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Biomedical subjects

M I Noble

Publications and source records attributed to M I Noble.

At least 91 records · Page 5Linked to original sources
PubMed1988

Effect of intravenous ketanserin on the human action potential duration at fixed heart rate.

In this study any changes in action potential duration or Q-T interval due to acute doses of ketanserin were monitored. The effect of a bolus dose (10 or 20 mg) followed by an infusion (10 or 20 mg over 20 minutes) of ketanserin on the Q-T interval and action potential duration was studied in six patients undergoing routine cardiac catheterization. Action potential duration was measured with a silver-silver chloride electrode catheter while heart rate was kept constant by atrial pacing and reflex effects avoided by beta-adrenergic blockade. There were some prolongations of the action potential duration but they were not in excess of 40 msec and did not reach statistical significance (control 263 +/- 46.0 msec; bolus 269 +/- 52.1 msec; infusion 262 +/- 53.6 msec; nor were there any significant changes in Q-T interval. Thus acute intravenous doses of ketanserin, in the absence of hypokalaemia or other Q-T interval-prolonging drugs, have no consistent effect on Q-T interval or action potential duration; prolongation of the action potential, when it occurs, is small.

Action Potentials↗
PubMed1988

Hemodynamic response to treadmill exercise in normal volunteers: an assessment by Doppler ultrasonic measurement of ascending aortic blood velocity and acceleration.

Accurate assessment of ascending aortic blood velocity indices and reproducibility of a Doppler ultrasonic system during exercise were determined; the Doppler technique was then used to assess the effects of age, sex, and beta blockade on exercise hemodynamics. Doppler-determined velocity correlated well with an invasive electromagnetic system. Reproducibility of Doppler variables during three exercise tests was high (coefficient of variation less than 10%) and did not deteriorate appreciably with exercise. Peak velocity (PV) and maximum acceleration (MA) were inversely related to age, the relationship being more significant during exercise, whereas the systolic velocity integral showed no such relationship either at rest or during exercise. Doppler variables showed no difference between sexes, except at high levels of exercise. Beta blockade markedly attenuated the exercise response as shown by significant decreases in both MA and PV during exercise. The Doppler velocity data presented in this study provide a reference against which previously documented changes in exercising ischemic patients can be better related.

Adult↗
PubMed1987

Atrial granules in the dog heart after cardiac denervation.

Because the increase in sodium excretion during left atrial distension in conscious dogs is abolished after chronic cardiac denervation, we have investigated whether this is a result of the disappearance of specific atrial granules. Electron microscopy and light-microscopical and ultrastructural immunohistochemistry of canine atria show that atrial granules displaying immunoreactivity for cardiac hormones of the cardiodilatin/atrial natriuretic polypeptide (CDD/ANP) family are still present in denervated left and right atria, although reduced in quantity. It is concluded that the "atrial-induced natriuresis" is not only related to the existence of specific atrial granules. The functional link between atrial-induced natriuresis provoked by atrial distension and the release of atrial polypeptide hormones remains uncertain because the denervated heart can secrete CDD although the diuretic-natriuretic effect is altered.

Animals↗
PubMed1987

Validation of beat by beat pulsed Doppler measurements of ascending aortic blood velocity in man.

The volume, velocity, and acceleration of ascending aortic blood were measured in man using a pulsed Doppler ultrasound instrument, with online spectral analysis and offline computer processing of velocity data. This system was firstly validated in a test rig capable of generating pulsatile flow of talc particles in water at physiological velocities and accelerations in a model aorta. Doppler measurements correlated well (r greater than or equal to 0.90) with simultaneous electromagnetic measurements of stroke volume, peak ejection velocity, and maximum acceleration in this rig. In vivo validation was performed firstly by comparing simultaneous Doppler and thermodilution cardiac output (Q) measurements; this yielded the following regression equation: Doppler Q = 0.90 X thermodilution Q + 0.03 litre.min-1, r = 0.92; n = 38. Beat by beat measurements were then validated against simultaneous invasive aortic blood velocity measurements made using a Mills electromagnetic cathetertip probe. When paced single beats of different size were compared within subjects the correlation coefficients between Doppler and electromagnetic measurements averaged 0.89 for stroke volume, 0.91 for peak ejection velocity, and 0.79 for maximum acceleration in five subjects. The absolute values for velocity and acceleration from the Doppler system differed significantly from the absolute values given by the electromagnetic system and this difference was not consistent between subjects. It is concluded that the Doppler system can non-invasively record relative changes in left ventricular ejection in man.

Aorta↗
PubMed1987

Effect of lack of noradrenaline on myocardial oxygen consumption in denervated dog hearts.

Surgical cardiac denervation was carried out in dogs under halothane anaesthesia. In a paired experimental design control biopsy specimens were obtained before surgical denervation. The dogs were allowed to recover and three weeks to elapse before the second biopsy specimen was taken. Both right and left ventricular specimens had higher in vitro oxygen consumption after denervation than before. Other specimens were immediately cooled in hexane at -60 degrees C and stored under liquid nitrogen until analysed. Succinate dehydrogenase and cytochrome oxidase activities were then measured histochemically in sequential 10 or 12 microns sections. There was no significant difference between the enzyme activities measured before or after cardiac denervation (succinate dehydrogenase 20.3(6.3) before, 19.4(4.02) pmol.H2.cm-2.s-1, after; cytochrome oxidase 223(73.4) before, 263(61.6) (measured as extinction coefficient) after). Thus the changes in oxygen consumption in the chronically denervated dog heart are not due to any lack of these mitochondrial enzymes.

Animals↗
PubMed1987

Problem of measuring the positive inotropic property of a vasodilating drug: an illustration using felodipine.

A study was undertaken to determine the presence or absence in patients of positive inotropic activity in a vasodilator drug that improves cardiac output by virtue of that vasodilatation. Felodipine is a dihydropyridine calcium antagonist that has a positive inotropic effect at low concentration in the dog in vivo. In nine patients undergoing coronary angiography in whom heart rate was kept constant by atrial pacing the solvent for the intravenous administration of the drug was infused followed by the active solution. Haemodynamic variables were measured with the Mills combined left ventricular cathetertip manometer and aortic electromagnetic blood velocity transducer. Reflex positive inotropic effects were blocked with the beta adrenergic blocking drug atenolol. An index of contractility was used to assess inotropic effects--the maximum rate of rise of left ventricular pressure measured by cathetertip micromanometry; this was an isovolumic event and therefore not sensitive to arterial pressure change, and it was unaffected by changes in left ventricular end diastolic pressure. In all patients peripheral vasodilatation was observed in the plasma felodipine concentration range of 2-40 nmol.litre-1. In eight patients this was accompanied by an 11-36% increase in maximum rate of rise of left ventricular pressure, indicating a small positive inotropic effect. Felodipine appears to show both agonist and antagonist properties in man as well as in the dog.

Adult↗
PubMed1987

Contractility of the heart as a function of sarcolemmal calcium handling.

Our previously published results suggest that contractile heart function may now be thought of in terms of calcium handling by the myocardial cells. We postulate that upon depolarisation the sarcolemma releases calcium bound to the inner leaflet which diffuses to the contractile proteins to control contraction. This calcium is taken up upon relaxation by intracellular binding sites, including sarcoplasmic reticulum. Upon repolarisation, some of this calcium is reaccumulated by the sarcolemma with a time course of approximately 500 ms. When this interval is allowed, the contractility of any beat, C, was found experimentally to be a function of that of the preceding beat, Cp, and of the duration of the preceding action potential, APDp, according to the multiple regression analysis: C = Bc X Cp + Ba(APDp - D). Bc is the fraction of calcium released on beat Cp which recirculates to beat C. The remainder is expelled and balanced in the steady state by calcium entry during the action potentials. The calcium influx from a given action potential (APDp) is not released until the subsequent beat (C). This calcium only enters during the latter half of the action potential, the first half being "dead time" (D). We speculate that the calcium entry channel is not specific for calcium but is inhibited by calcium bound to the inner leaflet of the sarcolemma. The channel is "opened" when this calcium is released upon depolarisation. The initial current is carried by sodium ions and subsequent calcium entry leads to reinhibition of the channel.

Action Potentials↗
PubMed1987

The positive inotropic effect of felodipine in isovolumically beating dog heart.

Felodipine is a potent arteriolar vasodilator. Its possible myocardial effects were studied by placing dogs anaesthetized with chloralose on cardiopulmonary bypass. A balloon was then inserted into the left ventricular cavity with a vent alongside it. Isovolumic contractions (developed pressure or maximal rate of rise of pressure) were studied as the intraventricular balloon was inflated to various levels. Total coronary venous return was collected to measure coronary blood flow and felodipine concentrations. In seven vagotomized and beta-blocked preparations, a small positive inotropic effect was found [32 +/- 11 (SEM)%, p less than 0.05]; the maximum effect was reached at arterial plasma felodipine concentrations of between 7 and 20 nM and was accompanied by appreciable coronary vasodilatation. In five dogs, infusion of the solvent vehicle (5% polyethylene glycol) alone had no effect. In three more dogs, an infusion of nitroprusside caused coronary vasodilatation, but no positive inotropic effect. The results show that at low concentrations, felodipine has a positive inotropic effect in vivo. These findings suggest that the properties of myocardial calcium agonist and vascular smooth muscle antagonist properties may coexist in the same dihydropyridine molecule. The favorable effects of this drug in the treatment of heart failure can be explained not only by reduction of peripheral resistance, but also by a moderate positive inotropic effect.

Animals↗
PubMed1987

Relation of human cardiac action potential duration to the interval between beats: implications for the validity of rate corrected QT interval (QTc).

Fourteen patients undergoing routine cardiac catheterisation were paced at a steady frequency; after this test, stimuli were introduced with a variable preceding interval (test pulse interval). The QT interval of the electrocardiogram and the duration of the monophasic action potential of the right ventricle were measured. QT interval is a function of action potential duration; the two variables were very closely correlated in this study. Both these variables increased in duration with increasing test pulse interval. A biphasic response, as previously reported, was not seen. An increase in steady state pacing frequency caused QT interval and action potential duration to decrease for any given R-R interval. When frequency of stimulation was suddenly increased and then maintained, there was an immediate action potential shortening followed by a further more gradual shortening occurring over several minutes. These results imply that a simple correction of QT interval for heart rate (QTc) is inadequate. It is concluded that the relation between action potential duration (or QT interval) and heart rate depends on both the instantaneous interval between beats and the duration of the prevailing heart rate.

Action Potentials↗
PubMed1987

Quantification of O2 consumption and arterial pressure as independent determinants of coronary flow.

The steady-state relationship between coronary arterial blood flow (CBF) and both myocardial O2 consumption (MVO2) and coronary arterial pressure (P) was explored in anesthetized dogs and goats. Both species were subjected to constant pressure perfusion of the left main coronary artery by an external pressure-controlling circuit. In addition a group of goats was studied with normal aortic perfusion using an occluder around the left main coronary artery to vary coronary arterial pressure. The statistical analysis revealed that despite the direct effect of P on MVO2 (the Gregg effect) the effects of both variables on CBF were independent and linear over a wide range of P and MVO2 so that multiple regression analysis with a linear equation (CBF = a X P + b X MVO2 + c) gave an excellent fit which was not improved by the introduction of an addition interactive term b3MVO2 X P. The mean correlation coefficient for all animals was greater than 0.9. From these data we conclude that any factor regulating coronary arterial flow would be influenced by both MVO2 and perfusion pressure in an independent way. This study characterizes the stationary behavior of local coronary flow control. Hence, it specifies quantitatively the relations to be predicted by hypotheses aiming to explain this control mechanism.

Analysis of Variance↗
PubMed1987

Intramyocardial blood volume change in first moments of cardiac arrest in anesthetized goats.

The effect of cardiac relaxation on the intramyocardial blood volume was studied by measuring the integrated difference between arterial inflow and great cardiac venous outflow. In nine anesthetized goats, the left main coronary artery was perfused under constant pressure. The great cardiac vein was drained under pressure control. The venous flow signal was amplified so that the integrated intramyocardial blood volume was constant in the beating heart. With normal vasomotor tone, the mean change in vascular volume was 3.01 +/- 0.18 (SE) ml/100 g left ventricle (LV); 67% of the volume change was achieved in 1.60 +/- 0.09 s. For the fully dilated bed (adenosine infusion), the values were 4.13 +/- 0.33 ml/100 g and 0.96 +/- 0.06 s, respectively. The volume change could be correlated with the venous pressure during cardiac arrest (Pvd) and the change in mean left ventricular pressure after cardiac arrest (r = 0.95). The correlation improved when data were selected for Pvd less than 6 mmHg to r = 0.98. We assumed that the change in vascular transmural pressure can be approximated as half the mean left ventricular pressure change. The intramyocardial vascular compliance was then estimated as 0.104 +/- 0.012 and 0.146 +/- 0.028 ml X mmHg-1 X 100 g-1 for control and adenosine conditions, respectively. The long time constants excluded the large epicardial veins as the site of volume change; they were much longer than the duration of diastole in the beating heart. We conclude that the intramyocardial vascular compartment is capable of volume expansion on the order of 20% of its normal volume when myocardial compression by ventricular systole is suspended.

Anesthesia↗
PubMed1987

The effects of felodipine on left ventricular function in beta-blocked patients.

Felodipine is a dihydropyridine calcium antagonist which has a positive inotropic effect in the dog in vivo. However to date, no inotropic effects have been described in man. Thus, the solvent for the intravenous administration of the drug was infused, followed by the active solution, in 9 beta-blocked patients undergoing coronary angiography; heart rate was held constant by atrial pacing. Haemodynamic variables were measured with the Mills combined left ventricular catheter-tip manometer and aortic electromagnetic blood velocity transducer. In all patients, peripheral vasodilatation was observed. In 8 patients, this was accompanied by a 9 to 50% increase in maximum rate of rise of left ventricular pressure indicating a small positive inotropic effect.

Adrenergic beta-Antagonists↗
PubMed1986

Comparison between the sarcomere length-force relations of intact and skinned trabeculae from rat right ventricle. Influence of calcium concentrations on these relations.

To investigate the extent to which the properties of the cardiac myofibrils contribute to the length-force relation of cardiac muscle, we determined the sarcomere length-force relations for rat ventricular trabeculae both before and after the muscles were skinned with the detergent Triton X-100. Sarcomere length was measured continuously by laser diffraction. In the unskinned trabeculae stimulated at 0.2 Hz, the relation between active force and sarcomere length at an extracellular calcium concentration of 1.5 mM was curved away from the sarcomere length axis, with zero force at sarcomere length of 1.5-1.6 micron. At 0.3 mM calcium, the sarcomere length-force relation was curved toward the sarcomere length axis. Chemical skinning of the muscle with 1% Triton X-100 in a "relaxing solution" caused an increase in intensity and decrease in dispersion of the first order diffraction beam, indicating an increased uniformity of sarcomere length in the relaxed muscle. During calcium-regulated contractures in the skinned muscles, the central sarcomeres shortened by up to 20%. As the calcium concentration was increased over the range 1-50 microM, the relation between steady calcium-regulated force and sarcomere length shifted to higher force values and changed in shape in a manner similar to that observed for changes in extracellular calcium concentration before skinning. The sarcomere length-force relations for the intact muscles at an extracellular calcium concentration of 1.5 mM were similar to the curves at calcium concentration of 8.9 microM in the skinned preparations, whereas the curves at an extracellular calcium concentration of 0.3 mM in intact muscles fell between the relations at calcium concentrations of 2.7 and 4.3 microM in the skinned preparations. A factor contributing to the shape of the curves in the skinned muscle at submaximal calcium concentrations was that the calcium sensitivity of force production increased with increasing sarcomere length. The calcium concentration required for 50% activation decreased from 7.71 +/- 0.52 microM to 3.77 +/- 0.33 microM for an increase of sarcomere length from 1.75 to 2.15 micron. The slope of the force-calcium concentration relation increased from 2.82 to 4.54 with sarcomere length between 1.75 and 2.15 micron. This change in calcium sensitivity was seen over the entire range of sarcomere lengths corresponding to the ascending limb of the cardiac length-force relation. It is concluded that the properties of the cardiac contractile machinery (including the length-dependence of calcium sensitivity) can account for much of the shape of the ascending limb in intact cardiac muscle.

Animals↗