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Biomedical subjects

W R Milnor

Publications and source records attributed to W R Milnor.

At least 19 recordsLinked to original sources
PubMed1988

Contributions of alpha 1- and alpha 2-adrenoceptors to contractile response in canine blood vessels.

Strips of canine saphenous vein, inferior vena cava, and femoral artery were studied isometrically in vitro to compare quantitatively the alpha 1- and postsynaptic alpha 2-adrenoceptor contributions to the contractile force generated by l-norepinephrine (NE). Effects mediated by each receptor type were measured independently by quantitative blockade of virtually all alpha 1-receptors with prazosin, or alpha 2-receptors with rauwolscine. Appropriate concentrations of the antagonists were calculated from dissociation constants previously determined by binding or competition with [3H]prazosin or [3H]rauwolscine in tissue homogenates. The contribution of alpha 1-adrenoceptors was larger than that of alpha 2-receptors in all vessels. The alpha 2-type was responsible for 38% of the maximum unblocked response to NE in saphenous vein, 32% in vena cava, and 28% in femoral artery. The occupation-response relationship for alpha 1-receptors was almost linear, without the marked upward convexity reported in some other vessels. alpha 2-Occupation-response curves were convex towards the occupation axis, with a relatively small response at low levels of occupation.

Animals↗
PubMed1988

Cholinergic receptors and contraction of smooth muscle in canine portal vein.

The properties of cholinergic receptors in homogenates of canine portal vein were determined with the radioligand [3H]quinuclinidyl benzilate [( 3H]QNB), and correlated with the functional responses of that vessel to carbamylcholine (CCh) in vitro. [3H]QNB bound to a single population of sites in the homogenates, with a dissociation constant (Kd) of 125 pM (+/- 19), and a total receptor capacity of 24.4 fmol/mg of protein, which corresponded to 224 (+/- 67.3) fmol/g wet weight of the initial vascular wall sample. Competition of CCh with [3H]QNB in eight experiments revealed two binding sites of different affinity, present in about equal numbers with Kd = 0.48 microM and 31 microM (in the absence of 5'-guanylylimidodiphosphate), and Kd = 1.5 microM and 42 microM (in the presence of 100 microM 5'-guanylylimidodiphosphate). Vascular strips in vitro contracted in response to CCh, with a threshold of approximately 0.3 microM, ED50 of 1.87 microM and maximum response of 344 g/cm2 (65% of the maximum response to l-norepinephrine). Strips precontracted by l-norepinephrine or by high potassium concentrations were slightly (4%) relaxed by 0.1 microM CCh, but further contracted by higher concentrations. The contractile responses were not altered by removal of the endothelium, and were blocked by atropine but not hexamethonium. The results demonstrate the existence in this vein of muscarinic cholinergic receptors that mediate smooth muscle contraction, and the receptor properties resemble those reported in cardiac muscle and brain.

Algorithms↗
PubMed1986

Limitations of Schild plots in a two-receptor system: alpha adrenoceptors of vascular smooth muscle.

The contractile response of vascular smooth muscle to l-norepinephrine is mediated almost exclusively by alpha-1 adrenoceptors in some blood vessels, and by a mixture of alpha-1 and postsynaptic alpha-2 receptors in others. To learn the sensitivity of the Schild plot as a test for the presence of more than one receptor type in such tissues, we constructed the plots to be expected from the dissociation constants of l-norepinephrine and prazosin for alpha-1 and alpha-2 adrenoceptors, using values determined by radioligand methods, and examining the effects of varying the proportions of the two types. The principles involved can be applied to other drugs and other two-receptor systems. Two occupation-response models were tested, one perfectly linear and the other convex toward the response axis. No receptor reserve was assumed, in accordance with experimental observations on vascular adrenoceptors. Schild plots over the range of antagonist concentrations customarily used did not deviate significantly from a straight line with a slope between 0.95 and 1.05 unless the second type amounted to more than 35% of the total receptors in the linear model, or more than 15% in the nonlinear model. Inasmuch as 95% CL of +/- 20% are often reported for experimental estimates of the slope, it may be difficult in practice to recognize from Schild plots the presence of a second receptor type unless it amounts to at least one-third of the total receptor pool.

Mathematics↗
PubMed1984

Regional differences in alpha 1-adrenoceptor numbers and responses in canine aorta.

The relationship between active force and alpha 1-adrenergic receptor binding in vascular smooth muscle was measured on strips of canine aorta. After measurement of the isometric force produced by l-phenylephrine and l-norepinephrine in vitro, [3H]prazosin was used to determine the affinity and numbers of alpha 1-receptors in homogenates prepared from the strips. Maximum active stress was 440 g/cm2 in the ascending, 317 in the descending thoracic, and 252 in the abdominal aorta. The total number of alpha 1-receptors per gram arterial wall averaged 576, 237, and 136 fmol/g, respectively. Affinity of the receptors was the same in all regions for prazosin (87 pM) and l-phenylephrine (9 microM). The relation between number of agonist-occupied receptors and response was similar in all regions but nonlinear; 50% of the maximum stress developed when only 2-11% of the receptors were occupied. Differences of contractile response within the vascular tree may thus arise from regional differences in the number of appropriate receptors present, rather than differences of affinity or occupation-response relationships.

Animals↗
PubMed1984

Relation between alpha adrenergic receptor occupation and contractile response: radioligand and physiologic studies in canine aorta.

The relation between occupation of alpha-1 adrenergic receptors by an agonist and the resulting force was examined in the canine aorta in vitro. Methods of preparing membrane preparations for radioligand studies were improved to maximize the yield of receptors from strips of aortic wall. [3H]Prazosin was a reliable ligand, binding to a single class of receptors with a dissociation constant of 97 (+/- 10) pM. Agonists and antagonists displaced [3H]prazosin in a manner consistent with binding to a single class of sites, with Hill coefficients near unity. The rank order of drug potencies determined by competition with [3H]prazosin was characteristic of alpha adrenergic receptors of the alpha-1 subtype. Conventional measurements of maximum isometric force and dose-response relations for l-phenylephrine in strips of ascending aorta in vitro were followed by radioligand studies on homogenates made from the same strips. The number of receptors was 38.8 (+/- 2.9) fmol/mg of protein in the homogenate, corresponding to 580 (+/- 41) fmol/g of aortic wall, a value at least twice as high as any reported previously. Maximum active stress was 440 (+/- 23) g/cm2. Concentration-response curves to l-phenylephrine were relatively shallow, with a Hill coefficient of 0.63 and an ED50 of 1.1 (+/- 0.24) microM. The curve relating receptor occupation to response (force development) in the ascending aorta was consequently nonlinear; 50% of the maximum response occurred when only 10% of the receptors were occupied. Occupation of virtually all receptors (greater than or equal to 97%) was required to produce maximum response, suggesting an absence of "spare" receptors.

Animals↗
PubMed1981

Role of aortic input impedance in the decreased cardiovascular response to exercise with aging in dogs.

The diminished cardiac output response to exercise with advancing age may be attributable to intrinsic inability of the old ventricle to respond appropriately and/or to an additional loading imposed upon the ventricle by the aged vascular system. The steady (resistance) and pulsatile (characteristic impedance) load components together comprise the vascular load faced by the ejecting ventricle. To study the effect of exercise on both vascular components of load, the aortic input impedance was measured in chronically instrumented young and old beagle dogs during graded treadmill exercise before and after beta blockade. Ascending aortic flow was measured by a cuff electromagnetic flow probe, and pressure was measured by a high-fidelity semiconductor transducer. At low levels of exercise the old animals demonstrated a striking 20% increase in characteristic impedance and a 28% decrease in peripheral resistance with no increase in stroke volume. This vascular loading and limitation in stroke volume persisted across the higher exercise levels. In contrast, the young group demonstrated no increase in characteristic impedence, a progressive decrease in peripheral resistance, and a progressive increase in stroke volume across the same exercise levels. These age differences in vascular response and ventricular output were abolished by beta blockade. The groups did not demonstrate a difference in heart rate response, but the young had a greater increase in external left ventricular power than the old across exercise. These data demonstrated a profound difference in the response of young and old vasculature to exercise. At low and intermediate exercise levels the pulsatile vascular load appeared to be a major factor in the limitation of stroke volume in old dogs. At high levels of exercise, the limited exercise response in the old dog may be caused in part by a diminished inotropic responsiveness as well as by the vascular loading.

Aging↗
PubMed1979

Aortic wavelength as a determinant of the relation between heart rate and body size in mammals.

Measurements of aortic input impedance in the rat, dog, and man suggest a new hypothesis to explain the inverse correlation between rate and body size: that pulse wavelength and arterial length are matched in a way that minimizes cardiac work. The optimal rate is fast enough to avoid the high impedances produced by reflections at relatively low frequencies, yet slow enough to permit orderly excitation and recovery of the myocardium.

Animals↗
PubMed1978

The relation between arterial viscoelasticity and wave propagation in the canine femoral artery in vivo.

The influence of arterial dimensions and viscoelasticity on pulse wave propagation has been expressed in many theoretical models of blood flow in arteries, but few experimental tests of these theories in vivo have been reported. The measurements required for such tests include not only the arterial viscoelasticity, diameter, and wall thickness, but also the true propagation coefficients and impedances, for comparison with the values "predicted" by solution of the model equations. We made such measurements in 16 experiments on the femoral artery in nine anesthetized dogs. A two-point pressure and flow technique was used to measure wave propagation, and an ultrasonic micrometer was used to measure vessel diameter as a function of time and pressure. Measured attenuation constants ranged from 0.010 at 1.3 Hz to 0.075 at 12.7 Hz, and were more than twice as large as those predicted by two representative linear models. True phase velocity, which increased from 6.71 m/sec at 1.3 Hz to 10.54 m/sec at 12.7 Hz, agreed closely with the values computed by the Cox model but were lower than those given by the Jager model. The resistive, but not the reactive, component of longitudinal impedance was significantly greater than predicted by the models at all frequencies. The experiments do not identify the source of these discrepancies. The use of linear models to calculate pulsatile blood flow from pressure gradients in relatively small vessels, or to calculate attenuation and characteristic impedance from arterial viscoelasticity in vessels of any size, produces significant errors.

Animals↗
PubMed1977

Input impedance of the systemic circulation in man.

To determine the systemic input impedance, pulsatile pressure and flow were measured in the ascending aorta in 16 human subjects who were undergoing diagnostic cardiac catheterization. Blood flow was measured with a catheter-tip electromagnetic velocity meter, and pressure with an external transducer connected with the fluid-filled lumen of the catheter. Five subjects were found to have no evidence of cardiovascular disease (group A, mean age 32 +/- 2 years, mean aortic pressure 97 +/- 4 mm Hg). Seven had clinical and angiographic signs of coronary arterial disease, and mean pressures less than 100 mm Hg (group B, mean age 48 +/- 2 years). Four subjects had signs of coronary disease and mean pressures greater than 100 mm Hg (group C, mean age 48 +/- 3 years). The frequency spectra of impedance were qualitatively similar in all three groups and resembled those previously observed in the canine aorta. Characteristic impedance was lower in the normal subjects (group A, average 53 dyn sec cm-5) than in the subjects with coronary artery disease (groups B and C, average 129 dyn sec cm-5). Among the subjects with coronary disease, characteristic impedance was higher in the hypertensive subjects (group C, average 202 dyn sec cm-5) than in those with lower mean pressures (group B, average 95 dyn sec cm-5). External left ventricular work per unit time (hydraulic power) averaged 1715 milliwatts (mW) in group A, 1120 mW in group B, and 2372 mW in group C. Cardiac outputs were within normal limits in all subjects, but tended to be lower in group B than in group C. These results suggest that the subjects of group C were better able to meet the increased energy demands imposed by an abnormally high aortic input impedance. Further investigation is needed to learn whether the high impedances in subjects with coronary disease represent an increase with age and transmural pressure alone, or whether some additional factor is involved. The data on relatively normal subjects permit a tentative definition of the normal limits for aortic input impedance in man: 26-80 dyn sec cm-5.

Adult↗
PubMed1975

A new method of measuring propagation coefficients and characteristic impedance in blood vessels.

True propagation coefficients of pulse wave harmonics in an artery can be determined in vivo by measuring pulsatile blood pressure and flow at each of two points along the length of the vessel. These coefficients, which are complex numbers that describe the attenuation and the phase shift imposed on a traveling wave, are independent of the reflected waves in the circulation and thus provide information about the viscoelastic state and other properties of an artery. The equations involved are implicit in standard transmission-line theory, but they have not previously been applied in this particular way to blood vessels. The femoral artery, exposed in situ, was studied in 11 anesthetized dogs. At 1.5 Hz, true attenuation constants averaged 0.0151 nepers/cm, and true phase constants averaged 0.0155 radians/cm. As frequency increased, the apparent phase velocity of flow, in contrast, was relatively low at the first harmonic and rose as frequency increased. True phase velocities lay between the apparent pressure and flow values. Characteristic impedance at 1.5 Hz had an average modulus of 1.76 times 10-4 dyne sec/cm5 and a phase of minus 0.31 radians. The modulus diminished as frequency increased, and the phase became less negative. These results show that true phase constants and characteristic impedances determined by this method are consistent with data reported by others and provide information not previously available about flow wave propagation.

Analog-Digital Conversion↗