Guinea pigs inhibitors

FIGURE 2.19 Potentiation and modulation of response through control of cellular processes, (a) Potentiation of inotropic response to isoproterenol in guinea pig papillary muscle by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX). Ordinates percent of maximal response to isoproterenol. Abscissa percent receptor occupancy by isoproterenol (log scale). Responses shown in absence (open circles) and presence (filled circles) of IBMX. Data redrawn from [7], (b) Effect of reduction in calcium ion concentration on carbachol contraction of guinea pig ileum. Responses in the presence of 2.5 mM (filled circles) and l.5mM (open circles) calcium ion in physiological media bathing the tissue. Data redrawn from [8],... 

FIGURE 9.13 Cardiovascular responses to the PDE inhibitor fenoximone in different contexts, (a) In vivo effects of fenoximone in anesthetized dogs. Ordinates reflect positive inotropy. Redrawn from [47]. (b) In vitro effects of fenoximone in guinea pig untreated isolated left atria (filled circles) and atria in the presence of sub threshold P-adrenoceptor stimulation with prenalterol (open circles). Redrawn from [48]. 

Summation The overall response is the arithmetic sum of the contribution brought by each receptor (e.g., NKX and NK2). Capsaicin-induced contraction of rat isolated urinary bladder, electrical field stimulation (EFS)-induced nonadrenergic, noncholinergic contraction of the isolated guinea pig bronchus or renal pelvis when SP metabolism is blocked by peptidase inhibitors are all examples of summation. Both NK and NK2r antagonists are required to abolish such kind of response, but each antagonist substantially reduces the response... 

Yeadon, M., Eve, D. and Payne, A.N. (1993c). Induction of airway hyperresponsiveness increases the potency of BW B70C, a 5-lipoxygenase inhibitor, to prevent allergic bron-choconstriction in sensitised guinea-pigs. Br. J. Pharmacol. 108, 186P. 

Anticonvulsant action of the nucleoside transport inhibitor, soluflazine, on synaptic and non-synaptic epileptogenesis in the guinea-pig hippocampus. Epilepsy Res. 2 (2), 65-71. 

Halicholactone (25) was reported to exhibit weak inhibitory activity against the 5-lipoxygenase from guinea pig polymorphonuclear leukocytes (IC50 = 630 pM) [38], A subsequent report detailing the three-dimensional structure of the co3 unsaturated neohalicholactone (26) described it as a potent lipoxygenase inhibitor , however, no additional experimental data were provided [39],... 

Unlike the previously discussed compounds, which inhibit MTP in both liver and intestine, an intestine-selective orally-active MTP inhibitor JTT-130 (structure not yet disclosed) has been reported to decrease plasma cholesterol and TG in guinea pigs with no hepatic lipid accumulation [16]. Although further studies in human are needed, inhibitors that selectively target intestinal MTP might be a safer alternative as a treatment for hyperlipidemia than the liver-targeting MTP inhibitors. 

SRI 63-072 (8) [ 114] is an inhibitor of PAF-induced guinea-pig, rabbit, dog, baboon and human platelet aggregation with IC50 values of 1.4,4.7, < 100,19.0 and 22.3 /iM, respectively [144]. The antagonist also prevents PAF-induced... 

Working with kidney homogenates from guinea-pigs, Peters has isolated an inhibitor containing a C—F link as the result of the enzymic action of kidney upon fumarate and fluoroacetate. This inhibitor is almost certainly fluorocitrate because... 

Involvement of tissue esterases is documented for zomepirac glucuronide, which undergoes rapid hydrolysis in vivo in the guinea pig and rabbit [30], Co-administration of (phenylmethyl)sulfonyl fluoride (an inhibitor of esterases) dramatically decreased the apparent plasma clearance of zomepirac glucuronide, and, in other experiments, strongly increased the apparent plasma clearance of zomepirac administered as such. 

Amino-substituted naphthoquinones and heterocyclic variants have been disclosed in the patent literature as 5-LO inhibitors. Compounds represented by (80) (X = C, N) from Lilly inhibited SRS-A release from sensitized guinea-pig lung tissue [218]. Similar compounds such as (81) (R = carboxylic ester, acyl, or aryl) and related naphthalene derivatives, from American Cyanamid, gave good inhibition in guinea-pig ISN (at 10 //g/ml) and in passive cutaneous anaphylaxis in mice (25-60 /zM i.p.) [219,220]. 

GT-1, the smallest of the three toxic fractions, was separated on silicic acid with chloroform methanol (9 1). At a concentration of 40 ng/ml it was found to be a reversible inhibitor of the guinea pig ileum. At concentrations less than 8 ng/ml the ileum response to histamine was augmented. 

GT-2, separated on silicic acid with chloroform methanol (1 1), constituted the largest fraction. At a concentration of 4 ng/ml, GT-2 was found to be a reversible inhibitor of the guinea pig ileum response to histamine. The separation of all three fractions up to the last step (see d. Table 1) was exactly the same procedure previously utilized by Tachibana (22) Scheuer ( ) and others ( 3, ). In the last step, when we attempted to utilize a Sephadex column and water for further purification of GT-2, we lost a considerable amount of toxin and also appeared to lose toxicity. 

GT-3 was separated from GT-1 and GT-2 on silicic acid using 100% methanol. The separation of this fraction is the same as that used by Tachibana (22) and Yasumoto (13) for maitotoxin. Unlike GT-1 and GT-2, this fraction was found to be an irreversible inhibitor of the guinea pig ileum preparation. The time studies of GT-3 are important in that they characterize GT-3 as a very toxic fraction but one which is very slow in its action. 

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