We studied the effects of the estrous cycle, ovariectomy and estrogen replacement on angiotensin-converting enzyme (ACE) (kininase II, EC 3.4.15.1) and angiotensin II (AT) receptors in the pituitary gland of the female rat. Quantitative autoradiography, with the use of consecutive pituitary sections, allowed for simultaneous determination of changes in binding and in the potential AT synthetic ability of individual pituitaries, and for a correlation between these two phenomena. In the anterior pituitary, ACE activity and binding of the ACE inhibitor [¹²⁵I]-351A were not changed during the estrous cycle. Ovariectomy produced a significant increase in ACE activity and binding, and both of these parameters returned to normal after estrogen replacement. There were no changes in ACE activity or binding in the posterior pituitary during the estrous cycle or after ovariectomy or hormone replacement. AT receptors were characterized as of the AT₁ type, since they were displaced by the selective AT₁ antagonist DuP 753 and not by the AT₂ competitor PD 123177. There were marked changes in the concentration of AT₁ receptors during the estrous cycle, with highest numbers in metestrus, lower in estrus and diestrus, and lowest during proestrus. Estrogen replacement in ovariectomized rats decreased AT₁ receptor number in the anterior pituitary. Our results indicate a dual effect of estrogen on anterior pituitary AT, physiologically on AT receptor expression and pharmacologically on ACE activity.

Since guinea pig and rat atria have been used as models to study acute anthracycline-induced cardiotoxicity, experiments were carried out in these preparations to evaluate possible acute cardiac effects mediated by mitoxantrone (MTX). After a latency period of approximately 90 min, MTX (10(-5)-10(-4) M) promoted a concentration-related and time-dependent decrease of spontaneous rate in guinea pig atria. A similar but less intense effect after a longer latency interval was observed in rat atria. In this preparation, MTX (10(-5)-10(-4) M) incubated up to 150 min., induced a gradual competitive beta-adrenergic blocking effect on the positive chronotropic action of isoproterenol. This was characterized by a progressive decline of pD2 values without altering Emax. A similar and stronger effect was found in isolated guinea pig atria incubated under same conditions with MTX, except that 10(-4) M exposed for 150 min. was able to depress the Emax to isoproterenol by 21.2%. In addition, MTX (10(-4) M) in this model promoted a non-competitive antagonistic effect on the chronotropic action of histamine. These data are compatible with the idea that MTX could induce cardiac acute effects qualitatively similar to but of lower potency than those produced by doxorubicin in these two models. In addition, guinea pig atria seemed to display higher sensitivity to MTX compared to rat atrial preparations.

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A progressive and reversible decrease of external pH accompanied the catecholamine release elicited by acetylcholine in decorticated bovine adrenal glands perfused with buffer-free Locke solution adjusted to an initial pH of 7.4. Both the secretory response as well as the extracellular acid shift promoted by the cholinergic agonist were antagonized by hexamethonium plus atropine, Mg2+ and verapamil. Experiments performed to assess the effects of the reduction of external pH on acetylcholine-induced release of catecholamines revealed that increasing the extracellular concentration of H+ significantly and reversibly reduced this secretory response. These findings are consistent with the idea that adrenomedullary activation of secretion by acetylcholine could be associated with a transient acidification of the extracellular fluid. This release of protons, arising mainly from the chromaffin granules, may be involved in a local automodulatory mechanism of the regulated secretory process.

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