Naunyn-Schmiedebergs Archiv für Pharmakologie und experimentelle Pathologie

Kinin-forming and esterolytic activity in human citrate plasma has been activated by treatment of the plasma with acetone. By far most of the esterolytic activity if not all of it was recovered in an α2-macroglobulin (α2M) kallikrein complex (SI) which was characterized and purified by chromatography. Little if any esterolytic activity was present which could be ascribed to free plasma kallikrein. The α2M-kallikrein complex had kinin-releasing activity though much less than free plasma kallikrein, relative to esterolytic potency. This explains that a considerable fraction of the kinin-forming potential of acetone-activated plasma resides in free plasma kallikrein although it represents only a very small portion of the total kallikrein store. Like free plasma kallikrein the α2M complex releases kinin from LMW-kininogen less efficiently than from HMW, in systems of purified components. In whole plasma, the efficiencies change: whereas plasma kallikrein is rapidly inactivated by endogenous inhibitors, the α2M complex is protected from further inactivation and capable of releasing kinin continuously if slowly, attacking also LMW-kininogen after HMW-kininogen has been consumed by free kallikrein. While the α2M-complex in this respect differs functionally from free plasma kallikrein and explains earlier observations suggesting the presence of two kininogenases, it seems doubtful now that two truly different kininogenases exist in human plasma. The results suggest that acetone predominantly inactivates full inhibitors of kallikrein such as C1INH whereas α2M is somewhat more resistant and (pre-)-kallikrein even more. Depending on the time and temperature of acetone treatment one obtains more or less total kallikrein and varying proportions of free to bound enzyme. It is likely that acetone does not truly trigger an activation of prekallikrein but supports spontaneous activation by slowing down the control of the feedback reinforcement of this activation, by damaging inhibitors.

The effect of respiratory acidosis and alkalosis on the vasoconstriction toα 1- andα 2-adrenoceptor stimulation was studied in pithed normotensive rats. The selectiveα 1-adrenoceptor agonists (-)amidephrine, cirazoline, (±)erythro methoxamine (-)phenylephrine, Sgd 101/75 and St 587 were used, as well as the selectiveα 2-adrenoceptor agonists B-HT 920, B-HT 933, DP-6,7-ADTN, M-7 and UK 14,304. The non-selectiveα-adrenoceptor agonists xylazine, noradrenaline and adrenaline were included as well. The latter two were also studied under selective doses of the antagonists rauwolscine and prazosin, thus yielding the respectiveα 1- andα 2-adrenoceptor components of the vasoconstriction to these agonists. The effect of acid-base balance disturbances on presynaptically released noradrenaline elicited by electrical stimulation of preganglionic nerves was studied as well. Dose response curves for the agonists were generated under various conditions of ventilation, yielding either alkalotic, normal or acidotic values of arterial blood pH. Pressor responses to all agonists were maximally affected by changes in acid-base status at the low doses of the agonists. Acidosis was found to inhibit increases in diastolic pressure mediated by theα 1- as well as theα 2-adrenoceptor agonists studied, although not to the same extent. Alkalosis exerted either an obvious potentiation or did not significantly influenceα 1-adrenoceptor mediated pressor responses. On the basis of acid-base sensitivity the following groups of agonists were distinguised: (1) Cirazoline, phenylephrine, methoxyamine, electrically released noradrenaline from presynaptic sites, of which pressor responses are obviously potentiated and attenuated by alkalosis and acidosis, respectively. (2) Sgd 101/75, St 587, noradrenaline-α 1, amidephrine and adrenaline-α 1, eliciting pressor responses which are strongly acid-sensitive and base-insensitive. (3) B-HT 920, B-HT 933, DP-6, 7-ADTN (lower doses), of which vasoconstriction is markedly inhibited by both acidosis and alkalosis. (4) Noradrenaline-α 2, UK 14,304, M-7 (lower doses), adrenaline-α 2 and high doses of the agonists of the former group. Pressor responses of these agonists were found to be not or slightly base-sensitive, but profoundly acid-sensitive. Xylazine does not fit into this classification. The present data are not in accordance with purported subdivisions ofα-adrenoceptor agonists by others. It is therefore concluded that the differential effect of acid-base status onα-adrenoceptor mediated vasoconstriction in pithed rats is an exponent of the differential way of interaction of the agonists with the adrenoceptors involved.

CNS′ und S2O3″ bleiben bevorzugt extracellulär verteilt und diffundieren schwer in Subarachnoidalraum und Vorderkammer. Li+ reichert sich auch im Zellwasser an und hat gegenüber dem Subarachnoidalraum und Vorderkammer nur einen geringen Widerstand zu überwinden. Die Versuche zeigen, daß sehr schwache Säuren, elektrisch nahezu neutrale Moleküle und Basen unabhängig vom Dissoziationsgrad gut permeieren. Die bei mäßig starken und starken Säuren auftretenden Widerstände werden mit der Ladung der Membran bzw. Grenzflächen in Beziehung gebracht. Das Verteilungsvolumen und das Verhältnis Blut/Liquorkonzentration ist ein geeignetes Kriterium für die Untersuchung von Permeabilitäten.

The actions of noradrenaline and isoprenaline on isolated guinea pig atria have been analyzed by a study of the modification by various drugs of the responses to these catechol amines. Drugs used were cocaine, reserpine, phenoxybenzamine, guanethidine, tyramine, hexamethonium and nialamide. While pretreatment with reserpine or nialamide had no detectable influence on the responses of the atria to catechol amines, the exposure of normal atria or of atria obtained from reserpine-treated animals to cocaine, guanethidine, phenoxybenzamine and tyramine resulted in potentiation of the responses to noradrenaline and subsensitivity to isoprenaline; hexamethonium was without influence on the responses to both catechol amines. The antagonism between cocaine and isoprenaline had, for the concentrations studied, the character of a competitive one, cocaine causing a parallel shift of the dose-response curve to the right; as was expected, the same concentrations of cocaine potentiated noradrenaline, shifting the dose-response curve to the left. Although in opposite senses, cocaine shifted the curves roughly by the same distance. In higher concentrations, cocaine depressed also the responses to noradrenaline; when added to the bath during the action of noradrenaline or isoprenaline, cocaine induced a faster termination of the stimulant effects of the catechol amines. Cocaine somewhat antagonized the responses of the atria to histamine, but not in the same degree as those to isoprenaline. The results are discussed in the light of present knowledge about the mechanism of supersensitivity to noradrenaline due to cocaine. It is concluded that it is not mandatory to accept two different sets of cardiac β-receptors (one activated by noradrenaline, another by isoprenaline) in order to explain the results obtained. Cocaine probably influences in two ways the cardiac actions of catechol amines, preventing their uptake by tissues and antagonizing their actions at the level of the receptors, the first action resulting in an increase of the concentration of the agonist drug. The overall effect should be supersensitivity to amines whose action is predominantly terminated by uptake (like noradrenaline) and subsensitivity to amines which are not, or only in a minor degree, taken up by tissues (like isoprenaline); higher concentrations of cocaine should be able to reduce the responses to all amines. This working hypothesis agrees fairly well with the referred results.