Engineering and physiological approaches to the study of cardiovascular function: alternative or complementary?
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Biophysical Phenomena↗
Biomedical subjects
M I Noble
Publications and source records attributed to M I Noble.
Dispersion of coronary artery thrombi by antagonism of platelet serotonin receptor in the dog.
OBJECTIVE: Blockade of platelet 5HT2 receptors prevents coronary artery thrombi. This study explores the dispersal of established thrombus by such 5HT2 antagonism. METHODS: Seven open chest anaesthetised beagles were used in a repeated measures study of the action of MDL 11,939 to remove the participation of platelet 5HT2 receptors in the natural history of intracoronary thrombosis with cyclic blood flow reduction. Endothelial damage and critical diameter constrictors were applied to the circumflex coronary artery, and systemic blood pressure and circumflex blood flow were measured continuously. RESULTS: Cyclic flow reductions, which were established by build up and embolisation of platelet thrombi, were completely abolished by the 5HT2 antagonist MDL 11,939. The dose given in the first two experiments was 0.5 mg.kg-1, reduced to 0.2 mg.kg-1 for the third. Subsequent animals received 0.1 mg.kg-1. Mean blood pressure rose slightly. Adrenaline infusion at 0.4 micrograms.kg-1.min-1 failed to restore cyclic flow reductions in any animal and caused a small flow increase without affecting mean blood pressure. The pattern of blood flow restitution after administration of MDL 11,939 was of great interest. In all the animals flow spontaneously increased in a stepwise fashion (a double step in five dogs). The step up was markedly different from the increase in flow seen during adrenaline infusion. CONCLUSIONS: (1) These results are further evidence of the importance of serotonin as a mediator of platelet thrombus in stenosed coronary arteries. (2) The apparent dissipation of thrombi by MDL 11,939 may be of importance.
Animals↗
Effect of adrenaline on cardiac force-interval relationship.
OBJECTIVE: The aim was to test the hypothesis that adrenaline affects the force-interval processes. METHODS: The force-interval processes were studied in eight guinea pig papillary muscles (isometric force) and five anaesthetised dogs with atrioventricular block (maximum rate of rise of left ventricular pressure, LVdP/dtmax). The contractility indices were measured during pacing sequences in which a steady state was interrupted after a variable interval by a premature beat followed by an immediate return to the steady state. RESULTS: The relationship between contractility of the premature beat and the preceding interstimulus interval displays an approximately monoexponential initial rising phase, ie, mechanical restitution. With increasing adrenaline dosage in the isolated preparation there was always a significant increase in the force, and in its rate of rise with interval in some cases. Adrenaline had a variable accelerating effect on the time course of this mechanical restitution in isolated papillary muscles, but no effect in the dog preparation. In the isolated preparation adrenaline also slowed the decay in potentiation of the two beats immediately following the premature contraction. A slope of the relationship between the contractility of the second potentiated beat and that of the first was thus increased. This difference was not apparent in the intact preparation. CONCLUSIONS: The speeding up of mechanical restitution by adrenaline may be interpreted as reflecting the time course of reavailability of contractile activator. The slope of the relationship of contractility to that of the previous beat during the decay of postextrasystolic potentiation may be interpreted as the recirculation fraction of contractile activator; this is increased by adrenaline. However, in addition, adrenaline exerts an inotropic effect by another mechanism.
Animals↗
Haemodynamic and neurohumoral response in heart failure produced by rapid ventricular pacing.
OBJECTIVE: The aim was to determine the exact sequence of hormone changes during the progression of fluid retention in a canine model of "congestive cardiac failure" induced by rapid right ventricular pacing, and during recovery when pacing is stopped. METHODS: Rapid ventricular pacing at a rate of 250 pulses.min-1 was used in six mongrel dogs with implanted right ventricular pacemakers. Right heart haemodynamics were measured by means of Swan Ganz catheterisation, allowing flow measurement by thermodilution and pressure measurement by external manometry. Plasma renin activity, arginine vasopressin, and atrial natriuretic factor were assayed on venous blood samples by radioimmunoassay. Noradrenaline was assayed by high pressure liquid chromatography. RESULTS: The onset of rapid pacing was accompanied by a fall in cardiac output and a rise in pulmonary arterial, pulmonary capillary wedge, and right atrial pressures. Noradrenaline and atrial natriuretic factor rose. Plasma renin activity showed an initial fall followed by a rise, and arginine vasopressin was unchanged in the first 8 h. When rapid pacing was continued for a further 35 d, clinical signs of fluid retention appeared by day 28, by which time cardiac output had fallen, and central pressures risen further. Atrial natriuretic factor peaked at around 14 d whereas plasma renin activity, arginine vasopressin, and noradrenaline tended to reach a plateau at about d 20 and then to show further increases as clinical signs of fluid retention appeared; this was most marked with plasma renin activity. Cessation of pacing at d 35 caused a rapid reversal (increase) of cardiac output but a more gradual reversal (decrease) of right heart pressures over 5 d; only wedge pressure returned to base line. Arginine vasopressin and plasma renin activity fell rapidly to around 40% of the final pacing levels and reached basal values after 8 h and 48 h respectively. Noradrenaline fell after 8 h and reached basal levels in 5 d. Atrial natriuretic factor fell quickly by 60% after 8 h but remained above basal levels for 5 d. At the end of pacing, body weight fell rapidly in conjunction with a large diuresis. CONCLUSIONS: These findings are compatible with a major role of one or more of renin, vasopressin, and noradrenaline in the pathophysiology of the fluid retention of heart failure; the manifestations are not counteracted by the rise in atrial natriuretic factor.
Animals↗
Enhancement of mechanical performance of striated muscle by stretch during contraction.
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Adenosine Triphosphate↗
Postextrasystolic potentiation and its contribution to the beat-to-beat variation of the pulse during atrial fibrillation.
BACKGROUND: Beat-to-beat variations in the pulse during atrial fibrillation (AF) have conventionally been attributed to time-dependent changes in filling. We have explored the possibility that they are dependent on the intrinsic myocardial interval force relation. METHODS AND RESULTS: Left ventricular (LV) contractility (maximum rate of rise of pressure, LV dP/dtmax) and ascending aortic blood velocity were measured during cardiac catheterization in 15 patients with AF. Beats preceded by an interval of less than 500 msec were excluded from analysis to reduce the confounding influence of incomplete mechanical restitution. The LV dP/dtmax was then related to the prepreceding interval. An inverse relation consistent with postextrasystolic potentiation was obtained in all 15 patients (Spearman's rank correlations, -0.56 to -0.86; p less than or equal to 0.0001). This relation was confirmed in three patients during pacing that overrode the AF and introduced single-interval variations into steady-state pacing. The ECG sequences from six of the AF patients were used to drive isometrically contracting guinea pig papillary muscle and human right ventricular tissue (n = 7); the same inverse relation was demonstrated. On a beat-by-beat basis, the maximum rate of rise of force in the isolated muscle correlated well with LV dP/dtmax in the patients (r = 0.50-0.86, p less than or equal to 0.0001). The relation of the integral of aortic velocity (AVI, proportional to stroke volume) to prepreceding interval was also inverse, whereas important correlations were demonstrated between LV dP/dtmax and AVI (Spearman's rank correlations, 0.27-0.95; p less than or equal to 0.0001). CONCLUSIONS: This study demonstrates that postextrasystolic potentiation contributes to the characteristic beat-to-beat variation of the pulse in AF.
Aged↗
The possible role of serotonin 5HT2 receptor antagonism in cardioprotection.
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Arrhythmias, Cardiac↗
Cardiac cell membrane repolarization is required for onset of mechanical restitution in papillary muscle.
In 10 voltage clamped ferret papillary muscles at 37 degrees C (single sucrose gap), the duration of resting (diastolic, holding) potential was varied in order to define the mechanical restitution process. Following a period of steady state voltage clamp depolarizations to +20 mV, a single test depolarization clamp of 200 or 500 ms duration was introduced. Then, the following period at resting (holding) potential was varied. All the mechanical restitution curves for the 500 ms clamps were delayed by 300 ms compared with the 200 ms clamps. When mechanical restitution was plotted as the relationship between contractile force and test electrical diastolic interval, all processes started from zero interval (i.e. the time of repolarization). Variation of diastolic holding potential between -70 mV and -40 mV did not affect the starting time, but the final force values at full restitution were approached faster and were higher for -70 mV than for -40 mV. There was an inverse relationship between force and second inward current during mechanical restitution after an initial phase of restitution of current. Mechanical restitution is postulated to be due to passage of contractile calcium with time from an uptake to a release compartment within the sarcoplasmic reticulum. Thus the rise of contractile force with increasing test cycle duration should have been independent of whether a 200 or 500 ms depolarization was used. In order to accommodate the discrepancy, we postulate either that (1) sarcoplasmic reticulum calcium release channels require sarcolemmal repolarization to begin to be reactivated or (2) that trigger calcium (calcium induced calcium release from the sarcoplasmic reticulum) is derived from the sarcolemma.
Animals↗
Effects of transient changes in membrane potential on twitch force in ferret papillary muscle. Possible effects on Na-Ca exchange.
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Animals↗
Use of an impedance meter for measuring airways responsiveness to histamine.
We compared spirometry (FEV1) and airway impedance (z) in the assessment of airway responsiveness to histamine. Airway impedance was measured by the oscillator technique during quiet breathing; both measurements were made twice after each increment of histamine during the challenge. Percentage change in impedance was related to percentage change in FEV1 according to: -delta z = 1.09-2.66 (delta FEV1), r = -0.73, p less than 0.01, ie, impedance increased on average 2.7 times as much as FEV1 fell. The cut-off point for the standard test is the histamine concentration giving a 20 percent fall of FEV1 (PC20(FEV1)). The corresponding cut-off value chosen for impedance was a 30 percent increase (PC30(z)). (PC30(z)) = 0.74 (PC20(FEV1))-0.48, rs = 0.88, where rs is the Spearman rank correlation coefficient. Thus, impedance is a more sensitive index than FEV1 because a smaller dose of histamine gave a diagnostic result. Impedance is a practical alternative to FEV1, being less arduous for the patient and requiring little cooperation.
Adult↗
Do studies of mechanical restitution tell us anything about the mechanism of Ca2+ release in myocardial cells?
We present information from the literature which is discordant with the idea that the trigger Ca2+ for Ca2(+)-induced Ca2+ release from the myocardial sarcoplasmic reticulum (SR) is carried by the inward current. In addition, evidence is emerging to show that recovery of contractility with increasing interval after an excitation-contraction-relaxation cycle (mechanical restitution) begins with repolarization of the sarcolemma, not mechanical relaxation (SR Ca2+ uptake). These two phenomena, if confirmed, would be compatible with a sarcolemmal source of trigger Ca2+.
Animals↗
Characterisation of decay of frequency induced potentiation and post-extrasystolic potentiation.
STUDY OBJECTIVE: The aim was to elucidate the processes underlying the beat by beat decay of frequency induced and post-extrasystolic potentiation. DESIGN: The ventricular pacing protocol consisted of a "priming period" followed by a "decay" period of pacing at 1 s intervals, characterised by a decaying potentiation of left ventricular (LV) dP/dtmax; these were identified as test beats 1,2,3,4,5. The magnitude of potentiation of test beat 1 (P1) was increased both by increased priming frequency (frequency potentiation) and by alternately shorter priming intervals (paired pulse stimulation) at a given average frequency (post-extrasystolic potentiation). The exponential decay constant (P2) and the asymptotic value (P3) were determined and compared with the measured values and with the slope of the linear relationship between the contractility of one beat and that of the preceding beat. The lowest values after decay were related to the magnitude of preceding potentiation. EXPERIMENTAL MATERIAL: Six anaesthetised dogs with induced heart block and beta adrenergic blockade were used. Beat to beat interval was controlled by ventricular pacing from a programmable stimulator. MEASUREMENTS AND MAIN RESULTS: Contractility of each beat was assessed from maximum rate of rise of LV pressure (LVdP/dtmax) obtained from an intraventricular micromanometer. The asymptotic value of the exponential fit to the decay of potentiation (P3) was found to be below the measured nadir value, which was followed by an increase in LVdP/dtmax to the final steady state value P4. The decay constant (P2) was found to be equivalent to the natural logarithm of the slope of the linear relationship between the contractility of one beat and that of the preceding beat; it was unaffected by priming frequency or interval at a given average priming frequency. The asymptote P3 was inversely related to P1. CONCLUSIONS: P1 was interpreted as the expression of accumulation of activator in an internal release store; P3 was interpreted as a manifestation of negative feedback control of activator entry by the released activator itself, and the slow recovery to P4 as due to the slow lengthening of action potential duration and/or recovery from accumulation of an intracellular metabolite or ion.
Action Potentials↗
Inhibition of acute platelet thrombosis formation in stenosed canine coronary arteries by specific serotonin 5HT2 receptor antagonist ritanserin.
STUDY OBJECTIVE: The aim of the study was to test the hypothesis that platelet serotonin 5HT2 receptors are important in the genesis of thrombosis in stenosed coronary arteries. DESIGN: The specific serotonin 5HT2 receptor antagonist, ritanserin was used as a pharmacological tool to examine the effect of removal of the participation of the 5HT2 receptors on thrombus growth, in a paired statistical design. EXPERIMENTAL MATERIAL: The study involved 10 open chest anaesthetised dogs, with constrictors of critical diameter applied to the left circumflex coronary artery. MEASUREMENTS AND MAIN RESULTS: Blood flow was monitored in the left circumflex coronary arteries, distal to the critical stenosis. Flow reductions occurred that have previously been shown to be caused by the accumulation of platelet thrombi. By embolising the thrombi, the process could be monitored cyclically (cyclic flow reductions). The specific serotonin 5HT2 receptor antagonist, ritanserin, abolished cyclic flow reductions at a dose of 0.5 mg.kg-1. There was no effect on blood pressure or heart rate on administration of ritanserin at any dose. The serotonin blockade by ritanserin also prevented the reestablishment of cyclic flow reductions by adrenaline infusion (0.4 micrograms.kg-1.min-1), but required ritanserin doses up to 1.5 mg.kg-1. Ex vivo aggregation of platelets was reduced in blood taken from the dogs after ritanserin administration. CONCLUSIONS: These results constitute further evidence of the possible importance of serotonin as a mediator of platelet thrombosis in stenosed coronary arteries.
Animals↗
Responses to changes in filling and contractility of indices of human left ventricular mechanical performance.
1. Beat-by-beat indices of contractility for assessment of inotropic effects in a given subject were studied using pacing with beta-adrenergic blockade, in eight patients undergoing routine left heart catheterization. A catheter-tip manometer was sited in the left ventricle and an electromagnetic velocity transducer was mounted further back on the same catheter so that it was sited in the ascending aorta. 2. The maximum rate of rise of left ventricular pressure (dPLV/dtmax), and of aortic velocity (maximum acceleration, MA) and stroke volume (SV) were all obtained with this catheter. Filling effects were assessed by head-up to head-down tilt, inotropic effects by paced post-extrasystolic potentiation. 3. Tilt produced a mean increase in left ventricular end-diastolic pressure (PLVED) of 8.1 mmHg (P less than 0.05), dPLV/dtmax decreased 4.3% (n.s.), peak velocity (PV) increased 23% (P less than 0.05), MA increased 5.4% (n.s.), and SV increased 17.5% (P less than 0.05). Post-extrasystolic potentiation produced a mean decrease in PLVED of 2.8 mmHg (n.s.), dPLV/dtmax increased 35% (P less than 0.05), PV increased 14% (P less than 0.05), MA increased 55% (P less than 0.05), and SV increased 8.7% (n.s.). 4. There was no difference in response between patients with normal and patients with impaired left ventricular ejection fraction. 5. It is concluded that increased left ventricular filling increases stroke volume greatly (Starling effect) but does not affect dPLV/dtmax, which (together with MA) nevertheless responds markedly to increased contractility. dPLV/dtmax appears to be a volume-insensitive index of contractility in the intact human, whether ejection fraction is normal or impaired.
Adrenergic beta-Antagonists↗
Mechanisms of impaired excretion of a fluid load after cardiac denervation in dogs.
The influence of cardiac innervation on the renal response to volume expansion was investigated. Systemic hemodynamic, plasma hormone, and renal clearance measurements were made before, during, and after intravenous administration of 1,000 ml 0.9% saline over 10 min to six control and six cardiac-denervated, chloralose-anesthetized mongrel dogs. Volume expansion resulted in a two- to threefold rise in plasma atrial natriuretic peptide (ANP) concentrations and a 50% rise in glomerular filtration rate (GFR) in both groups. Plasma renin activity (PRA) and plasma arginine vasopressin remained higher throughout in cardiac-denervated compared with control dogs. The marked increases in urine flow rate and sodium and free water clearances seen in the controls were attenuated or abolished after cardiac denervation. These differences were due to the influence of higher PRA and vasopressin in these animals compared with the controls, rather than differences in hemodynamic responses operating via GFR or in direct humoral responses via ANP secretion.
Animals↗
Evidence for a role of serotonin in initiation of coronary arterial thrombosis in dog and man.
We report recently published results in dogs by Torr et al. in which the accumulation of platelet thrombi in canine coronary arteries was abolished by the specific serotonin 5HT2 receptor antagonist, ritanserin. The serotonin blockade by ritanserin also prevented the re-establishment of thrombi by adrenaline infusion. 61 humans with critical coronary artery stenoses shown by coronary angiography were divided into control and serotonin antagonist (31 ketanserin administration) groups. While awaiting coronary artery bypass grafting or angioplasty, 7 of the subjects in the control group had coronary arterial occlusions, 4 of whom died. The only occlusion in the serotonin antagonism group occurred in a subject who died suddenly after 2 years of study. The probability of the occlusion rate in subjects subjected to serotonin antagonism being the same as that of the control subjects was less than 0.0245, by Fisher's exact test. It is concluded that serotonin may be as important in mediating coronary thrombosis in man as it is in animals.
Animals↗
Atrial natriuretic peptide response to rapid atrial pacing in cardiac-denervated dogs.
The effects of rapid atrial pacing on central hemodynamics, plasma hormones, and renal function were investigated in eight control and nine cardiac-denervated dogs under chloralose anesthesia. Pacing at approximately 250 ppm for 60 min caused similar increases in pulmonary wedge and right atrial pressures, systemic vascular resistance, and plasma atrial natriuretic peptide (ANP) in both groups. In control dogs, pacing produced a fall in both plasma vasopressin (AVP) and plasma renin activity (PRA) and a rise in urine flow rate associated with an increase in free water but not sodium clearance. In contrast, in cardiac-denervated dogs, both plasma AVP and PRA increased during pacing; urine flow rate did not change, and marked sodium retention occurred. This study supports the concept that the increase in urine flow during rapid atrial pacing is mediated by inhibition of renin and AVP secretion through intact cardiac nerves. The secretion of ANP is unaffected by cardiac denervation. The natriuretic and vasodilator actions of high plasma ANP concentrations during rapid atrial pacing can be inhibited either by neurally mediated cardiorenal effects in normal animals or by stimulation of the renin-angiotensin system after cardiac denervation.
Animals↗
Cellular abnormalities in chronically denervated myocardium. Implications for the transplanted heart.
Heart transplantation involves chronic effects due to denervation, rejection, and treatment of rejection. The chronically denervated dog heart provides a model for the effects of denervation alone. These hearts have been shown to contain intrinsic neurons with VIP and NPY as possible neurotransmitters. Myocardial tissue noradrenaline concentration falls to very low levels after degeneration of postganglionic sympathetic neurons, but dopamine remains in near-normal concentration and is probably synthesized extraneuronally. ANP is present and released normally; however, the natriuretic response to atrial distension is blunted, suggesting that this response is mainly due to a reflex mechanism. Chronically denervated myocardial tissue exhibits increased oxygen consumption in vitro and increased Na-K, ATPase activity but has normal tissue levels of ATP and creatine phosphate. Glucose oxidation is inhibited in vivo, associated with increased levels of fructose-6-phosphate but normal glucose-6-phosphate, suggesting inhibition of phosphofructokinase activity. However, the enzyme protein concentration of phosphofructokinase, as judged by maximal in vitro activity, is normal. Maximal in vitro activities of succinate dehydrogenase, cytochrome oxidase, monoamine oxidase, calcium-dependent ATPase, and glyceraldehyde-3-dehydrogenase are also normal. From these findings, we would predict that patients with transplanted hearts are likely to show myocardial metabolic inefficiency.
Animals↗