Effects of forskolin on inotropic performance and phospholamban phosphorylation in exercise-trained hypertensive myocardium.

Beta-adrenergic receptor (beta-AR) responsiveness is downregulated in left ventricular (LV) hypertrophy induced by chronic hypertension. While exercise training in hypertension enhances beta-AR responsiveness, the role of adenylyl cyclase remains unclear. The purpose of the present study was to test whether treadmill running in the spontaneously hypertensive rat (SHR) model improves LV responsiveness to forskolin (FOR) or the combination of FOR + isoproterenol (FOR+ISO). Female SHR (16-wk) were randomly placed into sedentary (SHR-SED; n = 7) or treadmill-trained (SHR-TRD; n = 8) groups. Wistar-Kyoto (WKY; n = 7) animals acted as normotensive controls. Langendorff, isovolumic LV performance was established at baseline and during incremental FOR infusion (1 and 5 micromol/l) and FOR+ISO (5 micromol/l + 1x10(-8) mol/l). Heart rate, systolic blood pressure, and heart-to-body weight ratio were lower in WKY relative to both SHR groups (P < 0.05). LV performance and heart rate significantly increased in all groups to a similar extent with incremental FOR infusion. However, in the presence of 5 micromol/l FOR, ISO increased LV developed pressure, positive change in LV pressure, and negative change in LV pressure to a greater extent in SHR-TRD relative to SHR-SED (P < 0.05). Phospholamban phosphorylation at the Thr17 was greater in SHR-TRD relative to SHR-SED and WKY (P < 0.05). Absolute LV developed pressure was moderately correlated with phospholamban phosphorylation at both the Ser16 (r = 0.64; P < 0.05) and Thr17 (r = 0.52; P < 0.05). Our data suggest that the adenylyl cyclase step in the beta-AR cascade is not downregulated in the early course of hypertension and that the enhanced beta-AR responsiveness with training is likely mediated at levels other than adenylyl cyclase. Our data also suggest that beta-AR inotropic responsiveness in the presence of direct adenylyl cyclase agonism is improved in trained compared with sedentary SHR hearts.     

Exercise training improves aging-induced downregulation of VEGF angiogenic signaling cascade in hearts

Exercise training improves aging-induced deterioration of angiogenesis in the heart. However, the mechanisms underlying exercise-induced improvement of capillary density in the aged heart are unclear. Vascular endothelial growth factor (VEGF) is implicated in angiogenesis, which activated angiogenic signaling cascade through Akt and endothelial nitric oxide synthase (eNOS)-related pathway. We hypothesized that VEGF angiogenic signaling cascade in the heart contributes to a molecular mechanism of exercise training-induced improvement of capillary density in old age. With the use of hearts of sedentary young rats (4 mo old), sedentary aged rats (23 mo old), and exercise-trained aged rats (23 mo old, swim training for 8 wk), the present study investigated whether VEGF and VEGF-related angiogenic molecular expression in the aged heart is affected by exercise training. Total capillary density in the heart was significantly lower in the sedentary aged rats compared with the sedentary young rats, whereas that in the exercise-trained rat was significantly higher than the sedentary aged rats. The mRNA and protein expressions of VEGF and of fms-like tyrosine kinase-1 (Flt-1) and fetal liver kinase-1 (Flk-1), which are main VEGF receptors, in the heart were significantly lower in the sedentary aged rats compared with the sedentary young rats, whereas those in the exercise-trained rats were significantly higher than those in the sedentary aged rats. The phosphorylation of Akt protein and eNOS protein in the heart corresponded to the changes in the VEGF protein levels. These findings suggest that exercise training improves aging-induced downregulation of cardiac VEGF angiogenic signaling cascade, thereby contributing to the exercise training-induced improvement of angiogenesis in old age.     

Exercise restores beta-adrenergic vasorelaxation in aged rat carotid arteries

Aging is associated with alterations in beta-adrenergic receptor (beta-AR) signaling and reduction in cardiovascular responses to beta-AR stimulation. Because exercise can attenuate age-related impairment in myocardial beta-AR signaling and function, we tested whether training could also exert favorable effects on vascular beta-AR responses. We evaluated common carotid artery responsiveness in isolated vessel ring preparations from 8 aged male Wistar-Kyoto (WKY) rats trained for 6 wk in a 5 days/wk swimming protocol, 10 untrained age-matched rats, and 10 young WKY rats. Vessels were preconstricted with phenylephrine (10-6 M), and vasodilation was assessed in response to the beta-AR agonist isoproterenol (10-10-3 x 10-8 M), the alpha2-AR agonist UK-14304 (10-9-10-6 M), the muscarinic receptor agonist ACh (10-9-10-6 M), and nitroprusside (10-8-10-5 M). beta-AR density and cytoplasmic beta-AR kinase (beta-ARK) activity were tested on pooled carotid arteries. beta-ARK expression was assessed in two endothelial cell lines from bovine aorta and aorta isolated from a 12-wk WKY rat. beta-AR, alpha2-AR, and muscarinic responses, but not that to nitroprusside, were depressed in untrained aged vs. young animals. Exercise training restored beta-AR and muscarinic responses but did not affect vasodilation induced by UK-14304 and nitroprusside. Aged carotid arteries showed reduced beta-AR number and increased beta-ARK activity. Training counterbalanced these phenomena and restored beta-AR density and beta-ARK activity to levels observed in young rat carotids. Our data indicate that age impairs beta-AR vasorelaxation in rat carotid arteries through beta-AR downregulation and desensitization. Exercise restores this response and reverts age-related modification in beta-ARs and beta-ARK. Our data support an important role for beta-ARK in vascular beta-AR vasorelaxation.     

Enhanced isoproterenol-induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen

We have previously shown that a permanent deficiency in the brain renin-angiotensin system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta-adrenoceptor (beta-AR) agonist isoproterenol (Iso). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, Iso induced a significantly greater increase in left ventricular (LV) pressure and maximal contraction (+dP/dt(max)) in the TGR than in the Sprague-Dawley (SD) rats. LV hypertrophy induced by Iso treatment was significantly higher in TGR than in SD rats (in g LV wt/100 g body wt, 0.28 +/- 0.004 vs. 0.24 +/- 0.004, respectively). The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of beta-AR and upregulation of LV beta-AR kinase-1 mRNA levels compared with those in SD rats. The decrease in the heart rate (HR) induced by the beta-AR antagonist metoprolol in conscious rats was significantly attenuated in TGR compared with SD rats (-9.9 +/- 1.7% vs. -18.1 +/- 1.5%), whereas the effect of parasympathetic blockade by atropine on HR was similar in both strains. These results indicate that TGR are more sensitive to beta-AR agonist-induced cardiac inotropic response and hypertrophy, possibly due to chronically low sympathetic outflow directed to the heart.     

Differential changes in beta-adrenoceptor signal transduction in left and right ventricles of infarcted rats

Although different experimental and clinical studies have revealed varying degrees of defects in beta-adrenoceptors (beta-ARs) during the development of heart failure, the mechanisms for differences in beta-AR signal transduction between the left (LV) and right ventricle (RV) are not understood. Because biochemical alterations in the myocardium depend on the stage of heart disease, this study was undertaken to assess the status of beta-ARs in the LV and RV at different stages of heart failure. Myocardial infarction was induced in rats by occluding the left coronary artery for 8 and 24 weeks. The beta-AR signal transduction was monitored by measuring beta1-AR density, the isoproterenol-induced positive inotropic effect, the increase in [Ca2+]i in cardiomyocytes, and the activation of adenylyl cyclase. The beta-AR signal transduction parameters in the 8- and 24-week failing LV were depressed, whereas the RV showed upregulation at 8 weeks and downregulation at 24 weeks of these mechanisms. These results suggest that beta-AR-mediated signal transduction in the LV and RV are differentially regulated and are dependent upon the stage of development of congestive heart failure due to myocardial infarction.     

Gender differences on the effects of aging on cardiac and peripheral adrenergic stimulation in old conscious monkeys

We examined the effects of gender and aging on cardiac and peripheral hemodynamic responses to beta-adrenergic receptor (beta-AR) stimulation in young (male = 5.9 +/- 0.4 yr old and female = 6.5 +/- 0.7 yr old) and old (male = 19.8 +/- 0.7 yr old and female = 21.2 +/- 0.2 yr old) conscious monkeys (Macaca fascicularis), chronically instrumented for measurements of left ventricular (LV) and arterial pressures as well as cardiac output. Baseline LV pressure, the first derivative of LV pressure (LV dP/dt), cardiac index, mean arterial pressure, total peripheral resistance (TPR), and heart rate in conscious monkeys were not different among the four groups. Increases in LV dP/dt in response to 0.1 microg/kg isoproterenol (Iso) were diminished (P < 0.05) in old males (+99 +/- 11%) compared with young males (+194 +/- 18%). In addition, the inotropic responses to norepinephrine (NE) and forskolin (FSK) were significantly depressed (P < 0.05) in old males. Iso-induced reductions of TPR were less (P < 0.05) in old males (-28 +/- 2%) than in young males (-49 +/- 2%). The changes of TPR in response to NE and FSK were also significantly attenuated (P < 0.05) in old males. However, the LV dP/dt responses to BAY y 5959 (15 microg. kg-1. min-1), a Ca2+ channel promotor independent of beta-AR signaling, were not significantly different between old and young males. In contrast to results in male monkeys, LV dP/dt and TPR responses to Iso, NE, and FSK in old females were similar to those observed in young females. Thus both cardiac contractile and peripheral vascular dynamic responses to beta-AR stimulation are preserved in old female but not old male monkeys. This may explain, in part, the reduced cardiovascular risk in the older female population.     

Alterations in myocardial signal transduction due to aging and chronic dynamic exercise

Roth, David A., Cynthia D. White, Deborah A. Podolin, andRobert S. Mazzeo. Alterations in myocardial signal transduction due to aging and chronic dynamic exercise. J. Appl. Physiol.84(1): 177-184, 1998.Normal aging without disease leads todiminished chronotropic and inotropic responses to catecholaminestimulation, resulting in depressed cardiac function with stress. Thepurpose of this study was to determine molecular mechanisms fordecrements in adrenergic responsiveness of the left ventricle (LV) dueto aging and to study the effects of chronic dynamic exercise on signaltransduction. We measured -adrenergic receptor (-AR) density,adenylyl cyclase (AC) activity, and G-protein content and distributionin LV from 66 male Fischer 344 rats from three age groups that wereeither sedentary or treadmill trained (60 min/day, 5 days/wk, 10 wk at75% of the maximal capacity). Final ages were 7 mo(young), 15 mo (middle-age), and 25 mo (old). There was no significantdifference in -AR density among groups as a function of age ortraining. AC production of adenosine 3,5-cyclic monophosphate (cAMP)with the use of five pharmacological stimulations revealed that oldsedentary myocardium had depressed basal, receptor-dependent, G-protein-dependent, and AC catalyst stimulation (30-43%)compared with hearts from young and middle-age sedentary rats. Training did not alter AC activity in either middle-age or old groups but didincrease G-protein-dependent cAMP production in young myocardium (12-34%). Immunodetectable concentrations of stimulatory andinhibitory G proteins (G_s and G_i, respectively)showed 43% less total G_s with similar G_icontent in hearts from old sedentary compared with middle-age sedentaryrats. When compared with young sedentary animals, G_icontent was 39 and 50% higher in middle-age sedentary and oldsedentary myocardium, respectively. With age, there was a significantshift in the -subunit of G_s distribution from cytosolic fractions of LV homogenates to membrane-bound fractions (8-12% redistribution in middle-age sedentary vs. old sedentary). The mostsignificant training effect was a decrease in G_i content inhearts from old trained rats (23%), which resulted in values comparable with young sedentary rats and reduced theG_i/G_s ratio by 27% in old-rat LV. We reportthat age-associated reductions in cardiovascular -adrenergicresponsiveness correspond with alterations in postreceptor adrenergicsignaling rather than with a decrease in receptor number. Chronicdynamic exercise partially attenuates these reductions throughalterations in postreceptor elements of cardiac signal transduction.

     

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.     

Alterations of adenylyl cyclase and G proteins in aortocaval shunt-induced heart failure

Unlike most other experimental models of congestive heart failure, the volume overload model induced by aortocaval shunt (AVS) in rats was found to exhibit enhanced beta-adrenoceptor (beta-AR) signaling. To study whether the adenylyl cyclase (AC)-G protein system is involved in such a change, we examined cardiac AC activity and protein content as well as G(s)alpha and G(i)alpha activities, protein contents, and mRNA levels in both left (LV) and right (RV) ventricles at the failing stage (16 wk after surgery). Basal and forskolin-stimulated AC activities were significantly increased in both LV and RV from the failing hearts; this change was associated with an upregulation of type V/VI AC protein. In contrast to 5'-guanylyl imidodiphosphate and NaF, the stimulatory effect of isoproterenol on AC was increased in the failing heart. Although G(s)alpha and G(i)alpha protein contents in the failing hearts were not altered, the mRNA level for G(s)alpha was decreased by 20% and that for G(i)alpha was increased by 20%. In addition, the activity of G(s)alpha, but not G(i)alpha, as assessed by toxin-catalyzed ADP ribosylation, was significantly decreased in the failing heart. Losartan and imidapril treatments improved cardiac function and attenuated alterations in mRNA levels for G(s)alpha and G(i)alpha proteins, as well as G(s)alpha activity, without affecting changes in AC protein content or activities in heart failure due to volume overload. These data suggest that increased AC activity may contribute to the enhanced beta-AR signaling in the AVS model of heart failure, whereas alterations in gene expression for G proteins may be of an adaptive nature at this stage of heart failure.     

Alterations in cardiac adrenergic terminal function and beta-adrenoceptor density in pacing-induced heart failure

Congestive heart failure is associated with cardiac adrenergic nerve terminal changes and beta-adrenoceptor density downregulation. To study the temporal sequence of these changes, we performed studies in rabbits at 2, 4, and 8 wk of cardiac pacing (360 beats/min) and at 1, 2, and 4 wk after cessation of pacing. Rapid pacing produced left ventricular (LV) dysfunction and an increase in plasma norepinephrine (NE) in 1-2 wk. At week 2, NE uptake activity, NE uptake-1 density, and adenylyl cyclase responses to isoproterenol, 5'-guanylyl imidodiphosphate [Gpp(NH)p], and forskolin reduced. However, immunostained tyrosine hydroxylase profile, beta-adrenoceptor density, and NE histofluorescence did not reduce until 4-8 wk of pacing. After cessation of cardiac pacing, LV function normalized quickly, followed by return of tyrosine hydroxylase and NE profiles in 1 wk and adenylyl cyclase responses to agonists and NE uptake activity in 2 wk. Myocardial beta-adrenoceptor density returned to normal by 4 wk after cessation of pacing. Our results suggest that there is no permanent structural neuronal damage in the myocardium within the first 8 wk of rapid cardiac pacing. Abnormal myocardial NE reuptake mechanism may play an important pathophysiological role in heart failure.     

Aging and respiratory muscle metabolic plasticity: effects of endurance training.

We examined the oxidative and antioxidant enzyme activities in respiratory and locomotor muscles in response to endurance training in young and aging rats. Young adult (4-mo-old) and old (24-mo-old) female Fischer 344 rats were divided into four groups: 1) young trained (n = 12), 2) young untrained (n = 12), 3) old trained (n = 10), and 4) old untrained (n = 6). Both young and old endurance-trained animals performed the same training protocol during 10 wk of continuous treadmill exercise (60 min/day, 5 days/wk). Compared with young untrained animals, the young trained group had significantly elevated (P less than 0.05) activities of 3-hydroxyacyl-CoA dehydrogenase (HADH), glutathione peroxidase (GPX), and citrate synthase (CS) in both the costal diaphragm and the plantaris muscle. In contrast, training had no influence (P greater than 0.05) on the activity of lactate dehydrogenase within the costal diaphragm in young animals. In the aging animals, training did not alter (P greater than 0.05) activities of CS, HADH, GPX, or lactate dehydrogenase in the costal diaphragm but significantly (P less than 0.05) increased CS, HADH, and GPX activities in the plantaris muscle. Furthermore, training resulted in higher activities of CS and HADH in the intercostal muscles in the old trained than in the old untrained animals. Finally, activities of CS, HADH, and GPX were significantly (P less than 0.05) lower in the plantaris in the old untrained than in the young untrained animals; however, CS, HADH, and GPX activities were greater (P less than 0.05) in the costal diaphragm in the old sedentary than in the young untrained animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise training alters the effect of chronic hypoxia on myocardial adrenergic and muscarinic receptor number.

Chronic hypoxic exposure results in elevated sympathetic activity leading to downregulation of myocardial alpha(1)- and beta-adrenoceptors (alpha(1)-AR, beta-AR). On the other hand, it has been shown that sympathetic activity is reduced by exercise training. The objective of this study was to determine whether exercise training could modify the changes in receptor expression associated with acclimatization. Four groups of rats were studied: normoxic sedentary rats (NS), rats living and training in normoxia (NTN), sedentary rats living in hypoxia (HS, inspired PO(2) = 110 Torr), and rats living and training in hypoxia (HTH, inspired PO(2) = 110 Torr). Training consisted of running in a treadmill at 80% of maximal O(2) uptake during 10 wk. Myocardial receptor density was measured by radioactive ligand binding. Right ventricular (RV) hypertrophy occurred in HS but not in HTH. No effect of exercise was detected in RV weight of normoxic rats. Acclimatization to hypoxia (HS vs. NS) resulted in a decrease in both alpha(1)- and beta-AR density, whereas muscarinic receptor (M-Ach) expression increased. Hypoxic exercise training (HS vs. HTH) moderated beta-AR downregulation and M-Ach upregulation and prevented the fall in alpha(1)-AR density. Normoxic training (NS vs. NTN) did not change beta-AR density. On the other hand, densities of alpha(1)-AR in both ventricles as well as RV M-Ach increased in NTN vs. NS. The data show that exercise training in hypoxia 1) prevents RV hypertrophy, 2) suppresses the downregulation of alpha(1)-AR in the left ventricle (LV) and RV, and 3) attenuates the changes in both beta-AR and M-Ach receptor density in LV and RV. Exercise training in normoxia increases M-Ach receptor expression in the RV.     

Characterization of cardiac hypertrophy and heart failure due to volume overload in the rat.

Alterations in general characteristics and morphology of the heart, as well as changes in hemodynamics, myosin heavy chain isoforms, and beta-adrenoceptor responsiveness, were determined in Sprague-Dawley rats at 1, 2, 4, 8, and 16 wk after aortocaval fistula (shunt) was induced by the needle technique. Three stages of cardiac hypertrophy due to volume overload were recognized during the 16-wk period. Developing hypertrophy occurred within the first 2 wk after aortocaval shunt was induced and was characterized by a rapid increase of cardiac mass in both left and right ventricles. Compensated hypertrophy occurred between 2 and 8 wk after aortocaval shunt where normal or mild depression in hemodynamic function was observed. Decompensated hypertrophy or heart failure occurred between 8 and 16 wk after aortocaval shunt and was characterized by circulatory congestion, decreased in vivo and in vitro cardiac function, and a shift in myosin heavy chain isozyme expression. However, the positive inotropic effect of isoproterenol was augmented at all times during the 16-wk period. Characterization of beta-adrenoceptor binding in failing hearts at 16 wk revealed a significant increase in beta(1)-receptor density, whereas beta(2)-receptor density was unchanged. Consistent with this, basal adenylyl cyclase activity was significantly increased, and both isoproterenol- and forskolin-stimulated adenylyl cyclase activities were also increased. These results indicate that upregulation of beta-adrenoceptor signal transduction is a unique feature of cardiac hypertrophy and failure induced by volume overload.     

Effects of exercise training on acclimatization to hypoxia: systemic O2 transport during maximal exercise.

Acclimatization to hypoxia has minimal effect on maximal O2 uptake (Vo2 max). Prolonged hypoxia shows reductions in cardiac output (Q), maximal heart rate (HR-max), myocardial beta-adrenoceptor (beta-AR) density, and chronotropic response to isoproterenol. This study tested the hypothesis that exercise training (ET), which attenuates beta-AR downregulation, would increase HRmax and Q of acclimatization and result in higher Vo2 max. After 3 wk of ET, rats lived at an inspired Po2 of 70 Torr for 10 days (acclimatized trained rats) or remained in normoxia, while both groups continued to train in normoxia. Controls were sedentary acclimatized and nonacclimatized rats. All rats exercised maximally in normoxia and hypoxia (inspired Po2 of 70 Torr). Myocardial beta-AR density and the chronotropic response to isoproterenol were reduced, and myocardial cholinergic receptor density was increased after acclimatization; all of these receptor changes were reversed by ET. Normoxic Vo2 max (in ml.min-1.kg-1) was 95.8 +/- 1.0 in acclimatized trained (n = 6), 87.7 +/- 1.7 in nonacclimatized trained (P < 0.05, n = 6), 74.2 +/- 1.4 in acclimatized sedentary (n = 6, P < 0.05), and 72.5 +/- 1.2 in nonacclimatized sedentary (n = 8; P > 0.05 acclimatized sedentary vs. nonacclimatized sedentary). A similar distribution of Vo2 max values occurred in hypoxic exercise. Q was highest in trained acclimatized and nonacclimatized, intermediate in nonacclimatized sedentary, and lowest in acclimatized sedentary groups. ET preserved Q in acclimatized rats thanks to maintenance of HRmax as well as of maximal stroke volume. Q preservation, coupled with a higher arterial O2 content, resulted in the acclimatized trained rats having the highest convective O2 transport and Vo2 max. These results show that ET attenuates beta-AR downregulation and preserves Q and Vo2 max after acclimatization, and support the idea that beta-AR downregulation partially contributes to the limitation of Vo2 max after acclimatization in rats.     

Changes in beta-adrenoceptors in heart failure due to myocardial infarction are attenuated by blockade of renin-angiotensin system

Earlier studies have revealed an improvement of cardiac function in animals with congestive heart failure (CHF) due to myocardial infarction (MI) by treatment with angiotensin converting enzyme (ACE) inhibitors. Since heart failure is also associated with attenuated responses to catecholamines, we examined the effects of imidapril, an ACE inhibitor, on the beta-adrenoceptor (beta-AR) signal transduction in the failing heart. Heart failure in rats was induced by occluding the coronary artery, and 3 weeks later the animals were treated with g/(kg x day) (orally) imidapril for 4 weeks. The animals were assessed for their left ventricular function and inotropic responses to isoproterenol. Cardiomyocytes and crude membranes were isolated from the non-ischemic viable left ventricle and examined for the intracellular concentration of Ca2+ [Ca2+]i and beta-ARs as well as adenylyl cyclase (AC) activity, respectively. Animals with heart failure exhibited depressions in ventricular function and positive inotropic response to isoproterenol as well as isoproterenol-induced increase in [Ca2+]i in cardiomyocytes; these changes were attenuated by imidapril treatment. Both beta1-AR receptor density and isoproterenol-stimulated AC activity were decreased in the failing heart and these alterations were prevented by imidapril treatment. Alterations in cardiac function, positive inotropic effect of isoproterenol, beta1-AR density and isoproterenol-stimulated AC activity in the failing heart were also attenuated by treatment with another ACE inhibitor, enalapril and an angiotensin II receptor antagonist, losartan. The results indicate that imidapril not only attenuates cardiac dysfunction but also prevents changes in beta-AR signal transduction in CHF due to MI. These beneficial effects are similar to those of enalapril or losartan and thus appear to be due to blockade of the renin-angiotensin system.     

Strain-dependent beta-adrenergic receptor function influences myocardial responses to isoproterenol stimulation in mice

Recently, we showed that compared with the A/J inbred mouse strain, C57BL/6J (B6) mice have an athlete's cardiac phenotype. We postulated that strain differences would result in greater left ventricular (LV) hypertrophy in response to isoproterenol in B6 than A/J mice and tested the hypothesis that a differential response could be explained partly by differences in beta-adrenergic receptor (beta-AR) density and/or coupling. A/J and B6 mice were randomized to receive daily isoproterenol (100 mg/kg sc) or isovolumic vehicle for 5 days. Animals were studied using echocardiography, tail-cuff blood pressure, histopathology, beta-AR density and percent high-affinity binding, and basal and stimulated adenylyl cyclase activities. One hundred twenty-eight mice (66 A/J and 62 B6) were studied. Isoproterenol-treated A/J mice demonstrated greater percent increases in echocardiographic LV mass/body weight (97 +/- 11 vs. 20 +/- 10%, P = 0.001) and in gravimetric heart mass/body weight versus same-strain controls than B6 mice. Histopathology scores (a composite of myocyte hypertrophy, nuclear changes, fibrosis, and calcification) were greater in isoproterenol-treated A/J vs. B6 mice (2.8 +/- 0.2 vs.1.9 +/- 0.3, P < 0.05), as was quantitation of myocyte damage (22.3 +/- 11.5 vs. 4.3 +/- 3.5%). Interstrain differences in basal beta-AR density, high-affinity binding, and adenylyl cyclase activity were not significant. However, whereas isoproterenol-treated A/J mice showed nonsignificant increases in all beta-AR activity measures, isoproterenol-treated B6 mice had lower beta-AR density (57 +/- 6 vs. 83 +/- 8 fmol/mg, P < 0.05), percent high-affinity binding (15 +/- 2 vs. 26 +/- 3%, P < 0.005), and GTP + isoproterenol-stimulated adenylyl cyclase activity (10 +/- 1.1 vs. 5.8 +/- 1.5 pmol cAMP.mg(-1).min(-1)) compared with controls. High-dose, short-term isoproterenol produces greater macro- and microscopic cardiac hypertrophy and injury in A/J than B6 mice. A/J mice, unlike B6 mice, do not experience beta-AR downregulation or uncoupling in response to isoproterenol. Abnormalities in beta-adrenergic regulation may contribute to strain-related differences in the vulnerability to isoproterenol-induced cardiac changes.     

Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity.

Doxorubicin (Dox) is a highly effective antineoplastic antibiotic associated with a dose-limiting cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. The purpose of this study was to examine the effects of low-intensity exercise training (LIET) during the course of Dox treatment on cardiac function, myosin heavy chain expression, oxidative stress, and apoptosis activation following treatment. Male Sprague-Dawley rats either remained sedentary or were exercise trained on a motorized treadmill at 15 m/min, 20 min/day, 5 days/wk (Monday through Friday) for 2 wk. During the same 2-wk period, Dox (2.5 mg/kg) or saline was administered intraperitoneally to sedentary and exercised rats 3 days/wk (Monday, Wednesday, Friday) 1-2 h following the exercise training sessions (cumulative Dox dose: 15 mg/kg). Five days following the final injections, hearts were isolated for determination of left ventricular (LV) function, lipid peroxidation, antioxidant enzyme protein expression, 72-kDa heat shock protein expression, caspase-3 activity, and myosin heavy chain isoform expression. Dox treatment significantly impaired LV function and increased caspase-3 activity in sedentary animals (P < 0.05). LIET attenuated the LV dysfunction and apoptotic signal activation induced by Dox treatment and increased glutathione peroxidase expression, but it had no significant effect on lipid peroxidation, protein expression of myosin heavy chain isoforms, 72-kDa heat shock protein, or superoxide dismutase isoforms. In conclusion, our data suggest that LIET applied during chronic Dox treatment protects against cardiac dysfunction following treatment, possibly by enhancing antioxidant defenses and inhibiting apoptosis.     

Regulation of fetal cardiac and hepatic beta-adrenoceptors and adenylyl cyclase signaling: terbutaline effects

Terbutaline (Ter), a beta(2)-adrenergic agonist used in preterm labor, stimulates fetal beta-adrenoceptors (beta-ARs). We administered Ter to pregnant rats on gestational days 17-20 and examined beta-ARs and adenylyl cyclase (AC) signaling in heart and liver. Ter produced less downregulation of cardiac beta-ARs than in adults, despite a higher proportion of the beta(2)-subtype, and failed to elicit desensitization of the receptor-mediated AC response. AC stimulants acting at different points indicated an offsetting of homologous desensitization at the level of the beta-AR by heterologous sensitization at the level of AC: induction of total AC catalytic activity and a shift in the catalytic profile or AC isoform. In fetal liver, Ter produced downregulation of beta-ARs, in keeping with the predominance of the beta(2)-subtype; hepatic receptor downregulation was equivalent in fetus and adult. Nevertheless, there was still no desensitization of beta-AR-mediated AC responses and again AC was induced. Our results indicate that, unlike in the adult, fetal beta-AR signaling is not desensitized by beta-agonists and, in fact, displays heterologous sensitization, thus sustaining responses during parturition. At the same time, the inability to desensitize beta-AR AC responses may lead to disruption of cardiac, hepatic, or neural cell development as a consequence of tocolytic therapy with beta-agonists.