摘要:

Background To elucidate the extent of the compensatory role of endogenous atrial natriuretic peptide (ANP) in severe congestive heart failure (CHF), we examined the changes in hemodynamics and neuroendocrine and renal functions after incremental administration of an ANP antagonist, HS-142-1 (HS), in dogs with CHF.Methods and Results We assessed the effects of HS on the suppression of plasma and urinary cGMP levels as a marker of endogenous ANP activity in dogs without CHF.Bolus injections of 0.3 and 1.0 mg/kg HS reduced plasma cGMP levels to 77% and 60% and urinary cGMP excretion to 78% and 61% of the relevant control levels, respectively. Then the study was performed in dogs with CHF induced by chronic rapid ventricular pacing, and the plasma ANP level was sixfold higher than that in the controls. Hemodynamic, hormonal, and renal variables were determined both before and after subsequent incremental administration (0.3, 1.0, and 3.0 mg/kg every 30 minutes) of HS. HS lowered the plasma and urinary cGMP levels dose dependently to 32% and 37% of the control levels, respectively. Mean arterial, pulmonary capillary wedge, and right atrial pressures and cardiac output did not change significantly. However, plasma renin activity, aldosterone level, and norepinephrine level increased rapidly to 226%, 179%, and 252% of the control values, respectively. Urine flow rate and urinary sodium excretion were significantly inhibited, with no concomitant change in glomerular filtration rate or renal plasma flow.Conclusions These findings suggest that endogenous ANP contributes to the suppression of the activation of the renin-aldosterone system and sympathetic nervous activity and body fluid retention but that the vasodilative action of this peptide is attenuated in advanced CHF. (Circulation. 1994;89:2232-2240.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background The mechanism of the alterations in the pattern of left ventricular (LV) filling during the development of congestive heart failure (CHF) is not fully understood.Methods and Results We studied six conscious dogs instrumented to measure LV and left atrial (LA) pressures and LV volume as CHF was induced by rapid pacing.Diastolic filling dynamics were serially measured over 4 weeks during normal sinus rhythm. Four days after we initiated pacing, the peak early diastolic filling rate decreased from 108+-24 to 88+-27 mL/s (P<.05) as the maximal early diastolic LA-LV pressure gradient decreased associated with a slowing of the rate of LV relaxation. Subsequently, the peak early filling rate progressively increased, returning to control at 1 week, and by the fourth week, it had increased to 168+-39 mL/s (P<.05). These changes in early filling rates occurred as the maximal early diastolic LA-LV pressure gradient increased in association with a progressive increase in LA pressure despite further progressive slowing of the rate of LV relaxation. Throughout the development of CHF, peak early filling rate and the maximal LA-LV pressure gradient correlated (r=.99, P<.001). The early filling deceleration rate increased and deceleration time progressively decreased over the 4 weeks as LV stiffness and net LA plus LV stiffness increased (P<.05). As predicted by a theoretical analysis, the deceleration time was linearly related to the reciprocal of the square root of LV stiffness (r=.94, P<.01).Conclusions Early in CHF, slowing of LV relaxation reduces the maximal early diastolic LA-LV pressure gradient, decreasing the peak early filling rate. As CHF progresses, this is overcome by an increase in LA pressure that augments the early diastolic LA-LV pressure gradient, increasing peak early filling rate. Increasing LV stiffness during the development of CHF progressively shortens the early filling deceleration time and augments the early filling deceleration rate. These observations suggest that the early filling deceleration time reflects LV stiffness. (Circulation. 1994;89:2241-2250.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Cardiovascular events are less prevalent in premenopausal women and women receiving estrogen replacement than in postmenopausal women or men.Endothelium-derived relaxing factor (EDRF) is an important local modulator of vascular tone, and abnormal endothelial function is related, in part, to the oxidative modification of low-density lipoprotein (LDL). Estrogens possess substantial antioxidant activity and inhibit LDL modification in vitro.Methods and Results We investigated the effects of 17 beta -estradiol (E2) on endothelial vasomotor function in cholesterol-fed miniature swine. Animals underwent ovariectomy or a sham procedure and received E2or placebo via implant yielding three groups: sham, ovariectomy (E2placebo), and implant (E2implant). After 16 weeks, coronary arteries were harvested and endothelial function was examined in vitro. Vessels from the sham and implant groups demonstrated preserved endothelium-dependent relaxation to bradykinin, substance P, and A23187. Vessels from the ovariectomy group exhibited impaired relaxation to bradykinin and substance P (P<.05 versus sham and implant groups) but not to A23187. Plasma E2levels were strongly correlated with the response to bradykinin (R=.82, P<.001), substance P (R=.64, P<.01), and A23187 (R=.65, P<.01). Compared with the ovariectomy group, LDL derived from the sham and implant groups was markedly resistant to ex vivo oxidation (P<.05), and this effect correlated with preserved endothelium-dependent relaxation to bradykinin (R=.62, P<.03) and substance P (R=.61, P<.03).Conclusions Thus, E2preserves endothelial function in cholesterol-fed swine in association with protection of LDL against oxidative modification. These data suggest that E2may, in part, favorably affect vascular function and coronary artery disease by virtue of its antioxidant properties. (Circulation. 1994;89:2251-2259.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background We previously demonstrated that exposure to environmental tobacco smoke (ETS) increases the development of atherosclerosis in lipid-fed rabbits. Clinical studies have suggested a protective effect of beta -blockers in smokers. Accordingly, we evaluated the effects of metoprolol in this animal model to see whether this beta -blocker would block the atherogenic effects of ETS.Methods and Results Thirty-two New Zealand White male rabbits on a 0.3% cholesterol diet were randomly divided into four groups: ETS-metoprolol (ETS-M), ETS-control (ETS-C), and non-ETS with metoprolol (NETS-M) and without metoprolol (NETS-C). The two metoprolol-treated groups received metoprolol at a dose of 0.4 mg x kg-1x h-1administered subcutaneously by an osmotic pump. Rabbits in the ETS groups were exposed to sidestream smoke from four Marlboro cigarettes per 15 minutes, 6 hours a day, for 10 weeks. Average air carbon monoxide (CO), nicotine, and total particulates (TP) in the exposure chambers were 67.2+-3.1 (SEM) ppm, 1133.7+-78.4 micrograms/m3, and 37.7+-3.0 mg/m3, respectively. Plasma nicotine was significantly higher in ETS-exposed rabbits than in nonexposed rabbits (7.1+-1.9 versus 0.5+-0.1 ng/mL, P<.01). Blood carbon monoxide hemoglobin (COHb) in the ETS-M group was significantly higher than that in the NETS-M group (4.0+-0.2% versus 1.3+-0.1%, P<.0001). The lipid lesions in the aorta and pulmonary artery were 57.2+-7.6% and 33.1+-6.4% (ETS-M), 62.8+-8.4% and 58.4+-6.1% (ETS-C), 38.7+-9.4% and 24.8+-7.7% (NETS-M), and 49.8+-8.7% and 32.7+-7.1% (NETS-C). There were significant differences in lipid deposits of the arteries between the controls and the ETS-exposed rabbits (37+-1% versus 53+-1%, P=.004) and between the controls and metoprolol-treated rabbits (51+-1% versus 38+-1%, P=.027). The benefit of metoprolol was independent of ETS exposure (ETS x metoprolol interaction, P=.595).Conclusions Exposure to ETS significantly accelerated and metoprolol decreased the development of atherosclerosis in lipid-fed rabbits, but there was no interaction between the effects of ETS exposure and metoprolol. Metoprolol did not protect against the effects of ETS on atherosclerosis, suggesting that the beta -adrenergic system is not the mechanism of ETS-induced atherosclerosis. (Circulation. 1994;89:2260-2265.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Platelet-vessel wall interaction plays an important role in acute cardiovascular disorders. Thrombin is a potent platelet activator but also has profound effects on the endothelium. Endothelial cells possess antithrombotic activity by releasing nitric oxide and prostacyclin, both potent vasodilators and platelet inhibitors. We studied the role of thrombin as a regulator of platelet-vessel wall interaction in isolated human arteries suspended in organ chambers for isometric tension recording.Methods and Results In arteries with endothelium, thrombin (0.01 to 1 U/mL) induced endothelium-dependent relaxations, which were reduced by the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME; 10-4mol/L) and/or indomethacin (10-5mol/L). Human platelets (75 000/microliters) evoked only marginal contractions in arteries with endothelium (3+-3% of the contraction to KCl 100 mmol/L; NS), which were markedly enhanced by endothelial removal (22+-4%; P<.05). Thrombin (1 U/mL) did not affect the response to platelets in arteries with (6+-5%; NS) but induced a huge contraction in rings without endothelium (53+-6%; P<.01 versus control without endothelium). The potent contraction to thrombin-activated platelets (1000 to 75 000/microliters) in arteries without endothelium was markedly inhibited by the thromboxane A2synthetase/receptor antagonist ridogrel (10-5mol/L; P<.005 versus control) and the single-acting thromboxane receptor blocker SQ-30741 (10-7mol/L; P<.01 versus control).Conclusions Thus, thrombin directly stimulates platelets to release thromboxane A2, inducing potent vasoconstriction, which is prevented by the simultaneous thrombin-induced release of prostacyclin and nitric oxide from endothelial cells. In arteries devoid of functional endothelial cells, as occurs in patients with coronary artery disease, a combined inhibition of thromboxane production and action provides a potent therapeutic tool to interfere with the thrombin-induced activation of platelet-vessel wall interaction. (Circulation. 1994;89:2266-2272.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background After myocardial infarction, the noninfarcted left ventricle develops reactive hypertrophy associated with a depressed coronary flow reserve, myocardial interstitial fibrosis, and reduced capillary density.The present study investigated the comparative cardiac effects of chronic angiotensin-converting enzyme (ACE) inhibition and selective angiotensin II type 1 receptor (AT1) blockade in the rat model of myocardial infarction and failure.Methods and Results Seven days after coronary ligation (MI), rats were randomized to enalapril (n=8; 500 micrograms x kg sup -1 x d-1), losartan (n=9; 3 mg x kg-1x d-1), or placebo (n=8) and treated for 6 weeks. Sham-operated rats (n=10) served as controls. Coronary blood flow was measured with radiolabeled microspheres during baseline and maximal coronary dilation induced by dipyridamole (2 mg x kg-1x min-1over 10 minutes). Right and left ventricular (LV) weight was increased in infarcted rats compared with sham-operated animals and enalapril- and losartan-treated MI rats. Minimal LV and right ventricular coronary vascular resistance was increased in MI rats but normalized with enalapril and losartan (LV:sham, 8.9; MI-placebo, 12.7; MI-enalapril, 9.2; MI-losartan, 8.8 mm Hg x mL-1x min-1x g-1, all P<.05 versus MI-placebo). Interstitial fibrosis determined from perfusion-fixed hearts was increased in infarcted rats but reduced by both enalapril and losartan. Myocardial capillary density improved with enalapril and losartan. In separate groups treated as above, plasma and tissue ACE activity was determined and demonstrated significantly higher ACE activity in noninfarcted LV tissue of MI-placebo rats compared with sham (0.64 vs 0.27 nmol x mg protein-1x min-1, P<.05). Enalapril and losartan reduced LV ACE activity (0.39 and 0.29 nmol x mg pro tein-1x min-1, P<.05 versus MI-placebo).Conclusions The present study demonstrates that both chronic ACE inhibition and AT1receptor blockade (1) reduces cardiac hypertrophy, (2) restores minimal coronary vascular resistance in postinfarction reactive hypertrophy, and (3) attenuates the development of myocardial interstitial fibrosis in the noninfarcted LV.These results suggest that inhibition of generation of angiotensin II and AT1receptor blockade are equally effective in preventing important features of ventricular remodeling after myocardial infarction. (Circulation. 1994;89:2273-2282.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The purpose of this study was to determine the effect of ischemic preconditioning on the changes in interstitial fluid (ISF) purine metabolites and lactate during prolonged regional myocardial ischemia. The study consisted of two groups of anesthetized dogs: a control group (n=13) that was exposed to 60 minutes of regional myocardial ischemia and a preconditioned group (n=10). In the preconditioned group, regional myocardial ischemia was induced for two 5-minute episodes, each followed by 10 minutes of reperfusion. These preconditioning episodes were followed by 60 minutes of sustained regional ischemia. Cardiac ISF was sampled by microdialysis probes implanted in the left ventricular myocardium; dialysate levels served as indices of ISF concentrations. In the preconditioned group, dialysate concentrations of adenosine, inosine, hypoxanthine, total purines, and lactate increased during each of the 5-minute ischemia episodes, with further increases occurring during the first 5 minutes of reperfusion. However, the increases in dialysate purine metabolites during the first period of ischemia/reperfusion were greater than those that occurred during the second ischemia/reperfusion. In addition, preconditioning reduced the rate of ISF purine metabolite and lactate accumulation during the prolonged ischemia when compared with nonpreconditioned animals. These data suggest that preconditioning reduces the energy imbalance that occurs during subsequent myocardial ischemia and thereby diminishes the rate of net adenine nucleotide degradation and cellular production and release of purine metabolites and lactate. In addition, the increase in ISF adenosine seen during the preconditioning episode is consistent with the notion that preconditioning-induced cardioprotection is mediated in part by the action of adenosine at extracellular A1adenosine receptors. (Circulation. 1994;89:2283-2289.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Stunned myocardium reflects postreperfusion dysfunction in myocardium that is destined to ultimately fully recover.Most investigators attribute postreperfusion stunning to a primary defect in excitation-contraction coupling or to an altered sensitivity of the myofilaments to calcium. The aim of the present study was to evaluate the interrelation between myocardial perfusion, oxidative metabolism, and function in an effort to better characterize the phenomenon of myocardial stunning, to define the regional efficiency of stunned myocardium, and to characterize its reserve capacity.Methods and Results Regional myocardial perfusion (measured with radiolabeled microspheres), myocardial oxygen consumption (MVo2) (quantified with positron emission tomography using 1-Carbon-11-acetate), and myocardial function (assessed with two-dimensional echocardiography) were evaluated in 12 anesthetized, closed-chest dogs subjected to 15 minutes of left anterior descending coronary artery occlusion followed by reperfusion. To evaluate flow, oxidative, and functional reserve after measurements were obtained 1 hour after reperfusion, dogs were subjected to paired pacing (an inotropic stimulus that does not alter systemic hemodynamics), and measurements were repeated. One hour after reperfusion, stunned myocardium was characterized by near-normal levels of myocardial perfusion (0.57+-0.13 mL/g per minute, 81+-13% of that in remote, normal regions) but severe dyskinesis (echo score, 2.6+-0.7; percent wall thickening, 14+-20%). Despite the low level of contractile function, MVo2averaged 1.72+-0.7 micromole/g per minute, 71+-27% of that observed in remote myocardium. Regional myocardial efficiency (systolic wall thickening divided by MVo2) was markedly diminished. With paired pacing, myocardial perfusion increased proportional to that in remote myocardium, systolic function improved (echo score, 1.4+-0.7; percent wall thickening, 30+-15%), and regional MVo2nearly doubled (to 3.41+-1.82 micromole/g per minute, P<.05 for each paired measurement). Importantly, with paired pacing, regional myocardial efficiency nearly normalized in reperfused myocardium.Conclusions Stunned myocardium is characterized by near-normal levels of perfusion and oxygen consumption despite marked dyskinesis. Myocardial efficiency is poor. With inotropic stimulation (in the present study, paired pacing), reperfused myocardium demonstrated considerable perfusion, oxidative, and functional reserve and a dramatic improvement in myocardial efficiency. These results may have implications for the treatment of postreperfusion pump failure. (Circulation. 1994;89:2290-2296.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background Prolonged nitrate therapy during healing between 2 days and 6 weeks after anterior myocardial infarction has the potential for limiting further left ventricular remodeling (or changes in topography) and preserving function.Long-term therapy throughout healing over 6 weeks might be more beneficial than short-term therapy over the first 2 weeks after infarction.Methods and Results The effect of prolonged nitrate therapy between 2 days and 6 weeks during healing after infarction on serial parameters of ventricular remodeling (scar expansion, scar thinning, ventricular dilation, and hypertrophy) and function (asynergy or akinesis plus dyskinesis and ejection fraction) by serial two-dimensional echocardiography, hemodynamics, postmortem topography (computerized planimetry, geometric maps, and radiographs), and collagen content (hydroxyproline) was studied in 64 instrumented dogs randomized 2 days after left anterior descending coronary artery ligation to various nitrate regimens (n=32) over the first 2 weeks (subgroup 1: 2% transdermal nitroglycerin at 8 am and 4 pm, n=6; subgroup 2: 2% transdermal nitroglycerin plus 2.6 mg of sustained-release oral nitroglycerin at 8 am, 3 pm, and 10 pm, n=5; subgroup 3: oral isosorbide dinitrate, 30 mg at 8 am and 4 pm, n=11) or 6 weeks (subgroup 4: isosorbide dinitrate, n=10) and in matching controls (n=32). Nitrate therapy reduced left atrial pressure, mean arterial pressure, and the rate-pressure product compared with controls over the 6 weeks. Postmortem scar mass and hydroxyproline were similar in control and nitrate groups. However, scar stretching and thinning, cavity dilation, noninfarct wall hypertrophy, and apical bulging were less with nitrates, especially in the long-term subgroup 4. In vivo remodeling parameters between 2 days and 6 weeks after ligation showed that, compared with controls, nitrate therapy prevented further stretching of the asynergic segment, decreased the expansion index, decreased further scar thinning, prevented the increase in ventricular volumes, reduced the frequency of ventricular aneurysm, prevented the increase in ventricular mass, reduced the extent of asynergy, and improved ejection fraction. Although the beneficial effect on topography and function was seen in all nitrate subgroups, the overall benefit was greater with long-term therapy over 6 weeks (subgroup 4) than short-term therapy confined to the first 2 weeks (subgroups 1, 2, and 3).Conclusions Prolonged nitrate therapy, in various regimens during healing after infarction, effectively reduced left ventricular loading and prevented infarct thinning, further infarct expansion, progressive ventricular dilation, and the increase in mass.These effects were associated with decreased asynergy and improved ejection fraction. The beneficial effects were greater with long-term therapy over 6 weeks than short-term therapy over the first 2 weeks. (Circulation. 1994;89:2297-2307.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Background The purpose of this study was to test the hypothesis that vasodilator responses of porcine coronary resistance arteries are increased by exercise training.Methods and Results Yucatan miniature swine were randomly divided into groups of exercise-trained (ET) and sedentary (SED) control pigs. ET pigs were placed on a progressive treadmill training program lasting 16 to 20 weeks, and SED pigs remained inactive during the same time period. Coronary resistance arteries 64 to 157 microns in diameter were isolated for in vitro evaluation of relaxation responses to the endothelium-independent dilators sodium nitroprusside (1 x 10-10to 1 x 10-4mol/L) and adenosine (1 x 10-10to 1 x 10-5mol/L) and to bradykinin (1 x 10-13to 3 x 10-7mol/L), an endothelium-dependent agent. Relaxation responses to adenosine and sodium nitroprusside were not altered by exercise training. Endothelium-dependent relaxation to bradykinin was enhanced in coronary resistance arteries from ET pigs (IC50: ET, 0.07+-0.02 nmol/L; SED, 1.59+-0.09 nmol/L). To determine whether prostanoids and/or the nitric oxide synthase pathway were involved in the ET-induced changes in bradykinin-induced vasodilation, responses to bradykinin were examined in coronary resistance arteries from both ET and SED pigs in the presence of indomethacin and in the presence of nitro-monomethyl l-arginine (L-NMMA). Both indomethacin and L-NMMA produced significant inhibition of the bradykinin-induced relaxation in vessels from both groups. Despite decreased bradykinin-induced relaxation after indomethacin, bradykinin-induced vasodilation was still enhanced in vessels from the ET group. L-NMMA caused greater inhibition of the bradykinin-induced relaxation in coronary resistance arteries from ET pigs relative to arteries from SED pigs and eliminated the training-induced enhancement of the bradykinin responses.Conclusions These results suggest that exercise training enhances bradykinin-induced vasodilation through increased endothelium-derived relaxing factor/nitric oxide production by the l-arginine/nitric oxide synthase pathway. (Circulation. 1994;89:2308-2314.)

ISSN:0009-7322    

出版商:OVID    

年代:1994

数据来源: OVID