Determination of cardiac contractility in awake unsedated mice with a fluid-filled catheter

Today, cardiac contractility in mice is exclusively measured under anesthesia or in sedated animals because the catheters available are too rigid to be used in awake mice. We therefore developed a new catheter (Pebax 03) to measure cardiac contractility in conscious mice. In this study, we evaluated the accuracy and utility of this new catheter for assessment of cardiac contractility in anesthetized and conscious mice. With the use of a balloon-pop test, the Pebax catheter with an inner diameter of 0.3 mm was found to exhibit a high natural frequency, a low damping coefficient, and a flat frequency of up to 50.5 +/- 0.6 Hz. Under anesthesia (0.5% or 1.0% halothane), no difference was found in heart rate (HR), left ventricular (LV) systolic pressure (LVSP), the maximum rates of LV pressure rise and fall (LV dP/dt(max) and LV dP/dt(min), respectively), ejection time (ET), and isovolumic relaxation time constant (tau) when measured with either the 1.4-Fr Millar or Pebax 03 catheter. However, when HR, LVSP, LV dP/dt(max), and LV dP/dt(min) were recorded with the Pebax catheter in awake mice, values were significantly higher, and ET and tau were lower, than under anesthesia, suggesting a major impact of anesthesia on these parameters. The Pebax catheter was also used in a normotensive one-renin gene mouse model of cardiac hypertrophy induced by DOCA and salt. In this model, DOCA-salt induced a severe decrease in cardiac contractility in the absence of changes in blood pressure. These data demonstrate that cardiac contractility can be measured very accurately in conscious mice. This new device can be of great help in the investigation of cardiac function in normal and genetically engineered mice.     

Adverse effects of atrioventricular synchronous right ventricular pacing on left ventricular sympathetic activity, efficiency, and hemodynamic status

Right ventricular (RV) pacing is now recognized to play a role in the development of heart failure in patients with and without underlying left ventricular (LV) dysfunction. We used the cardiac norepinephrine spillover method to test the hypothesis that RV pacing is associated with cardiac sympathetic activation. We studied 8 patients with normal LV function using temporary right atrial and ventricular pacing wires. All measurements were carried out during a fixed atrial pacing rate. The radiotracer norepinephrine spillover technique was employed to measure total body and cardiac sympathetic activity while changes in LV performance were evaluated with a high-fidelity manometer catheter. Atrioventricular synchronous RV pacing, compared with atrial pacing alone, was associated with a 65% increase in cardiac norepinephrine spillover, an increase in LV end-diastolic pressure, and a reduction in myocardial efficiency. These responses may play a role in the development of heart failure and poor outcomes that are associated with chronic RV pacing.     

Pressor effect of electroacupuncture on hemorrhagic hypotension

Neiguan (PC-6) is a traditional acupoint in each forearm and overlies the trunk of the median nerve. Previous studies show that electroacupuncture (EA) at the Neiguan acupoint could improve not only myocardial ischemic dysfunction by inducing a depressor response but also recover hemorrhagic hypotension by inducing a pressor response. However, their physiological mechanisms are not yet elucidated. We investigated the pressor effect of Neiguan EA and its mechanism by focusing on left ventricular (LV) performance in a canine hemorrhagic hypotension model. We hemorrhaged 36 anesthetized and thoracotomized mongrel dogs and decreased LV end-systolic pressure (ESP) to approximately 70 mmHg (35% decrease). We obtained LV pressure-volume (P-V) data with a micromanometer catheter and a conductance catheter. One-hour Neiguan EA significantly recovered the decreased ESP, end-diastolic volume, and stroke volume by 32 +/- 13%, 27 +/- 13%, and 39 +/- 17%, respectively (P < 0.05), without changing heart rate and the slope of the end-systolic P-V relation. Neiguan EA inhibited a hemorrhage-induced increase in plasma catecholamines. However, vecuronium (neuromuscular blocking agent) administration abolished the antihypotension effect of Neiguan EA. Furthermore, Neiguan EA was much more effective than a nonacupoint thigh EA. We conclude that Neiguan EA achieved the antihypotension effect by improving LV filling of the hemorrhage-depressed LV performance despite the inhibition of the hemorrhage-increased plasma catecholamines. This pressor effect seemed to accompany an increased venous return by Neiguan EA-increased vasomotor tone and muscle pump. This study demonstrated a scientific basis for the therapeutic efficacy of acupuncture in the treatment of hemorrhagic hypotension and shock.     

Effects of coupled pacing on cardiac performance during acute atrial tachycardia and fibrillation: an old therapy revisited for a new reason

Atrial tachycardia (AT) and fibrillation (AF) result in rapid ventricular rates that are detrimental to optimal cardiac function. The purpose of this study was to determine whether the application of a coupled pacing (CP) regimen would improve ventricular function by decreasing the ventricular rate of mechanical contractions (VRMCs). We simulated AT by pacing either atrium at a rate that resulted in a rapid but regular ventricular rate in seven anesthetized dogs. AF was induced by increasing the atrial pacing rate until atrial activation did not follow the pacing. After the induction of either AT or AF, we applied CP after each intrinsic ventricular activation. We measured the VRMCs and left ventricular (LV) pressures and volumes via a pressure-conductance catheter. The marked reductions in VRMCs during CP resulted in increases in LV end-diastolic volume. The CP resulted in virtually no mechanical contractions, whereas the strength of contractions from the normal electrical activation increased. The increases in the positive LV rate of pressure development over time and LV ejection fraction during CP were the result of postextrasystolic potentiation. The average stroke work (area of the pressure-volume loops) increased as a result of CP during both AT and AF. Despite the large increases in stroke volume (approximately 2x) during CP, the changes in cardiac output were moderate because the VRMCs markedly decreased (approximately 1/2). We conclude that CP therapy may be a viable therapy for slowing the heart rate and improving cardiac performance in patients with AT and AF.     

Volume loading reduces pulmonary vascular resistance in ventilated animals with acute lung injury: evaluation of RV afterload

During mechanical ventilation, increased pulmonary vascular resistance (PVR) may decrease right ventricular (RV) performance. We hypothesized that volume loading, by reducing PVR, and, therefore, RV afterload, can limit this effect. Deep anesthesia was induced in 16 mongrel dogs (8 oleic acid-induced acute lung injury and 8 controls). We measured ventricular pressures, dimensions, and stroke volumes during positive end-expiratory pressures of 0, 6, 12, and 18 cmH(2)O at three left ventricular (LV) end-diastolic pressures (5, 12, and 18 mmHg). Oleic acid infusion (0.07 ml/kg) increased PVR and reduced respiratory system compliance (P < 0.05). With positive end-expiratory pressure, PVR was greater at a lower LV end-diastolic pressure. Increased PVR was associated with a decreased transseptal pressure gradient, suggesting that leftward septal shift contributed to decreased LV preload, in addition to that caused by external constraint. Volume loading reduced PVR; this was associated with improved RV output and an increased transseptal pressure gradient, which suggests that rightward septal shift contributed to the increased LV preload. If PVR is used to reflect RV afterload, volume loading appeared to reduce PVR, thereby improving RV and LV performance. The improvement in cardiac output was also associated with reduced external constraint to LV filling; since calculated PVR is inversely related to cardiac output, increased LV output would reduce PVR. In conclusion, our results, which suggest that PVR is an independent determinant of cardiac performance, but is also dependent on cardiac output, improve our understanding of the hemodynamic effects of volume loading in acute lung injury.     

Aortic wave dynamics and its influence on left ventricular workload

The pumping mechanism of the heart is pulsatile, so the heart generates pulsatile flow that enters into the compliant aorta in the form of pressure and flow waves. We hypothesized that there exists a specific heart rate at which the external left ventricular (LV) power is minimized. To test this hypothesis, we used a computational model to explore the effects of heart rate (HR) and aortic rigidity on left ventricular (LV) power requirement. While both mean and pulsatile parts of the pressure play an important role in LV power requirement elevation, at higher rigidities the effect of pulsatility becomes more dominant. For any given aortic rigidity, there exists an optimum HR that minimizes the LV power requirement at a given cardiac output. The optimum HR shifts to higher values as the aorta becomes more rigid. To conclude, there is an optimum condition for aortic waves that minimizes the LV pulsatile load and consequently the total LV workload.     

Hemodynamic effects of cardiac cycle-specific increases in intrathoracic pressure

Changes in intrathoracic pressure (ITP) can influence cardiac performance by affecting ventricular loading conditions. Because both systemic venous return and factors determining left ventricular (LV) ejection may vary over the cardiac cycle, phasic increases in ITP may differentially affect preload or afterload if delivered at specific points within the cardiac cycle. We studied the hemodynamic effects of cardiac cycle-specific increases in ITP (pulses) delivered by a high-frequency jet ventilator in an acute closed-chested canine model (n = 11), using electromagnetic flow probes to measure biventricular stroke volume. Measurements were taken during a control condition after the induction of acute ventricular failure (AVF) by propranolol hydrochloride and volume infusion. ITP was independently varied without changing lung volume by the inflation of thoracoabdominal binders. Although synchronous pulses had minimal hemodynamic effects in unbound controls, binding pulses timed to occur in early diastole resulted in decreases in LV filling pressure and left ventricular stroke volume (SVlv) (P less than 0.05). In the AVF condition, pulses increased LV performance, evidenced by increases in SVlv (P less than 0.01), despite decreases in LV filling pressure (P less than 0.05). This effect is maximized by binding and by timing the pulses to occur in systole. We conclude that cardiac cycle-specific increases in ITP can significantly affect cardiac performance. These effects appear to be related to the ability of such timed pulses to selectively affect LV preload and afterload.     

Minimally invasive aortic banding in mice: effects of altered cardiomyocyte insulin signaling during pressure overload

We developed a minimally invasive method for producing left ventricular (LV) pressure overload in mice. With the use of this technique, we quickly and reproducibly banded the transverse aorta with low surgical morbidity and mortality. Minimally invasive transverse aortic banding (MTAB) acutely and chronically increased LV systolic pressure, increased heart weight-to-body weight ratio, and induced myocardial fibrosis. We used this technique to determine whether reduced insulin signaling in the heart altered the cardiac response to pressure overload. Mice with cardiac myocyte-restricted knockout of the insulin receptor (CIRKO) have smaller hearts than wild-type (WT) controls. Four weeks after MTAB, WT and CIRKO mice had comparably increased LV systolic pressure, increased cardiac mass, and induction of mRNA for beta-myosin heavy chain and atrial natriuretic factor. However, CIRKO hearts were more dilated, had depressed LV systolic function by echocardiography, and had greater interstitial fibrosis than WT mice. Expression of connective tissue growth factor was increased in banded CIRKO hearts compared with WT hearts. Thus lack of insulin signaling in the heart accelerates the transition to a more decompensated state during cardiac pressure overload. The use of the MTAB approach should facilitate the study of the pathophysiology and treatment of pressure-overload hypertrophy.     

Determinants of LV diastolic function during atrial fibrillation: beat-to-beat analysis in acute dog experiments

Left ventricular (LV) diastolic function during atrial fibrillation (AF) remains poorly understood due to the complex interaction of factors and beat-to-beat variability. The purpose of the present study was to elucidate the physiological determinants of beat-to-beat changes in LV diastolic function during AF. The RR intervals preceding a given cardiac beat were measured from the right ventricular electrogram in 12 healthy open-chest mongrel dogs during AF. Doppler echocardiography and LV pressure and volume beat-to-beat analyses were performed. The LV filling time (FT) and early diastolic mitral inflow velocity-time integral (E(vti)) were measured using the pulsed Doppler method. The LV end-diastolic volume (EDV), peak systolic LV pressure (LVP), minimum value of the first derivative of LV pressure curve (dP/dt(min)), and the time constant of LV pressure decay (tau) were evaluated with the use of a conductance catheter for 100 consecutive cardiac cycles. Beat-to-beat analysis revealed a cascade of important causal relations. LV-FT showed a significant positive linear relationship with E(vti) (r = 0.87). Importantly, there was a significant positive linear relationship between the RR interval and LV-EDV in the same cardiac beat (r = 0.53). Consequently, there was a positive linear relationship between LV-EDV and subsequent peak systolic LVP (r = 0.82). Furthermore, there were significant positive linear and negative curvilinear relationships between peak systolic LVP and dP/dt(min) (r = 0.95) and tau (r = -0.85), respectively, in the same cardiac beat. In addition, there was a significant negative curvilinear relationship between dP/dt(min) and tau (r = -0.86). We have concluded that the determinants of LV diastolic function in individual beats during AF depend strongly on the peak systolic LVP. This suggests that the major benefit of slower ventricular rate appears related to lengthening of LV filling interval, promoting subsequent higher peak systolic LVP and greater LV relaxation.     

Cardiac-specific norepinephrine mass transport and its relationship to left ventricular size and systolic performance

Objectives of this study were to develop a technique for quantifying cardiac-specific norepinephrine (NE) mass transport and determine whether cardiac NE kinetic modeling parameters were related to physiological variables of left ventricular (LV) size and systolic performance in nine patients with chronic mitral regurgitation. Biplane contrast cineventriculograms were used to determine LV size and ejection fraction (EF), micromanometer LV pressures and radionuclide LV volumes from a range of loading conditions to calculate LV end-systolic elastance, and [(3)H]NE infusions with LV and coronary sinus sampling for [(3)H]NE and endogenous NE during and after termination of infusions to model NE mass transport. Total NE release rate into cardiac interstitial fluid (M(IF)(R)) averaged 859 +/- 214 and NE released de novo into cardiac interstitial fluid (M(IF)(u,r,en)) averaged 546 +/- 174 pmol/min. Both M(IF)(R) and M(IF)(u,r,en)correlated directly with LV end-systolic volume (r = 0.84, P = 0.005; r = 0.86, P = 0.003); inversely with LV EFs (r = -0.75, P = 0.02; r = -0.81, P = 0.008); and inversely with LV end-systolic elastance values, optimally fit by a nonlinear function (r = 0.89, P = 0.04; r = 0.96, P = 0.01). We conclude that total and newly released NE into interstitial fluid of the heart, determined by regional mass transport kinetic model, are specific measures of regional cardiac-specific sympathetic nervous system activity and are strongly related to measures of LV size and systolic performance. These data support the concept that this new model of organ-specific NE kinetics has physiological relevance.     

Validation of echocardiographic methods for assessing left ventricular dysfunction in rats with myocardial infarction

The rat infarct model is widely used in heart failure research, but few echocardiographic indexes of left ventricular (LV) function are validated in this model. Accordingly, the objective of this study was to validate a 13-segment LV wall motion score index (WMSI) and the myocardial performance index (MPI) in infarcted rats. Twenty-nine male Wistar rats underwent left coronary artery ligation or sham operation and were evaluated with two-dimensional and Doppler flow echocardiography 8 wk later. After echocardiography, invasive indexes were obtained using a high-fidelity catheter. WMSI and MPI were correlated with the invasive and noninvasive measurements of LV function. WMSI and MPI significantly correlated directly with end-diastolic pressure (r=0.72 and 0.42 for WMSI and MPI, respectively) and the time constant of isovolumic relaxation (r=0.68 and 0.48) and inversely with peak rate of rise of LV pressure (+dP/dt; r=-0.68 and -0.50), peak rate of decline in LV pressure (r=-0.57 and -0.44), LV developed pressure (r=-0.58 and -0.42), area fractional shortening (r=-0.85 and -0.53), and cardiac index (r=-0.74 and -0.74). Stepwise linear regression analyses revealed that LV end-diastolic pressure, +dP/dt, area fractional shortening, and cardiac index were independent determinants of WMSI (r=0.994) and that cardiac index and +dP/dt were independent determinants of MPI (r=0.781). We conclude that the 13-segment WMSI and MPI are reproducible and correlate strongly with established echocardiographic and invasive indexes of systolic and diastolic function. These findings support the use of WMSI and MPI as indexes of global LV function in the rat infarction model of heart failure.     

Rapid microcomputed tomography suggests cardiac enlargement occurs during conductance catheter measurements in mice

Conductance catheters (CC) represent an established method of determining cardiac function in mice; however, the potentially detrimental effects a catheter may have on the mouse heart have never been evaluated. The present study takes advantage of rapid three-dimensional (3D) microcomputed tomography (CT) to compare simultaneously acquired micro-CT and CC measurements of left ventricular (LV) volumes in healthy and infarcted mice and to determine changes in LV volume and function associated with CC insertion. LV volumes were measured in C57BL/6 mice (10 healthy, 10 infarcted, 2% isoflurane anesthesia) using a 1.4-Fr Millar CC. 3D micro-CT images of each mouse were acquired before CC insertion as well as during catheterization. Each CT scan produced high-resolution images throughout the entire cardiac cycle in <1 min, enabling accurate volume measurements as well as direct visualization of the CC within the LV. Bland-Altman analysis demonstrated that CC measurements underestimate volume compared with CT measurements in both healthy [bias of -18.4 and -28.9 μl for end-systolic (ESV) and end-diastolic volume (EDV), respectively] and infarcted mice (ESV = -51.6 μl and EDV = -71.7 μl); underestimation was attributed to the off-center placement of the catheter. Individual evaluation of each heart revealed LV dilation following CC insertion in 40% of mice in each group. No change in ejection fraction was observed, suggesting the enlargement was caused by volume overload associated with disruption of the papillary muscles or chords. The enlargement witnessed was not significant; however, the results suggest the potential for CC insertion to detrimentally affect mouse myocardium, necessitating further investigation.     

New technique for measurement of left ventricular pressure in conscious mice

Concern about the effects of anesthesia on physiological measurements led us to develop methodology to assess left ventricular (LV) pressure in conscious mice. Polyethylene-50 tubing filled with heparinized saline was implanted in the LV cavity through its apex via an abdominal approach and exteriorized to the back of the animal. This surgery was done under anesthesia with either an intraperitoneal injection of ketamine (80 mg/kg) and xylazine (5 mg/kg) (K+X) in 11 mice or isoflurane (ISF; 1.5 vol%) by inhalation in 14 mice. Postoperatively, mice were trained daily to lie quietly head first in a plastic cone. LV pressure, the first derivative of LV pressure (dP/dt), and heart rate (HR) in the conscious state were compared between the two groups at 3 days and 1 wk after recovery from surgery using a 1.4-Fr Millar catheter inserted into the LV through the tubing, with the mice lying quietly in the plastic cone. Acutely during anesthesia, K+X decreased HR (from 698 to 298 beats/min), LV systolic pressure (from 107 to 65 mmHg), and maximal dP/dt (dP/dt(max)) (from 15,724 to 4,445 mmHg/s), all P < 0.01. Similar but less marked negative chronotropic and inotropic effects were seen with ISF. HR and dP/dt(max) were decreased significantly in K+X mice 3 days after surgery compared with those anesthetized with ISF (655 vs. 711 beats/min, P < 0.05; 14,448 vs. 18,048 mmHg/s, P < 0.001) but increased to the same level as in ISF mice 1 wk after surgery. In ISF mice, recovery of function occurred rapidly and there were no differences in LV variables between 3 days and 1 wk. LV pressure and dP/dt can be measured in conscious mice with a micromanometer catheter inserted through tubing implanted permanently in the LV apex. Anesthesia with either K+X or, to a lesser extent, ISF, depressed LV function acutely. This depression of function persisted for 3 days after surgery with K+X (but not ISF) and did not recover completely until 1 wk postanesthesia.     

Pressure overload-induced hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes

The role of the angiotensin II type 2 (AT2) receptor in cardiac hypertrophy remains controversial. We studied the effects of AT2 receptors on chronic pressure overload-induced cardiac hypertrophy in transgenic mice selectively overexpressing AT2 receptors in ventricular myocytes. Left ventricular (LV) hypertrophy was induced by ascending aorta banding (AS). Transgenic mice overexpressing AT2 (AT2TG-AS) and nontransgenic mice (NTG-AS) were studied after 70 days of aortic banding. Nonbanded NTG mice were used as controls. LV function was determined by catheterization via LV puncture and cardiac magnetic resonance imaging. LV myocyte diameter and interstitial collagen were determined by confocal microscopy. Atrial natriuretic polypeptide (ANP) and brain natriuretic peptide (BNP) were analyzed by Northern blot. Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2, inducible nitric oxide synthase (iNOS), endothelial NOS, ERK1/2, p70S6K, Src-homology 2 domain-containing protein tyrosine phosphatase-1, and protein serine/threonine phosphatase 2A were analyzed by Western blot. LV myocyte diameter and collagen were significantly reduced in AT2TG-AS compared with NTG-AS mice. LV anterior and posterior wall thickness were not different between AT2TG-AS and NTG-AS mice. LV systolic and diastolic dimensions were significantly higher in AT2TG-AS than in NTG-AS mice. LV systolic pressure and end-diastolic pressure were lower in AT2TG-AS than in NTG-AS mice. ANP, BNP, and SERCA2 were not different between AT2TG-AS and NTG-AS mice. Phospholamban (PLB) and the PLB-to-SERCA2 ratio were significantly higher in AT2TG-AS than in NTG-AS mice. iNOS was higher in AT2TG-AS than in NTG-AS mice but not significantly different. Our results indicate that AT2 receptor overexpression modified the pathological hypertrophic response to aortic banding in transgenic mice.     

Dependence of changes in beta-adrenoceptor signal transduction on type and stage of cardiac hypertrophy.

To examine whether cardiac hypertrophy is associated with changes in beta-adrenoceptor signal transduction mechanisms, pressure overload (PO) was induced by occlusion of the abdominal aorta and volume overload (VO) by creation of an aortocaval shunt for 4 and 24 wk in rats. After hemodynamic assessment of the animals, the left ventricular (LV) particulate fraction was isolated for measurement of beta(1)-adrenoceptors and adenylyl cyclase activity, and cardiomyocytes were isolated for monitoring of the intracellular Ca(2+) concentration. Although PO and VO produced cardiac hypertrophy and increased LV end-diastolic pressure at 4 wk, cardiac function was increased in animals subjected to PO but remained unaltered in animals subjected to VO. Cardiac hypertrophy and increased LV end-diastolic pressure were associated with depressed cardiac function at 24 wk of PO or VO, but clinical signs of congestive heart failure were evident only in animals subjected to VO. Isoproterenol-induced increases in cardiac function, activation of adenylyl cyclase activity, and increase in intracellular Ca(2+) concentration, as well as beta(1)-adrenoceptor density, were unaltered by PO at 4 wk, augmented by VO at 4 wk, and attenuated by PO and VO at 24 wk. These results suggest that alterations in beta(1)-adrenoceptor signal transduction are dependent on the type and stage of cardiac hypertrophy.     

Differences in distensibility between the anterior and posterior walls of the left ventricle in dogs

Nonuniformity of myocardial systolic and diastolic performance in the normal left ventricle has been recognized by a number of investigators. Lack of homogeneity in diastolic properties might be caused by or related to differences in the distensibility of different regions of the left ventricular (LV) wall. Thus, we compared the end-diastolic transmural pressure-strain relations in both the anterior and posterior LV walls in seven anesthetized dogs during two interventions (pulmonary artery constriction and aortic constriction). Transmural pressure was defined as the difference between LV intracavitary pressure and local pericardial pressure. LV pressure was measured using a micromanometer; pericardial pressures over the LV anterior and posterior walls were measured with balloon transducers. Circumferentially oriented pairs of sonomicrometer crystals were implanted in the midwall of the anterior and posterior walls of the LV to measure segment lengths. Strains were calculated as (L-L0)/L0, where L was the instantaneous segment length and L0 was the segment length when transmural pressure was zero. The pattern of end-diastolic transmural pressure--strain relations was similar in all dogs. The change in strain in the posterior wall was always greater than that in the anterior wall. Opening the pericardium did not affect the difference in distensibility of the anterior and posterior walls. The results suggest that the posterior wall is more compliant than the anterior wall (that is, for a given difference in transmural pressure, the local segment length change of the posterior wall was greater). This seems consistent with other observations, which suggest that the posterior wall might make a greater contribution to diastolic filling.     

Protein remodeling of the heart ventricles in hereditary hypertriglyceridemic rat: effect of ace-inhibition

The aim of this study was to determine whether protein remodeling of the heart ventricles and remodeling of the aorta were present in hereditary hypertriglyceridemic (hHTG) rats and whether treatment with the angiotensin-converting enzyme inhibitor, captopril could prevent these alterations. Three groups of rats were investigated in a four week experiment control Wistar /C/rats, hHTg rats, hHTg rats given captopril (100 mg/kg/day) (hHTg + CAP). In the hHTg group, the increased systolic blood pressure (SBP) was associated with hypertrophy of the LV and RV. Protein profile analysis revealed an enhancement of metabolic protein concentration in both ventricles. The concentration of total collagenous proteins was not changed in either ventricles. However, alterations in composition of cardiac collagen were detected, characterized by higher concentration of hydroxyproline in pepsin-insoluble fraction and lower concentration of hydroxyproline in pepsin soluble faction in the LV. Hypertrophy of aorta, associated with the reduction of nitric oxide dependent relaxation, was also present in hHTG rats. Captopril normalized SBP, reduced left ventricular hypertrophy (LVH), diminished metabolic protein concentration in both ventricles, and improved NO-dependent relaxation of the aorta. Furthermore, captopril partially reversed alterations in hydroxyproline concentration in soluble and insoluble collagenous fractions of the LV. We conclude that hypertrophy of both ventricles and the aorta are present in hHTG rats, along with protein remodeling of both ventricles. Captopril partially prevented left ventricular hypertrophy development and protein remodeling of the myocardium.     

Myocardial functional correlates of cardiac myosin light chain 2 phosphorylation

In vitro and in situ studies have proposed a potentiation of submaximal force production after myosin light chain 2 (P-light chain) phosphorylation in mammalian striated muscle. The purpose of this study was to ascertain the relationship between the augmentation in left ventricular pressure development and cardiac myosin P-light chain phosphorylation at different times during and after submaximal treadmill exercise involving adult female Sprague-Dawley rats. In vivo hemodynamic measurements were monitored with an indwelling high-fidelity solid-state pressure transducer. Exercise heart rate, peak left ventricular (LV) pressure, and rate of LV pressure development/relaxation (LV +/- dP/dt) were significantly elevated compared with a normal sedentary group (P less than 0.001). Peak LV pressure remained significantly elevated throughout 20 min of postexercise recovery (P less than 0.01), and heart rate, LV end-diastolic pressure, and LV +/- dP/dt returned rapidly to preexercise values. Corresponding to these in vivo hemodynamic changes, increased levels of P-light chain phosphorylation were observed during both exercise (16%, P less than 0.01) and subsequent recovery periods (14%, P less than 0.02) compared with the NC group. A quasi-temporal relationship was observed between postexercise peak LV pressure potentiation and P-light chain phosphorylation. These results demonstrate that cardiac myosin P-light chain phosphorylation is associated, in part, with the augmentation of peak LV pressure observed during both exercise and recovery.     

Increased insulin-like growth factor-I gene expression precedes left ventricular cardiomyocyte hypertrophy in a rapidly-hypertrophying rat model system

Chronic pressure overload leads to an increase in the size, i.e. hypertrophy, of cardiomyocytes in the heart. However, the molecular mechanisms underlying this hypertrophy are not understood. Insulin-like growth factor-I (IGF-I) synthesized locally in the heart is known to be associated with the hypertrophic process. So far, however, cardiac IGF-I gene expression in the widely used rat model system has only been shown to be increased when the hypertrophy induced by pressure-overload was already established. Therefore, the question of whether IGF-I serves as an initiating or early-enhancing factor for the cardiac hypertrophy remains unanswered. Here, cardiac hypertension and hypertrophy were rapidly induced in the rat by complete constriction of the abdominal aorta between the origins of the renal arteries. Carotid arterial systolic blood pressure remained unchanged in sham rats but increased rapidly in the pressure-overloaded constricted rats with a sustained hypertension established by 3 days. Hypertrophy of left ventricular (LV) cardiomyocytes in constricted rats also occurred by 3 days. However, this hypertrophy was preceded by increases in LV IGF-I mRNA and protein which occurred within 1 day. These results support the hypothesis that cardiac-synthesized IGF-I is an initiating or early-enhancing factor for hypertrophy of LV cardiomyocytes.     

Attenuation of left ventricular dysfunction by an ACE inhibitor after myocardial infarction in a kininogen-deficient rat model

Bradykinin (BK) coronary outflow and left ventricular (LV) performance of kininogen-deficient Brown Norway Katholiek (BNK) rats and Brown Norway Hannover (BNH) controls were investigated. We analyzed whether the angiotensin-converting enzyme (ACE) inhibitor ramipril is able to attenuate LV dysfunction after induction of myocardial infarction (MI) in this animal model. Ex vivo, the basal BK content in the coronary outflow of buffer-perfused, isolated hearts was measured by specific radioimmunoassay. In vivo, left ventricular pressure (LVP), the maximal rate of LVP increase, LV end-diastolic pressure, the maximal rate of LVP decrease and heart rate were determined using a tip catheter 3 weeks after induction of MI. Compared to BNK rats, basal BK outflow was increased 30-fold in controls (p<0.01). In vivo, we found no significant differences between sham-ligated BNK and BNH rats in basal LV function. After MI, the impairment of LV function was significantly worse in BNK rats when compared to BNH rats. ACE inhibition significantly attenuated this LV dysfunction in both groups, when compared to untreated animals. Reduced basal BK level resulting from kininogen deficiency has no effect on basal LV function, but remains to be a risk factor for the ischemic heart. However, ACE inhibition is sufficient to improve LV function despite kininogen deficiency.