Furchgott

Three years later Robert F Furchgott discov ered that the relaxing of smooth muscles such as blood vessel walls was stimulated by an unknown substance produced in the lining of the blood vessels (the endothelium) He called this substance the endothelium-dependent relaxing factor or EDRF and in 1986 showed that EDRF was NO Louis J Ignarro reached the same conclusion at about the same time Further support was provided by Salvador Moncada who showed that endothelial cells did in deed produce NO and that the l arginine to l citrulline conversion was responsible... 

It can be seen that efficacy in this model is both an agonist and a tissue-specific term. Furchgott [9] separated the tissue... 

Furchgott, R. F. (1972). The classification of adrenoreceptors (adrenergic receptors) An evaluation from the standpoint of receptor theory. In Handbook of experimental pharmacology, catecholamines, Vol. 33, edited by H. Blaschko and E. Muscholl, pp. 283—335. Springer-Verlag, Berlin. 

The Furchgott method can be effectively utilized by fitting the dose-response curves themselves to the operational model with fitted values of x (before and after alkylation) and a constant KA value. When fitting experimental data, the slopes of the dose-response curves may not be unity. This is a relevant factor in the operational model since the stimulus-transduction function of cells is an integral part of the modeling of responses. Under these circumstances, the data is fit to (see Section 3.13.3 and Equation 3.49)... 

The affinity of partial agonists can be made in functional experiments by the method of Barlow, Scott, and Stephenson [9] and for full agonists by the method of Furchgott [11],... 

Furchgott, R. F. (1966). The use of P-haloalkylamines in the differentiation of receptors and in the determination of dissociation constants of receptor-agonist complexes. In Advances in drug research, edited by N. J. Harper, A. B. Simmonds, Vol. 3, pp. 21-55. Academic Press, London, New York. 

Method of Furchgott for the Measurement of the Affinity of a Full Agonist... 

FIGURE 12.6 Measurement of full agonist affinity by the method of Furchgott. (a) Dose-response curve to oxotremorine obtained before (filled circles) and after (open circles) partial alkylation of the receptor population with controlled alkylation with phenoxybenzamine (10 jiM for 12 minutes followed by 60 minutes of wash). Real data for the curve after alkylation was compared to calculated concentrations from the fit control curve (see arrows), (b) Double reciprocal of equiactive concentrations of oxotremorine before (ordinates) and after (abscissae) alkylation according to Equation 5.12. The slope is linear with a slope of 609 and an intercept of 7.4 x 107 M-1. 

Furchgott method, 92, 95, 97-98 G-protein coupling effects on, 76 partial, 89-91, 97, 124, 260-261 potency and, 80f Agonist occupancy, 115 Aikake s information criteria, 243, 243f Alleles, 6... 

Free drug concentration description of, 36-37 measurement of, in receptor compartment, 39 Frovatriptan, 163f Full agonism, 200-202 Full agonists affinity of, 261 description of, 27—30 dose-response curves for, 90, 200-202 Furchgott method for affinity measurements, 261 potency ratios for, 202—204, 219—220 Functional assays... 

Furchgott and Zawadzki [1] first discovered that endothelial cells release a substance(s) responsible for the relaxation of vascular smooth muscle by acetylcholine this substance was named endothelium-derived relaxing factor (EDRF). This epoch-making discovery answers the question raised for nearly one hundred years by pharmacologists about why vascular smooth muscle is relaxed by acetylcholine, which however elicits contraction of the other smooth muscles. Because of its instability, the true chemical nature of EDRF was not easily identified. Several years later, several research groups independently found that the biological activities and biochemical properties of EDRF were identical... 

Furchgott RF, Zawadzki JV (1980) Obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature (Lond) 288 373-376... 

When Murad, Furchgott, and Ignarro received their Nobel Prizes, however, scientists still did not know exactly how nitroglycerin was broken down by the body and converted into nitric oxide. In 2002, researchers at Duke University in North Carolina found an enzyme in mitochondria, the cell s powerhouse, that they believe is responsible for this process. This discovery also explained a phenomenon that doctors had long observed—over time, nitroglycerin stops working and no longer relieves the patient s chest pain. 

R. F. Furchgott later suggested a refinement of Stephenson s concept. Recognizing that the response of a tissue to an agonist is influenced by the number of receptors as well as by the ability of the agonist to activate them, he wrote ... 

Method 3. This method is more general than the other two in the sense that it is also applicable to full agonists, at least in principle. Suppose that we had some reliable means of determining the dissociation equilibrium constant for the combination of the agonist with its receptors. One procedure that has been used in the past is Furchgott s irreversible antag-... 

This term has increasingly come to be employed (as here) in a rather different sense from that introduced by R. F. Furchgott (Section 1.4.2). With this newer usage, intrinsic efficacy indicates the maximum receptor activation (often expressed as the fraction of receptors in the active state) that can be achieved by an agonist acting through a mechanism that can be formulated and studied at the molecular level, as in the present example. The intention of this redefinition is to focus on the receptor itself and its immediate transduction mechanism (e.g., G-protein activation), rather than on the cellular events that follow. 

FIGURE 1.21 Schild plots for the antagonism by propranolol of the actions of noradrenaline (open circles) and isoprenaline (closed circles) on the contractile force of the isolated atrium of the guinea pig. The x shows the value obtained with noradrenaline as agonist but in the presence of cocaine (20 pM). (From Furchgott, R. F., Handbook of Experimental Pharmacology, Vol. 23, 1972, pp. 283-335 based on the results of Blinks, J. R Ann. N.Y.Acad. Sci., 139, 673-685, 1967.)... 

FIGURE 1.23 Effect of a 10-min exposure to two concentrations of a phenoxybenzamine-like compound, dibenamine (DB), on the contractile response of a strip of rabbit aorta to adrenaline (epinephrine). (From Furchgott, R. F., Adv. Drug Res., 3, 21-55, 1966.)... 

Classical approach, following Furchgott, and based on the early view that all the receptors occupied by an agonist are activated First, we recall one of our two earlier definitions of pAR, the proportion of binding sites occupied by A ... 

Furchgott then went on to assume that the same (submaximal) response of the tissue before and after the application of antagonist corresponds to the same receptor occupancy by the agonist. Hence, he equated ... 

Applying the analysis in the left-hand column to the results of Figure 1.24, Furchgott estimated Ka to be 10 pM for the combination of histamine with its receptors. He used this figure, and the values of q obtained as just described, to construct the dashed curves in the illustration. These lie close to the experimental points, which is certainly in keeping with the predictions of the approach taken. Just as certainly, this does not provide decisive proof that either the experimental or the theoretical suppositions that underlie it are correct. An important assumption, and one that is difficult to test, is that the irreversible antagonist has had no action other than to inactivate the receptors under study. Were it, for example, to have interfered with one or more of the steps that link receptor activation to the observed response, the approach would be invalid. Furchgott later showed that this was not a complication under the conditions he used. 

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