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Biomedical subjects

M I Noble

Publications and source records attributed to M I Noble.

At least 109 records · Page 6Linked to original sources
PubMed1985

The mechanisms of action of noradrenaline on ouabain-sensitive rubidium uptake in guinea-pig myocardium.

The mechanism by which noradrenaline stimulates ouabain-sensitive rubidium uptake in guinea-pig myocardial tissue has been studied. The stimulatory action of low concentrations of noradrenaline was reversed by high doses of propranolol (10(-5) mol/l) in atrial tissue, but was not reversed by alpha- or beta-, or combined alpha- and beta- adrenoceptor antagonists in ventricular tissue. Rubidium uptake was also found to increase with increasing extracellular potassium concentration [( K]o). The percentage values of stimulation by noradrenaline decreased with increasing [K]o. Noradrenaline had no effect on the rate of ATP splitting by an isolated membrane preparation of Na,K-ATPase. It is proposed that noradrenaline stimulates active cation transport by either (a) an effect secondary to increased passive efflux of K ions, or (b) an action at a novel adrenergic receptor, distinct from the ATPase enzyme itself.

Animals↗
PubMed1985

On the change of cardiac action potential with age: a study in dogs.

The action potential duration (APD) was measured using an Ag-AgCl electrode, in open chest anaesthetised dogs (n = 8) and puppies, 4 to 6 months old (n = 8), with complete atrio-ventricular dissociation and beta-adrenergic blockade. They were paced in the control period at a frequency of 120 beats . min-1. Both adults and puppies showed maximum action potential duration at a test pulse interval of over 700 ms. Below this the adult dogs showed a progressive shortening of the action potential duration (mean APD 81.5% at 200 ms). In contrast, the puppies showed much less shortening (91% at 200 ms; p less than 0.001). Measurements of Na+, K+-ATPase activity by the Rb uptake method gave values of 13.4 +/- 1.3 (puppies, n = 4) and 6.1 +/- 1.1 (adults, n = 6). These results may be consistent with the idea of a greater influx and efflux of sodium in the myocardial cells of the puppy compared with the adult dog.

Action Potentials↗
PubMed1985

Mioflazine, a potentially protective drug against ischaemic damage: a study in dogs.

The protective effect of intravenous mioflazine pretreatment was examined in intact dogs on cardiopulmonary bypass. The mechanical function of the left ventricle was measured by isovolumic pressure-volume relationships. Mioflazine alone had no inotropic effect. After one hour of normothermic (37 degrees C) global ischaemia of the whole heart, no control hearts, pretreated with solvent, recovered sufficiently to support the animal's circulation; this was not the case with animals pretreated with mioflazine, they all survived. After the 30-min reperfusion period, the solvent (control) pretreated hearts had a significantly lower (P = 0.05) systolic and higher (P = 0.001) diastolic pressure-volume curve than those given mioflazine.

Animals↗
PubMed1985

Effect of chronic surgical denervation of dog heart on myocardial Na+-K+ pump.

The effect of chronic denervation of the myocardium on myocardial Na+-K+ pump activity and numbers of pump sites was studied in dogs. Right ventricular biopsies were taken immediately before and 4 wk after chronic surgical denervation, when depletion of norepinephrine is complete. Na+-K+ pump activity was assayed by ouabain-sensitive 86Rb uptake into ventricular tissue slices. The number of pump sites was measured by [3H]ouabain binding in ventricular tissue slices. Ouabain-sensitive Rb uptake was increased after denervation by an average of 147%. [3H]-ouabain binding at a concentration of 1.25 X 10(-6) M increased by an average of 27.6% after denervation. Acutely applied norepinephrine (2 X 10(-7) M) stimulated ouabain-sensitive Rb uptake both before and after denervation. The stimulation was greater after denervation, indicating supersensitivity. The cause of these changes is not known.

Animals↗
PubMed1985

Effects of noradrenaline on the sodium pump of guinea pig ventricle.

The effect of noradrenaline on myocardial sodium-pump activity has been studied, using a direct measure of active ion transport via the pump; namely, the ouabain-sensitive uptake of the radioisotope and potassium analogue rubidium-86 into guinea pig ventricular tissue slices. Physiological concentrations of noradrenaline caused a dose-dependent stimulation of rubidium uptake (peak response at 2 X 10(-7) M). With higher concentrations, the uptake fell progressively. At 6 X 10(-5) M, noradrenaline uptake was lower than control. The stimulatory action is not mediated by classic adrenergic mechanisms. It was not blocked by either alpha- or beta-blockade. Indirect actions via changes in membrane permeability to sodium and potassium ions are also considered. The inhibitory effect of high concentrations of noradrenaline, however, was mediated by alpha-receptors. Stimulation of the pump by noradrenaline could stabilize cellular ion concentrations and resting membrane potential. Since the pump is electrogenic, this is one mechanism by which noradrenaline will cause shortening of action potential. This may provide an explanation for the greater Q-T shortening during exercised-induced tachycardia, compared with atrial pacing. At high concentrations, attained locally during maximal sympathetic stimulation, these advantageous effects may be lost.

Animals↗
PubMed1984

Stretch of contracting muscle fibres: evidence for regularly spaced active sites along the filaments and enhanced mechanical performance.

Single frog skeletal muscle fibres were stretched during fused tetanic contractions. The force increase during stretch exhibited a breakpoint at a mean critical length change of 16.6 nm per half sarcomere that was independent of stretch velocity and sarcomere length. The early decaying extra force after stretch (component 2) was removed by a small quick release, leaving a longer lasting component (component 3). The amplitude of release required increased with time up to the angle in the force record during stretch, was constant for the remainder of the stretch and decreased with time after the end of stretch; it was consistently less than the critical amplitude of stretch (above). Component 3 occurred at sarcomere lengths above 2.3 microns and was amplitude dependent. The final force after stretch was usually higher than the isometric force at the starting length of the stretch. Non-uniformity as a cause of this component was examined by (a) laser diffraction studies which showed sarcomere stretch at all locations and (b) 0.6-0.7 mm long segments along the entire fibre which all elongated during stretch. After stretch the sarcomeres and segments were significantly more stable than during control isometric tetani. Segments which were clamped by a servo system demonstrated component 3. Shortening during contraction followed by stretch back to the starting length led to nearly as much force enhancement as stretch alone, suggesting that component 3 is not due to a passive elastic element recruited during activation. An increase in temperature decreased components 1 (velocity dependent force during stretch) and 2 but increased component 3. The critical length features of component 2 suggest a cross-bridge mechanism. However, the sarcomere length dependence of all components differs from that of isometric force and from predictions based on filament overlap.

Animals↗
PubMed1984

Oxygen and coronary vascular resistance during autoregulation and metabolic vasodilation in the dog.

The hypothesis that tissue oxygen tension controls coronary vascular resistance during changes in perfusion pressure and oxygen consumption was expressed in a simplified mathematical form capable of making quantitative predictions. The predictive value of this formulation of the hypothesis was tested in experiments on anaesthetized mongrel dogs subjected to constant-pressure perfusion of the left main coronary artery, with measurements of coronary blood flow and arterio-venous oxygen content differences. Coronary venous oxygen content was used as an index of tissue oxygenation. The responses of coronary blood flow and arterio-venous oxygen content difference, made over a range of perfusion pressures (which caused autoregulation) and heart rates (which caused metabolic regulation) were predicted qualitatively by the model. Coronary vascular conductance was positively related to metabolic rate only during metabolic regulation (heart rate changes); during autoregulation the relationship between these two variables was inverse. Coronary vascular conductance and resistance values taken from both interventions (both perfusion pressure and heart rate variations) were closely related to coronary venous oxygen content and calculated PO2. These findings suggest that further examination of oxygen tension, as the controller of the coronary vascular bed under physiological conditions should be considered.

Animals↗
PubMed1984

Velocity of sarcomere shortening in rat cardiac muscle: relationship to force, sarcomere length, calcium and time.

The relation between force and velocity was determined in sixteen trabeculae of rat right ventricle as a function of time during a twitch, of sarcomere length and of external Ca2+ concentration, [Ca2+]o. The trabeculae were studied in modified Krebs-Henseleit solution at 25 degrees C. Force was measured with a semiconductor strain gauge. Sarcomere length was measured with a laser diffraction system. A servomotor system was used in which control could be switched between sarcomere length, muscle length and force. Force-velocity relations were derived from load clamps and from contractions in which sarcomere length was initially held constant followed by a quick release and slower release of the sarcomeres at controlled velocity. Force-velocity relations were fitted by Hill's equation (Hill, 1938), (Po-P) b = (P+a) V, where P = force, V = velocity, Po = isometric force in mN/mm2 and a and b are constants. For [Ca2+]o = 2.5 mM, with both interventions the values (mean +/- S.D.) were: b = 1.00 +/- 0.45 micron/s; a = 9.52 +/- 5.60 mN/mm2; Vo measured = 13.6 +/- 3.0 micron/s; Vo calculated = 13.4 +/- 3.4 micron/s; Po measured = 96.5 +/- 25.0 mN/mm2; Po calculated = 119.3 +/- 34.5 mN/mm2. Vo rose with [Ca2+]o to a maximum at [Ca2+]o = 1.2 mM when Po was about 50% of maximum, while Po rose with [Ca2+]o to a maximum at above 2.5 mM. Vo rose with time during the twitch to a maximum at 25 ms following onset of contraction; Po was then about 50% of the maximum that was obtained at 120 ms. Vo increased with sarcomere length from zero at a sarcomere length of 1.6 micron to a maximum at 1.85 micron. Between 1.85 micron and 2.3 micron, Vo was constant. At 1.85 micron, Po was about 60% of maximum Po. These results are compatible with the hypothesis that Vo is more sensitive than Po to the amount of Ca2+ bound to the contractile proteins, and that Vo reaches a maximal value with an amount of Ca2+ bound to the contractile proteins at which Po has obtained only about 50% of its maximal value.

Animals↗
PubMed1984

Relationships between beat-to-beat interval and the strength of contraction in the healthy and diseased human heart.

Twenty-six adult patients, classified by clinical and catheter criteria into groups of those with normal and abnormal left ventricular function, were studied during cardiac catheterization. Right heart pacing was established, and left ventricular dP/dt was measured with end-catheter manometers. By varying the interval preceding a test beat after periods of steady pacing it was confirmed that recovery of left ventricular mechanical function (maximum dP/dt) occurs approximately 800 msec (optimum interval) after a beat. The augmentation of maximum dP/dt of the first 2 beats after an extrasystole, each spaced at the optimum interval, was also studied; the amount of potentiation was varied by alterations in extrasystolic interval. Potentiation decayed from the first to the second postextrasystolic beat with a ratio that was fixed in each individual patient. The ratio (recirculation fraction) was higher in patients with normal than in those with abnormal left ventricular function (mean +/- SD 0.52 +/- 0.10 vs 0.37 +/- 0.11, p less than .005). There was an inverse relationship between this ratio and the degree of potentiation of the first postextrasystolic beat (r = .80, p less than .001). We postulate a disturbance of excitation-contraction coupling mechanisms to explain these effects.

Adult↗
PubMed1983

The effect of cardiac denervation and beta-blockade on control of cardiac output in exercising dogs.

Normal and cardiac denervated dogs, with an electromagnetic aortic flowprobe implanted at least 14 days before the experiments, ran at different speeds on a 25% graded treadmill. The experiments were carried out before and after blockade of betareceptors in the heart by PO administration of 125 mg X kg-1 practolol per day. Changes in stroke volume, heart rate, and cardiac output were measured. After beta-adrenergic blockade, only two of the seven dogs with denervated hearts were prepared to run at a limited number of speeds. Time constants of the cardiac output changes at the onset of exercise were significantly different (P less than 0.001) for the normal (11.5 +/- 0.7 s, mean +/- SEM) and the denervated dogs (29.5 +/- 1.1 s), but in normal dogs did not change with practolol (11.8 +/- 0.8 s). The steady state relationship between cardiac output (CO) and work per unit time performed on the treadmill (P) was for normal dogs: CO = 156 + 1.55P, for normal dogs after practolol treatment: CO = 156 + 0.43P (slope significantly different, P less than 0.05), and for dogs with denervated hearts: CO = 121 + 2.06P (not significantly different from normal dogs). It was concluded that changes in the venous or arterial system alone are not sufficient to increase cardiac output appreciably during exercise. The magnitude of the cardiac output increase depends more on the presence of intact beta-receptors than on the presence of intact cardiac nerves.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Mechanism of the inotropic action of inosine on canine myocardium.

The positive inotropic effect of inosine in intact dog hearts was approximately halved by beta-adrenergic blockade with sotalol. The same result was obtained in dogs with chronic denervation of the heart, in which the sympathetic nerve terminals had degenerated. Therefore part of the positive inotropic action of inosine appears to be non-adrenergic. Inosine infusion caused supersensitivity of the positive inotropic effect over a wide range of doses of adrenaline. It is postulated that inosine may act by blocking the desensitising action of cyclic AMP on the reaction between calcium ions and the contractile proteins.

Animals↗
PubMed1983

The effect of palmitate and lactate on mechanical performance and metabolism of cat and rat myocardium.

Fourteen isolated ejecting hearts were perfused with a suspension of red cells in Tyrode solution. In five hearts comparison was made between glucose alone as substrate and glucose plus free fatty acid (palmitate). In five hearts the effect of additional lactate was studied. In the remaining hearts no substrate changes were made (controls). There were only transient changes in cardiac output of the hearts (at fixed mean aortic pressure) when the perfusion media were switched from one to another. There were no consistent steady-state changes in myocardial oxygen consumption, mean external power, efficiency, cardiac output or coronary blood flow associated with any of the changes in substrate consumption. Thus we were unable to confirm an increase in oxygen consumption and decrease in efficiency associated with either free fatty acid or lactate as substrates. Isolated rat trabeculae were deprived of exogenous substrate; their mechanical performance remained constant for approximately 10 min. Subsequent deterioration was restored by any of the three exogenous substrates. We conclude that there is no oxygen wasting effect of these substrates as has previously been postulated, nor any deleterious effect of changing exogenous or endogenous carbohydrate or lipid substrate.

Animals↗
PubMed1983

Cardiac action potential duration and contractility in the intact dog heart.

The maximum rate of rise of left ventricular pressure (DP) and action potential duration (a.p.d.) were measured in closed-chest anaesthetized dogs with atrioventricular dissociation and beta-adrenergic blockade. Right ventricular stimulation was carried out with protocols consisting of a conditioning 'priming' period and a test period. When a single test stimulus was introduced at varying intervals after the priming period, DP was found to be maximal at 800-1000 ms. With this single test stimulus fixed at the optimum, DP was found to be a variable inverse function of the a.p.d. of the same beat; no positive correlation could be found between DP and a.p.d. When a second test stimulus at the optimum interval was introduced after the first, the DP (DP2) was found to be strongly dependent on that elicited by the first test stimulus (DP1); the relationship was positive, linear, independent of the method used to vary DP, and independent of whether DP1 was depressed or potentiated. The slope of the relationship was less than 1.0 and the line passed through the point where DP2 = DP1; this is the point of continuous stimulation at the optimum interval in a steady state. This result is consistent with the hypothesis that the coefficient relating DP1 to DP2, at constant a.p.d. of the first test pulse (AP1), is an index of the proportion of the activator of contraction stored during relaxation of test beat 1 which is released again on beat 2. In order to test the hypothesis that the remaining contractility depended on the action potential of test beat 1, AP1 was varied by changing the intervals between the priming stimuli. In order to determine the relationship between DP2 and AP1 it was necessary to carry out multiple regression analysis because DP2 was already known to be strongly dependent on DP1 (point 3 above), i.e. DP2 = BDP(DP1) + BAP(AP1 - D). This analysis yielded highly significant positive values for the coefficients BDP and BAP. This result is compatible with the postulate that a.p.d. influences the amount of the activator of contraction entering the intracellular store, but that this activator is not available for release to the contractile proteins until the next depolarization.

Action Potentials↗
PubMed1983

Electrical and mechanical restitution of the human heart at different rates of stimulation.

Action potential duration and contractility are reduced following premature excitations, and gradually increase as the stimulus interval is lengthened. To examine these phenomena of electrical and mechanical restitution in the human heart, we simultaneously measured action potential duration and the maximum rate of left ventricular pressure in five patients undergoing electrophysiological study. Test beats were introduced at varying intervals after the last of a series of steady state intervals. By plotting action potential duration and maximum rate of left ventricular pressure as a function of the test interval, we formed electrical and mechanical restitution curves. When the rate of steady state pacing was increased, there was a decrease in action potential duration and an increase in the maximum rate of left ventricular pressure for all test intervals; i.e., a change in pacing rate affected action potential duration and maximum rate of left ventricular pressure of test responses in a reciprocal fashion. In addition, a higher steady state pacing rate allowed action potentials and contractile responses to be elicited at shorter test intervals, thereby displacing the electrical and mechanical restitution curves to the left. The magnitude of the leftward shift of both curves corresponded closely to the shortening of the steady state action potential duration induced by the increase in pacing rate. These findings confirm for the human heart that both electrical and mechanical restitution occur after membrane repolarization, i.e., as a function of the electrical diastolic interval preceding a beat, and not the stimulus interval.

Action Potentials↗
PubMed1982

Effect of vagotomy on the breathing pattern and exercise ability in emphysematous patients.

1. The potential value of right vagotomy for the relief of breathlessness has been explored in five patients with emphysema. Two patients had symptomatic improvement, two had minor symptomatic improvement, and one was unchanged. 2. Exercise ventilation was not noticeably depressed by unilateral right vagotomy in the two patients investigated fully, but the pattern of breathing was altered. After vagotomy, breathing was deeper, and the rise in the frequency of breathing with exercise was depressed. 3. After right vagotomy the response to rebreathing carbon dioxide also consisted of slower deeper breaths. 4. Right vagotomy sometimes appears to remove an influence preventing slow deep breathing and exacerbating dyspnoea. 5. Results of bilateral pulmonary denervation, attempted in one patient, were complicated by the need for left thoracotomy, which removed any possible beneficial effects.

Aged↗