PubMed Health⌕ Search

Biomedical subjects

B H Lorell

Publications and source records attributed to B H Lorell.

At least 55 records · Page 3Linked to original sources
PubMed1995

Alteration of growth responses in established cardiac pressure overload hypertrophy in rats with aortic banding.

We examined the acute effects of elevated wall stress, norepinephrine, and angiotensin II on cardiac protein synthesis as well as protooncogene expression in hearts with established pressure overload left ventricular hypertrophy. Isolated rat hearts with chronic hypertrophy (LVH) were studied 12 wk after ascending aortic banding when systolic function was fully maintained. New protein synthesis (incorporation of [3H]phenylalanine [Phe]) was analyzed in isolated perfused rat hearts after a 3-h protocol; c-fos, c-jun, c-myc, and early growth response gene-1 (EGR-1) mRNA levels (Northern blot) were studied over a time course from 15 to 240 min of perfusion. Under baseline conditions (i.e., before mechanical or neurohormonal stimulation), [3H]-Phe-incorporation (280 nmoles/gram protein/h) and protooncogene mRNA levels were similar in age-matched control and LVH hearts. However, hearts with chronic LVH were characterized by a markedly blunted or absent [3H]-Phe-incorporation after acute imposition of isovolumic systolic load (90 mmHg/gram left ventricle), as well as norepinephrine (10(-6)M), or angiotensin II infusion (10(-8)M plus prazosin 10(-7)M) compared with nonhypertrophied control hearts. Similarly, stimulation of LVH hearts with acute systolic load or norepinephrine was associated with a significantly blunted increase of protooncogene mRNA levels relative to control hearts. The blunted induction of c-fos mRNA in LVH hearts was not due to feedback inhibition, since cycloheximide perfusion of hearts exposed to elevated wall stress further increased the differences between age-matched control and LVH hearts. The data suggest that acute molecular growth responses to mechanical or neurohormonal stimulation are altered in rat hearts with established LVH relative to nonhypertrophied control hearts. This alteration of molecular adaptations in hearts with compensatory hypertrophy may prevent inappropriate excess cardiac growth in response to mechanical and neurohormonal stimuli.

Angiotensin II↗
PubMed1995

Cardiac renin-angiotensin system: role in development of pressure-overload hypertrophy.

Recent studies are reviewed dealing with the putative roles of the cardiac renin-angiotensin system in the development of pressure-overload hypertrophy and the subsequent transition from adaptive hypertrophy to diastolic dysfunction, impaired systolic function and cardiac failure. The results of these studies, which employed the aortic banded rat model of cardiac hypertrophy, indicate that the intracardiac conversion of angiotensin I (Ang I) to angiotensin II (Ang II) is significantly increase in hypertrophied hearts compared with hearts from age-matched, sham-operated controls, and that Ang II may have a direct effect of slowing relaxation and altering diastolic tone in the hypertrophied heart. Furthermore, in patients with aortic stenosis and severe baseline abnormalities of diastolic relaxation and filling, acute intracardiac angiotensin-converting enzyme (ACE) inhibition, totally in the absence of any systemic effect on neurohormones, improved diastolic function. ACE inhibition was found to reduce net ACE activity and to increase plasma renin activity in aortic banded animals compared with untreated banded controls. There was also a trend for circulating noradrenaline levels to be increased at this stage of transition to failure in the untreated banded animals but ACE inhibition tended to restore the levels back to normal. In ACE inhibitor-treated animals, left ventricular (LV) diastolic pressure was significantly reduced, despite the persistent elevation of systolic pressure, but not yet restored completely to normal. In untreated, banded animals the transition to cardiac failure was evidenced as an increase in both systolic and diastolic dimensions with a reduction in fractional shortening.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗
PubMed1994

Effects of angiotensin II on intracellular Ca2+ and pH in isolated beating rabbit hearts and myocytes loaded with the indicator indo-1.

1. Angiotensin II increases myocardial contractility in several species, including the rabbit and man. However, it is controversial whether the predominant mechanism is an increase in free cytosolic [Ca2+]i or a change in myofilament Ca2+ sensitivity. To address this question, we infused angiotensin II in isolated perfused rabbit hearts loaded with the Ca2+ indicator indo-1 AM and measured changes in beat-to-beat surface transients of the Ca2+i-sensitive 400:500 nm ratio and left ventricular contractility. The effects of angiotensin II were compared with the response to a Ca(2+)-dependent increase in the inotropic state produced by a change in the perfusate [Ca2+] from 0.9 to 3.6 nM. 2. In the isolated beating heart, an increase in perfusate [Ca2+] caused an increase in left ventricular pressure +dP/dt in association with an increase in peak systolic [Ca2+]i. Angiotensin II perfusion caused a similar increase in left ventricular +dP/dt in the absence of any increase in peak systolic [Ca2+]i. 3. To exclude any contribution of non-myocyte sources of Ca(2+)-sensitive fluorescence which may be present in the intact heart, we also compared the effects of angiotensin II and a change in superfusate [Ca2+] in collagenase-dissociated paced adult rabbit ventricular myocytes loaded with indo-1 AM. In the isolated rabbit myocytes a change in perfusate [Ca2+] from 0.9 to 3.6 mM caused an increase in peak systolic cell shortening coincident with an increase in peak systolic [Ca2+]i. In contrast, angiotensin II caused a similar increase in peak systolic cell shortening whereas there was no increase in peak systolic [Ca2+]i. There was also no change in inward Ca2+ current (ICa) in response to angiotensin II. 4. To investigate further the mechanism of the positive inotropic action of angiotensin II, its effects on intracellular pH were studied in isolated rabbit myocytes loaded with the fluorescent H+ probe SNARF 1. These experiments demonstrated that angiotensin II induced a 0.2 pH unit increase coincident with the development of a positive inotropic effect in isolated rabbit myocytes. 5. In summary, angiotensin II has a direct positive inotropic effect in beating rabbit hearts and in isolated paced rabbit myocytes. These experiments provide support for the hypothesis that the predominant mechanism is not an increase in free cytosolic Ca2+ but is due in part to an increase in myofilament Ca2+ sensitivity due to intracellular alkalosis.

Angiotensin II↗
PubMed1994

Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy.

BACKGROUND: Epidemiologic studies have shown that left ventricular hypertrophy is often found in the absence of an elevated cardiac workload. To investigate whether such hypertrophy is determined in part by genetic factors, we studied the association between this condition, as assessed by electrocardiographic criteria, and a deletion (D)-insertion (I) polymorphism of the angiotensin-converting-enzyme (ACE) gene. METHODS: A population-based random sample of 711 women and 717 men 45 to 59 years of age was studied cross-sectionally in Augsburg, Germany. Electrocardiographic indexes, including the Sokolow-Lyon index, Minnesota Code 3.1, and the Rautaharju equations, were used to detect left ventricular hypertrophy. The status of the ACE gene with respect to the deletion-insertion allele was determined by the polymerase chain reaction in all subjects with left ventricular hypertrophy and an identical number of control subjects without the condition who were matched for age, sex, and blood-pressure status. RESULTS: We identified 141 women and 149 men with evidence of left ventricular hypertrophy. Among these subjects, an excess were homozygous for the D allele of the ACE gene (odds ratio, 1.76; 95 percent confidence interval, 1.22 to 2.53; P = 0.003). The association of the DD genotype with left ventricular hypertrophy was stronger in men (odds ratio, 2.63; 95 percent confidence interval, 1.50 to 4.64; P < 0.001) than in women and was most prominent when blood-pressure measurements were normal (odds ratio, 4.05; 95 percent confidence interval, 1.76 to 9.28; P = 0.001). This association was evident for each of the scores recorded in the electrocardiographic testing for left ventricular hypertrophy. CONCLUSIONS: The findings suggest that left ventricular hypertrophy is partially determined by genetic disposition. They identify the DD genotype of ACE as a potential genetic marker associated with an elevated risk of left ventricular hypertrophy in middle-aged men.

Aged↗
PubMed1994

Distribution and function of cardiac angiotensin AT1- and AT2-receptor subtypes in hypertrophied rat hearts.

To determine distribution and function of cardiac angiotensin (ANG) II receptor AT1 and AT2 subtypes in left ventricular (LV) hypertrophy (LVH), ANG II (10(-8) M) was infused into isolated rat hearts with hypertrophy from aortic banding and into sham-operated controls. ANG II was infused alone or in the presence of AT1 inhibitor [losartan (10(-5) M) or CL-329167 (10(-7) M)] or AT2 inhibitor [CG-42112A (10(-8) M]. ANG II alone caused less increase in coronary vascular resistance (CVR) in LVH compared with control hearts (19 vs. 39%; P < 0.01), although baseline CVR was higher in LVH hearts. This was prevented by AT1 but not AT2 antagonists. ANG II also increased LV end-diastolic pressure in LVH hearts, signifying decreased diastolic relaxation that was prevented by AT1 but not AT2 inhibition. Characterization of ANG II binding sites in LV membrane preparations revealed similar dissociation constants between groups (1.6 +/- 0.95 vs. 2.2 +/- 2.0 nM; not significant) but lower maximum binding capacity in the LVH group (21.1 +/- 5.9 vs. 33.5 +/- 3.0 fmol/mg protein; P < 0.05). Competition assays demonstrated that control left ventricles contain predominantly the AT1 subtype (68.8 +/- 20%), whereas LVH ventricles contain primarily the putative AT2 subtype (59.8% +/- 10.8%; P < 0.05). This suggests that receptor subtype redistribution occurs in LVH with AT1 subtype down-regulation. Nonetheless, the AT1 subtype mediates the effects of ANG II on coronary tone and diastolic dysfunction in pressure-overload hypertrophy.

Angiotensin II↗
PubMed1994

Angiotensin-converting enzyme inhibition prolongs survival and modifies the transition to heart failure in rats with pressure overload hypertrophy due to ascending aortic stenosis.

BACKGROUND: We tested the hypotheses that long-term administration of the angiotensin-converting enzyme (ACE) inhibitor fosinopril will regress hypertrophy, modify the transition to heart failure, and prolong survival in rats with chronic left ventricular (LV) pressure overload due to ascending aortic stenosis. METHODS AND RESULTS: Aortic stenosis was created in weanling male Wistar rats by a stainless steel clip placed on the ascending aorta. Age-matched control animals underwent a sham operation (Sham group, n = 57). Six weeks after surgery, rats with aortic stenosis were randomized to receive either oral fosinopril 50 mg.kg-1.d-1 (Fos/LVH group, n = 38) or no drug (LVH group, n = 36) for 15 weeks. Pilot studies confirmed that this dosage produced significant inhibition of LV tissue ACE in vivo. Animals were monitored daily, and survival during the 15-week treatment period was assessed by actuarial analysis. At 15 weeks, in vivo LV systolic and diastolic pressures and heart rate were measured. To assess contractile function, the force-calcium relation was evaluated by use of the isovolumic buffer-perfused, balloon-in-LV heart preparation at comparable coronary flow rates per gram LV weight. Quantitative morphometry was performed. Mortality during the 15-week trial was significantly less in the Fos/LVH group than in the LVH group (3% versus 31%, P < .005). No deaths occurred in the Sham group. In vivo LV systolic pressure was similar between Fos/LVH and LVH hearts (223 +/- 10 versus 232 +/- 9 mm Hg) and significantly higher than the Sham group (99 +/- 3 mm Hg, P < .05). In vivo LV diastolic pressure was significantly lower in Fos/LVH hearts than in LVH hearts (10 +/- 2 versus 15 +/- 2 mm Hg), and both were significantly higher than in the Sham group (5 +/- 1 mm Hg, P < .05). Heart rate was similar among all groups. Despite equivalent elevation of LV systolic pressure, fosinopril resulted in regression of myocyte hypertrophy in Fos/LVH versus LVH (myocyte cell width, 14.8 +/- 0.5 versus 20.8 +/- 2.2 microns, P < .05) to normal levels (Sham, 16.3 +/- 0.9 microns). Quantitative morphometry demonstrated that the regression of LV myocyte hypertrophy in the Fos/LVH group was associated with a relative increase in the fractional volume of fibrillar collagen and noncollagen interstitium. In the isolated heart experiments, LV systolic developed pressure relative to perfusate [Ca2+] was significantly higher in Fos/LVH hearts than in LVH hearts. The improvement in systolic function was not related to any difference in myocardial high-energy phosphate levels, since LV ATP and creatine phosphate levels were similar in Fos/LVH and LVH hearts. CONCLUSIONS: In rats with ascending aortic stenosis, chronic ACE inhibition with fosinopril improved survival, decreased the extent of LV hypertrophy, and improved cardiac function despite persistent elevation of LV systolic pressure. The favorable effects of fosinopril may be related in part to inhibition of the effects of cardiac ACE on myocyte hypertrophy rather than to systemic hemodynamic mechanisms.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Intracardiac angiotensin-converting enzyme inhibition improves diastolic function in patients with left ventricular hypertrophy due to aortic stenosis.

BACKGROUND: Cardiac hypertrophy is associated with elevated intracardiac angiotensin-converting enzyme activity, which may contribute to diastolic dysfunction. METHODS AND RESULTS: We infused enalaprilat (0.05 mg/min) for 15 minutes into the left coronary arteries of 20 adult patients with left ventricular (LV) hypertrophy due to aortic stenosis (mean aortic valve area, 0.7 +/- 0.2 cm2) and 10 patients with dilated cardiomyopathy (mean ejection fraction, 35 +/- 4%) and assessed (1) simultaneous changes in LV micromanometer pressure and dimensions, (2) LV regional wall motion analyzed by the area method, and (3) Doppler flow-velocity profiles. Systemic neurohormonal activation did not occur with the selective left coronary artery infusion; there were no changes in plasma renin activity, angiotensin-converting enzyme activity, or atrial natriuretic peptide. In patients with aortic stenosis, LV end-diastolic pressure declined from 25 +/- 2 to 20 +/- 2 mm Hg (P < .05). LV pressure-volume and LV pressure-dimension relations showed downward shifts by ventriculography and echocardiography, respectively, indicating improved diastolic distensibility. Regional area change during isovolumic relaxation increased in the anterior segments perfused with enalaprilat but decreased in the inferior segments, indicating acceleration of isovolumic relaxation in the anterior segments and reciprocal shortening in the inferior segments. Regional peak filling rate increased in the anterior segments but not in the inferior segments, and the regional area stiffness constant decreased in the anterior segments but not in the inferior segments. There were no changes in heart rate, cardiac output, or right atrial pressure, excluding alterations in right ventricular/pericardial constraint. In contrast, in the patients with dilated cardiomyopathy the decrease in LV end-diastolic pressure from 22 +/- 2 to 18 +/- 2 mm Hg (P < .05) was accompanied by a significant fall in right atrial pressure (9 +/- 1 to 6 +/- 1 mm Hg), implicating alterations in pericardial constraint. The patients with dilated cardiomyopathy showed no improvement in regional diastolic relaxation, filling, or distensibility. CONCLUSIONS: Intracoronary enalaprilat at a dosage that did not cause systemic neurohormonal activation improved LV diastolic chamber distensibility and regional relaxation and filling in patients with LV hypertrophy due to aortic stenosis. In contrast, these effects of intracoronary enalaprilat on diastolic function were not observed in patients with dilated cardiomyopathy who did not have concentric hypertrophy. These observations support the hypothesis that the cardiac renin-angiotensin system is activated in patients with concentric pressure-overload hypertrophy and that this activation may contribute to impaired diastolic function.

Aged↗
PubMed1993

Use of 2,3-butanedione monoxime to estimate nonmechanical VO2 in rabbit hearts.

The purpose of the present study was to evaluate the feasibility of partitioning myocardial O2 consumption (VO2) into mechanical and nonmechanical components in the whole heart preparation using a negative inotrope, 2,3-butanedione monoxime (BDM), which has been reported to have a selective effect on the contractile proteins in a low concentration range (< 6 mM). In six isolated bovine red blood cell-perfused rabbit hearts, VO2 and force-time integral (FTI) were measured during infusion of varying concentrations of BDM at a constant left ventricular volume chosen such that control left ventricular peak isovolumic pressure was approximately 100 mmHg. The VO2-FTI relation with BDM concentrations < or = 5 mM was highly linear (median r = 0.98). Its VO2-axis intercept at zero FTI had a positive value (mean 23% of control, 0.014 ml O2.beat-1 x 100 g-1). To confirm the selective effect of BDM on the contractile proteins, the intracellular free Ca2+ transient was measured with the fluorescent indicator indo 1 in three isolated buffer-perfused rabbit hearts. The amplitude of the Ca2+ transient was not altered by BDM at concentrations < or = 10 mM, although left ventricular developed pressure was markedly depressed. This finding indicates that BDM < or = 10 mM does not affect excitation-contraction coupling. We conclude that the VO2-axis intercept value of the VO2-FTI relation during BDM infusion in a low concentration range represents VO2 for nonmechanical energy utilization. The BDM method to partition VO2 into mechanical and nonmechanical components is thus feasible in the whole rabbit heart.

Animals↗
PubMed1993

Distribution and functional significance of cardiac angiotensin converting enzyme in hypertrophied rat hearts.

BACKGROUND: The intracardiac conversion rate of angiotensin (Ang) I to Ang II and the expression of angiotensin converting enzyme (ACE) mRNA are amplified in rat hearts with left ventricular hypertrophy (LVH). To examine whether the accelerated intracardiac Ang II generation in LVH is related to an induction of cardiac ACE, we studied localization and function of cardiac ACE in hypertrophied rat hearts using specific ACE inhibitors. METHODS AND RESULTS: Cardiac ACE was localized and quantified in hearts from male Wistar rats with LVH due to chronic experimental aortic stenosis and from control rats. With the ACE inhibitor 125I-351A, a derivative of lisinopril, as a radioligand on coronal sections of LVH and control hearts, in vitro autoradiography demonstrated ACE binding in aorta, coronary arteries, atria, and ventricles of both groups. Quantitative analyses revealed that ACE density (counts per minute per cross-sectional area of tissue) was twofold higher within the myocardium of hypertrophied left ventricles compared with controls (p < 0.005). Quantitative morphometry demonstrated a modest increase in the fractional volume of myocytes as well as capillary volume without an increase in the fractional volume of endothelial cells in left ventricular tissue from aortic stenosis rats. These data suggest that an increase in endothelial cell volume per se cannot alone account for the observed doubling of ACE density and support an upregulation of ACE production in hypertrophied tissue. The role of cardiac ACE in intracardiac conversion of Ang I to Ang II and its specific inhibition was studied in isolated, isovolumic beating, buffer-perfused LVH and control hearts. Biochemical conversion rates as well as functional changes in response to 3 x 10(-7) M Ang I were examined in the absence or presence of the ACE inhibitor enalaprilat (4 x 10(-6) M). After a brief stabilization period, groups of LVH and control hearts were subjected to the following infusion protocols: 15 minutes of vehicle followed by 30 minutes of Ang I plus vehicle, 15 minutes of enalaprilat followed by 30 minutes of Ang I plus enalaprilat (enal/Ang I), or 45 minutes of vehicle only to allow comparison with a time control. Intracardiac Ang I-to-Ang II conversion rate was fourfold higher in LVH than in control hearts (p < 0.05). Infusion of enalaprilat reduced the intracardiac Ang I-to-Ang II conversion rate in LVH hearts by 70% (p < 0.05 versus Ang I). At similar levels of constant coronary flow per gram, Ang I increased coronary perfusion pressure by 23 +/- 5 mm Hg (p < 0.01 versus vehicle) in LVH hearts and by 36 +/- 10 mm Hg (p < 0.005 versus vehicle) in control hearts. When enalaprilat was infused with Ang I, the increase in perfusion pressure was limited to 5 +/- 5 mm Hg (NS versus vehicle) in LVH hearts and 12 +/- 3 mm Hg (p < 0.05 versus vehicle) in control hearts and was significantly lower than in hearts infused with Ang I only (p < 0.05 in LVH and p < 0.05 in control hearts, respectively). Systolic function was not affected by either infusion protocol. In contrast, Ang I infusion was associated with diastolic dysfunction. In LVH hearts, left ventricular end-diastolic pressure (LVEDP) increased from 10 +/- 1 mm Hg at baseline to 25 +/- 2 mm Hg at the end of the Ang I infusion (p < 0.001 versus vehicle), which was inhibited by infusion of enalaprilat. In control hearts, there was a lesser increase in LVEDP from 10 +/- 1 mm Hg to 15 +/- 1 mm Hg in response to Ang I (p < 0.05 versus LVH). Control hearts treated with enalaprilat with Ang I displayed no increase in LVEDP: CONCLUSIONS: These observations indicate that ACE protein is increased within the myocardium of LVH hearts, extending recent findings of increased cardiac ACE activity and mRNA levels in this model of pressure-overload LVH in the rat. Blockade of the enzyme by an ACE inhibitor decreases intracardiac Ang I-to-Ang II conversion rate and prevents the functional changes of Ang I-to-Ang II activation

Angiotensin I↗
PubMed1993

Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding.

Left ventricular hypertrophy (LVH) is associated with reinduction of the fetal program of gene expression. It is unclear whether this pattern of cardiac gene expression changes with the development of left ventricular decompensation and failure. To answer these questions, we quantified steady-state levels of mRNA by the polymerase chain reaction in the left ventricular myocardium of rats 8 and 20 weeks after ascending aortic banding. Clinical and hemodynamic assessment identified two distinct groups of animals 20 weeks after aortic banding. The first group (20-week nonfailed LVH) demonstrated substantial LVH but no depression in systolic developed pressure per gram left ventricular weight compared with the age-matched control group. In contrast, a second group of rats exhibited clinical signs of congestive failure as well as a marked diminution in left ventricular developed pressure per gram. Assessment of the levels of mRNA encoding a panel of cardiac proteins demonstrated a greater than twofold increase in beta-myosin heavy chain mRNA and an approximately sixfold increase in atrial natriuretic factor mRNA in left ventricular myocardium of all three groups (8-week LVH, 20-week nonfailed LVH, 20-week failed LVH) when compared with appropriate age-matched control groups. In contrast, Ca(2+)-ATPase mRNA levels were decreased by 50% only in the left ventricular myocardium of animals with both clinical signs and hemodynamic indexes consistent with cardiac decompensation (20-week failed LVH). These results suggest that in rats with ascending aortic banding the hypertrophic phenotype is associated with a selective reinduction of the fetal gene program, which persists even after the development of left ventricular failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of brief repetitive ischemia on contractility, relaxation, and coronary flow. Exaggerated postischemic diastolic dysfunction in pressure-overload hypertrophy.

The recovery of systolic and diastolic function during unstable angina may be modified by the repetition of brief episodes of ischemia and by the presence of left ventricular hypertrophy (LVH). We studied the effects of six consecutive 5-minute cycles of no-flow ischemia and reperfusion followed by 25 minutes of recovery in isovolumic red blood cell-perfused hearts from aortic-banded rats with chronic LVH (n = 8) and sham-operated control rats (n = 8). At baseline (left ventricular end-diastolic pressure [LVEDP], 10 mm Hg), left ventricular developed pressure (123 +/- 5 versus 114 +/- 5 mm Hg/g) and coronary flow [2.5 +/- 0.3 versus 2.2 +/- 0.2 (mL/min)/g] were similar in LVH versus control rats. Repetitive ischemia was associated with progressive depression of postischemic recovery of left ventricular systolic function, and the recovery of left ventricular developed pressure after the final 25-minute reperfusion period was similar in LVH versus control rats (61 +/- 6% versus 72 +/- 4% of baseline, P = NS). Although there was no increase in isovolumic LVEDP during the initial cycle of transient ischemia, both groups showed a rapid and similar rise in LVEDP during subsequent ischemic cycles (delta 82 +/- 8 versus delta 89 +/- 7 mm Hg/g in response to the final ischemia cycle for LVH versus control rats, respectively; P = NS). The control hearts showed complete restoration of LVEDP to baseline during final reperfusion, whereas the LVH hearts showed prolonged and severe postischemic diastolic dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Left ventricular hypertrophy and diastolic dysfunction.

The hypertrophied heart generally preserves systolic function, but it pays a price in diastolic dysfunction. Coronary reserve is impaired and susceptibility to myocardial ischemia increased. The pathophysiology is managed by addressing causes of pressure overload, preventing tachycardia, or, of course, by specific strategies to reduce or eliminate ischemia.

Adaptation, Physiological↗
PubMed1992

Diastolic dysfunction in pressure-overload hypertrophy and its modification by angiotensin II: current concepts.

Cardiac hypertrophy is an adaptive response to an increased load imposed on the myocyte which allows the heart to perform increased work while maintaining normal myocardial fiber stress and shortening in systole. A deleterious consequence of pressure-overload hypertrophy is the prolongation of Ca(2+)-sensitive force inactivation (impaired myocardial relaxation) which is related to intrinsic alterations in cytosolic Ca2+ transport and reuptake in diastole. Additional factors appear to adversely modify myocardial relaxation in the hypertrophied heart, including the imposition of ischemia. There is also evidence that the expression and activity of the cardiac tissue renin angiotensin system (RAS) may be modified in the hypertrophied heart and contribute to diastolic dysfunction. Recent studies have demonstrated the presence of increased cardiac angiotensin converting enzyme (ACE) mRNA expression and activity in animal models of hypertrophy, including the aortic-banded rat with compensatory pressure-overload hypertrophy and rats with post-infarction remodeling. In the beating, isovolumic aortic-banded rat heart, the increased intracardiac activation of angiotensin I to II has been shown to be associated with a dose-dependent depression of diastolic relaxation. Preliminary studies suggest that the depression of diastolic function by angiotensin II in the hypertrophied heart can be prevented by the specific inhibition of cardiac ACE. In addition, the well-recognized susceptibility of the hypertrophied heart to severe ischemic diastolic dysfunction also appears to be favorably modified by the inhibition of cardiac ACE activity. The mechanisms responsible for the adverse effects of angiotensin II on diastolic relaxation in the hypertrophied heart are likely to be complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1992

Exacerbation of left ventricular ischemic diastolic dysfunction by pressure-overload hypertrophy. Modification by specific inhibition of cardiac angiotensin converting enzyme.

Hearts with compensatory pressure-overload hypertrophy show an increased intracardiac activation of angiotensin II that may contribute to ischemic diastolic dysfunction. We studied whether pressure-overload hypertrophy in response to aortic banding would result in exaggerated diastolic dysfunction during low-flow ischemia and whether the specific inhibition of the cardiac angiotensin converting enzyme by enalaprilat would modify systolic and diastolic function during ischemia and reperfusion in either hypertrophied or nonhypertrophied hearts. Isolated, red blood cell-perfused isovolumic nonhypertrophied and hypertrophied rat hearts were subjected to enalaprilat (2.5 x 10(-7) M final concentration) infusion during 20 minutes of baseline perfusion and during 30 minutes of low-flow ischemia and 30 minutes of reperfusion. Coronary flow per gram was similar in nonhypertrophied and hypertrophied hearts during baseline perfusion, ischemia, and reperfusion. At baseline, left ventricular developed pressure was higher in hypertrophied than nonhypertrophied hearts in untreated groups (224 +/- 8 versus 150 +/- 9 mm Hg; p less than 0.01) and in enalaprilat-treated groups (223 +/- 9 versus 145 +/- 8 mm Hg; p less than 0.01). During low-flow ischemia, left ventricular developed pressure was depressed but similar in all groups. All groups showed deterioration of diastolic function; however, left ventricular end-diastolic pressure increased to a significantly higher level in untreated hypertrophied than in nonhypertrophied hearts (65 +/- 7 versus 33 +/- 3 mm Hg; p less than 0.001). Enalaprilat had no effect in nonhypertrophied hearts, but it significantly attenuated the greater increase in left ventricular end-diastolic pressure in hypertrophied hearts treated with enalaprilat compared with no drug (65 +/- 7 versus 50 +/- 5 mm Hg; p less than 0.01). The beneficial effect could not be explained by differences in coronary blood flow per gram left ventricular weight, glycolytic flux as reported by lactate production, myocardial water content, oxygen consumption, and tissue levels of glycogen and high energy phosphate compounds. During reperfusion, all hearts showed a partial recovery of developed pressure to 70-74% of initial values. No effect of enalaprilat could be detected during reperfusion on systolic and diastolic function or restoration of tissue levels of high energy compounds. In conclusion, our experiments show that hypertrophied red blood cell-perfused hearts manifest a severe impairment of left ventricular diastolic relaxation in response to low-flow ischemia in comparison with control hearts. Further, our experiments support the hypothesis that the enhanced conversion of angiotensin I to angiotensin II in rats with pressure-overload hypertrophy contributes to the enhanced sensitivity of hypertrophied hearts to diastolic dysfunction during low-flow ischemia.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Exacerbation of ischemic dysfunction by angiotensin II in red cell-perfused rabbit hearts. Effects on coronary flow, contractility, and high-energy phosphate metabolism.

We studied the effects of angiotensin II during low-flow ischemia and reperfusion using red cell-perfused isovolumic rabbit hearts. Under baseline conditions where coronary perfusion pressure (CPP) was 100 mm Hg and left ventricular end-diastolic pressure (LVEDP) was set at 10 mm Hg, 10(-8) M angiotensin II caused a mild increase in LV developed pressure (+12%) and decrease in coronary flow (-8%). Low-flow ischemia was imposed by reducing CPP to 15 mm Hg for 30 min followed by 30 min of reperfusion. During ischemia, the angiotensin II group showed a gradual further reduction in coronary flow in association with a greater depression of LV developed pressure and increase in LVEDP relative to the no-drug group. To separate the effect of angiotensin II on coronary flow from a direct myocardial effect, the angiotensin II group was compared with an additional no-drug group with a matched progressive reduction in coronary flow during ischemia. In these groups, the ischemic depression of LV developed pressure, myocardial ATP levels, and lactate production were similar. However, the ischemic rise in LVEDP was greater (42.0 +/- 5.4 vs. 19.9 +/- 1.3 mm Hg, P less than 0.01) and recovery was incomplete in the angiotensin II group. These observations suggest that angiotensin II exerts a direct adverse effect on LV diastolic relaxation during low-flow ischemia and recovery.

Adenosine Triphosphate↗
PubMed1992

The advantage of d-sotalol over dl-sotalol in a patient with ventricular arrhythmias and comorbid bronchospasm.

The anti-arrhythmic agent sotalol, a racemic mixture of d- and l-isomers, has inherent beta-adrenoceptor blocking activity due to the l-isomer form. For patients with contraindications to beta-adrenoreceptor blockade, dl-sotalol has potentially untoward effects that may limit its usefulness. The case of a man with resistant life-threatening ventricular arrhythmias who responded favorably to dl-sotalol, but developed worsening of underlying bronchospastic lung disease, is presented. A change in therapy to the d-isomer form of sotalol, d-sotalol, was effective in suppressing his ventricular arrhythmias without further aggravation of bronchospasm.

Bronchial Spasm↗