, creatinine, and potassium. Treatment with enalapril (n = 7) during pacing reduced the decrease in aortic flow by 33% and prevented changes in plasma urea, potassium, and sodium. We conclude that this is due to enalapril-induced retardation of heart failure progression.

Hemodynamic effects of intravenous lecithin-based perfluorocarbon emulsions in dogs.

We evaluated and compared the acute hemodynamic effects of perfluorooctylbromide-100% (PFOB), a fluorocarbon emulsified in lecithin without pluronic-F68 (F68), to those of a standard iodinated contrast agent, renografin-76% (R76), and Fluosol-DA 20% (Fluosol), a fluorocarbon emulsified in part by F68. Five open chest dogs were instrumented to evaluate hemodynamic changes after iv injection of PFOB (1 ml.1 g/kg) and R76 (1 ml.0.37 g of iodine/kg). Fluosol (1 ml.0.2 g/kg) was given to two of the five dogs at the end of their study. Fluosol caused transient hemodynamic collapse in both dogs. R76 caused the known transient effect of hypotension (-15.4 +/- 3.3%) followed by hypertension (6.5 +/- 2.7%) and an increase in aortic flow (29.3 +/- 3.9% at 30 sec). PFOB caused minimal, clinically insignificant decrease in aortic flow (4 +/- 1% at 10 sec).

An investigation of the cardiotoxic action of vancomycin in the isolated working rat heart

The mechanism of cardiotoxic action of vancomycin was examined in preparations of isolated working rat hearts and spontaneously beating right atria. Vancomycin produced a concentration-dependent decrease in aortic flow, coronary flow and heart rate in the isolated working rat heart, with no significant effect on other haemodynamic parameters. At 5 m m, vancomycin produced a statistically significant decrease (compared with control values) in aortic flow (24.1 ± 7.5%) and in the basal heart rate (34.3 ± 3.5%) after 15 min incubation. Coronary flow was also reduced by 23.5 ± 9.2%. Prolonged exposure of the preparation to 5 m m-vancomycin produced a marked time-dependent bradycardia accompanied by a time-dependent increase in the leakage of lactic dehydrogenase (LDH) into the perfusion medium. Moreover, a correlation ( r = −0.94) was found between the time-dependent bradycardia and LDH leakage induced by Vancomycin. In the isolated spontaneously beating right atria pretreated with atropine, vancomycin (5 m m) also produced a time-dependent bradycardia similar to that found in the isolated working rat heart. Moreover, 45Ca 2+-flux studies indicated that vancomycin had no significant effect on the 45Ca 2+ uptake into the right atrial muscle. These data suggest that: (1) vancomycin has a direct and acute cardiotoxic action at high concentrations (> 1 m m); (2) time-dependent bradycardia is a sensitive functional index for the cardiotoxicity induced by vancomycin; (3) the bradycardia elicited by vancomycin is due neither to the release of acetylcholine from the parasympathetic nerves innervating the heart nor to blockade of Ca 2+ entry.

Influence of intracellular acidosis on contractile function in the working rat heart.

The decrease in myocardial contractility during ischemia, hypoxia, and extracellular acidosis has been attributed to intracellular acidosis. Previous studies of the relationship between pH and contractile state have utilized respiratory or metabolic acidosis to alter intracellular pH. We developed a model in the working perfused rat heart to study the effects of intracellular acidosis with normal external pH and optimal O2 delivery. Intracellular pH and high-energy phosphates were monitored by 31P nuclear magnetic resonance spectroscopy. Hearts were perfused to a steady state with a medium containing 10 mM NH4Cl (extracellular pH, 7.4). The subsequent washout of NH3 from the cytosol generated a slight acidosis (from intracellular pH 7.0 to 6.8) which was associated with little change in the determinants of O2 consumption (rate-pressure product) and O2 delivery (coronary flow). Acidosis induced a substantial decrease in aortic flow and stroke volume which was associated with little change in peak systolic pressure. Results were qualitatively similar at different external [Ca2+] (1.75, 2.5, 3.15 mM) and preload (12 or 21 cmH2O) but were most prominent at the lowest external [Ca2+] and left atrial pressure. In contrast to this model of isolated intracellular acidosis, hearts subject to a respiratory (extracellular plus intracellular) acidosis showed a marked reduction in pressure development. It was concluded that 1) for the same intracellular acidosis the influence on tension development was more pronounced with a combined extra- and intracellular acidosis than with an isolated intracellular acidosis, and 2) stroke volume at constant preload was impaired by intracellular acidosis even though changes in developed pressure were minimal. These observations suggest that isolated intracellular acidosis has adverse effects on diastolic compliance and/or relaxation.

Neurohemodynamics of Pulmonary Edema. I. Autonomic Influence on Pulmonary Vascular Pressures and the Acute Pulmonary Edema State: A Preliminary Report

1)The intracisternal injection of thrombin and fibrinogen produces acute pulmonary edema in the rabbit and dog.2)The immediate post-injection period is characterized by the development of arterial and venous hypertension in both the pulmonary and systemic circulations, with pulmonary venous pressures that may reach 75 mm. Hg in the dog.3)This cardiovascular response is also accompanied by a significant decrease in aortic flow.4)Concomitantly there occurs a grossly observable increase in the size of the left auricle and engorgement of the pulmonary veins providing presumptive evidence of an increase in pulmonary blood volume.5)In some experiments pulsus alternans occurred during the period of low aortic flow and elevated aortic and pulmonary venous pressures.6)The elevation of pulmonary and systemic vascular pressures was not prevented either by vagotomy or upper thoracic sympathectomy, nor did vagotomy lower these elevated pressures after they had developed.7)The administration of sympathetic blockage by either spinal anesthesia or RO 2–2222 was followed by a fall in aortic, vena caval, pulmonary arterial, and pulmonary venous pressures simultaneously with a rise in aortic flow. Pulsus alternans, when it occurred, reverted to normal rhythm soon after sympathetic blockade.8)It is believed that the intracisternal injection of fibrin, among other things, stimulates cardiovascular centers and that this in turn increases the resistance against which the left ventricle is made to work. This increase in peripheral resistance may then exceed the work-failure threshold of the left ventricle resulting in elevated pulmonary vascular pressures.9)The shift of significant amounts of blood from the peripheral to the pulmonary circulation is probably enhanced by systemic vasoconstriction, since this latter phenomenon decreases the volume of the peripheral vascular bed.10)Since markedly elevated pulmonary vascular pressures can be returned to normal levels with only a moderate decrease in arterial pressure in hypertensive dogs, it seems reasonable to attempt to treat clinical pulmonary edema in this manner. It is felt that a carefully graded peripheral vasodilation, such as seems to be obtainable with RO 2–2222, would provide the means for: a) decreasing the work of the left ventricle per unit of flow, and b) shifting blood from the pulmonary to the peripheral circulation. Clinical evidence supporting this hypothesis may be found in the observation that spinal anesthesia confers a therapeutic effect on the acute pulmonary edema state of the hypertensive patient. The intracisternal injection of thrombin and fibrinogen produces acute pulmonary edema in the rabbit and dog. The immediate post-injection period is characterized by the development of arterial and venous hypertension in both the pulmonary and systemic circulations, with pulmonary venous pressures that may reach 75 mm. Hg in the dog. This cardiovascular response is also accompanied by a significant decrease in aortic flow. Concomitantly there occurs a grossly observable increase in the size of the left auricle and engorgement of the pulmonary veins providing presumptive evidence of an increase in pulmonary blood volume. In some experiments pulsus alternans occurred during the period of low aortic flow and elevated aortic and pulmonary venous pressures. The elevation of pulmonary and systemic vascular pressures was not prevented either by vagotomy or upper thoracic sympathectomy, nor did vagotomy lower these elevated pressures after they had developed. The administration of sympathetic blockage by either spinal anesthesia or RO 2–2222 was followed by a fall in aortic, vena caval, pulmonary arterial, and pulmonary venous pressures simultaneously with a rise in aortic flow. Pulsus alternans, when it occurred, reverted to normal rhythm soon after sympathetic blockade. It is believed that the intracisternal injection of fibrin, among other things, stimulates cardiovascular centers and that this in turn increases the resistance against which the left ventricle is made to work. This increase in peripheral resistance may then exceed the work-failure threshold of the left ventricle resulting in elevated pulmonary vascular pressures. The shift of significant amounts of blood from the peripheral to the pulmonary circulation is probably enhanced by systemic vasoconstriction, since this latter phenomenon decreases the volume of the peripheral vascular bed. Since markedly elevated pulmonary vascular pressures can be returned to normal levels with only a moderate decrease in arterial pressure in hypertensive dogs, it seems reasonable to attempt to treat clinical pulmonary edema in this manner. It is felt that a carefully graded peripheral vasodilation, such as seems to be obtainable with RO 2–2222, would provide the means for: a) decreasing the work of the left ventricle per unit of flow, and b) shifting blood from the pulmonary to the peripheral circulation. Clinical evidence supporting this hypothesis may be found in the observation that spinal anesthesia confers a therapeutic effect on the acute pulmonary edema state of the hypertensive patient.