Global longitudinal strain to predict left ventricular dysfunction in asymptomatic patients with severe mitral valve regurgitation: literature review

Netherlands Heart Journal - The optimal treatment strategy for asymptomatic patients with severe mitral valve regurgitation (MR) and preserved left ventricular (LV) function is challenging. This...     

PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease

In autosomal recessive polycystic kidney disease (ARPKD), progressive enlargement of fluid-filled cysts is due to aberrant proliferation of tubule epithelial cells and transepithelial fluid secretion leading to extensive nephron loss and interstitial fibrosis. Congenital hepatic fibrosis associated with biliary cysts/dilatations is the most common extrarenal manifestation in ARPKD and can lead to massive liver enlargement. Peroxisome proliferator-activated receptor γ (PPAR-γ), a member of the ligand-dependent nuclear receptor superfamily, is expressed in a variety of tissues, including the kidneys and liver, and plays important roles in cell proliferation, fibrosis, and inflammation. In the current study, we determined that pioglitazone (PIO), a PPAR-γ agonist, decreases polycystic kidney and liver disease progression in the polycystic kidney rat, an orthologous model of human ARPKD. Daily treatment with 10 mg/kg PIO for 16 wk decreased kidney weight (% of body weight), renal cystic area, serum urea nitrogen, and the number of Ki67-, pERK1/2-, and pS6-positive cells in the kidney. There was also a decrease in liver weight (% of body weight), liver cystic area, fibrotic index, and the number of Ki67-, pERK1/2-, pERK5-, and TGF-β-positive cells in the liver. Taken together, these data suggest that PIO inhibits the progression of polycystic kidney and liver disease in a model of human ARPKD by inhibiting cell proliferation and fibrosis. These findings suggest that PPAR-γ agonists may have therapeutic value in the treatment of the renal and hepatic manifestations of ARPKD.     

Effect of PPAR-gamma agonist treatment on markers of endothelial dysfunction in patients with type 2 diabetes mellitus

Thiazolidinediones are insulin-sensitizing drugs acting through peroxisome proliferator-activated receptor (PPAR)-gamma. The aim of our study was to evaluate the effect of 5-month treatment with PPAR-gamma agonist--rosiglitazone (4 mg/day), on the circulating markers of endothelial dysfunction and to evaluate the role of changes in endocrine function of adipose tissue in this process. Biochemical and metabolic parameters, circulating adiponectin, resistin, ICAM-1, VCAM-1, E-selectin, P-selectin, PAI-1, myeloperoxidase (MPO), and matrix metalloproteinase-9 (MMP-9) concentrations were assessed in 10 women with type 2 DM before and after rosiglitazone treatment and in a control group of healthy women. At baseline, diabetic group had significantly higher serum concentrations of glucose, glycated hemoglobin, V-CAM and PAI-1 compared to control group. Adiponectin levels tended to be lower in diabetic group, while resistin concentrations did not differ from control group. Rosiglitazone treatment improved diabetes compensation, significantly reduced VCAM-1, PAI-1 and E-selectin concentrations and increased adiponectin levels, while it did not affect serum resistin concentrations. Adiponectin concentrations at baseline were inversely related to E-selectin and MPO levels, this correlation disappeared after rosiglitazone treatment. We conclude that 5-month rosiglitazone treatment significantly reduced several markers of endothelial dysfunction. This effect could be at least in part attributable to marked increase of circulating adiponectin levels.     

Benefits of long-term beta-blockade in experimental chronic aortic regurgitation

The objective of this study was to assess the long-term effects of beta-blockade on survival and left ventricular (LV) remodeling in rats with aortic valve regurgitation (AR). The pharmacological management of chronic AR remains controversial. No drug has been definitively proven to delay the need for valve replacement or to affect morbidity and/or mortality. Our group has reported that the adrenergic system is activated in an animal model of AR and that adrenergic blockade may help maintain normal LV function. The effects of prolonged treatment with a beta-blocker are unknown. Forty Wistar rats with severe AR were divided into 2 groups of 20 animals each and treated with metoprolol (Met, 25 mg.kg(-1).day(-1)) or left untreated for 1 yr. LV remodeling was evaluated by echocardiography. Survival was assessed by Kaplan-Meir curves. Hearts were harvested for tissue analysis. All Met-treated animals were alive after 6 mo vs. 70% of untreated animals. After 1 yr, 60% of Met-treated animals were alive vs. 35% of untreated animals (P = 0.028). All deaths, except one, were sudden. There were no differences in LV ejection fraction (all >50%) or LV dimensions. LV mass tended to be lower in the Met-treated group. There was less subendocardial fibrosis in this group, as well as lower LV filling pressures (LV end-diastolic pressure). beta-Adrenergic receptor ratio (beta(1)/beta(2)) was improved. One year of treatment with Met was well tolerated. Met improved 1-yr survival, minimized LV hypertrophy, improved LV filling pressures, decreased LV subendocardial fibrosis, and helped restore the beta-adrenergic receptor ratio.     

Mitral tetrahedron as a geometrical surrogate for chronic ischemic mitral regurgitation

The present study tests the hypothesis that a mitral tetrahedron (MT) is a useful geometrical surrogate for assessment of chronic ischemic mitral regurgitation (CIMR). Fifty-eight subjects were divided into three groups on the basis of left ventricular ejection fraction (LVEF) and the presence or absence of CIMR: LVEF > or =0.5 and negative CIMR (group 1, n = 28), LVEF <0.5 and negative CIMR (group 2, n = 12), and LVEF <0.5 and positive CIMR (group 3, n = 18). MT was defined by its four vertices at the anterior annulus, posterior annulus, and medial and lateral papillary muscle roots, determined by MRI at peak systole. The results showed no clear cutoff values of MT parameters between groups 2 and 1. In contrast, all MT indexes were significantly different between groups 3 and 2 (P < 0.05), and significant cutoff values differentiated the two groups. A scoring system employing parameters of the whole MT confirmed the absence of CIMR with total edge length index <268 mm/BSA(1/3), total surface area index <2,528 mm(2)/BSA(2/3), and volume index <5,089 mm(3)/BSA (where BSA is body surface area). The sensitivity, specificity, and positive and negative predictive values were 1.00. This preliminary study demonstrates that MT might serve as a good geometrical surrogate for assessing CIMR. The derived geometrical criteria of MT may be useful in surgical correction of CIMR.     

Regional differences in the force-frequency relation of human left ventricular myocardium in mitral regurgitation: implications for ventricular shape

Sphericalization of the left ventricular (LV) chamber shape in patients with mitral regurgitation (MR) contributes to increased LV wall stress and energy consumption. On the basis of previous observations, we hypothesized the existence of regional differences in the force-frequency relation (FFR) within the LV that may contribute to its shape. Accordingly, in the present study, we assessed regional variation in the FFR in patients undergoing surgery for chronic, nonischemic MR with class II-III heart failure symptoms and related our findings to the in vivo LV shape. FFRs (steady-state isometric twitches, 0.2-3.4 Hz, 37 degrees C) were evaluated in MR myocardium from the LV subepicardial free wall (MR-FW) and papillary muscle (MR-PM) and from the subepicardial free wall in coronary artery bypass graft patients with normal LV contraction patterns [nonfailing (NF)]. Ascending slope, optimal stimulation frequency, and maximal twitch tension of the FFR were depressed in MR-FW and MR-PM compared with NF (P < 0.05). FFR depression was greater in MR-PM than in MR-FW. Between 107 and 134 beats/min, twitch tension became weaker in MR-PM, whereas it increased in MR-FW. Elevation of intracellular cAMP with forskolin eliminated FFR depression in MR-FW but not in MR-PM. MR-PM also had a 35% lower myosin heavy chain content and slowed twitch kinetics. In MR patients, the echocardiographic end-diastolic LV shape (end-diastolic eccentricity index = long axis/short axis) correlated with the ratio of ascending FFR slopes such that the end-diastolic eccentricity index increased 10% per 15% increase in slope ratio (r = 0.88, P = 0.01). These regional differences in the frequency dependence of contractility between the free wall and papillary myocardium may contribute to changes in LV shape in MR as well as during exercise.     

Quantitative analysis of mitral valve morphology in atrial functional mitral regurgitation using real-time 3-dimensional echocardiography atrial functional mitral regurgitation

Background

Atrial fibrillation (AF) can result in atrial functional mitral regurgitation (MR), but the mechanism remains controversial. Few data about the relationship between the 3-dimensional morphology of the MV and the degree of MR in AF exist.

Methods

Real-time 3-dimensional transesophageal echocardiography (3D-TEE) of the MV was acquired in 168 patients with AF (57.7% persistent AF), including 25 (14.9%) patients with moderate to severe MR (the MR+ group) and 25 patients without AF as controls. The 3-dimensional geometry of the MV apparatus was acquired using dedicated quantification software.

Results

Compared with the group of patients with no or mild MR (the MR- group) and the controls, the MR+ group had a larger left atrium (LA), a more dilated mitral annulus (MA), a reduced annular height to commissural width ratio (AHCWR), indicating flattening of the annular saddle shape, and greater leaflet surfaces and tethering. MR severity was correlated with the MA area (r²?=?0.43, P?<?0.01) and the annulus circumference (r²?=?0.38, P?<?0.01). A logistic regression analysis indicated that the MA area (OR: 1.02, 95% CI: 1.01–1.03, P?<?0.01), AHCWR (OR: 0.24, 95% CI: 0.14–0.35, P?=?0.04) and MV tenting volume (OR: 3.24, 95% CI: 1.16–9.08, P?=?0.03) were independent predictors of MR severity in AF patients.

Conclusions

The mechanisms of “atrial functional MR” are complex and include dilation of the MA, flattening of the annular saddle shape and greater leaflet tethering.

     

Left ventricular dysfunction following rewarming from experimental hypothermia

This study was aimed at elucidating whetherventricular hypothermia-induced dysfunction persisting after rewarmingthe unsupported in situ dog heart could be characterized as a systolic,diastolic, or combined disturbance. Core temperature of 8 mongrel dogswas gradually lowered to 25°C and returned to 37°C over aperiod of 328 min. Systolic function was described by maximum rate ofincrease in left ventricular (LV) pressure(dP/dt_max),relative segment shortening (SS%), stroke volume (SV), and theload-independent contractility index, preload recruitable stroke work(PRSW). Diastolic function was described by the isovolumic relaxationconstant () and the LV wall stiffness constant(K_p). Comparedwith prehypothermic control, a significant decrease in LV functionalvariables was measured at 25°C:dP/dt_max 2,180 ± 158 vs. 760 ± 78 mmHg/s, SS% 20.1 ± 1.2 vs.13.3 ± 1.0%, SV 11.7 ± 0.7 vs. 8.5 ± 0.7 ml, PRSW 90.5 ± 7.7 vs. 29.1 ± 5.9 J/m · 10²,K_p 0.78 ± 0.10 vs. 0.28 ± 0.03 mm¹, and  78.5 ± 3.7 vs. 25.8 ± 1.6 ms. After rewarming, the significant depression ofLV systolic variables observed at 25°C persisted: dP/dt_max 1,241 ± 108 mmHg/s, SS% 10.2 ± 0.8 J, SV 7.3 ± 0.4 ml, and PRSW52.1 ± 3.6 m · 10², whereasthe diastolic values ofK_p and  returned to control. Thus hypothermia induced a significant depressionof both systolic and diastolic LV variables. After rewarming, diastolicLV function was restored, in contrast to the persistently depressed LVsystolic function. These observations indicate that cooling inducesmore long-lasting effects on the excitation-contraction coupling and the actin-myosin interaction than on sarcoplasmicreticulum Ca²⁺trapping dysfunction or interstitial fluid content, makingposthypothermic LV dysfunction a systolic perturbation.

     

Progressive nature of chronic mitral regurgitation and the role of tissue Doppler-derived indexes

The aim of this study was to determine whether severe mitral regurgitation (MR) is progressive and whether tissue-Doppler (TD)-derived indexes can detect early left ventricular (LV) dysfunction in chronic severe MR. Percutaneous rupture of mitral valve chordae was performed in pigs (n = 8). Before MR (baseline), immediately after MR (post-MR), and at 1 and 3 mo after MR, cardiac function was assessed using conventional and TD-derived indexes. The severity of MR was quantified using regurgitant fraction and effective regurgitant orifice area (EROA). In all animals, MR was severe. On follow-up, the LV dilated progressively over time, but LV ejection fraction did not decrease. With the increase in LV dimensions, the forward stroke volume remained unchanged, but the mitral annular dimensions, EROA, and regurgitant fraction increased (EROA = 41 +/- 2 and 51 +/- 2 mm(2) post-MR and at 3 mo, respectively, P < 0.01). Peak systolic myocardial velocities, strain, and strain rate increased acutely post-MR and remained elevated at 1 mo but declined by 3 mo (anterior strain rate = 2.9 +/- 0.1 and 2.4 +/- 0.2 s(-1) post-MR and at 3 mo, respectively, P < 0.001). Therefore, in a chronic model of MR, serial echocardiography demonstrated that MR begets MR and that those TD-derived indexes that initially increased post-MR decreased to baseline before any changes in LV ejection fraction.     

Sudden interruption of leaflet opening by ventricular contractions: a mechanism of mitral regurgitation.

The motion of both mitral cusps and the presence of valvular regurgitation during ventricular contractions were investigated in seven experiments on dogs in which radiopaque markers had been sutured to the cusps and the valve annulus 1-32 wk before the studies. Cineangiograms of the left ventricle were obtained during ventricular ectopic beats, interposed throughout the cardiac cycle (20-99% of cycle length) and during induced variations in the P-R interval (0-200 ms). Mitral regurgitation was observed only during a) weak, early ectopic beats (peak pressure below 34 mmHg) which were incapable of closing the cusps and b) when ventricular contractions suddenly interrupted normal leaflet motion toward the ventricle, during three well-defined periods of diastole (diastolic valve opening, diastolic rebound, and atrial opening). Valve closure following sudden reversal of cusp opening was slow and the leaflets often did not arrive simultaneously at their closed positions. These findings suggest that sudden interruption of leaflet opening by ventricular contractions is an important mechanism of transient mitral regurgitation in the normal heart.     

PPAR-gamma knockout in pancreatic epithelial cells abolishes the inhibitory effect of rosiglitazone on caerulein-induced acute pancreatitis

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, such as the thiazolidinediones (TZDs), decrease acute inflammation in both pancreatic cell lines and mouse models of acute pancreatitis. Since PPAR-gamma agonists have been shown to exert some of their actions independent of PPAR-gamma, the role of PPAR-gamma in pancreatic inflammation has not been directly tested. Furthermore, the differential role of PPAR-gamma in endodermal derivatives (acini, ductal cells, and islets) as opposed to the endothelial or inflammatory cells is unknown. To determine whether the effects of a TZD, rosiglitazone, on caerulein-induced acute pancreatitis are dependent on PPAR-gamma in the endodermal derivatives, we created a cell-type specific knock out of PPAR-gamma in pancreatic acini, ducts, and islets. PPAR-gamma knockout animals show a greater response in some inflammatory genes after caerulein challenge. The anti-inflammatory effect of rosiglitazone on edema, macrophage infiltration, and expression of the proinflammatory cytokines is significantly decreased in pancreata of the knockout animals compared with control animals. However, rosiglitazone retains its effect in the lungs of the pancreatic-specific PPAR-gamma knockout animals, likely due to direct anti-inflammatory effect on lung parenchyma. These data show that the PPAR-gamma in the pancreatic epithelia and islets is important in suppressing inflammation and is required for the anti-inflammatory effects of TZDs in acute pancreatitis.     

Left ventricular myofilament dysfunction in rat experimental hypertrophy and congestive heart failure

It is currently unclear whether left ventricular (LV) myofilament function is depressed in experimental LV hypertrophy (LVH) or congestive heart failure (CHF). To address this issue, we studied pressure overload-induced LV hypertrophy (POLVH) and myocardial infarction-elicited congestive heart failure (MICHF) in rats. LV myocytes were isolated from control, POLVH, and MICHF hearts by mechanical homogenization, skinned with Triton, and attached to micropipettes that projected from a sensitive force transducer and high-speed motor. A subset of cells was treated with either unphosphorylated, recombinant cardiac troponin (cTn) or cTn purified from either control or failing ventricles. LV myofilament function was characterized by the force-[Ca(2+)] relation yielding Ca(2+)-saturated maximal force (F(max)), myofilament Ca(2+) sensitivity (EC(50)), and cooperativity (Hill coefficient, n(H)) parameters. POLVH was associated with a 35% reduction in F(max) and 36% increase in EC(50). Similarly, MICHF resulted in a 42% reduction in F(max) and a 30% increase in EC(50). Incorporation of recombinant cTn or purified control cTn into failing cells restored myofilament Ca(2+) sensitivity toward levels observed in control cells. In contrast, integration of cTn purified from failing ventricles into control myocytes increased EC(50) to levels observed in failing myocytes. The F(max) parameter was not markedly affected by troponin exchange. cTnI phosphorylation was increased in both POLVH and MICHF left ventricles. We conclude that depressed myofilament Ca(2+) sensitivity in experimental LVH and CHF is due, in part, to a decreased functional role of cTn that likely involves augmented phosphorylation of cTnI.     

Left atrial dilatation resulting from chronic mitral regurgitation decreases spatiotemporal organization of atrial fibrillation in left atrium

Atrial conduction properties have been shown to differ among animal atrial fibrillation (AF) models of rapid atrial pacing (RAP), chronic mitral regurgitation (MR), and control. We hypothesized that these conduction differences would continue with the onset of AF, which would affect AF spatiotemporal organization, resulting in model-specific characteristics of AF. With frequency domain analysis of electrograms acquired from high-density optical mapping, AF from the right (RA) and left (LA) atrium in animals with RAP and MR were compared with control animals. At follow-up, the hearts were excised and perfused, and optical action potentials were recorded from a 2 x 2-cm area each of the RA and LA free wall with a 16 x 16 photodiode array. AF was induced with extra stimuli, several 2.4-s AF episodes were recorded in each dog, and a fast Fourier transform was calculated. The dominant frequency (DF) was determined, and the organization (organization index, OI) was calculated as the ratio of the area under the dominant peak and its harmonics to the total area of the spectrum. All possible pairs of electrograms for each episode were cross-correlated. LA AF in the chronic MR model showed an increase in the highest DF, the number of DF domains, and in frequency gradient compared with AF in control or RAP models. In addition, there was a decrease in OI and in the correlation coefficients in the LA of the MR model. These results suggest that the AF substrate in the MR model may be different from that of control or RAP models.     

Angiotensin-converting enzyme inhibitor captopril prevents volume overload cardiomyopathy in experimental chronic aortic valve regurgitation

The efficacy of angiotensin-converting enzyme inhibitors (ACEIs) in the treatment of chronic aortic regurgitation (AR) is not well established and remains controversial. The mechanisms by which ACEIs may protect against left-ventricular (LV) volume overload are not well understood, and clinical trials performed until now have yielded conflicting results. This study was therefore performed to assess the effectiveness of two different doses of the ACEI captopril in a rat model of chronic AR. We compared the effects of a 6-month low-dose (LD) (25 mg/kg) or higher dose (HD) (75 mg/kg) treatment with captopril on LV function and hypertrophy in Wistar rats with severe AR. Untreated animals developed LV eccentric hypertrophy and systolic dysfunction. LD treatment did not prevent hypertrophy and provided modest protection against systolic dysfunction. HD treatment preserved LV systolic function and dimensions and tended to slow hypertrophy. The cardiac index remained high and similar among all AR groups, treated or not. Tissue renin-angiotensin system (RAS) analysis revealed that ACE activity was increased in the LVs of AR animals and that only HD treatment significantly decreased angiotensin II receptor mRNA levels. Fibronectin expression was increased in the LV or AR animals, but HD treatment almost completely reversed this increase. The ACE inhibitor captopril was effective at high doses in this model of severe AR. These effects might be related to the modulation of tissue RAS and the control of fibrosis.     

Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) ameliorates experimental autoimmune encephalomyelitis

Peroxisome proliferator-activated receptors (PPAR) are members of a nuclear hormone receptor superfamily that includes receptors for steroids, retinoids, and thyroid hormone, all of which are known to affect the immune response. Previous studies dealing with PPAR-gamma expression in the immune system have been limited. Recently, PPAR-gamma was identified in monocyte/macrophage cells. In this study we examined the role of PPAR-gamma in experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. The hypothesis we are testing is whether PPAR-gamma plays an important role in EAE pathogenesis and whether PPAR-gamma ligands can inhibit the clinical expression of EAE. Initial studies have shown that the presence of the PPAR-gamma ligand 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ2) inhibits the proliferation of Ag-specific T cells from the spleen of myelin basic protein Ac(1-11) TCR-transgenic mice. 15d-PGJ2 suppressed IFN-gamma, IL-10, and IL-4 production by both Con A- and myelin basic protein Ac(1-11) peptide-stimulated lymphocytes as determined by ELISA and ELISPOT assay. Culture of encephalitogenic T cells with 15d-PGJ2 in the presence of Ag reduced the ability of these cells to adoptively transfer EAE. Examination of the target organ, the CNS, during the course of EAE revealed expression of PPAR-gamma in the spinal cord inflammatory infiltrate. Administration of 15d-PGJ2 before and at the onset of clinical signs of EAE significantly reduced the severity of disease. These results suggest that PPAR-gamma ligands may be a novel therapeutic agent for diseases such as multiple sclerosis.     

Hemodynamic effects of synchronous high-frequency jet ventilation in mitral regurgitation

We tested the hypothesis that increases in intrathoracic pressure (ITP), by decreasing the pressure gradient for anterograde left ventricular (LV) ejection, should augment cardiac output in acute mitral regurgitation (MR). In a pentobarbital-anesthetized closed-chest canine model, LV stroke volume (SLLV) was measured by integration from an aortic flow probe signal. MR was induced by a regurgitant ring. ITP was elevated over apnea by means of intermittent positive-pressure ventilation (IPPV), asynchronous (asynch) high-frequency jet ventilation (HFJV), and cardiac cycle-specific (synch) HFJV. IPPV resulted in the greatest increase in ITP. MR caused a fall in SVLV and a rise in LV filling pressure that were not altered by IPPV. Compared with IPPV or apnea, both asynch and synch HFJV increased SVLV and reduced LV filling pressures (P less than 0.05). Systolic synch HFJV induced a greater increase in SVLV (32%) than diastolic synch HFJV (26%) despite similar ventilatory settings. Our data suggest that when LV contractility is normal but MR impairs forward flow, cardiac cycle-specific increases in ITP will augment forward flow.     

Naringenin ameliorates Cyclophosphamide-induced nephrotoxicity in experimental model

Cyclophosphamide (CP) is widely described in the management of several nonneoplastic and neoplastic disorders. Renal damage is the most reported toxic effect of CP in clinical practice.Our study aimed to evaluate the effect of Naringenin (NG) in attenuating renal damage induced by CP in an experimental model.A total of 32 rats were divided into four groups (n = 8): negative control: rats fed on a basal diet, positive control: rats injected intraperitoneally with CP 50 mg/kg of body weight/day, NG 100: rats treated with NG 100 mg/kg/day body orally with concomitant administration of CP as described before, and NG 200: rats treated with NG 200 mg/kg/day body orally daily + CP. At the end of the experimental protocol (21 days), blood creatinine and urea levels were measured. The antioxidant activities and lipid peroxidation products were measured in the renal tissues as indicators of oxidative damage. Histopathological examination and immunohistochemistry staining were also performed on renal tissues.Coadministration of NG along with CP significantly (p < 0.001) improved the renal function and antioxidant capacities compared with positive control animals. Furthermore, histopathological, and immunological examination of renal tissue confirmed the protective effect of NG against CP-induced nephrotoxicity.The current study showed that NG has the potential to protect CP-induced renal damage, which may be beneficial for further studies and the design of NG analogs to be useful in clinical practice against CP-induced nephrotoxicity.     

Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction

Left ventricular (LV) dysfunction caused by myocardial infarction (MI) is accompanied by endothelial dysfunction, most notably a loss of nitric oxide (NO) availability. We tested the hypothesis that endothelial dysfunction contributes to impaired tissue perfusion during increased metabolic demands as produced by exercise, and we determined the contribution of NO to regulation of regional systemic, pulmonary, and coronary vasomotor tone in exercising swine with LV dysfunction produced by a 2- to 3-wk-old MI. LV dysfunction resulted in blunted systemic and coronary vasodilator responses to ATP, whereas the responses to nitroprusside were maintained. Exercise resulted in blunted systemic and pulmonary vasodilator responses in MI that resembled the vasodilator responses in normal (N) swine following blockade of NO synthase with N(omega)-nitro-L-arginine (L-NNA, 20 mg/kg iv). However, L-NNA resulted in similar decreases in systemic (43 +/- 3% in N swine and 49 +/- 4% in MI swine), pulmonary (45 +/- 5% in N swine and 49 +/- 4% in MI swine), and coronary (28 +/- 4% in N and 35 +/- 3% in MI) vascular conductances in N and MI swine under resting conditions; similar effects were observed during treadmill exercise. Selective inhibition of inducible NO synthase with aminoguanidine (20 mg/kg iv) had no effect on vascular tone in MI. These findings indicate that while agonist-induced vasodilation is already blunted early after myocardial infarction, the contribution of endothelial NO synthase-derived NO to regulation of vascular tone under basal conditions and during exercise is maintained.