1 The actions of the a 1 -adrenoceptor antagonist indoramin have been examined against the contractions induced by noradrenaline in the rat vas deferens and aorta taking into account a putative neuronal uptake blocking activity of this antagonist which could result in self-cancelling actions.2 Indoramin behaved as a simple competitive antagonist of the contractions induced by noradrenaline in the vas deferens and aorta yielding pA 2 values of 7.38+0.05 (slope=0.98+0.03) and 6.78+0.14 (slope=1.08+0.06), respectively. 3 When the experiments were repeated in the presence of cocaine (6 mM) the potency (pA 2 ) of indoramin in antagonizing the contractions of the vas deferens to noradrenaline was increased to 8.72+0.07 (slope=1.10+0.05) while its potency remained unchanged in the aorta (pA 2 =6.69+0.12; slope=1.04+0.05). 4 In denervated vas deferens, indoramin antagonized the contractions to noradrenaline with a potency similar to that found in the presence of cocaine (8.79+0.07; slope=1.09+0.06). 5 It is suggested that indoramin blocks a 1 -adrenoceptors and neuronal uptake in rat vas deferens resulting in Schild plots with slopes not di erent from unity even in the absence of selective inhibition of neuronal uptake. As a major consequence of this double mechanism of action, the pA 2 values for this antagonist are underestimated when calculated in situations where the neuronal uptake is active, yielding spurious pK B values.
We investigated whether or not surgical denervation of the rat vas deferens changes the alpha(1)-adrenoceptor subtypes involved in the contractions to noradrenaline. Denervated vas deferens was approximately 22 times more sensitive to noradrenaline (pD(2)=7.35+/-0.04) than control vas (pD(2)=6.01+/-0.03). This difference in noradrenaline potency was eliminated when cocaine (6 microM) was added to control vas (pD(2)=7.22+/-0.04). The noradrenaline-induced contractions of control and denervated vas deferens were insensitive to the alpha(1B)/alpha(1D)-adrenoceptor alkylating agent chloroethylclonidine (100 microM, 45 min). The concentration-response curves to noradrenaline in control and denervated vas deferens were competitively antagonised by prazosin (pA(2) approximately equal to 9.6), WB-4101 (pA(2) approximately equal to 9.5), 5-methyl urapidil (pA(2) approximately equal to 8.4), phentolamine (pA(2) approximately equal to 8.7), yohimbine (pA(2) approximately equal to 6.9), BMY 7378 (pA(2) approximately equal to 6.9) and indoramin (pA(2) approximately equal to 8.7). After the treatment of control and denervated vas deferens with phenoxybenzamine, the partial agonist oxymetazoline antagonised competitively the concentration-response curves to noradrenaline showing pA(2) values approximately 7.4 in both groups. We conclude that noradrenaline-induced contractions in control and denervated rat vas deferens are mediated by alpha(1A)-adrenoceptors and that surgical denervation of the rat vas deferens is not able to change the alpha(1)-adrenoceptor subtypes involved in the contractions to noradrenaline.
Presented by A.C.M. PaivaDentate granule cells are generally considered to be relatively resistant to excitotoxicity and have been associated to robust synaptogenesis after neuronal damage. Synaptic reorganization of dentate granule cell axons, the mossy fibers, has been suggested to be relevant for hyperexcitability in human temporal lobe epilepsy and animal models. A recent hypothesis has suggested that mossy fiber sprouting is dependent on newly formed dentate granule cells. However, we have recently demonstrated that cycloheximide (CHX) can block the mossy fiber sprouting that would be otherwise induced by different epileptogenic agents and do not interfere with epileptogenesis in those models. Here, we investigated cell damage and neurogenesis in the dentate gyrus of pilocarpine-or kainate-treated animals with or without the co-administration of CHX. Dentate granule cells were highly vulnerable to pilocarpine induced-status epilepticus (SE), but hardly damaged by kainate induced-SE. CHX-pretreatment markedly reduced the number of injured neurons after pilocarpine-induced SE. Induction of SE dramatically increased the mitotic rate of KA and KA + CHX treated animals. Induction of SE in animals injected with pilocarpine alone led to increases of between two to sevenfold in the mitotic rate of dentate granule cells as compared to increases of between five and thirtyfold for pilocarpine+CHX animals. These observations indicate that in presence of cycloheximide the increase of the mitotic rate after pilocarpine-induced SE may be due to protection of a vulnerable precursor cell population that would otherwise degenerate. We further suggest that the mossy fiber sprouting and neurogenesis of granule cells are not necessarily related events. - ( September 14, 1999 The α1-adrenoceptor antagonist indoramin was used in the rat vas deferens and aorta, against contractions induced by noradrenaline. Indoramin behaved as a competitive antagonist yielding pA 2 values of 7.38 ± 0.05 in rat vas deferens and 6.78 ± 0.14 in aorta. In the presence of cocaine (6µM), the potency (pA 2 ) of indoramin in antagonizing the contractions of the vas deferens to noradrenaline was increased to 8.72 ± 0.07 while its potency remained pratically unchanged in the aorta (6.69 ± 0.12).
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