RESUMO
The performance of a new and simplified flow probe construction and the Iowa 545C-4 pulsed Doppler velocimeter was evaluated for measurement of blood flow over several months in small arteries of awake animals. Calibrations were performed over a wide range of intraluminal pressures and physiological flow velocities. Pressure-dependent differences in slope of the Doppler shift-volume flow relationship were detected in some probes. Signal strength was maintained at hematocrits > 10%. Distortion of pulsed Doppler signal peaks occurred in the conscious rabbit at peak aortic velocities, at which Reynold's number for turbulence was exceeded and the Doppler shift surpassed the Nyquist limit of 31.25 kHz for the velocimeter. Although the Doppler shift-volume flow relationship is linear at < 5 kHz, in some cases at higher Doppler shifts and blood flow velocities the relationship may become nonlinear, thus causing the volume flow rate to be underestimated by up to 38%. The cause of this phenomenon may be "aliasing" and/or the consequence of the range control capability of the velocimeter selectively sampling changing velocity profiles and flow disturbances in the central stream at higher velocities.
Assuntos
Microcirculação/fisiologia , Reologia/instrumentação , Animais , Aorta Abdominal/fisiologia , Circulação Coronária/fisiologia , Cães , Artéria Femoral/fisiologia , Hematócrito , Coelhos , Artéria Renal/fisiologia , UltrassomRESUMO
The postulate that venous adaptation assists postural baroreflex regulation by shifting the hydrostatic indifference point (HIP) toward the heart was investigated in eight midazolam-sedated newborn piglets. Whole body head-up (+15, +30, and +45 degrees ) and head-down (-15 and -30 degrees ) tilt provided a physiological range of orthostatic strain. HIP for all positive tilts shifted toward the heart (P < 0.05), +45 degrees HIP shifted most [6.7 +/- 0.3, 5.9 +/- 0.5, and 3.6 +/- 0.3 (SE) cm caudal to right atrium on days 1, 3, and 6, respectively]. HIP for negative tilts (3.0 +/- 0.2 cm caudal to right atrium) did not shift with postnatal age. Euthanasia on day 6 caused 2.1 +/- 0.3-cm caudal displacement of HIP for positive and negative tilts (P < 0.05). HIP proximity to right atrium was not altered by alpha-, beta-adrenoceptor and cholinoceptor blockade on day 5. It is concluded that early HIP migration reflects enhancement of venous pressure control to head-up orthostatic strain. The effect is independent of baroreflex-mediated adrenoceptor and cholinoceptor mechanisms.
Assuntos
Adaptação Fisiológica/fisiologia , Animais Recém-Nascidos/fisiologia , Pressão Venosa Central/fisiologia , Postura/fisiologia , Adaptação Fisiológica/efeitos dos fármacos , Antagonistas Adrenérgicos/farmacologia , Algoritmos , Animais , Biomarcadores , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Pressão Venosa Central/efeitos dos fármacos , Antagonistas Colinérgicos/farmacologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Pressão Hidrostática , Masculino , Suínos , Teste da Mesa InclinadaRESUMO
This article argues that dopamine infused in low doses has not been shown to avert the onset of or ameliorate the course of acute renal failure in critically ill patients. The inotropic and diuretic effects of dopamine are discussed, and its adverse effects are described. An attempt is made to offer an evidence-based role for low-dose dopamine, namely as a diuretic in ventilated, euvolemic patients, resistant to conventional diuretic therapy.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Dopamina/uso terapêutico , Injúria Renal Aguda/fisiopatologia , Cuidados Críticos , Estado Terminal , Dopamina/farmacologia , Resistência a Medicamentos , Medicina Baseada em Evidências , Humanos , Respiração Artificial , Resultado do TratamentoRESUMO
The relative roles of neural and pressure gradient factors, causing a fall or maintenance of bronchial blood flow in exercising sheep, are unknown. These were examined in sheep prepared under thiopentone/isoflurane general anaesthesia with a pulsed Doppler probe mounted on the bronchial artery, and aortic pressure (Pa) catheter in superficial cervical artery. After recovery, Swan-Ganz catheters were inserted under local anaesthesia into the pulmonary artery. Bronchial flow and conductance (Qbr, Cbr), and pressure gradients (Pg; i.e. aortic minus right atrial, Pg_RAP; pulmonary artery, Pg_Ppa; and, left atrial (wedge) Pg_LAP) were derived from continuous records, after switching between downstream sites during and after moderately severe treadmill exercise (3.8 km.h(-1), for 1.7 min, 6 min recovery). The protocol was repeated after combined alpha1,alpha2-adrenoceptor/cholinoceptor blockade using phentolamine methanesulfonate and methscopolamine bromide. Bronchial flow fell in both receptor intact (INT) and (BL) blocked state. Pa rose in INT, but downstream pressures rose only 3.7 (RAP), 2.8 (Ppa) and 2.0 (LAP) mmHg (P for each < 0.05) in both INT and BL. Pg_RAP and Pg_Ppa did not rise, but Pg_LAP rose 4.0 mmHg (P < 0.05). In BL, Pa fell, as did Pg_RAP (7.0 mmHg, P < 0.05), Pg_Ppa (8.9 mmHg, P < 0.001), but Pg_LAP did not change. Thus, downstream pressures change by small amounts, and pressure gradients to RAP and Ppa sites do not change during moderately severe exercise in normal sheep. The fall in Qbr in INT is due to neural factors, but in BL is due to a fall in Pg. The relative rise in Pg_LAP in both INT and BL favours redistribution within total Qbr to the pulmonary capillary/vein/left atrium site.
Assuntos
Pressão Sanguínea/fisiologia , Brônquios/irrigação sanguínea , Condicionamento Físico Animal , Ovinos/fisiologia , Animais , Aorta/fisiologia , Feminino , Receptores Adrenérgicos alfa/metabolismo , Receptores Colinérgicos/metabolismoAssuntos
Brônquios/irrigação sanguínea , Resistência Vascular/fisiologia , Animais , Cães , Feminino , Masculino , OvinosRESUMO
Exercise stimulus-response relationships for airway blood supply and dimensions have not been described in mammalian species. These relationships are vital for postulates concerning integrated reflex factors normally controlling the airways and which may underlie the asthma syndromes of exercise. This study defines airways stimulus-response relationships in exercising sheep. Ewes between 35 and 40kg were instrumented at left thoracotomy under thiopentone/isoflurane general anaesthesia. Pulsed Doppler ultrasonic transducers were mounted on the bronchial artery, and transit-time plus single-crystal sonomicrometers on the left main bronchus. These recorded simultaneously and continuously bronchial blood flow (Q(br)) and conductance (C(br)), bronchial circumference (Circ(br)) and wall thickness (Th(br)). In Protocol 1 (P1), four sheep ran duplicate 5min protocols on a horizontal treadmill at continuous step-up-and-down speeds of 1min duration, namely, 0.8, 1.6, 2.2, 1.6 and 0.8mph (moderate exercise), followed by 10min recovery. In P2, four sheep ran duplicate 2min protocols at constant 4mph (strenuous exercise), and in P3, one sheep ran duplicate protocols each of 3min at 2.2, 4.4 and 6mph (severe exercise). Regression analysis and repeated measures ANOVA were used to assess differences between times, runs and exercise intensity. In P1, airway effects were directly related to graded exercise effort sustained over 5min. Peak effects occurred at 2.2mph, except for Th(br). Heart rate and P(a) rose (to 156% and 111% of resting, respectively), and Q(br) and C(br) fell (to 83% and 75%; both P<0.001). Circ(br) fell to 96% (P=0.02), and Th(br) rose at low speeds early and late, and thinned at the highest speed. In P2 and P3 for all variables the steady-state effects were systematically greater than for P1 (4.4mph: C(br) to 43%, Circ(br) to 93%; 6.6mph: C(br) to 25%, Circ(br) to 82%). There was no significant recovery hyperaemia, but there was residual post-exercise bronchoconstriction. The exercise stimulus-response relationships from rest to a maximal 6mph for sheep airway circumference and its bronchial circulation are inverse and functionally constrictor.
Assuntos
Brônquios/irrigação sanguínea , Condicionamento Físico Animal/fisiologia , Circulação Pulmonar/fisiologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Função do Átrio Direito/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Brônquios/anatomia & histologia , Brônquios/efeitos dos fármacos , Broncoconstrição/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , N-Metilescopolamina/farmacologia , Parassimpatolíticos/farmacologia , Condicionamento Físico Animal/métodos , Circulação Pulmonar/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Ovinos , Fatores de TempoRESUMO
BACKGROUND: During exercise and recovery the transient and steady-state changes in autonomic activity regulating lower airway blood flow and dimensions are unknown. The aim of this study was to define changes in bronchial blood flow (Q(br)) and dimensions during moderate and strenuous exercise, and to analyse the role of vagal and sympathetic nerves. METHODS: Nine ewes (34-44kg) underwent left thoracotomy during general anaesthesia (thiopentone/isoflurane) and either (5 sheep=Group 1) a pulsed Doppler transducer was placed on the bronchial artery, or (4 sheep=Group 2) a pulsed Doppler transducer was placed on the bronchial artery, and transit-time and single crystal sonomicrometers were mounted on the left main bronchus. These measured continuously Q(br), bronchial circumference (Circ(br)) and wall thickness (Th(br)). Aortic pressure (P(a)) and central venous pressure catheters were placed in the superficial cervical artery and vein. Trained sheep exercised on a horizontal treadmill, i.e. Group 1, moderate exercise 2.2mph over 1.6, 6min recovery, for analysis of changes in Q(br) before and after cholinoceptor blockade; Group 2, strenuous exercise 4.4mph over 2, 10min recovery for analysis of changes in Q(br) and airway dimensions, before and after cholinoceptor plus alpha(1)-, alpha(2)-adrenoceptor blockade. beta-adrenoceptor systems were intact. RESULTS: In Group 1 during moderate exercise P(a) and heart rate (HR) rose. Q(br) and blood flow conductance (C(br)) fell immediately to 83% (P<0.001) before returning toward resting levels, but fell when exercise ceased to 89% (P<0.01) before recovering. Prior cholinoceptor blockade abolished the immediate fall in Q(br) and C(br), but not the recovery vasoconstriction. Later in recovery the bronchial bed dilated progressively over 6min (P<0.05). In Group 2 during strenuous exercise P(a) and HR rose substantially. Q(br) and C(br) fell to 68% and 54% (P<0.001), respectively, and there was early vasoconstriction in recovery. Circ(br) fell immediately and remained at 93% (P<0.01), and did not recover fully when exercise ceased. Th(br) did not change during or after exercise. Prior cholinoceptor plus alpha-adrenoceptor block caused P(a) and Q(br) to fall slightly during exercise, but the bronchovascular constriction during and after exercise was abolished, as was circumferential shortening in the airway. CONCLUSIONS: At exercise onset and steady-state, resetting the arterial baroreflex upward in sheep increases parasympathetic cholinergic vasoconstrictor activity and causes bronchial wall and bronchovascular smooth muscle contraction in concert with sympathetic adrenergic constriction of systemic vascular beds. Whether the known sigmoid baroreflex control of tracheal smooth muscle tension at rest is extended to tracheobronchial smooth muscle and its circulation during exercise is yet to be determined.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Brônquios/irrigação sanguínea , Condicionamento Físico Animal/fisiologia , Circulação Pulmonar/fisiologia , Acetilcolina/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Brônquios/anatomia & histologia , Brônquios/inervação , Colinérgicos/farmacologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Fluxometria por Laser-Doppler/métodos , N-Metilescopolamina/farmacologia , Parassimpatolíticos/farmacologia , Fentolamina/farmacologia , Condicionamento Físico Animal/métodos , Circulação Pulmonar/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , OvinosRESUMO
1. Previous work from this laboratory and others has shown that powerful autonomic influences modulate coronary flow. In particular, the parasympathetic nervous system produces vasodilatation when activated by baroreceptors via the vagus nerve. 2. Differences exist in baroreflex coronary vasodilator mechanisms among the right, circumflex and anterior descending coronary vascular beds in the awake chronically instrumented dog. 3. Our hypothesis is that neurogenic acetylcholine acting from the adventitial side and endothelial nitric oxide from the luminal aspect of coronary smooth muscle compete with powerful intrinsic myogenic constrictor mechanisms to regulate regional flow conductance. 4. There is also increasing evidence that heterogeneity of control systems exists in different-sized coronary vessels within an individual coronary vascular bed. 5. It is concluded that coronary vessels in vascular beds can no longer be assumed to respond in a uniform manner to neural, myogenic, metabolic or humoral factors. 6. These new perspectives of regional control mechanisms have important implications for understanding pathophysiological mechanisms inducing and sustaining tachyarrhythmias involved in ischaemic heart disease.
Assuntos
Circulação Coronária/fisiologia , Acetilcolina/fisiologia , Animais , Barorreflexo , Vasos Coronários/anatomia & histologia , Vasos Coronários/inervação , Vasos Coronários/metabolismo , Cães , Hemodinâmica , Humanos , Músculo Liso Vascular/anatomia & histologia , Músculo Liso Vascular/inervação , Músculo Liso Vascular/metabolismo , Óxido Nítrico Sintase/fisiologia , Óxido Nítrico Sintase Tipo III , Resistência VascularRESUMO
1. Fentanyl, a synthetic mciro-opioid receptor agonist, is the preferred induction and maintenance anaesthetic agent in cardiac surgery. 2. Its actions on myocardial blood flow are poorly understood. There are reports of intra-operative myocardial ischaemia. Its reported actions on cardiorespiratory control vary widely, but do involve hypertension, bradycardia and peripheral vasoconstriction. 3. Accordingly, the postulate that fentanyl would cause coronary vasoconstriction and myocardial disadvantage was examined in awake dogs with a continuous wave Doppler flow probe mounted on the circumflex coronary artery. 4. Continuous intravenous infusion of fentanyl citrate (550 ng/kg per min) raised plasma concentrations of fentanyl to 3.37 ng/mL in a linear fashion at 20 min. There was a fall in core temperature of 0.7 degrees C and, although no apparent depression of ventilation or fall in arterial or coronary sinus PO2, there was a rise in PCO2 and H+ concentration. Some dogs salivated and panted transiently. Thus, fentanyl may reset temperature regulation in low doses but, at higher doses, is associated with metabolic acidosis. 5. In sinus rhythm, the arterial pressure of the dogs fell slightly, then rose to 115% of resting control. Circumflex flow and conductance rose early, then conductance steadily declined to 83%. Heart rate fell, then rose before returning to pre-infusion levels. The early circumflex coronary vasodilator effects, but not the later vasoconstrictor effects, were reduced in dogs with paced hearts. 6. In dogs with paced hearts, a dose-effect study using 138, 275, 550 and 1100 ng/kg per min fentanyl suggested that, at low plasma concentrations of 1-2 ng/mL, vasodilatation does occur in both coronary and systemic circulations; however, at higher doses, intense coronary and systemic vasoconstriction supervenes. 7. The dose-response effect of fentanyl on arterial baroreflex control of circumflex conductance was examined during the immediate 8 s circumflex vasodilator response to a step rise in aortic pressure caused by inflation of an intra-aortic balloon. At low plasma concentrations of fentanyl, baroreflex control of circumflex conductance appears to be enhanced but, with increasing plasma concentrations of fentanyl, appears to be depressed. 8. Therefore, the effects of fentanyl are dose dependent. At low plasma concentrations, left ventricular blood flow and its baroreflex control is enhanced but, at higher concentrations, it is depressed.
Assuntos
Analgésicos Opioides/farmacologia , Anestésicos Intravenosos/farmacologia , Barorreflexo , Circulação Coronária/fisiologia , Fentanila/farmacologia , Animais , Pressão Sanguínea , Cães , Relação Dose-Resposta a Droga , Feminino , Infusões Intravenosas , Masculino , Resistência Vascular , VasodilataçãoRESUMO
1. The regional coronary circulation is under the control of local metabolic and myogenic factors, but is also influenced by autonomic systems, including sympathetic and parasympathetic nerves. 2. General anaesthetic agents influence not only local control through changes in metabolic demand, but also neural control through suppression of autonomic influence. 3. Anaesthetic agents have differing effects on reflex control systems, which are dependent on coronary territory and ventricular rate. 4. Effects of anaesthesia should be taken into account when interpreting results in anaesthetized models of coronary control.
Assuntos
Anestésicos Inalatórios/farmacologia , Circulação Coronária/fisiologia , Enflurano/farmacologia , Halotano/farmacologia , Isoflurano/farmacologia , Animais , Barorreflexo , Pressão Sanguínea/efeitos dos fármacos , Células Quimiorreceptoras , Cães , Frequência Cardíaca/efeitos dos fármacos , Receptores Colinérgicos/fisiologiaRESUMO
1. We have an incomplete understanding of integrative cardiopulmonary control during exercise and particularly during the postexercise period, when symptoms and signs of myocardial ischaemia and exercise-induced asthma not present during exercise may appear. 2. The hypothesis is advanced that baroreflex de-resetting during exercise recovery is normally associated with (i) a dominant sympathetic vasoconstrictor effect in the coronary circulation, which, when associated with obstructive coronary disease, may initiate a potentially positive-feedback cardiocardiac sympathetic reflex (variable myocardial ischaemia with symptoms and signs); and (ii) a dominant parasympathetic bronchoconstrictor effect in the presence of bronchovascular dilatation, which, when associated with raised mediator release in the bronchial wall, reinforces the tendency for airway obstruction (variable dyspnoea results). 3. There is a need for new techniques to examine hypotheses concerning autonomic control, during and after exercise, of the coronary and bronchial circulations and the dimensions of airways. Accordingly, a new ultrasonic instrument has been designed named an 'Airways Internal Diameter Assessment (AIDA) Sonomicrometer'. It combines pulsed Doppler flowmetry with transit-time sonomicrometry of airway circumference and single-crystal sonomicrometry of airway wall thickness. Initial evaluation suggests it is relatively easy to apply during thoracotomy in recovery animals. The component devices are linear and will measure target variables with excellent accuracy. 4. In anaesthetized sheep, intubated with controlled ventilation, intravenous isoproterenol causes large increases in bronchial blood flow, a fall in arterial pressure and a reduction in airway circumference. This may reflect the dominant action of reflex vagal activity over direct beta-adrenoceptor inhibition of bronchial smooth muscle, the reflex source being baroreflex secondary to the fall in arterial pressure. These findings provide insight into the integrative mechanisms underlying the paradoxical negative effects sometimes observed when beta-adrenoceptor agonists are used in asthma.
Assuntos
Brônquios/anatomia & histologia , Brônquios/irrigação sanguínea , Circulação Coronária/fisiologia , Exercício Físico/fisiologia , Animais , Asma/patologia , Asma/fisiopatologia , Humanos , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Fluxo Sanguíneo Regional/fisiologiaRESUMO
1. Baroreflex responses to changes in aortic pressure were measured simultaneously in three main coronary regions of awake dogs. 2. Pulsed Doppler flow probes were mounted at prior surgery on the right, circumflex and anterior descending coronary arteries; the animals were placed in complete heart block and the left ventricle was paced. After 2-4 weeks recovery, baroreflexes were evoked by inflating a balloon catheter placed in the mid-thoracic aorta via the femoral arteriotomy. Flow and pressure data were collected at rest, and during acute (8s) and steady-state (25s) baroreflex challenge. 3. Changing ventricular rate alone caused a fall in aortic pressure at low rates; however, over the range 60 to 180 b.p.m., circumflex and anterior descending coronary flow and conductance changed directly with ventricular rate, but right coronary flow and conductance remained unchanged. 4. Acute aortic pressure elevation increased flow at 8s in all beds at all rates. Conductance effects at 60 b.p.m. were negligible in all three beds, but rose at 100 and 180 b.p.m. in the right and circumflex beds. 5. Sustained aortic pressure elevation (25s) caused flow to return towards control in all beds ventricular rates, but in the right coronary at 60 b.p.m. flow fell below control. Conductance at this time was unchanged at all rates in the anterior descending bed, fell modestly in the circumflex, and decreased to below resting in the right coronary bed. 6. Baroreflex control of coronary flow and conductance thus varies between territories, and within territories, depending on ventricular rate. The right coronary bed appears to be regulated by a bidirectional, baroreflex-linked mechanism, which is functionally opposite in action to that found in most vascular beds.
Assuntos
Barorreflexo/fisiologia , Circulação Coronária/fisiologia , Animais , Aorta/fisiologia , Benzopiranos/farmacologia , Pressão Sanguínea/fisiologia , Cães , Etanolaminas/farmacologia , Feminino , Coração/fisiologia , Frequência Cardíaca/fisiologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Masculino , Nebivolol , Artéria Pulmonar/fisiologia , Vasodilatadores/farmacologia , Função Ventricular , Função Ventricular Direita/fisiologia , VigíliaRESUMO
1. The Darwin hypothesis that human and animal expressions of emotion are the product of evolution and are tied to patterns of autonomic activity specified to progress the emotion remains under challenge. 2. The sigh is a respiratory behaviour linked with emotional expression in animals and humans from birth to death. The aim of the present study was to explore Darwin's hypothesis with respect to tied autonomic activity underlying sigh-induced changes in the bronchial and coronary circulations. 3. Awake dogs were prepared using pulsed ultrasonic flow probes on the right bronchial artery, parent intercostal artery and brachial artery, or on the right, circumflex and anterior descending coronary arteries. Central venous (CVP) and arterial pressures (AP) were measured; heart rate and flow conductances were derived. Three spontaneous sighs were monitored before and during random blockade of individual and combinations of cholinoceptors, alpha-adrenoceptors and beta-adrenoceptors using methscopolamine, phentolamine and propranolol infusions. The data were subject to a 2(3) factorial analysis. 4. A spontaneous sigh is marked by a transient fall and return (< 3 s) in CVP of 18 mmHg (from 4 +/- 1 to -14 +/- 2 mmHg), usually followed by apnoea lasting 23 +/- 2 s. There is an immediate tachycardia and small rise in AP (phase 1) then, during apnoea, bradycardia and a fall in AP (phase 2). During phase 2, bronchial and coronary blood flow and conductance rise two- to three-fold over 30s (peak at 8s). The vascular changes are absent in parent intercostal and brachial beds.
Assuntos
Sistema Nervoso Autônomo , Comportamento Animal , Brônquios/irrigação sanguínea , Circulação Coronária/fisiologia , Mecânica Respiratória/fisiologia , Animais , Pressão Sanguínea , Pressão Venosa Central , Cães , Emoções , Frequência Cardíaca , Óxido Nítrico Sintase/antagonistas & inibidores , Receptores Adrenérgicos alfa/fisiologia , Receptores Adrenérgicos beta/fisiologia , Receptores Colinérgicos/fisiologiaRESUMO
The Kubicek thoracic cylinder model of impedance cardiography (IC) for measuring beat-by-beat stroke volume (SV) was evaluated in controlled studies using the electromagnetic flowmeter (FM) as the reference technique. Assuming the validity of the Kubicek equation for stroke volume calculation, IC stroke volume was found to be a linear function of EM values at any one haematocrit over a wide range of SV, but the slope of the relationship fell as haematocrit fell. Experiments using the same equation in dogs, in which blood resistivity in vivo (rho tau) was made the dependent variable, and the EM-derived value was used for stroke volume, showed that rho tau was almost constant over a wide range of haematocrits. These findings were supported by studies in man and rabbit where Fick and thermodilution-derived values were used for stroke volume. When these data were applied to normotensive and hypertensive human subjects with normal hearts and lungs in controlled studies at rest, during tilting, with drug therapy and on exercise, IC measured stroke volume and cardiac output with a variability at least as good as the 9-11% acceptable for clinical use. This conclusion applied to thoracic configurations of different sizes and shapes from adult man to the neonate. In chronic disease states, while assessments of relative changes are valuable, absolute data are questionable. Further research is required under these conditions, as it is also for other models of IC, which are based on different assumptions.