Role of total arterial compliance and peripheral resistance in the determination of systolic and diastolic aortic pressure.

The goal of the study was to define the major arterial parameters that determine aortic systolic (Ps) and diastolic (Pd) pressure in the dog. Measured aortic flows were used as input to the two-element windkessel model of the arterial system, with peripheral resistance calculated as mean pressure over mean flow and total arterial compliance calculated from the decay time in diastole. The windkessel model yielded an aortic pressure wave from which we obtained the predicted systolic (Ps, wk) and diastolic (Pd, wk) pressure. These predicted pressures were compared with the measured systolic and diastolic pressures. The measurements and calculations were carried out in 7 dogs in control conditions, during aortic occlusion at four locations (the trifurcation, between trifurcation and diaphragm, the diaphragm and the proximal descending thoracic aorta) and during occlusion of both carotid arteries. Under all conditions studied the predicted systolic and diastolic pressure matched the experimental ones very well: Ps, wk = (1.000 +/- 0.0055) Ps with r = 0.958 and Pd, wk = (1.024 +/- 0.0035) Pd with r = 0.995. Linear regression for pulse pressure gave PPwk = (0.99 +/- 0.016) PP (r = 0.911). We found the accuracy of prediction equally good under control conditions and in presence of aortic or carotid artery occlusions. Multiple regression between pulse pressure and arterial resistance and total arterial compliance yielded a poor regression constant (r2 = 0.19) suggesting that the two arterial parameters alone cannot explain pulse pressure and that flow is an important determinant as well. We conclude that, for a given ejection pattern (aortic flow), two arterial parameters, total arterial resistance and total arterial compliance are sufficient to accurately describe systolic and diastolic aortic pressure.     

Viscoelasticity modulates resonance in the terminal aortic circulation.

We used an inertance-viscoelastic windkessel model (IVW) to interpret aortic impedance patterns as seen in the terminal aortic circulation of the dog, and to explain evident oscillatory phenomena in flow measurements. This IVW model consists of an inertance, L, connected in series with a viscoelastic windkessel (VW) where the peripheral resistance, Rp, is connected in parallel with a Voigt cell (a resistor, Rd, in series with a capacitor, C) to account for viscoelasticity. Pressure and flow measurements were taken from the terminal aorta, just downstream of the origin of renal arteries, in three anaesthetised open-chest dogs, under a variety of haemodynamic conditions induced by administering a vasoconstrictor agent (methoxamine) and a vasodilator (sodium nitroprusside). Mean pressure ranged from 40 to 140 mm Hg. The resistance Rp was calculated as the ratio of mean pressure to mean flow. Parameters L, C and Rd were estimated by fitting measured to model predicted flow waves. We found that prominent oscillations observed in flow waves, from midsystole to diastole, are related to resonance that occurs at a frequency, f(o), where reactance of inertance of blood motion matches the reactance of arterial compliance. Estimates of f(o) increased from 2.4 to 10 Hz with increasing pressure and showed a correlation with values of static elastic moduli plotted against mean pressure of dogs' peripheral arteries previously reported by others. Viscous losses, Rd, of arterial wall motion limited the amplitude of resonance peak. We conclude that viscoelasticity, rather than pure elasticity, is a key issue to interpret terminal aortic impedance as it relates to resonance.     

Wave intensity analysis and the development of the reservoir–wave approach

The parameters of wave intensity analysis are calculated from incremental changes in pressure and velocity. While it is clear that forward- and backward-traveling waves induce incremental changes in pressure, not all incremental changes in pressure are due to waves; changes in pressure may also be due to changes in the volume of a compliant structure. When the left ventricular ejects blood rapidly into the aorta, aortic pressure increases, in part, because of the increase in aortic volume: aortic inflow is momentarily greater than aortic outflow. Therefore, to properly quantify the effects of forward or backward waves on arterial pressure and velocity (flow), the component of the incremental change in arterial pressure that is due only to this increase in arterial volume—and not, fundamentally, due to waves—first must be excluded. This component is the pressure generated by the filling and emptying of the reservoir, Otto Frank’s Windkessel.     

A sensitivity analysis of a personalized pulse wave propagation model for arteriovenous fistula surgery. Part A: Identification of most influential model parameters

Previously, a pulse wave propagation model was developed that has potential in supporting decision-making in arteriovenous fistula (AVF) surgery for hemodialysis. To adapt the wave propagation model to personalized conditions, patient-specific input parameters should be available. In clinics, the number of measurable input parameters is limited which results in sparse datasets. In addition, patient data are compromised with uncertainty. These uncertain and incomplete input datasets will result in model output uncertainties. By means of a sensitivity analysis the propagation of input uncertainties into output uncertainty can be studied which can give directions for input measurement improvement. In this study, a computational framework has been developed to perform such a sensitivity analysis with a variance-based method and Monte Carlo simulations. The framework was used to determine the influential parameters of our pulse wave propagation model applied to AVF surgery, with respect to parameter prioritization and parameter fixing. With this we were able to determine the model parameters that have the largest influence on the predicted mean brachial flow and systolic radial artery pressure after AVF surgery. Of all 73 parameters 51 could be fixed within their measurement uncertainty interval without significantly influencing the output, while 16 parameters importantly influence the output uncertainty. Measurement accuracy improvement should thus focus on these 16 influential parameters. The most rewarding are measurement improvements of the following parameters: the mean aortic flow, the aortic windkessel resistance, the parameters associated with the smallest arterial or venous diameters of the AVF in- and outflow tract and the radial artery windkessel compliance.     

Simple and accurate way for estimating total and segmental arterial compliance: The pulse pressure method

We derived and tested a new, simple, and accurate method to estimate the compliance of the entire arterial tree and parts thereof. The method requires the measurements of pressure and flow and is based on fitting the pulse pressure (systolic minus diastolic pressure) predicted by the two-element windkessel model to the measured pulse pressure. We show that the two-element windkessel model accurately describes the modulus of the input impedance at low harmonics (0–4th) of the heart rate so that the gross features of the arterial pressure wave, including pulse pressure, are accounted for. The method was tested using a distributed nonlinear model of the human systemic arterial tree. Pressure and flow were calculated in the ascending aorta, thoracic aorta, common carotid, and iliac artery. In a linear version of the systemic model the estimated compliance was within 1% of the compliance at the first three locations. In the iliac artery an error of 7% was found. In a nonlinear version, we compared the estimates of compliance with the average compliance over the cardiac cycle and the compliance at the mean working pressure. At the first three locations we found the estimated and “actual” compliance to be within 12% of each other. In the iliac artery the error was larger. We also investigated an increase and decrease in heart rate, a decrease in wall elasticity and exercise conditions. In all cases the estimated total arterial compliance was within 10% of mean compliance. Thus, the errors result mainly from the nonlinearity of the arterial system. Segmental compliance can be obtained by subtraction of compliance determined at two locations.     

Physiological interpretation of inductance and low-resistance terms in four-element windkessel models: assessment by generalized sensitivity function analysis

Physiological relevance of parameters of three arterial models, denominated W4P, W4S and IVW, was assessed by computation of parameter-related generalized sensitivity functions (GSFs), which allow the definition of heart-cycle time intervals where the information content of experimental data, useful for estimation of each model parameter, is concentrated. The W4P and W4S are derived from the three-element windkessel by connecting an inductance, L, in parallel or in series, respectively, with aortic characteristic impedance, R(c). In the IVW, L is placed in series at the input of a viscoelastic windkessel, incorporating a Voigt cell (a resistor, R(d), in series with a capacitor, C). Pressure and flow measured in the ascending aorta of five ferrets and five dogs were used to estimate all model parameters, by fitting to pressure. For each model structure, parameter-related GSFs were generated. Focusing on controversial L, R(c) and R(d) physical meaning, our GSF analysis yielded the conclusion that, in both the W4S and the IVW, but not in the W4P, the L-term is suitable to represent the inertial properties of blood motion. Moreover, the meaning of aortic characteristic impedance ascribed to R(c) is questionable; while R(d) is likely to account for viscous losses of arterial wall motion.     

Sustained forearm vasodilation in humans during mental stress is not neurogenically mediated

To evaluate the possible neurogenic influence on forearm vasodilation during mental stress (Stroop's colour word conflict test), haemodynamic and catecholamine responses were registered in 12 healthy men after axillary blockade. Forearm blood flow was measured with venous occlusion plethysmography and forearm vascular resistance was calculated, with intra-arterial blood pressure data. Blood samples for arterial and venous adrenaline and noradrenaline determinations were collected. Basal forearm blood flow increased markedly after axillary blockade, but the relative responses of forearm blood flow and forearm vascular resistance to mental stress were the same as in previously studied unblocked individuals (about +125% and about -40%, respectively). There was no increase in noradrenaline overflow from the forearm during mental stress in the nerve blocked arm. Heart rate and arterial systolic pressure responses as well as catecholamine responses to mental stress were augmented in the nerve blocked group, presumably due to a certain arousal caused by the experimental procedure. Increases in forearm blood flow and decreases in forearm vascular resistance during infusion of adrenaline were similar in the nerve blocked and in the control arm. In conclusion, vasodilation in the forearm during mental stress occurs in the absence of nervous control of the vascular bed. The reactivity of the vascular bed to an exogenous vasodilator (adrenaline) remains unchanged after axillary blockade.     

Computer identification of models for the arterial tree input impedance: Comparison between two new simple models and first experimental results

Two new simple models for the arterial tree input impedance are presented. The first is a 4-element windkessel model, obtained by paralleling the characteristic resistance of the 3-element windkessel model (Westerhof, 1968) with an inductance. The second is a tube model with a complex load, which is characterised by four parameters also. The parameters of these models are estimated from aortic root pressure and flow, which are either simulated by a complex numerical model of the peripheral arterial tree or measured in dogs. The parameter estimation is carried out using an automatic procedure based on the Powell optimisation algorithm. The importance of the evaluation of the achievable accuracy in the estimation of parameters and its relationship to model identifiability is emphasised.     

Photoplethysmography and ultrasonic-measurement-integrated simulation to clarify the relation between two-dimensional unsteady blood flow field and forward and backward waves in a carotid artery

Understanding the spatiotemporal change in hemodynamics is essential for the basic research of atherosclerosis. The objective of this study was to establish a methodology to clarify the relation between a two-dimensional (2D) unsteady blood flow field and forward and backward propagating waves in a carotid artery. This study utilized photoplethysmography (PPG) for blood pressure measurement and two-dimensional ultrasonic-measurement-integrated (2D-UMI) simulation for flow field analysis. The validity of the methodology was confirmed in an experiment for a carotid artery of a healthy volunteer. Synchronization between the pressure measurement and flow field analysis was achieved with an error of <10 ms. A 2D unsteady blood flow field in the carotid artery was characterized in relation to forward and backward waves. 2D-UMI simulation reproduced the flow field in which the wall shear stress takes a maximum at the time of the backward wave superiority in the systolic phase, whereas 2D ordinary simulation failed to reproduce this feature because of poor reproducibility of velocity distribution. In conclusion, the proposed methodology using PPG and 2D-UMI simulation was shown to be a potential tool to clarify the relation between 2D unsteady blood flow field and the forward and backward waves in a carotid artery.     

The central arterial pulses

Summary In order to examine the contours of central aortic and coronary flow pulses as well as those of pressure and flow pulses along the aorta, a hybrid model of the arterial system and the heart was designed. The digitally programmed model of the aortic system is an inhomogeneous transmission line with adjustable reflection factors at the end and at three intermediate locations. For the reflection factor at the entrance different values may be chosen for the ejection time and the diastole. The influence of a stenosis and of frequency-independent damping may be examined.The model of the ventricle is the analog solution of a system consisting of an internal isometric pressure source and an internal resistance and capacitance.The model of the coronary artery is the analog solution of a windkessel model of the system.The digital and analog models are interlocked by AD and DA converters. All programs can be executed in real time.The characteristic contour of the aortic flow is determined by the relation between the internal impedance of the ventricle and the magnitude of the characteristic impedance of the aorta. Furthermore, the influence of reflections within the arterial system is shown to be quite remarkable. Natural pressure pulses can be simulated by the model under normal and pathological conditions including aortic coarctation.The contour of the left coronary artery flow is determined on the one hand by the fraction of the ventricular pressure which acts as a counterpressure at the site of the peripheral resistance, and by the time constant of the coronary windkessel on the other hand.This work was supported by the Austrian research fund (Österreichischer Fonds zur Förderung der wissenschaftlichen Forschung).     

Non-invasive measurement of pulmonary arterial pressure: I. A haemodynamic modelling approach

In order to monitor pulmonary arterial pressure (P) by any non-invasive imaging technique, a haemodynamic model of blood flow kinetics and wall mechanics has been developed. It is a one-dimensional model of pulsatile flow in an elastic pulmonary arterial trunk, assuming that blood is an incompressible fluid and viscous effects are negligible. The equations are P(t)-Pd = rho c2lnS(t)/Sd-1/2pw-2(t) Pd = (Sd/Ss)1/2Pp where, at any time of the ejection phase of systole, P(t), S(t) and w(t) are the pulmonary arterial pressure, cross-sectional area of the pulmonary artery and blood velocity averaged on the cross section S, respectively, PP is the pulse pressure, the difference between the peak systolic pressure and the diastolic pressure Pd; rho is blood density, c pulse wave velocity, and Ss and Sd are maximum (systolic) and minimum (diastolic) values of the cross-sectional area S. Using these equations, P(t) can be calculated if the three parameters, i.e. c, S(t) and w(t) are measured. So far, it has been impossible to measure the pulse wave velocity c non-invasively. We have investigated the calculation of c from S(t) and w(t) using the equation of continuity in the absence and presence of reflected pressure waves. The hypotheses of the haemodynamic model are discussed.     

A comparative study of pulsatile arterial hemodynamics in rabbits and guinea pigs.

Pulsatile pressure and flow were measured in the ascending aorta and other arteries of 22 anesthetized rabbits and 16 anesthetized guinea pigs. Pressure/flow relationships were expressed as vascular impedance. Aortic flow waves were almost identical in the two species, but pressure waves were quite different. Reflected pressure waves returned earlier from the periphery in guinea pigs, augmenting pressure during late systole and resulting in relatively high external left ventricular work, an inappropriately larger difference between mean systolic and mean diastolic pressure and absence of any aortic diastolic pressure wave. Values of impedance modulus and phase were similar but differed in the frequency at which maxima and minima occurred. In both species, impedance curves were interpreted to indicate a functionally discrete reflecting site in the lower body whose position corresponded to the region of the aortic bifurcation. In addition, rabbits showed evidence of an upper body reflecting site approximately one-third as far distant from the heart. As in dogs, the arterial system in both species can be represented by an asymmetrical T-shaped model of realistic dimensions.     

Central cardiovascular dynamics of ducks.

Blood pressures and flows have been recorded from the heart and arterial arches of ducks in order to present a complete picture of central hemodynamics in an avian species. An attempt has also been made to define the characteristics of the avian central circulation in terms of either "windkessel", or wave-transmission models. Mean arterial pressure (143 plus or minus 2.2 mmHg) and cardiac output (219 plus or minus 7ml/kg per min) were high compared with those of similarly sized mammals, although therewas no evidence of elevated pulmonary pressures, perhaps because of the unusual structure of the avian lung. Only 25% of the total systemic flow was distributed by the aorta, the remainder supplying the wing, flight muscles, and head via the brachiocephalic arteries. The contours of central pressure and flow waves ressembled those recorded inmammal except that significant circulation impedance modulus graphs indicated that resistance to pulsatile flow fell sharply to a minimum of 1/30th the DC value at 9-12 Hz. Flow led pressure at frequencies below 9-12Hz and pressure led flow at higherfrequencies. Impedance modulus in the pulmonary circulation fell to one-half the DC value and remained constant over a wide range of frequencies with pressure and flow being in a phase at all frequencies. Aortic pulse wave velocity varied with position inthe aorta as did the pressure pulse profile: these factors obviously limit the applicability of a windkessel model to the avian circulation.     

Effect of systemic α1-adrenergic receptor blockade on central blood pressure response during exercise

The aortic pulse pressure (PP), which consists mainly of the incident wave and the reflected wave, has emerged as an important property of systemic blood vessels underlying the pathophysiology of cardiovascular disease. To determine the role of sympathetic nerve activity on the aortic PP response during dynamic exercise, we evaluated aortic hemodynamics during the right-leg knee-extension (40 and 60 % of maximal voluntary contraction) in six young adults with and without the systemic α1-adrenergic receptor blockade using prazosin (1 mg/20 kg body weight). The use of prazosin attenuated the exercise-induced increase in aortic PP (P < 0.05) but not in radial arterial PP. The amplitude of the reflected waves (via augmentation index) significantly decreased with the exercise and decreased more with the use of prazosin. These results suggest that during dynamic exercise the α1-adrenergic-mediated vasoconstrictor tone of the peripheral resistance vessels is manifestly involved in the magnitude of the reflected wave and the modulation of the aortic PP responses.     

Attenuation of forearm vasodilator responses to mental stress by regional beta-blockade,but not by atropine

Forearm blood flow during mental stress (Stroop's colour word conflict test) was studied in 18 healthy men before and during regional β-adrenoceptor blockade (propranolol 0.5 mg), muscarinic receptor blockade (atropine 0.2 mg) and combined blockade, and compared with results obtained in untreated controls. Forearm blood flow was measured with venous occlusion plethysmography, and forearm vascular resistance was calculated. Arterial and venous blood sampling was performed for determination of adrenaline and noradrenaline in plasma. Mental stress increased heart rate, systolic and diastolic blood pressures and forearm blood flow, and lowered the forearm vascular resistance, to the same degree as in our previously studied controls. Neither of the intra-arterially administered drugs had any discernible systemic effects. Beta-blockade increased forearm vascular resistance by 32% and decreased forearm blood flow by 21% compared with unblocked levels during mental stress, whereas forearm vasodilation was maintained throughout the stress test in the control group (P < 0.05). Intra-arterial atropine had no certain effects. Arterial adrenaline levels during mental stress were similar in the receptor-blocked and control groups. In conclusion, the sustained forearm vasodilation during mental stress appears to be partly mediated via β₂-adrenoceptor stimulation (i.e. by adrenaline), but we obtained no support for a cholinergic vasodilating mechanism.     

Systolic Hypertension Mechanisms: Effect of Global and Local Proximal Aorta Stiffening on Pulse Pressure

Decrease in arterial compliance leads to an increased pulse pressure, as explained by the Windkessel effect. Pressure waveform is the sum of a forward running and a backward running or reflected pressure wave. When the arterial system stiffens, as a result of aging or disease, both the forward and reflected waves are altered and contribute to a greater or lesser degree to the increase in aortic pulse pressure. Two mechanisms have been proposed in the literature to explain systolic hypertension upon arterial stiffening. The most popular one is based on the augmentation and earlier arrival of reflected waves. The second mechanism is based on the augmentation of the forward wave, as a result of an increase of the characteristic impedance of the proximal aorta. The aim of this study is to analyze the two aforementioned mechanisms using a 1-D model of the entire systemic arterial tree. A validated 1-D model of the systemic circulation, representative of a young healthy adult was used to simulate arterial pressure and flow under control conditions and in presence of arterial stiffening. To help elucidate the differences in the two mechanisms contributing to systolic hypertension, the arterial tree was stiffened either locally with compliance being reduced only in the region of the aortic arch, or globally, with a uniform decrease in compliance in all arterial segments. The pulse pressure increased by 58% when proximal aorta was stiffened and the compliance decreased by 43%. Same pulse pressure increase was achieved when compliance of the globally stiffened arterial tree decreased by 47%. In presence of local stiffening in the aortic arch, characteristic impedance increased to 0.10 mmHg s/mL vs. 0.034 mmHg s/mL in control and this led to a substantial increase (91%) in the amplitude of the forward wave, which attained 42 mmHg vs. 22 mmHg in control. Under global stiffening, the pulse pressure of the forward wave increased by 41% and the amplitude of the reflected wave by 83%. Reflected waves arrived earlier in systole, enhancing their contribution to systolic pressure. The effects of local vs. global loss of compliance of the arterial tree have been studied with the use of a 1-D model. Local stiffening in the proximal aorta increases systolic pressure mainly through the augmentation of the forward pressure wave, whereas global stiffening augments systolic pressure principally though the increase in wave reflections. The relative contribution of the two mechanisms depends on the topology of arterial stiffening and geometrical alterations taking place in aging or in disease.     

Visually evoked blood flow responses and interaction with dynamic cerebral autoregulation: Correction for blood pressure variation

Visually evoked flow responses recorded using transcranial Doppler ultrasonography are often quantified using a dynamic model of neurovascular coupling. The evoked flow response is seen as the model's response to a visual step input stimulus. However, the continuously active process of dynamic cerebral autoregulation (dCA) compensating cerebral blood flow for blood pressure fluctuations may induce changes of cerebral blood flow velocity (CBFV) as well. The effect of blood pressure variability on the flow response is evaluated by separately modeling the dCA-induced effects of beat-to-beat measured blood pressure related CBFV changes.Parameters of 71 subjects are estimated using an existing, well-known second order dynamic neurovascular coupling model proposed by Rosengarten et al. [1], and a new model extending the existing model with a CBFV contributing component as the output of a dCA model driven by blood pressure as input.Both models were evaluated for mean and systolic CBFV responses. The model-to-data fit errors of mean and systolic blood pressure for the new model were significantly lower compared to the existing model: mean: 0.8% ± 0.6 vs. 2.4% ± 2.8, p < 0.001; systolic: 1.5% ± 1.2 vs. 2.2% ± 2.6, p < 0.001. The confidence bounds of all estimated neurovascular coupling model parameters were significantly (p < 0.005) narrowed for the new model.In conclusion, blood pressure correction of visual evoked flow responses by including cerebral autoregulation in model fitting of averaged responses results in significantly lower fit errors and by that in more reliable model parameter estimation. Blood pressure correction is more effective when mean instead of systolic CBFV responses are used. Measurement and quantification of neurovascular coupling should include beat-to-beat blood pressure measurement.     

Identification of the three-element windkessel model incorporating a pressure-dependent compliance

A new one-step computational procedure is presented for estimating the parameters of the nonlinear three-element windkessel model of the arterial system incorporating a pressure-dependent compliance. The data required are pulsatile aortic pressure and flow. The basic assumptions are a steadystate periodic regime and a purely elastic compliant element. By stating two conditions, zero mean flow and zero mean power in the compliant element, peripheral and characteristic resistances are determined through simple closed form formulas as functions of mean values of the square of aortic pressure, the square of aortic flow, and the product of aortic pressure with aortic flow. The pressure across as well as the flow through the compliant element can be then obtained so allowing the calculation of volume variation and compliance as functions of pressure. The feasibility of this method is studied by applying it to both simulated and experimental data relative to different circulatory conditions and comparing the results with those obtained by an iterative parameter optimization algorithm and with the actual values when available. The conclusion is that the proposed method appears to be effective in identifying the three-element windkessel even in the case of nonlinear compliance.     

Hemodynamic and hormonal responses to a short-term low-intensity resistance exercise with the reduction of muscle blood flow

We investigated the hemodynamic and hormonal responses to a short-term low-intensity resistance exercise (STLIRE) with the reduction of muscle blood flow. Eleven untrained men performed bilateral leg extension exercise under the reduction of muscle blood flow of the proximal end of both legs pressure-applied by a specially designed belt (a banding pressure of 1.3 times higher than resting systolic blood pressure, 160–180 mmHg), named as Kaatsu. The intensity of STLIRE was 20% of one repetition maximum. The subjects performed 30 repetitions, and after a 20-seconds rest, they performed three sets again until exhaustion. The superficial femoral arterial blood flow and hemodynamic parameters were measured by using the ultrasound and impedance cardiography. Serum concentrations of growth hormone (GH), vascular endothelial growth factor (VEGF), noradrenaline (NE), insulin-like growth factor (IGF)-1, ghrelin, and lactate were also measured. Under the conditions with Kaatsu, the arterial flow was reduced to about 30% of the control. STLIRE with Kaatsu significantly increased GH (0.11±0.03 to 8.6±1.1 ng/ml, P < 0.01), IGF-1 (210±40 to 236±56 ng/ml, P < 0.01), and VEGF (41±13 to 103±38 pg/ml, P < 0.05). The increase in GH was related to neither NE nor lactate, but the increase in VEGF was related to that in lactate (r = 0.57, P < 0.05). Ghrelin did not change during the exercise. The maximal heart rate (HR) and blood pressure (BP) in STLIRE with Kaatsu were higher than that without Kaatsu. Stroke volume (SV) was lower due to the decrease of the venous return by Kaatsu, but, total peripheral resistance (TPR) did not change significantly. These results suggest that STLIRE with Kaatsu significantly stimulates the exercise-induced GH, IGF, and VEGF responses with the reduction of cardiac preload during exercise, which may become a unique method for rehabilitation in patients with cardiovascular diseases.     

Fibrinogen synthesis stimulation by prostaglandin E1 and some other vasodilators.

Three-hour constant-rate intravenous infusion into rabbits of 1-3 mg prostaglandin E1 (PGE1) per kilogram markedly increased plasma fibrinogen 24 h later. 131I-labeled fibrinogen and model studies showed increased synthesis underlay this. Similar PGE1 doses lowered systolic blood pressure. Maintaining systolic blood pressure by infusing noradrenaline with the PGE1 did not alter plasma fibrinogen response to PGE1; plasma fibrinogen was unchanged by noradrenaline infusion. Regression equations relating plasma fibrinogen increment to PGE1 dose, plasma fibrinogen increment to dose and systolic blood pressure change, and systolic blood pressure change to dose are given as well as the constants relating plasma fibrinogen increment to dose using the Michaelis-Menten equation. Infusions of cyclic AMP, dibutyryl cyclic AMP, and cyclic GMP intravenously led to only small plasma fibrinogen increases. Daily intravenous infusions of PGE1 led to loss of both plasma fibrinogen and systolic blood pressure responses in two animals; a third animal showed only loss of the former and a fourth only loss of the latter response. PGE1 slightly enhanced the small plasma fibrinogen increase following intravenous bradykinin. Approximate arterial blood PGE1 concentrations resulting from the intravenous infusion of 1 mg mg PGE1 kg-1 3 h-1 are calculated. These are compared with measured values.