Some Quantitative Uses of Drug Antagonists

Arunlakshana, O; Schild, H. O.

doi:10.1111/j.1476-5381.1997.tb06793.x

Cited by 208 publications

(224 citation statements)

References 25 publications

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“…The pA 2 value for antagonists, as defined by Arunlakshana and Schild,14 was obtained from linear regression of mean log values (Dr−1) against the negative log of the antagonist concentration. Computer analysis was performed according to Tallarida and Murray 15…”

Section: Methodsmentioning

confidence: 99%

Functional assessment of beta adrenoceptor subtypes in human colonic circular and longitudinal (taenia coli) smooth muscle

Manara¹,

Croci²,

Aureggi³

et al. 2000

Gut

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Background and aims-The subtype and species related heterogeneity of adrenoceptors prompted a functional reappraisal of these molecular targets of motility inhibition in the human colon. -6 mol/l) had no eVect on taenia relaxation by SR 58611A and rendered isoprenaline and terbutaline virtually inactive on circular strips, although not on taenia, which was relaxed at higher than control concentrations and maximally by isoprenaline. Propranolol, a 1 , 2 non-selective antagonist, at high concentrations (10 -5 mol/l) prevented taenia relaxation by CGP 12177 and SR 58611A; its quantitative antagonism of isoprenaline (in common with that of CGP 12177 used as an antagonist) was competitive in circular strips but not on taenia. Conclusions-1 , 2 , and 3 adrenoceptors are functionally detectable in the human colon; agonist stimulation of any one type relaxed taenia but only isoprenaline was fully eVective at the 3 subtype. (Gut 2000;47:337-342) Methods-Relaxation

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Section: Methodsmentioning

confidence: 99%

Functional assessment of beta adrenoceptor subtypes in human colonic circular and longitudinal (taenia coli) smooth muscle

Manara¹,

Croci²,

Aureggi³

et al. 2000

Gut

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“…The pA 2 for antagonists, as defined by Arunlakshana and Schild, 34 was obtained from linear regression of the mean of the log (DR-1) against the negative log of the antagonist concentration. The negative logarithm of the dissociation constant (pK B ) was calculated using the Cheng-Prusoff equation.…”

Section: Calculations and Statistical Analysismentioning

confidence: 99%

Neural contractions in colonic strips from patients with diverticular disease: role of endocannabinoids and substance P

Guagnini

Valenti²,

Mukenge³

et al. 2006

Gut

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Background and aims: Diverticulosis is a common disease of not completely defined pathogenesis. Motor abnormalities of the intestinal wall have been frequently described but very little is known about their mechanisms. We investigated in vitro the neural response of colonic longitudinal muscle strips from patients undergoing surgery for complicated diverticular disease (diverticulitis). Methods: The neural contractile response to electrical field stimulation of longitudinal muscle strips from the colon of patients undergoing surgery for colonic cancer or diverticulitis was challenged by different receptor agonists and antagonists. Results: Contractions of colonic strips from healthy controls and diverticulitis specimens were abolished by atropine. The b adrenergic agonist (2) isoprenaline and the tachykinin NK 1 receptor antagonist SR140333 had similar potency in reducing the electrical twitch response in controls and diseased tissues, while the cannabinoid receptor agonist (+)WIN 55,212-2 was 100 times more potent in inhibiting contractions in controls (IC50 42 nmol/l) than in diverticulitis strips. SR141716, a selective antagonist of the cannabinoid CB 1 receptor, had no intrinsic activity in control preparations but potentiated the neural twitch in diseased tissues by up to 196% in a concentration dependent manner. SR141716 inhibited (+)WIN 55,212-2 induced relaxation in control strips but had no efficacy on (+)WIN 55,212-2 responses in strips from diverticular disease patients. Colonic levels of the endogenous ligand of cannabinoid and vanilloid TRPV1 receptors anandamide were more than twice those of control tissues (54 v 27 pmol/g tissue). The axonal conduction blocker tetrodotoxin had opposite effects in the two preparations, completely inhibiting the contractions of control strips but potentiating those in diverticular preparations, an effect selectively inhibited by SR140333. Conclusions: Neural control of colon motility is profoundly altered in patients with diverticulitis. Their raised levels of anandamide, apparent desensitisation of the presynaptic neural cannabinoid CB 1 receptor, and the SR141716 induced intrinsic response, suggest that endocannabinoids may be involved in the pathophysiology of complications of colonic diverticular disease.

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“…Concentration response curves were generated for each insert and an EC50 determined for each insert by fitting the data with a logistic equation using Origin (Originlab). These data were then used to calculate "dose ratio – 1" values for use in a Schild plot [24] as discussed below.…”

Section: Methodsmentioning

confidence: 99%

“…These values were then used to estimate the shift of the concentration-response relationships for ACh, by the various antagonists used. The shifts in these relationships were plotted as log (dose ratio-1) versus -log (inhibitor concentration) according to the method of Arunlakshana and Schild [24]. This should yield a plot with a slope of 1 and an X-intercept equal to pA 2 , an estimate of the antagonist affinity for the particular receptor being activated.…”

Section: Methodsmentioning

confidence: 99%

Effects of first and second generation antihistamines on muscarinic induced mucus gland cell ion transport

Liu

Farley

2005

BMC Pharmacol

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BackgroundThe first generation antihistamines, such as diphenhydramine, are fairly potent muscarinic antagonists in addition to being H1 selective antihistamines. The antimuscarinic action is often not desirable since it is in part responsible for the drying of secretions in the airways and the sedative effect. We therefore examined a number of antihistamines for antimuscarinic effects on ion transport by mucus gland cells isolated from the airways of swine. Enzymatically isolated airway mucus gland cells were purified utilizing density gradients and grown in culture on porous inserts (Millicell HA™) at an air interface. Cells grown in this manner maintain phenotype and polarity. Transport of ions, as short-circuit current measured under voltage-clamp, was measured in response to acetylcholine (ACh) or histamine applied to the serosal side of the gland cell layers. Concentration-response relationships for ACh or histamine were generated in the presence and absence of various drugs. The potencies against muscarinic receptor activation were estimated using the dose-ratio method of Schild.ResultsThree known muscarinic antagonists were used to validate the system. Atropine had a pA2 of 9.4 ± 0.1 (n = 9). 4-DAMP and methoctramine had pA2 values of 8.6 ± 0.1 and 5.6 ± 0.1, respectively (n = 12, 11) all consistent with inhibition of an M3 subtype muscarinic receptor. The rank order of potency of the antihistamines against the inhibition of M3 receptors was desloratadine = diphenhydramine > hydroxyzine (pA2; 6.4, 6.2, 4.8, respectively). pA2 values for fexofenadine, loratadine and cetirizine were not determined since they had no effect on the cholinergic response at the highest drug concentrations tested (10, 10 and 100 μM, respectively). The pA2 values for the antihistamines against the histamine response could not be calculated, but the estimates of the rank order of potency were estimated to be desloratadine> cetirizine ≈ hydroxyzine > fexofenadine > loratadine > diphenhydramine.ConclusionThe rank order of selectivity for histamine receptors over muscarinic receptors was estimated to be cetirizine ≈ fexofenadine > loratadine > desloratadine ≥ hydroxyzine ≥ diphenhydramine.

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Some Quantitative Uses of Drug Antagonists

Cited by 208 publications

References 25 publications

Functional assessment of beta adrenoceptor subtypes in human colonic circular and longitudinal (taenia coli) smooth muscle

Functional assessment of beta adrenoceptor subtypes in human colonic circular and longitudinal (taenia coli) smooth muscle

Neural contractions in colonic strips from patients with diverticular disease: role of endocannabinoids and substance P

Effects of first and second generation antihistamines on muscarinic induced mucus gland cell ion transport

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