Comparison of two aquaretic drugs (niravoline and OPC-31260) in cirrhotic rats with ascites and water retention.
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kappa-Opioid receptor agonists (niravoline) or nonpeptide antidiuretic hormone (ADH) V2 receptor antagonists (OPC-31260) possess aquaretic activity in cirrhosis; however, there is no information concerning the effects induced by the chronic administration of these drugs under this condition. To compare the renal and hormonal effects induced by the long-term oral administration of niravoline, OPC-31260, or vehicle, urine volume, urinary osmolality, sodium excretion, and urinary excretion of aldosterone (ALD) and ADH were measured in basal conditions and for 10 days after the daily oral administration of niravoline, OPC-31260, or vehicle to cirrhotic rats with ascites and water retention. Creatinine clearance, serum osmolality, ADH mRNA expression, and systemic hemodynamics were also measured at the end of the study. Niravoline increased water excretion, peripheral resistance, serum osmolality, and sodium excretion and reduced creatinine clearance, ALD and ADH excretion, and mRNA expression of ADH. OPC-31260 also increased water metabolism and sodium excretion and reduced urinary ALD, although the aquaretic effect was only evident during the first 2 days, and no effects on serum osmolality, renal filtration, and systemic hemodynamics were observed. Therefore, both agents have aquaretic efficacy, but the beneficial therapeutic effects of the long-term oral administration of niravoline are more consistent than those of OPC-31260 in cirrhotic rats with ascites and water retention. (+info)
RSD1000: a novel antiarrhythmic agent with increased potency under acidic and high-potassium conditions.
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This study reports the use of a novel agent, RSD1000 [(+/-)-trans-[2-(4-morpholinyl)cyclohexyl]naphthalene-1-acetate mono hydrochloride], to test the hypothesis that a drug with pKa close to the pH found in ischemic tissue may have selective antiarrhythmic actions against ischemia-induced arrhythmias. The antiarrhythmic ED50 for RSD1000 against ischemic arrhythmias was 2.5 +/- 0.1 micromol/kg/min in rats. This value was significantly lower than doses that suppressed electrically induced arrhythmias. In isolated rat hearts, RSD1000 was approximately 40 times more potent in producing ECG changes (i.e., P-R and QRS prolongation) in acid (pHo = 6.4) and high [K+]o (10.8 mM) buffer than in normal buffer (pHo = 7.4; [K+]o = 3.4 mM). In patch-clamped, whole-cell rat cardiac myocytes, inhibition of sodium (INa) currents by RSD1000 was pH- and use-dependent. The IC50 for INa blockade was lower (P <.05) in acid (0.8 +/- 0.1 microM) than in pH 7.3 (2.9 +/- 0.3 microM), respectively, whereas the IC50 for blockade of transient outward potassium current (ITO) at pH = 6.4 and 7.3 was 3.3 +/- 0.4 and 2.8 +/- 0.1 microM, respectively. Mixed ion channel block in ischemic myocardium with minimal effects on normal cardiac tissue, as governed by the low pKa of RSD1000, may account for its antiarrhythmic activity against ischemia-induced arrhythmias. (+info)
Haemodynamic adaptation at rest and during exercise to long-term antihypertensive treatment with combination of beta-receptor blocking and vasodilator agent.
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Systemic and pulmonary haemodynamics were studied at rest in the supine and upright position, and during exercise in the sitting position at 75 and 150 Watt, in 13 hypertensive men aged 50-8 +/- 8-7 years before and after 13 months treatment with oral oxprenolol (120 to 160 mg t.i.d.) supplemented by oral hydrallazine (50 to 75 mg t.i.d.) during the last 6 months. Pressures were recorded by means of catheters inserted percutaneously into the pulmonary and brachial artery; cardiac output was determined according to Fick. Treatment resulted in a significant reduction of systemic systolic, diastolic, and mean pressures at rest in the supine position and during exercise, and of systolic pressures in the upright posture. Pulmonary systolic and mean pressures increased slightly at rest in the supine position and during exercise, and no changes occurred at rest in the upright position. The left ventricular filling pressure was unchanged at rest both in the supine and upright position; it increased slightly during exercise. The haemodynamic changes by which systemic pressure was reduced were those typical of beta-adrenergic blockade: reduction of cardiac output resulting from a decrease of both heart rate and stroke volume, while the total systemic vascular resistance was unchanged at rest in the supine position but increased in the upright posture and during exercise. The A-V O2 difference increased remarkably. This long-term observation again suggests that the acute haemodynamic effects of an antihypertensive regimen can be modified during long-term application. It did not give evidence of a readjustment of the vascular resistance occurring, at least not in the upright position and during exercise, as has been suggested for long-term beta-adrenergic blockade. (+info)
Beta-adrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a post hoc analysis of the Studies of Left Ventricular Dysfunction.
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OBJECTIVES: This analysis was performed to assess whether beta-adrenergic blocking agent use is associated with reduced mortality in the Studies of Left Ventricular Dysfunction (SOLVD) and to determine if this relationship is altered by angiotensin-converting enzyme (ACE) inhibitor use. BACKGROUND: The ability of beta-blockers to alter mortality in patients with asymptomatic left ventricular dysfunction is not well defined. Furthermore, the effect of beta-blocker use, in addition to an ACE inhibitor, on these patients has not been fully addressed. METHODS: This retrospective analysis evaluated the association of baseline beta-blocker use with mortality in 4,223 mostly asymptomatic Prevention trial patients, and 2,567 symptomatic Treatment trial patients. RESULTS: The 1,015 (24%) Prevention trial patients and 197 (8%) Treatment trial patients receiving beta-blockers had fewer symptoms, higher ejection fractions and different use of medications than patients not receiving beta-blockers. On univariate analysis, beta-blocker use was associated with significantly lower mortality than nonuse in both trials. Moreover, a synergistic reduction in mortality with use of both a beta-blocker and enalapril was suggested in the Prevention trial. After adjusting for important prognostic variables with Cox multivariate analysis, the association of beta-adrenergic blocking agent use with reduced mortality remained significant for Prevention trial patients receiving enalapril. Lower rates of arrhythmic and pump failure death and risk of death or hospitalization for heart failure were observed. CONCLUSIONS: The combination of a beta-blocker and enalapril was associated with a synergistic reduction in the risk of death in the SOLVD Prevention trial. (+info)
Endothelin B receptors are functionally important in mediating vasoconstriction in the systemic circulation in patients with left ventricular systolic dysfunction.
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OBJECTIVES: This study was designed to assess the functional importance of endothelin (ET)B receptors in patients with left ventricular systolic dysfunction (LVSD) by comparing the hemodynamic effects of ET-1, a nonselective ET(A) and ET(B) agonist, with ET-3, a selective ET(B) receptor agonist. BACKGROUND: Knowledge of the functional importance of ET(B) receptors in mediating vasoconstriction in chronic heart failure will help determine whether antagonists at both ET(A) and ET(B) receptors are required to fully prevent vasoconstriction to endogenously produced ET-1. METHODS: We infused ET-1 (5 and 15 pmol/min) and ET-3 (5 and 15 pmol/min) into two separate groups of eight patients with LVSD with similar baseline hemodynamic indices. Hemodynamics were measured using a pulmonary thermodilution catheter and an arterial line. RESULTS: Endothelin-1 infusion led to systemic vasoconstriction, with a rise in mean arterial pressure (mean +/- SEM 100 +/- 3 to 105 +/- 3 mm Hg, p < 0.02) and systemic vascular resistance (1,727 +/- 142 to 2,055 +/- 164 dyn/s/cm(-5), p < 0.001) and a fall in cardiac index (2.44 +/- 0.21 to 2.22 +/- 0.20 liters/min/m , p < 0.01). Endothelin-3 infusion also led to systemic vasoconstriction, with a rise in mean arterial pressure (99 +/- 6 to 105 +/- 6 mm Hg, p < 0.01) and systemic vascular resistance (1,639 +/- 210 to 1,918 +/- 245 dyn/s/cm(-5), p < 0.01) and a fall in cardiac index (2.66 +/- 0.28 to 2.42 +/- 0.24 liters/min/m2, p < 0.05). Pulmonary hemodynamic measurements did not change significantly in either group. CONCLUSIONS: Both ET-1 and ET-3 infusions led to systemic vasoconstriction; the hemodynamic changes observed were of a similar magnitude at the same molar concentration. This suggests that ET(B) receptors are functionally important in mediating vasoconstriction, at least in the systemic circulation, in patients with LVSD. (+info)
Use of cardiopulmonary exercise testing with hemodynamic monitoring in the prognostic assessment of ambulatory patients with chronic heart failure.
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OBJECTIVES: We studied whether direct assessment of the hemodynamic response to exercise could improve the prognostic evaluation of patients with heart failure (HF) and identify those in whom the main cause of the reduced functional capacity is related to extracardiac factors. BACKGROUND: Peak exercise oxygen consumption (VO2) is one of the main prognostic variables in patients with HF, but it is influenced also by many extracardiac factors. METHODS: Bicycle cardiopulmonary exercise testing with hemodynamic monitoring was performed, in addition to clinical evaluation and radionuclide ventriculography, in 219 consecutive patients with chronic HF (left ventricular ejection fraction, 22 +/- 7%; peak VO2, 14.2 +/- 4.4 ml/kg/min). RESULTS: During a follow-up of 19 +/- 25 months, 32 patients died and 6 underwent urgent transplantation with a 71% cumulative major event-free 2-year survival. Peak exercise stroke work index (SWI) was the most powerful prognostic variable selected by Cox multivariate analysis, followed by serum sodium and left ventricular ejection fraction, for one-year survival, and peak VO2 and serum sodium for two-year survival. Two-year survival was 54% in the patients with peak exercise SWI < or = 30 g x m/m2 versus 91% in those with a SWI >30 g x m/m2 (p < 0.0001). A significant percentage of patients (41%) had a normal cardiac output response to exercise with an excellent two-year survival (87% vs. 58% in the others) despite a relatively low peak VO2 (15.1 +/- 4.7 ml/kg/min). CONCLUSIONS: Direct assessment of exercise hemodynamics in patients with HF provides additive independent prognostic information, compared to traditional noninvasive data. (+info)
A physiological evaluation of professional soccer players.
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The purpose of this study was to evaluate the physiological functions of a professional soccer team in the North American Soccer League (NASL). Eighteen players were evaluated on cardiorespiratory function, endurance performance, body composition, blood chemistry, and motor fitness measures near the end of their competitive season. The following means were observed: age, 26 yrs; height, 176 cm; weight 75.5 kg; resting heart rate, 50 beats/min; maximum heart rate (MHR), 188 beats/min; maximum oxygen intake (VO2 max), 58.4 ml/kg-min-1; maximum ventilation (VEmax BTPS), 154 L/min; body fat, 9.59%; 12-min run, 1.86 miles; and Illinois agility run, 15.6 secs. Results on resting blood pressure, serum lipids, vital capacity, flexibility, upper body strength, and vertical jump tests were comparable to values found for the sedentary population. Comparing the results with previously collected data on professional American Football backs indicated that the soccer players were shorter; lighter in body weight; higher in VO2 max (4 ml/kg-min-1) and body fat (1.8%); and similar in MHR, VE max, and VC. The 12-min run scores were similar to the initial values observed for the 1970 Brazilian World Cup Team. The agility run results were superior to data collected from other groups. Their endurance capabilities, agility, and low percent of body fat clearly differentiate them from the sedentary population and show them to be similar to that of professional American football backs. (+info)
In vitro and in vivo comparison of three MR measurement methods for calculating vascular shear stress in the internal carotid artery.
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BACKGROUND AND PURPOSE: Vascular abnormalities, such as atherosclerosis and the growth and rupture of cerebral aneurysms, result from a derangement in tissue metabolism and injury that are, in part, regulated by hemodynamic stress. The purpose of this study was to establish the feasibility and accuracy of determining wall shear rate in the internal carotid artery from phase-contrast MR data. METHODS: Three algorithms were used to generate shear rate estimates from both ungated and cardiac-gated 2D phase-contrast data. These algorithms were linear extrapolation (LE), linear estimation with correction for wall position (LE*), and quadratic extrapolation (QE). In vitro experiments were conducted by using a phantom under conditions of both nonpulsatile and pulsatile flow. The findings from five healthy volunteers were also studied. MR imaging-derived shear rates were compared with values calculated by solving the fluid flow equations. RESULTS: Findings of in vitro constant-flow experiments indicated that at one or two excitations, QE has the advantage of good accuracy and low variance. Results of in vitro pulsatile flow experiments showed that neither LE* nor QE differed significantly from the predicted value of wall shear stress, despite errors of 17% and 22%, respectively. In vivo data showed that QE did not differ significantly from the predicted value, whereas LE and LE* did. The percentages of errors for QE, LE, and LE* in vivo measurements were 98.5%, 28.5%, and 36.1%, respectively. The average residual of QE was low because the residuals were both above and below baseline whereas, on average, LE* tended to be a more biased overestimator of the shear rate in volunteers. The average and peak wall shear force in five volunteers was approximately 8.10 dyne/cm2 and 13.2 dyne/cm2, respectively. CONCLUSION: Our findings show that LE consistently underestimates the shear rate. Although LE* and QE may be used to estimate shear rate, errors of up to 36% should be expected because of variance above and below the true value for individual measurements. (+info)