Biography:

In the past Rachel Rubinstein has collaborated on articles with Moshe Rehavi and Zipora Pittel. One of their most recent publications is Affinity of nortriptyline to muscarinic receptors in the bladder and ileum of man and guinea-pig. Which was published in journal European Journal of Pharmacology.

More information about Rachel Rubinstein research including statistics on their citations can be found on their Copernicus Academic profile page.

Rachel Rubinstein's Articles: (4)

Affinity of nortriptyline to muscarinic receptors in the bladder and ileum of man and guinea-pig

AbstractThe antagonism by nortriptyline of carbachol- or urecholine-induced contractions was studied in strips of ileum and bladder derived from man and guinea-pig. Analyses of the results by the dose ratio method (Schild plots) showed significant differences in the affinities of the relevant muscarinic receptors to the antagonist: The Ki values in μM were as follows: Human ileum, 0.938; human bladder, 0.298; guinea-pig ileum, 0.159; guinea-pig bladder, 0.333 and 0.453. In man, the higher affinity of the drug to the receptors in the bladder than to those in the ileum may be of consequence in its therapeutic application as an antienuretic agent.

Antihistaminic properties of AF-14, an experimental quinuclidine derivative: Discrimination between two histaminergic sites in both guinea-pig ileum and bladder

AF-14 (1-aza-4-phenyltricyclo[6.2.2.02,7]dodecan-5-one), a selective antimuscarinic agent, was shown to block the histamine-induced contractile response in Krebs solution in guinea-pig ileum and bladder. Careful linear regression analyses of the concentration-response relationship revealed that AF-14 antagonism consisted of two sequential and distinct phases, corresponding to an early phase and a late phase of the contractile response to histamine. In the late phase, the action of AF-14 was consistent with competitive antagonism, its pA2 (95% confidence limits) being 5.80–6.06 (ileum) and 5.66–5.80 (bladder). In the early phase, AF-14 almost completely blocked the contractile response at a concentration of 100–300 nM, which was much less than required to block the late phase or cholinergic contractions of the ileum or bladder. It is concluded that AF-14 discriminates between two histamine-sensitive sites that mediate muscle contraction in each of the two organs.

A comparative study of the affinities of some tricyclic antidepressants for the muscarinic cholinergic receptor in human and guinea-pig bladder, ileum and brain in relation to differential drug potency

AbstractFollowing a report that nortriptyline was found useful in the control of enuresis in adults, presumably as an anticholinergic, its likely mechanism of action and apparent bladder specificity have now been investigated in vitro. The ratios of anticholinergic potencies (reciprocal of dissociation contants, Ki) for four different tricyclic antidepressants, derived from competitive binding assays with (−)[3H]QNB in tissue homogenates, in the order (human) detrusor muscle / ileal longitudinal muscle / caudate, are as follows: Nortriptyline, 5/4/7; desipramine, 2/1/5/; clomipramine, 4/3/27; amitriptyline, 25/14/56. The apparent selective effect of nortriptyline on the bladder cannot be ascribed to its higher affinity to bladder receptors. Still, this drug is the least discriminatory of the four. Hence, at a given concentration, it is expected to affect tissue embodying a low density receptor pool sooner than tissue having a large receptor reserve. The ratios of the densities of (−)[3H]QNB binding sites in the order detrusor muscle / ileal muscle / cortex is 1/3/5, supporting the present contention. In the guinea-pig, the ratios of the anticholinergic potency in the order bladder / proximal ileum / distal ileum / cortex are as follows: Nortriptyline, 25/5/6/33; desipramine, 8/2/2/14; amitriptyline, 100/14/20/100; clomipramine, 17/3/5/33. Also, the ratios of the densities of binding sites are 1/6/5/2. Hence, data derived from assays in the guinea-pig are not representative of those derived from human tissue

Inhibition of choline efflux results in enhanced acetylcholine synthesis and release in the guinea-pig corticocerebral synaptosomes

AbstractSynthesis and release of [3H]acetylcholine ([3H]ACh) were measured in synaptosomes from the guinea pig cerebral cortex after preloading with [3H]choline ([3H]Ch). We demonstrate here that inhibition of choline (Ch) efflux results in an increase in acetylcholine (ACh) synthesis and release. Our findings are as follows: (1) inhibition of [3H]Ch efflux by hemicholinium-3 (HC-3) (100 μM), increased the levels of both the released (116% of control) and the residing (115% of control) [3H]ACh. (2) The muscarinic agonist, McN-A-343 (100 μM), which was previously shown to inhibit Ch efflux, also increased the released (121% of control) and the residing (109% of control) [3H]ACh. (3) Omission of Na+ ions (which are required for Ch transport) from the incubation medium had similar effects to those observed with McN-A-343 and HC-3. These results suggest inverse relationships between Ch efflux on one hand, and ACh synthesis and release on the other hand. (4) Depolarization with 50 mM K+, or with the K+ channel blocker, 4-aminopyridine (100 μM), also increased the total level of [3H]ACh (113 and 107% of nondepolarized synaptosomes, respectively). However, whereas conditions that inhibit Ch transport such as HC-3, McN-A-343 and “no sodium” increased both the residing and the released [3H]ACh depolarization with high K+ or 4-aminopyridine reduced the residing (79 and 87% of control, respectively) and increased only the released [3H]ACh (182 and 148% of control, respectively). Taken as a whole, our data suggest that inhibition of Ch efflux reduces the loss of Ch from the nerve terminal and that the accumulating intrasynaptosomal Ch is incorporated into ACh, which is then released under the control of muscarinic presynaptic receptors.

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