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Biomedical subjects

R Zelis

Publications and source records attributed to R Zelis.

At least 19 recordsLinked to original sources
PubMed1992

Endothelial function in chronic congestive heart failure.

There is evidence that the endothelium plays an important role in the control of human vascular tone by releasing endothelium-derived nitric oxide. The hypothesis that an impairment of this mechanism is involved in the increased peripheral vasoconstriction of patients with chronic congestive heart failure (CHF) was tested. Acetylcholine and N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthesis from L-arginine, were infused in the brachial artery of healthy volunteer subjects (controls) and patients with severe CHF. The radial artery diameter was determined by a high-precision A-mode ultrasound device, using a 10 MHz probe. Forearm blood flow was calculated from vessel diameter and blood flow velocity measured simultaneously by Doppler. The blood flow response to acetylcholine was blunted in patients with CHF compared with that in control subjects. In contrast, the decrease in blood flow induced by L-NMMA was exaggerated in CHF, and the blood flow response to nitroglycerin was preserved. The changes in radial artery diameter induced by acetylcholine and L-NMMA were not significant in control subjects and CHF patients, but dilation of the radial artery by nitroglycerin was significantly reduced in CHF. The results demonstrate an impaired endothelium-dependent dilation of forearm resistance vessels in CHF, suggesting a reduced release of nitric oxide on stimulation. In contrast, the basal release of nitric oxide from endothelium of forearm resistance vessels is preserved or may even be enhanced, and may play an important compensatory role in chronic CHF by antagonizing neurohumoral vasoconstrictor forces in CHF.

Acetylcholine↗
PubMed1992

Regulation of tissue noradrenaline in the rat myocardial infarction model of chronic heart failure.

OBJECTIVE: The aim was to evaluate mechanisms regulating tissue noradrenaline in congestive heart failure. METHODS: Tissue noradrenaline was measured in the conscious post myocardial infarction rat model of congestive heart failure and in sham operated rats (1) under control conditions, (2) 6 h after inhibition of tyrosine hydroxylase by the intraperitoneal administration of alpha-methyl-para-tyrosine (AMPT) (100 mg.kg-1 every 2 h), (3) 6 h after AMPT with desipramine pretreatment (0.3 mg.kg-1), and (4) following exhaustive exercise after AMPT. Tissue noradrenaline was extracted with perchloric acid and measured by high performance liquid chromatography with electrochemical detection. RESULTS: In control animals without drug, tissue noradrenaline concentration was lower in the following tissues in the rats with myocardial infarction compared with the sham operated group: left and right ventricles, spleen, soleus and white gastrocnemius muscles, kidney cortex, and tail artery. After AMPT, tissue noradrenaline concentration in the sham operated group was significantly lower than control; in the myocardial infarction group the fall in noradrenaline was only significant in the kidney, and group differences were no longer present. In the sham operated animals, coadministration of desipramine with AMPT attenuated the fall in tissue noradrenaline caused by AMPT in the heart and spleen. With exercise to exhaustion, cardiac noradrenaline was lower in rats with myocardial infarction than in sham operated rats, but higher in the soleus muscle. CONCLUSIONS: These data suggest that tissue noradrenaline depletion in congestive heart failure is not isolated to the heart, and it occurs despite activation of mechanisms that might be operating to conserve neuronal noradrenaline. One mechanism may be reduced organ blood flow to retard diffusion of noradrenaline into the circulation. If this increases interstitial noradrenaline concentration, it would facilitate prejunctional alpha 2 receptor restraint on noradrenaline release. Metabolic coronary vasodilatation during exercise reverses this process, and makes the heart most susceptible to noradrenaline depletion in congestive heart failure.

Animals↗
PubMed1992

Comparison of norepinephrine and isoproterenol clearance in congestive heart failure.

Congestive heart failure (CHF) is accompanied by increased sympathetic nervous activity. Previous studies have demonstrated that plasma norepinephrine (NE), a marker of sympathetic nervous activity, is elevated in CHF due to increased NE spillover into the circulation and decreased NE clearance. In this study we compared the clearance of NE and isoproterenol (ISO) in eight CHF subjects (plasma NE 601 +/- 133 pg/ml), and in nine controls (plasma NE 285 +/- 53 pg/ml) by using steady-state infusions of tritiated NE ([3H]NE) and tritiated ISO ([3H]ISO). Because ISO is not a substrate of neuronal reuptake but is removed from the circulation in a way that is similar to NE after neuronal reuptake blockade with desipramine, ISO clearance may permit a gross estimation of non-neuronal uptake of circulating NE. The NE clearance was lower in CHF than in the control group (CHF 1.25 +/- 0.13, controls 2.04 +/- 0.22 l.min-1.m-2; P = 0.009). The ISO clearance was reduced similarly in CHF (CHF 0.90 +/- 0.09, controls 1.59 +/- 0.12 l.min-1.m-2; P less than 0.001). Because the ratio of ISO to NE clearance was similar in both groups, our findings suggest that a low cardiac output in CHF decreases the availability of circulating catecholamines to tissue elimination sites.

Aged↗
PubMed1992

Arterial dilatory reserve in congestive heart failure.

AIM: The purpose of this study was to determine whether there are abnormalities in flow-mediated large vessel relaxation in patients with congestive heart failure (CHF). METHODS: The radial arterial diameter and flow responses upon the release of 10 min of forearm arterial occlusion (reactive hyperemia) were measured with ultrasound and Doppler devices. RESULTS: In patients with CHF there was a 26% reduction in peak blood flow (P = 0.09) compared to age-matched controls. However, the increase in arterial diameter that followed the peak blood flow was reduced by 49% in CHF (P < 0.01). CONCLUSIONS: The causes of the abnormal flow-mediated large artery relaxation in CHF are unclear; both structural and endothelial abnormalities may contribute.

Blood Flow Velocity↗
PubMed1991

Time-constant adaptations in heart failure.

The circulatory compensatory mechanisms designed to cope quickly with physiological stress (e.g. sympathetic nervous system and the Frank-Starling mechanism) are less effective when there is chronic pathological stress, such as congestive heart failure (CHF). Other mechanisms come into play that operate over a longer time (e.g. activation of the renin-angiotensin-aldosterone system, myocardial hypertrophy and physiological deconditioning). Changes in blood vessels and skeletal muscle metabolism that result from inadequate delivery of oxygenated blood to working muscles belong to the group of mechanisms that develop slowly. When CHF therapy is successful, the abnormalities produced by this latter group of mechanisms will improve, but slowly. The concept that compensatory mechanisms have either short or long time constants for activation and reversal may explain why exercise tolerance improves much later than haemodynamics, which can be reversed acutely with vasodilator therapy.

Adaptation, Physiological↗
PubMed1991

Baroreflex and atrial natriuretic factor concentration correlate with myocardial infarct size and predict early death in rabbits: implications for drug studies.

The severity of myocardial infarction (MI) and its functional consequences are difficult to assess in small animals. We searched for criteria to achieve such an assessment in rabbits 1 week after MI. Thirteen large mongrel rabbits (3-4 kg) were anesthetized with pentobarbitone for ligating a branch of the circumflex coronary artery and 7 rabbits were subject to a sham operation without ligation. All sham-operated rabbits and 12 MI animals survived for 1 week, when blood was obtained for biochemical analyses and the baroreflex was tested. Six animals survived to the third week (survivors) and six died earlier (nonsurvivors). The MI size, measured immediately after death, was 42 +/- 3% of the left ventricular mass in nonsurvivors and 20 +/- 7% in survivors. The plasma atrial natriuretic factor (ANF) concentration was correlated linearly with MI size (r = 0.77) over the whole range of infarct sizes and, like the MI size itself, was associated with the risk of early death (critical limit: 80 pM). Plasma renin activity and catecholamines yielded less prognostic information. The baroreflex control of the heart rate (tested using phenylephrine and nitroprusside) of nonsurvivors was severely impaired and the slopes correlated with MI size (r = 0.90 for phenylephrine and r = 0.67 for nitroprusside). The plasma ANF concentration and the baroreflex both accurately reflected MI size and also correctly classified 11/12 rabbits into survivors and nonsurvivors. An ANF- and baroreflex-based stratification of animals for future studies on therapeutic interventions after MI will reduce the number of animals required by at least 65%, making such studies far more feasible than in the past.

Animals↗
PubMed1991

Norepinephrine clearance is increased during acute hypoxemia in humans.

Acute hypoxemia leads to activation of the sympathetic nervous system (SNS), yet adrenergic vasoconstriction does not occur and venous plasma norepinephrine (NE) fails to rise as expected. To examine whether this dissociation between SNS tone and plasma NE is due to altered metabolism of NE, we measured arterial NE kinetics ([3H]NE infusion technique) and sympathetic nervous outflow to muscle (peroneal microneurography) during 25-30 min of hypoxemia (spontaneous breathing, mean O2 saturation 74%) in six healthy young men. During hypoxemia, muscle sympathetic nervous activity (MSNA) rose significantly from 12.2 +/- 3.3 to 18.6 +/- 3.5 bursts/min, and the total amplitude increased from 123 +/- 36 to 255 +/- 50 mm/min. NE spillover, an index of NE release at the sympathetic nerve terminals, rose from 1.66 +/- 0.30 to 2.33 +/- 0.40 nmol.min-1.m-2 (P = 0.014). However, NE clearance increased also from 0.99 +/- 0.05 to 1.19 +/- 0.11 l.min-1.m-2 (P = 0.014), and arterial NE rose from 281 +/- 50 to 339 +/- 64 pg/ml (P = 0.023). Hypoxemia resulted in a significant rise in forearm blood flow and a decrease in forearm vascular resistance. The fact that skin blood flow and vascular resistance did not change implies that forearm vasodilation was localized to skeletal muscle. Our results suggest that during acute hypoxemia in humans the SNS is activated but the rise in plasma NE is attenuated because NE clearance is increased.

Adult↗
PubMed1991

Norepinephrine response to exercise of rats with a chronic myocardial infarction.

Plasma and tissue norepinephrine (NE) concentrations were determined at rest and after 45 min of swimming in rats with a surgically induced myocardial infarction (MI) and in rats having undergone a sham operation (SHAM). The MI rats had moderate-sized infarcts and demonstrated decreases in maximal O2 uptake (VO2max) that are consistent with the contention that the animals possessed a significant amount of left ventricular (LV) dysfunction and chronic heart failure (CHF). Plasma NE concentrations measured at rest were not significantly different between the SHAM and MI groups of rats, although a strong trend was found for the plasma NE concentrations to be elevated in the MI group. The plasma NE responses to 45 min of swimming at the same absolute submaximal workload were similar in the two groups of rats in light of the fact that the MI group of rats exercised at a greater percentage of their VO2max when compared with their SHAM counterparts. Exercise produced significant reductions in the NE concentrations of the diaphragm, vastus lateralis, red portion of the gastrocnemius, plantaris, and vastus intermedius muscles for both the SHAM and MI groups of rats. In addition, the NE concentrations measured in both the soleus and red portion of the gastrocnemius muscle were significantly greater in the MI rats when compared with their SHAM counterparts for both rest and exercise conditions. The results from the present study support the hypothesis that the sympathetic response to exercise is either unchanged or attenuated in MI rats that have a significant amount of LV dysfunction and CHF.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effects of desipramine on norepinephrine clearance in congestive heart failure.

Elevated plasma norepinephrine (NE) in congestive heart failure (CHF) is caused by increased NE spillover and decreased NE clearance. To evaluate the effects of neuronal uptake blockade on NE clearance, we studied NE kinetics during steady-state infusions of [3H]NE, before and after oral desipramine (DMI, 50 mg) in 11 patients with CHF and 8 normal volunteers. Baseline plasma NE was greater in the CHF group (637 +/- 56 vs. 271 +/- 32 pg/ml; P less than 0.001), NE clearance was lower in CHF (1.31 +/- 0.21 vs. 1.94 +/- 0.17 l.min-1.m-2; P = 0.026), and NE spillover was greater in CHF (4.71 +/- 0.78 vs. 3.04 +/- 0.35 nmol.min-1.m-2, P = 0.054). After DMI, plasma NE rose significantly in CHF (778 +/- 67; P = 0.008), and NE clearance decreased further in CHF (0.97 +/- 0.16; P = 0.024), but neither changed in normal subjects. NE spillover did not change in either group. There appears to be an enhanced effect of DMI on NE clearance in CHF patients. Two general mechanisms may be responsible for this finding, an increased concentration of drug, possibly caused by a decreased volume of distribution, and an increased sensitivity of neuronal amine pumps to DMI. Both mechanisms may reflect a more general abnormality of clearance of drugs and hormones related to abnormalities of tissue perfusion in CHF.

Adult↗
PubMed1990

Direct neurohumoral evidence for isolated sympathetic nervous system activation to skeletal muscle in response to cardiopulmonary baroreceptor unloading.

It has been postulated that cardiopulmonary baroreceptor unloading in humans results in nonuniform activation of the sympathetic nervous system. We reasoned that simultaneous measurements of arterial and venous norepinephrine (NE) spillover and clearance (using NE kinetics), muscle sympathetic neural activity (using microneurography), forearm blood flow (using plethysmography), and skin blood flow (using laser Doppler velocimetry) during lower body negative pressure at -15 mm Hg would isolate the location and extent of cardiopulmonary baroreceptor-mediated sympathetic nervous system activation. We exposed normal subjects (n = 8) to lower body negative pressure for 30 minutes, with measurements obtained at baseline, 5-10 minutes (EARLY), and 25-30 minutes (LATE). We found that arterial NE spillover, reflecting systemic sympathetic nervous system activation, did not increase significantly, whereas arterial NE clearance decreased significantly. In contrast, forearm venous NE spillover, reflecting skin and muscle sympathetic nervous system activation, increased by 17% and muscle sympathetic neural activity by 35% EARLY, whereas venous clearance did not change significantly. Although laser Doppler skin blood flow did not change, plethysmographic forearm blood flow (combined muscle and skin blood flow) decreased by 28%. All changes were sustained throughout 30 minutes of lower body negative pressure. Our data suggest that sympathetic vasoconstriction to muscle is greater than it is to skin in response to cardiopulmonary baroreceptor unloading. Moreover, our data suggest that reduced NE clearance in the arterial circulation is the primary mechanism by which arterial NE concentrations rise. Conversely, NE spillover appears to be the primary mechanism responsible for increasing venous NE concentrations measured from the forearm during cardiopulmonary baroreceptor unloading.

Adult↗
PubMed1989

Aging reduces venous distensibility and the venodilatory response to nitroglycerin in normal subjects.

To determine if aging alters venous tone, venous distensibility was measured during control conditions and after the administration of nitroglycerin (0.8-mg spray) to 50 subjects ranging in age from 21 to 78 years. The mean arterial pressure decreased and the heart rate increased significantly after nitroglycerin. Control venous distensibility, measured after the inflation of an upper arm cuff to 30 mm Hg above cuff zero (VV[30]) was 2.69 +/- 1.26 (standard deviation) cc/100 cc arm. The VV[30] increased to 3.06 +/- 1.43 cc/100 cc arm after the administration of nitroglycerin. There was a significant relation between age and baseline venous distensibility (r = 0.53, p less than 0.001) and between age and the change in venous distensibility after nitroglycerin (r = 0.56, p less than 0.001). Both baseline venous distensibility and the venodilatory response to nitroglycerin decreased with age. There was no significant relation between systemic arterial pressure and baseline venous distensibility or between arterial pressure and the venodilatory response to nitroglycerin. Aging appears to diminish baseline venous distensibility and attenuate the venodilatory response to nitroglycerin.

Adult↗
PubMed1989

Effect of the venodilated state on sympathetic-induced venoconstriction in normal subjects.

The interaction between venoconstriction induced by application of ice to the forehead and nitroglycerin-induced venodilation was examined in 19 healthy male volunteers, ages 25 +/- 5 years (mean +/- standard deviation). Venous tone was determined by the equilibration technique. Mercury-in-silastic plethysmography was used to measure changes in forearm volume before and after ice application during control conditions, and before and after ice application in the venodilated state (nitroglycerin spray, 0.8 mg). Venous tone and arterial pressure increased significantly after the application of ice to the forehead in both the control and venodilated states, indicating that ice increased sympathetic tone. Nitroglycerin increased venous volume by 0.28 cc/100 cc arm. The venoconstrictive effect of ice after nitroglycerin (a decrease in venous volume of 0.53 cc/100 cc arm) was quantitatively similar to the venoconstrictive effect of ice during control conditions (a decrease in venous volume of 0.54 cc/100 cc arm). These results suggest that sympathetic-induced venoconstriction is not attenuated in the venodilated state.

Adult↗
PubMed1989

High precision Compton backscatter maps of myocardial wall dynamics. Theory and applications.

Compton backscatter imaging (CBI) is a technique that uses x-rays scattered from the closed-chest surface of the heart to obtain high frequency (5 msec) and high precision (+/- 0.1 mm SD) measurements of regional surface displacements and velocities. These measurements are acquired in a three-dimensional format that allows the reconstruction of the epicardial surface and the creation of color coded displacement and velocity maps at many time points during the cardiac cycle. Applications of the technique are shown to characterize detailed regional normal wall displacement and velocity patterns, and the significant alteration of those patterns after coronary embolization. The technique is also applied to the characterization of early diastolic wall dynamics. CBI measurements show that a brief and somewhat paradoxical inward displacement of the anterior ventricular wall occurs during early diastole in normal canines. The wall dynamics associated with this inward displacement suggest a brief collapse of the ventricle subsequent to aortic valve closure. Diastolic collapse velocities and displacements are significantly altered subsequent to coronary occlusion with mean and maximum collapse velocities decreasing by 50% and concomitant inward displacements decreasing by 40%. Data acquisition with CBI is non-invasive, does not require contrast agents or radioisotopes, and uses low irradiation levels (125 kVp, 3-5 ma). The average radiation dose to the heart for a typical study is 250 mrem, significantly lower than that of other radiation based imaging techniques.

Animals↗
PubMed1989

Muscle acidosis during static exercise is associated with calf vasoconstriction.

In this study we measured (n = 6) the phosphocreatine-to-inorganic phosphate ratio (PCr/Pi), Pi, and pH with 31P-nuclear magnetic resonance (31P-NMR) in the human forearm during static work at 30% of maximal voluntary contraction (MVC) for 2 min followed immediately by 3 min of circulatory arrest (forearm arterial occlusion). Static exercise, with its central volitional and skeletal muscle metabolic and mechanical afferent components, caused a rise in heart rate (HR, 32%), blood pressure (BP, 29%), and calf vascular resistance (calf R, 30%). During forearm occlusion after static exercise, HR returned to base line, the increase in BP was attenuated by 30%, and calf R remained elevated and unchanged. The percent change in calf R was correlated with forearm cellular pH (R = 0.56, P less than 0.001) but only weakly associated with PCr/Pi (R = 0.33, P less than 0.042). 30% MVC for 1 min followed by arterial occlusion (3 min) reduced PCr/Pi by 65% and pH by 0.16 U (P less than 0.05). Calf R was unchanged. Circulatory arrest alone (20 min) caused no change in either pH or calf R but large changes in PCr/Pi (50% reduction). We conclude that 1) there is an association between forearm cellular acidosis and calf vasconstriction during static forearm exercise and 2) large changes in PCr/Pi without concomitant changes in pH are not associated with changes in calf R.

Acidosis↗
PubMed1989

Cardiac adaptations to endurance training in rats with a chronic myocardial infarction.

The hemodynamic response to maximal exercise was determined in sedentary and trained rats with a chronic myocardial infarction (MI) produced by coronary artery ligation and in rats that underwent sham operations (SHAM). Infarct size in the MI groups of rats comprised 28-29% of the total left ventricle and resulted in both metabolic and hemodynamic changes that suggested that these animals had moderate compensated heart failure. The training regimen used in the present study produced significant increases in maximal O2 uptake (VO2max) when expressed in absolute terms (ml/min) or when normalized for body weight (ml.min-1.kg-1) and consisted of treadmill running at work loads that were equivalent to 70-80% of the animal's VO2max for a period of 60 min/day, 5 days/wk over an 8- to 10-wk interval. This training paradigm produced two major cardiocirculatory adaptations in the MI rat that had not been elicited previously when using a training paradigm of a lower intensity. First, the decrement in the maximal heart rate response to exercise (known as "chronotropic incompetence") found in the sedentary MI rat was completely reversed by endurance training. Second, the downregulation of cardiac myosin isozyme composition from the fast ATPase V1 isoform toward the slower ATPase (V2 and V3) isoforms in the MI rat was partially reversed by endurance training. These cardiac adaptations occurred without a significant increase in left ventricular pump function as an increase in maximal cardiac output (Qmax) and maximal stroke volume (SVmax) did not occur in the trained MI rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗