Search PubMed⌕ Search

Biomedical subjects

S F Vatner

Publications and source records attributed to S F Vatner.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cyclosporine attenuates pressure-overload hypertrophy in mice while enhancing susceptibility to decompensation and heart failure.

Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload. Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced by aortic banding in 53 mice (32 treated with cyclosporine [25 mg. kg-1. d-1], 21 treated with vehicle). There were 17 sham-operated mice (9 treated with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, LV weight to body weight was greater in the nontreatment banded group (4.39+/-0. 16 mg/g) than in the cyclosporine-treated banded group (3.95+/-0.14 mg/g, P<0.05), with both groups being greater compared with the entire group of sham-operated mice (3.02+/-0.04 mg/g). The pressure gradient between the ascending and abdominal aorta was not different between the cyclosporine-treated (49.6+/-6.1 mm Hg) and nontreatment groups (48.7+/-4.6 mm Hg). Although LV systolic pressure was lower in the cyclosporine-treated banded animals, LV systolic wall stress was similar in the nontreatment banded group and in the cyclosporine-treated group. However, LV dP/dt was lower (P=0.05) in the cyclosporine-treated banded group (4774+/-656 mm Hg/s) than in the nontreatment banded group (6604+/-516 mm Hg/s). During the protocol, 23 of 32 mice in the cyclosporine-treated group and 9 of 21 mice in the nontreatment group died. All deaths occurred within 10 days after surgery. Deaths caused by heart failure were 7.2-fold higher (P<0.05) in the cyclosporine-treated group, whereas deaths due to other causes were not different between the 2 groups. In addition, LV function of mice was assessed at 48 hours after banding; LV ejection fraction measured with echocardiography was lower (P<0.05) in the cyclosporine-treated banded group (66+/-3.0%) than in the nontreatment banded group (79+/-1.5%), whereas LV systolic wall stresses were similar. Calcineurin phosphatase activity was depressed similarly in both cyclosporine-treated groups compared with both nontreatment groups. Thus, cyclosporine could attenuate, but not prevent, LVH at the expense of inhibiting an important compensatory mechanism in response to pressure overload, resulting in reduced LV wall stress and function and increased susceptibility to decompensation and heart failure.

Animals↗
PubMed1999

An adenosine agonist and preconditioning shift the distribution of myocardial blood flow in conscious pigs.

The goal of this study was to determine whether the cardioprotective effects of an A1-receptor agonist and ischemic preconditioning (IPC) involve a shift in the pre-coronary artery occlusion (CAO) spatial distribution of myocardial blood flow, which might shed light on the mechanism of IPC and explain its heterogeneous effects. Accordingly, 60 min of CAO followed by 72 h of coronary artery reperfusion (CAR) was examined in three groups of conscious pigs 10-14 days after instrumentation with aortic and left atrial catheters and coronary artery occluders. Myocardial infarct size, expressed as a fraction of the area at risk (AAR), was reduced significantly (P < 0.05) by infusion of the A1 agonist (27.1 +/- 6.6%) and to a greater extent (P < 0.05) by IPC (11.6 +/- 5.1%) compared with infarct size in vehicle-treated animals (55.1 +/- 2.9%). Transmural myocardial blood flow (radioactive microspheres) in the AAR shifted toward lower levels after infusion of the A1 agonist (1.27 +/- 0.19 vs. 0.74 +/- 0.10 ml. min-1. g-1) or IPC (1.27 +/- 0.11 vs. 0.96 +/- 0.09 ml. min-1. g-1) but not after infusion of the vehicle (1.20 +/- 0.10 vs. 1.23 +/- 0.09 ml. min-1. g-1). This study demonstrated that both pretreatment with an adenosine A1 agonist and also IPC altered the spatial distribution of pre-CAO myocardial blood flow, which might reflect a downregulation of metabolic state and thus play a role in the cardioprotective effects of IPC.

Animals↗
PubMed1999

Mechanisms of desensitization to a PDE inhibitor (milrinone) in conscious dogs with heart failure.

The goal of this study was to determine the extent to which the effects of milrinone were desensitized in heart failure (HF) and to determine the mechanisms, i.e., whether these effects could be ascribed to changes in cAMP or phosphodiesterase (PDE) activity in HF. Accordingly, we examined the effects of milrinone in seven conscious dogs before and after HF was induced by rapid ventricular pacing at 240 beats/min. The dogs were chronically instrumented for measurements of left ventricular (LV) pressure and first derivative of LV pressure (dP/dt), arterial pressure, LV internal diameter, and wall thickness. Milrinone (10 micrograms . kg-1. min-1 iv) increased LV dP/dt by 1,854 +/- 157 from 2,701 +/- 105 mmHg/s (P < 0.05) before HF. After HF the increase in LV dP/dt in response to milrinone was attenuated significantly (P < 0.05); it increased by 615 +/- 67 from 1,550 +/- 107 mmHg/s, indicating marked desensitization. In the presence of ganglionic blockade the increases in LV dP/dt (+445 +/- 65 mmHg/s) in response to milrinone were markedly less (P < 0.01), and milrinone increased LV dP/dt even less in HF (+240 +/- 65 mmHg/s). cAMP and PDE activity were measured in endocardial and epicardial layers in normal and failing myocardium. cAMP was decreased significantly (P < 0.05) in LV endocardium (-26%) but not significantly in LV epicardium (-14%). PDE activity was also decreased significantly (P < 0.05) in LV endocardium (-18%) but not in LV epicardium (-4%). Thus significant desensitization to milrinone was observed in conscious dogs with HF. The major effect was autonomically mediated. The biochemical mechanism appears to be due in part to the modest reductions in PDE activity in failing myocardium, which, in turn, may be a compensatory mechanism to maintain cAMP levels in HF. Reductions in cAMP and PDE levels were restricted to the subendocardium, suggesting that the increased wall stress and reduced coronary reserve play a role in mediating these changes.

Animals↗
PubMed1999

An alpha-cardiac myosin heavy chain gene mutation impairs contraction and relaxation function of cardiac myocytes.

Left Ventricular (LV) myocytes were isolated from 15-wk-old male mice bearing the Arg403 --> Gln alpha-cardiac myosin heavy chain missense mutation (alpha-MHC403/+), a model of familial hypertrophic cardiomyopathy. LV myocytes were classified morphologically: type I, rod shaped with parallel myofibrils; type II, irregularly shaped, shorter and wider than wild-type (WT) control cells, with parallel myofibrils; and type III, irregularly shaped with disoriented myofibrils. Compared with WT myocytes, alpha-MHC403/+ myocytes had fewer type I cells (WT = 74 +/- 3%, alpha-MHC403/+ = 41 +/- 4%, P < 0.01) and more type III cells (WT= 12 +/- 3%, alpha-MHC403/+ = 49 +/- 7%, P < 0.01). In situ histology also demonstrated marked myofibrillar disarray in the alpha-MHC403/+ hearts. With the use of video edge detection, myocytes were paced at 1 Hz (37 degrees C) to determine the effects of the mutation on myocyte function. End-diastolic length was reduced in mutant myocytes, but fractional shortening (% contraction) and sarcomere length were not. Velocity of contraction (-dL/dtmax) was depressed in mutant cells, but more in type II and III cells (-31%) than in type I cells (-18%). Velocity of relaxation (+dL/dt) was also depressed more in type II and III cells (-38%) than in type I cells (-16%). Using fura 2 dye with intracellular Ca2+ transients, we demonstrated that in alpha-MHC403/+ myocytes, the amplitude of the Ca2+ signal during contraction was unchanged but that the time required for decay of the signal to decrease 70% from its maximum was delayed significantly (WT = 159 +/- 8 ms; alpha-MHC403/+ = 217 +/- 14 ms, P < 0.01). Sarco(endo)plasmic reticulum Ca2+-ATPase mRNA levels in alpha-MHC403/+ and WT mice were similar. These data indicate that the altered cardiac dysfunction of alpha-MHC403/+ myocytes is directly due to defective myocyte function rather than to secondary changes in global cardiac function and/or loading conditions.

Action Potentials↗
PubMed1999

Differential regulation of inotropy and lusitropy in overexpressed Gsalpha myocytes through cAMP and Ca2+ channel pathways.

We investigated the mechanisms responsible for altered contractile and relaxation function in overexpressed Gsalpha myocytes. Although baseline contractile function (percent contraction) in Gsalpha mice was similar to that of wild-type (WT) mice, left ventricular myocyte contraction, fura-2 Ca2+transients, and Ca2+ channel currents (ICa) were greater in Gsalpha mice in response to 10(-8) M isoproterenol (ISO) compared with WT mice. The late phase of relaxation of the isolated myocytes and fura-2 Ca2+ transients was accelerated at baseline in Gsalpha but did not increase further with ISO. In vivo measurements using echocardiography also demonstrated enhanced relaxation at baseline in Gsalpha mice. Forskolin and CaCl2 increased contraction similarly in WT and Gsalpha mice. Rp-cAMP, an inhibitor of protein kinase, blocked the increases in contractile response and Ca2+ currents to ISO in WT and to forskolin in both WT and Gsalpha. It also blocked the accelerated relaxation in Gsalpha at baseline but not the contractile response to ISO in Gsalpha myocytes. Baseline measurements of cAMP and phospholambation phosphorylation were enhanced in Gsalpha compared with WT. These data indicate that overexpression of Gsalpha accelerates relaxation at end diastolic but does not affect baseline systolic function in isolated myocytes. However, the enhanced responses to sympathetic stimulation partly reflect increased Ca2+ channel activity; i.e the cellular mechanisms mediating these effects appear to involve a cAMP-independent as well as a cAMP-dependent pathway.

Animals↗
PubMed1999

Beta-adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic G(salpha) mouse.

Transgenic (TG) mice with cardiac G(salpha) overexpression exhibit enhanced inotropic and chronotropic responses to sympathetic stimulation, but develop cardiomyopathy with age. We tested the hypothesis that cardiomyopathy in TG mice with G(salpha) overexpression could be averted with chronic beta-adrenergic receptor (beta-AR) blockade. TG mice and age-matched wild-type littermates were treated with the beta-AR blocker propranolol for 6-7 months, starting at a time when the cardiomyopathy was developing but was not yet severe enough to induce significant cardiac depression (9.5 months of age), and ending at a time when cardiac depression and cardiomyopathy would have been clearly manifest (16 months of age). Propranolol treatment, which can induce cardiac depression in the normal heart, actually prevented cardiac dilation and the depressed left ventricular function characteristic of older TG mice, and abolished premature mortality. Propranolol also prevented the increase in myocyte cross-sectional area and myocardial fibrosis. Myocyte apoptosis, already apparent in 9-month-old TG mice, was actually eliminated by chronic propranolol. This study indicates that chronic sympathetic stimulation over an extended period is deleterious and results in cardiomyopathy. Conversely, beta-AR blockade is salutary in this situation and can prevent the development of cardiomyopathy.

Adenylyl Cyclases↗
PubMed1998

Voltage-dependent calcium channel promoter restores baroreflex sensitivity in conscious dogs with heart failure.

BACKGROUND: The aim of this study was to determine the mechanism by which the calcium channel promoter BAY y 5959 affects the control of heart rate and baroreflex sensitivity in conscious dogs with pacing-induced heart failure (HF). METHODS AND RESULTS: We compared responses to BAY y 5959, which increases inotropy and decreases chronotropy, with those to norepinephrine (NE), which coincidentally exerts the same directional effects on inotropy and chronotropy, albeit through different mechanisms, in the presence and absence of ganglionic blockade both in control and in HF. Both BAY y 5959 and NE elicit direct effects on the heart and indirect effects through activation of reflexes, primarily the sinoaortic baroreceptor reflex. BAY y 5959 still reduced heart rate in dogs with arterial baroreceptor denervation, but not after ganglionic blockade. HF induced classic catecholamine desensitization to the inotropic effects of NE and blunted reflex bradycardia. In contrast, inotropic responses to BAY y 5959 were preserved in HF. Surprisingly, the autonomically mediated bradycardia induced by BAY y 5959 was also preserved in HF. Baroreflex sensitivity was assessed in control and in HF by pulse interval-systolic arterial blood pressure (PI/SAP) slopes constructed in response to pharmacological alterations in arterial pressure. HF depressed the PI/SAP slope from 11.5+/-1.3 to 4.8+/-0.9 ms/mm Hg, but during BAY y 5959 infusion in HF, the PI/SAP slope was restored to 24.1+/-5.2 ms/mm Hg. To assess central versus peripheral actions of BAY y 5959, the agent was infused with intra-carotid artery perfusion at a low dose, which acted centrally but did not have an effect peripherally. Under these conditions, it still decreased heart rate and restored baroreflex sensitivity (PI/SAP slope, 12.7+/-2.8 ms/mm Hg). CONCLUSIONS: Thus, the calcium promoter restores arterial baroreflex sensitivity in HF. Based on intra-carotid artery experiments, this occurs through a central nervous system and vagal mechanism.

Animals↗
PubMed1998

Cardiac Gsalpha overexpression enhances L-type calcium channels through an adenylyl cyclase independent pathway.

The alpha subunit of the stimulatory heterotrimeric G protein (Gsalpha) is critical for the beta-adrenergic receptor activation of the cAMP messenger system. The role of Gsalpha in regulating cardiac Ca2+ channel activity, however, remains controversial. Cultured neonatal cardiac myocytes from transgenic mice overexpressing cardiac Gsalpha were used to assess the role of Gsalpha on the whole-cell Ca2+ currents (ICa). Cardiac myocytes from transgenic mice had a 490% higher peak ICa compared with those of either wild-type controls or Gsalpha-nonexpressing littermates. The effect of Gsalpha overexpression was mimicked by intracellular dialysis of wild-type cardiac myocytes with GTPgammaS-activated Gsalpha. This effect was not mediated by protein kinase A activation as intracellular perfusion with a protein kinase A inhibitor rendered the same degree of activation in either transgenic or wild-type myocytes also dialyzed with activated Gsalpha. The data indicate that Gsalpha overexpression is associated with a constitutive enhancement of ICa which is independent of the cAMP pathway and activation of endogenous adenylyl cyclase.

Adenylyl Cyclases↗
PubMed1998

Ineffective perfusion-contraction matching in conscious, chronically instrumented pigs with an extended period of coronary stenosis.

Several models purported to represent hibernating myocardium involve a coronary stenosis (CS) to reduce blood flow (BF) and function without eliciting necrosis in anesthetized pigs. The goal of the present study was to determine whether sustained moderate reduction in coronary BF in conscious pigs induced hibernating myocardium, ie, perfusion-contraction matching with no necrosis. These experiments were conducted in conscious pigs chronically instrumented with a coronary artery BF probe and hydraulic occluder, left ventricular (LV) pressure gauge, and wall thickening (WT) crystals in the potentially ischemic and nonischemic zones. The hydraulic occluder was inflated to induce a stable 41+/-4% reduction in BF for 24 hours. Ischemic zone systolic WT fell initially with CS and then continued to decline during the period of CS even though blood flow did not change further, suggesting the induction of myocardial stunning. At 2 days after release of CS, WT was still depressed by 48+/-15%. Assessment of necrosis by histology or triphenyltetrazolium chloride showed 40+/-5% multifocal patchy necrosis interspersed with normal tissue involving the inner one third to one half of the ventricular wall. Regional myocardial BF (radioactive microsphere technique) was assessed by dividing the entire LV into an average of 488+/-59 pieces and examining the spatial distribution of BF within the area at risk (AAR). BF in the samples in the area of patchy necrosis was reduced (-66+/-4% from a baseline of 1.55+/-0.27 mL x min(-1) x g(-1)), whereas BF was maintained in samples in the AAR without necrosis (-2+/-7% from a baseline of 1.25+/-0.22 mL x min(-1) x g(-1)). These findings indicate that when hypoperfusion induced by CS in conscious pigs is sustained, the result is necrosis rather than hibernating myocardium. The remainder of the AAR, which lacked necrosis, might have been mistaken for hibernating myocardium had only histology been evaluated and BF not been measured and found to be at normal levels.

Animals↗
PubMed1998

Overexpression of myocardial Gsalpha prevents full expression of catecholamine desensitization despite increased beta-adrenergic receptor kinase.

Inotropic and chronotropic responses to catecholamines in young adult transgenic mice overexpressing myocardial Gsalpha are enhanced. One might predict that over the life of the animal, this chronically enhanced beta-adrenergic receptor stimulation would result in homologous catecholamine desensitization. To test this hypothesis, old transgenic Gsalpha mice and age-matched controls were studied physiologically in terms of responsiveness of left ventricular function (ejection fraction) to isoproterenol in vivo and in vitro in terms of beta-adrenergic receptor signaling. Old transgenic mice still responded to isoproterenol with augmented (P < 0.05) left ventricular ejection fraction (+44+/-3%) compared with age-matched controls (+24+/-1%). Although total beta-adrenergic receptor density was reduced in the old transgenic mice, and G protein receptor kinase 2 (beta-adrenergic receptor kinase) levels were increased, the fraction of receptors binding agonist with high affinity as well as isoproterenol- and G protein-stimulated adenylyl cyclase activities were enhanced. Thus, classical catecholamine desensitization is not effective in attenuation of persistently enhanced responses to sympathetic stimulation in mice overexpressing myocardial Gsalpha. To support this conclusion further, experiments were performed with chronic isoproterenol, which elicited effective desensitization in wild-type controls, but failed to elicit desensitization in overexpressed Gsalpha mice. The results of this study suggest that the lack of protective desensitization mechanisms may be responsible in part for the dilated cardiomyopathy which develops with chronic sympathetic stress over the life of these animals.

Adenylyl Cyclases↗
PubMed1998

Depressed heart rate variability and arterial baroreflex in conscious transgenic mice with overexpression of cardiac Gsalpha.

Recently, we developed a transgenic mouse with cardiac-specific Gsalpha overexpression (TG mouse), which exhibits enhanced postsynaptic beta-adrenergic receptor signaling, ultimately developing a cardiomyopathy. The goal of the present study was to determine whether cardiac Gsalpha overexpression alters autonomic cardiovascular control, which could shed light on the mechanism responsible for the later development of cardiomyopathy. Mean arterial pressure was increased (P<.05) in conscious, chronically instrumented TG mice (123+/-1 mm Hg) compared with age-matched wild-type (WT) control mice (103+/-1 mm Hg). Respiratory frequency was increased (P<.05) in TG mice (269+/-26/min) compared with WT mice (210+/-20/min). By use of telemetric techniques, baseline heart rate (HR) was elevated (P<.05) in conscious, untethered TG mice (696+/-13 bpm) compared with WT mice (568+/-28 bpm). Intrinsic HR, after propranolol and atropine or after ganglionic blockade with hexamethonium, was not different between TG and WT mice. Both the normal minute-to-minute and circadian variations of HR observed in WT mice were markedly blunted in TG mice. HR variability was assessed by the time-domain and frequency-domain methods. At baseline, time-domain analysis indices were reduced (P<.05) in TG mice compared with WT mice. Although the low frequency (LF) component was higher (P<.05) than the high frequency (HF) component in WT mice, the LF component was less (P<.05) than the HF component in TG mice. In addition, arterial baroreflex regulation of HR was markedly blunted in TG mice in response to both nitroglycerin-induced hypotension and phenylephrine-induced hypertension. The reduced LF/HF ratio in TG mice was surprising in view of enhanced beta-adrenergic signaling and may be due to reduced neural tone secondary to the elevated arterial pressure or alterations in arterial baroreflex control. Dobutamine infusion in WT mice also resulted in depressed HR variability. The combination of elevated baseline HR, arterial pressure, and respiratory frequency suggests that enhanced beta-adrenergic signaling in TG mice results in reduced HR variability, in terms of both minute-to-minute variability and the lack of circadian variations in HR. The lack of normal HR variability in general and the failure of HR to decline, even during sleep, may actually be critical mechanisms contributing to the ultimate development of cardiomyopathy in these animals.

Adrenergic beta-Agonists↗
PubMed1998

Selective large coronary endothelial dysfunction in conscious dogs with chronic coronary pressure overload.

Coronary vascular responses to acetylcholine (ACh, 3 micrograms/kg i.v.), nitroglycerin (NTG, 25 micrograms/kg i.v.), and a 20-s coronary artery occlusion (reactive hyperemia, RH) were investigated in seven conscious dogs with severe left ventricular (LV) hypertrophy and chronic coronary pressure overload (CCPO) due to supravalvular aortic banding and in seven control dogs. All dogs were instrumented for measurement of ultrasonic coronary diameter (CD) and Doppler coronary blood flow (CBF). LV-to-body weight ratio was increased by 82% in CCPO dogs. In control dogs, ACh increased CD (+ 5.9 +/- 1.7%). This response was reduced (P < 0.05) in CCPO dogs (+ 1.9 +/- 0.9%). Similarly, flow-mediated increases in CD after RH were blunted (P < 0.01) in CCPO (+ 2.1 +/- 0.8) vs. control dogs (+ 6.8 +/- 1.8%). In contrast, ACh and RH increased CBF similarly in both groups. Increases in both CD and CBF to NTG were not different between control dogs and CCPO. Peak systolic CBF velocity was greater, P < 0.01, in CCPO (94 +/- 17 cm/s) compared with control (35 +/- 7 cm/s) dogs, most likely secondary to the increased systolic coronary perfusion pressure (215 vs. 130 mmHg). Histological analyses of large coronary arteries in CCPO revealed medial thickening, intimal thickening, and disruption of the internal elastic lamina and endothelium. In contrast, small intramyocardial arterioles failed to show the intimal and endothelial lesions. Thus, in CCPO selective to the coronary arteries, i.e., a model independent from systemic hypertension and enhanced levels of plasma renin activity, endothelial control was impaired for both flow-mediated and receptor-mediated large coronary artery function, which could be accounted for by the major morphological changes in the large coronary arteries sparing the resistance vessels. The mechanism may involve chronically elevated systolic coronary perfusion pressure, CBF velocity, and potential disruption of laminar flow patterns.

Acetylcholine↗
PubMed1998

Lack of desensitization and enhanced efficiency of calcium channel promoter in conscious dogs with heart failure.

The goal of this study was to compare responses to a calcium promoter, BAY y 5959, and dobutamine (Dob) in heart failure (HF). Dogs (n = 9) were chronically instrumented and studied in the conscious state before and after pacing-induced HF. In the control state, BAY y 5959 (20 microgram. kg-1. min-1) increased the first derivative of left ventricular (LV) pressure (dP/dt) by 83 +/- 8% and mean arterial pressure (MAP) by 8 +/- 2% and decreased heart rate (HR) by 30 +/- 3%. With Dob (10 microgram. kg-1. min-1) LV dP/dt rose similarly (+80 +/- 6%), but HR also rose (+25 +/- 4%) (P < 0.05 vs. BAY y 5959). After HF developed, BAY y 5959 still increased LV dP/dt by 108 +/- 8% and MAP by 21 +/- 2% and decreased HR by 28 +/- 4%, whereas Dob increased LV dP/dt by only 50 +/- 7% (P < 0.05 vs. BAY y 5959) and MAP by 7 +/- 3%, and HR did not change (+3 +/- 3%) (P < 0.05 vs. BAY y 5959). In HF, cardiac work increased more (P < 0. 05) with BAY y 5959 (+105 +/- 13%) compared with Dob (+47 +/- 11%), yet myocardial oxygen consumption increased similarly with the two drugs. Accordingly, mechanical efficiency increased more (P < 0.05) with BAY y 5959 (+73 +/- 14%) than with Dob (+17 +/- 12%). These data indicate that 1) increases in contractility mediated directly by Ca2+ are relatively resistant to desensitization in HF; and 2) the calcium-channel promoter can produce increases in myocardial contractility and cardiac work similar to those of Dob at a significantly lower oxygen cost, thereby enhancing mechanical efficiency in HF.

Animals↗
PubMed1998

Physiological and biochemical adrenergic regulation of the stunned myocardium.

A dual approach was employed to study beta-adrenergic receptor signal transduction in post ischemic (stunned) myocardium, examining physiological interventions in awake, chronically instrumented pigs and biochemical, cellular mechanisms in sarcolemmal preparations from the stunned hearts using the contralateral non-ischemic zone as a control. Ten min of coronary artery occlusion (CAO) and 30 min coronary artery reperfusion (CAR) resulted in depressed posterior wall-thickening (myocardial stunning). Isoproterenol increased transmural wall thickening more in stunned myocardium than in non-ischemic myocardium. In contrast, the responses of wall thickening to forskolin, actually decreased during stunning compared with control. NKH 477, a water soluble forskolin derivative, that does not activate cardiac nerves, increased wall thickening in non-ischemic tissue similarly to the effects on stunned myocardium. Increasing cardiac neural tone reflexly with inferior venal caval occlusion (IVCO) elicited similar results to forskolin, i.e., stunned myocardium responded with less of an increase in wall thickening as compared with non-ischemic myocardium. Beta-adrenergic receptor density, as determined with 125I-cyanopindolol binding, was significantly increased in stunned subendocardium and subepicardium compared with respective values in non-ischemic myocardium. There were no differences in the response of adenylyl cyclase to isoproterenol in stunned and non-ischemic myocardium. The enhanced responsiveness of the beta-adrenergic receptor to isoproterenol stimulation in stunned myocardium corresponded to the increase in beta-adrenergic receptor density. The combination of enhanced responses to isoproterenol, and decreased responses to forskolin and to IVCO and preserved responsiveness to NKH 477, suggest that stunned myocardium is characterized by transient sympathetic neural stunning. The enhanced sensitivity to beta-adrenergic receptor stimulation has important clinical implications, both in terms of therapy of stunned myocardium and detection of stunned and/or hibernating myocardium, i.e., low dose dobutamine echocardiography.

Adenylyl Cyclases↗
PubMed1997

Identification of a cis-acting regulatory element conferring inducibility of the atrial natriuretic factor gene in acute pressure overload.

To identify the cis-acting regulatory element(s) which control the induction of the atrial natriuretic factor (ANF) gene in acute pressure overload, DNA constructs consisting of promoter elements linked to a reporter gene were injected into the myocardium of dogs, which underwent aortic banding or were sham-operated. Expression of a reporter gene construct harboring the ANF promoter (-3400ANF) was induced 6-12-fold after 7 d of pressure overload. An internal deletion of 556 bp (nucleotide sequence -693 to -137) completely abrogated the inducibility of the ANF reporter gene construct. An activator protein-1 (AP1)-like site (-496 to -489) and a cAMP regulatory element (CRE) (-602 to -596) are located within the deleted sequence. Site-directed mutagenesis of the AP1-like site but not the CRE completely prevented the induction of this construct to acute pressure overload. Further, the AP1-like site was able to confer inducibility of a heterologous promoter (beta-myosin heavy chain) to higher values than controls. Gel mobility shift assay (GMSA) supershift analysis was performed using a radiolabeled probe of the ANF promoter (-506/-483) that included the AP1-like site (ATGAATCA) sequence, as well as a probe converted to contain an AP1 consensus sequence (ATGACTCA). GMSA analysis demonstrated that the ANF AP1-like element could bind both a constitutively expressed factor and the AP1 proteins, and conversion to a true AP1 site increased its affinity for AP1. However, 7 d after the onset of pressure overload, the AP1 proteins were present only at low levels, and the major complex formed by the ANF AP1-like probe was not supershifted by a jun antibody. Using a large animal model of pressure overload, we have demonstrated that a unique cis-acting element was primarily responsible for the overload induction of the ANF gene.

Animals↗
PubMed1997

Effects of cardiac denervation on development of heart failure and catecholamine desensitization.

BACKGROUND: Two signatures of heart failure are activation of the sympathetic nervous system and catecholamine desensitization. However, whether or not the elimination of cardiac nerves affects either the progression of heart failure or catecholamine desensitization is not clear. METHODS AND RESULTS: We studied 8 dogs with selective ventricular denervation (VD) (surgical technique) and 10 intact dogs, chronically instrumented for measurement of left ventricular (LV) and arterial pressures, LV dP/dt, LV internal diameter, and wall thickness before and after heart failure was induced by rapid pacing (240 bpm) for 3 to 4 weeks. VD was confirmed by the absence of reflex effects induced by intracardiac veratrine and depletion of tissue norepinephrine and by supersensitive responses to norepinephrine. During the development of heart failure, LV end-systolic and end-diastolic stresses and heart rate increased, while myocardial contractility, as reflected by LV dP/dt and mean velocity of circumferential fiber shortening corrected for heart rate (Vcf(c)), decreased in both intact and VD dogs. However, the increases in LV end-diastolic stress and decreases in LV dP/dt as well as the relationship between LV systolic stress and Vcf(c) in heart failure were less (P<.05) in VD dogs. The responses of LV dP/dt and heart rate to both isoproterenol and norepinephrine in intact dogs were reduced in heart failure. The physiological desensitization to the inotropic effects of isoproterenol and norepinephrine was less in dogs with VD (P<.05), but chronotropic responses were similar because atrial innervation remained intact. Plasma norepinephrine levels were not different in VD dogs (592+/-79 pg/mL) compared with intact dogs (576+/-81 pg/mL) in heart failure. CONCLUSIONS: Dogs with selective VD tolerated the development of heart failure better than intact dogs and demonstrated significantly less catecholamine desensitization. The latter indicates that intact ventricular innervation is required for physiological expression of catecholamine desensitization despite comparable elevation of plasma catecholamines during the development of heart failure.

Adrenergic alpha-Agonists↗