Angiotensin-converting enzyme and other peptidolytic enzymes in human semen and relations to its spermatologic parameters.

Angiotensin-converting enzyme (ACE) and other enzymes of the renin-angiotensin system (RAS) occur in human semen in high activities. In contrast to bull ejaculates, not all zinc-dependent metallopeptidases are found to be in close correlation to the microscopically determined semen parameters; such a relationship was established only partly for the ACE. On the other hand, the RAS-dependent spermatozoa-bound enzymes, inclusive ACE, uniformly show negative correlations to the spermatologic parameters of human semen. These results, for the first time, point to different functions of the sperm-cell-bound (testicular) and of the seminal plasma (pulmonary) ACE activities.

[Characteristics of the course of the wound process in spontaneously hypertensive rats and the effect of morphine, substance P and its fragment SP1-4]. / Osobennosti techeniia ranevogo protsessa u spontanno gipertenzivnykh krys i vliianie morfina, substantsii P i ee fragmenta SP1-4.

The paper demonstrates that in spontaneously hypertensive rats (SHR) as compared with normotensive controls exudative processes at the sites of lesions are much more prominent. Such exudative processes include edema, fibrinous exudation as well as permeability of capillaries and venular walls for leukocytes. These effects prolong the phase of its inflammation and retard the regeneration phase in wound healing. Morphine and SP1-11 stimulate in a similar fashion repair during wound healing in the both rat strains. Their effect is similar to the effect of opioid peptides. SP1-4 does not affect vessel reactivity and wound healing in SHR, which is related to disturbed expression of receptors to SP fragments. Synergism in the effect of two functional antagonists i.e. opioids and SP on wound healing confirms our hypothesis about the role of pain as an inducer of a variety of mechanisms underlying repair regeneration.

Occurrence and potential importance of selected peptidases in bull ejaculates.

The zinc containing peptidases angiotensin-converting enzyme (ACE), neutral metalloendopeptidase (NEP), and leucine aminopeptidase (LAP) occur in bull ejaculates in high activities. These enzyme activities are in close correlation with some routineously determined semen parameters. These ejaculat parameters are used for quality classification and selection of ejaculates and are according to long term experience in good correlation to the male fertility. Semen quality related correlations could not be found for the dipeptidyl aminopeptidase (DPIV) and the aminopeptidase A (APA). Origin and possible function of the zinc containing peptidases in the semen are examined and discussed.

[Possible involvement of the renin-angiotensin system in reproduction. II. Occurrence and role in the female reproductive tract]. / Zur möglichen Mitbeteiligung des Renin- Angiotensin-Systems am Fortpflanzungsgeschehen. II. Vorkommen und Rolle im weiblichen Reproduktionstrakt.

Biochemical and immunological studies of the last years reveal the existence of an "ovarian renin-angiotensin system (RAS)". Despite of the low angiotensin-conterting enzyme (ACE) activity in the ovary the follicular fluid is rich in angiotensin II (AII). The detection of AII receptors on cells within maturating follicles proves them as AII targets. Therefore, it is supposed that AII may be involved in the regulation of fundamental processes of follicle maturation and/or corpus luteum formation. Further interesting findings are the high concentration of prorenin in the follicle fluid of women causing an increase of the prorenin blood plasma level at time of ovulation, and a second increase of the blood prorenin concentration in the middle of the luteal phase. With respect to the ACE activity in the ejaculate it is imaginable that the smooth muscle tonus of the uterus and the oviduct could be affected by local generation von AII and/or degradation of bradykinin and thus the transit of the semen may be facilitated. Further systematic research is necessary to bring more light into the physiological context and to replace hypothetical interpretations of the findings by exact knowledge.

[Possible involvement of the renin-angiotensin system in reproduction. III. Occurrence and role in pregnancy]. / Zur möglichen Mitbeteiligung des Renin-Angiotensin-Systems am Fortpflanzungsgeschehen. III. Vorkommen und Rolle bei der Gravidität.

To clarify a possible participation of the renin-angiotensin-system (RAS) in physiological processes of pregnancy, findings are listed about occurrence and variations of RAS components in uterus, placenta, amniotic fluid, fetal membranes, fetus and serum. There exist complete and independent RAS in the respective organs and tissues. During pregnancy concentrations and/or activities of the components change, but in different ways and non-uniforming. The information now available does not yet allow a definite view on the role of RAS during pregnancy and on the correlations to estrogens, progesterone, chorionic gonadotropin, prostaglandins etc. Supposedly RAS may be involved to a high degree in the local regulation of blood flow and the maintenance of fetal vascular homeostasis. Furthermore, there are relations between fetoplacental components of RAS and pregnancy-induced hypertension. Further investigations are necessary. They are expected to offer therapeutic possibilities for influencing pathological processes in which RAS plays a role.

[Possible involvement of the renin-angiotensin system in reproduction. I. Occurrence and role in the male reproductive tract]. / Zur möglichen Mitbeteiligung des Renin-Angiotensin-Systems am Fortpflanzungsgeschehen. I. Vorkommen und Rolle im männlichen Reproduktionstrakt.

With regard to the blood pressure the regulative function of the renin-angiotensin-system (RAS) is well known. Knowledge of the last years is that components of the RAS are available also in organs and excrets of the male reproductive tract. So, the angiotensin-converting-enzyme (ACE) - a key enzyme of the RAS - exists in the testes in an extraordinary high activity exceeding those of the lung tissue. In the ejaculate this so-called "testicular ACE" is associated with sperms, whereas the seminal plasma contains the higher molecular "pulmonary ACE". Because both isoenzymes posses the same catalytic effectiveness, the occurrence of adequate substrates (angiotensin I, bradykinin) and degrading products as effectors (angiotensin II), respectively, is of high importance for the valuation of the physiological relevance of the RAS in the process of fertility. Up to date, the knowledge is still insufficient, partly even contradictory. Therefore at present the regulative function(s) of the RAS in the male reproductive tract can only be expressed as postulates.

Prenatal influence of substance P on blood pressure and stress sensitivity of spontaneously hypertensive rats.

Substance P, administered i.p. to female spontaneously hypertensive rats in the last 6 d of gestation, diminishes the age dependent increase of blood pressure especially in male offspring and the additionally stress related blood pressure increase in both sexes.

Influence of adrenal demedullation on stress-related behaviour in Wistar rats.

The influence of adrenal demedullation on stress-related behaviour (chronic immobilization) was investigated in respect to the following parameters and physiological processes: number of animals surviving the exposure, blood pressure behaviour, endogenous opioid system, pain sensitivity, endogenous level of substance P (SP) in pituitary and hypothalamus. The results showed that chronic immobilization stress and adrenal demedullation induce the same direction of alterations of physiological processes and parameters. This fact suggests the involvement of common regulatory mechanisms both in demedullation and chronic stress. An important process in this respect may be the induction of functional insufficiency of the adrenal medulla especially concerning the adrenal peptidergic mechanisms. Contrary to the sham operated rats the demedullated animals showed differences in their stress-related behaviour of parameters of adaptive regulatory processes. In rats with demedullation either no additional stress-related alterations of parameters in relation to the general adaptation processes were induced or the demedullation-induced alterations were antagonized partially or completely by chronic immobilization.

Prevention of stress-induced involution of the thymus in rats by substance P (SP1-11) and its N-terminal fragment SP1-4.

Selye found that in response to different stressors the body reacts with a characteristic stress syndrome: adrenal enlargement, gastrointestinal ulcera, and thymicolymphatic involution. In this paper we demonstrate that i.p. injected Substance P (SP) can prevent stress-induced involution of thymus in Wistar rats. This protecting effect on the immune system of SP, in addition to the "normalizing" effects of this peptide on stress-induced disorders in vegetative and central functions first described by Oehme and co-workers and Hecht and co-workers is a new hint to the function of SP as an "anti-stress" agent. The mode of action of the anti-stress effect of SP in adrenals as well as in the thymus is discussed. It is suggested that the anti-stress effect of SP1-11 and its N-terminal fragment SP1-4 is mediated by specific receptors in adrenals and/or thymus which are different from the so called SP-P and SP-E receptors.

[The role of the N-terminal of the substance P molecule in its action in stress-related behavioral and blood pressure disorders]. / Zur Bedeutung des N-Terminus des Substanz P-Moleküls für die Wirkung auf stressbedingte Verhaltens- und Blutdruckstörungen.

Substance P and the N-terminal sequences SP1-9, SP1-7, SP1-4 and SP1-2 were investigated in their action on stress related alterations in blood pressure behaviour, stress related disturbances in conditioned reflex learning behaviour, alterations in the endogenous opioid system and on the blood pressure behaviour of spontaneously hypertensive rats. In addition the occurrence of vegetative effects such as acute hypertension and histamine release from mast cells were investigated. The results of this work show that N- and C-terminal sequences of the Substance P molecule differ in their actions. Whereas the vegetative effects decrease if the SP molecule is shortened from the C to the N-terminus the "antistress effect" of the Substance P molecule remains unchanged. Whereas the N-terminal tetrapeptide SP1-4 can be considered "essential" for the "antistress effect", the C-terminal pentapeptide of SP is considered to be the "essential sequence" for the vegetative effects. These results will open new possibilities for the synthesis of selectively acting SP-agonists.

Influence of substance P on nociception and stress.

In 1980 Oehme and co-workers [11] reported that Substance P (SP) has a dual effect on nociception, which is related to the pain threshold before SP administration. Our recent results showed that the N-terminal part of the SP sequence may be important to the hyperalgesic action, and the C-terminal part to the analgesic action of this peptide. The hyperalgesic effect of SP (and N-terminal fragments of SP) seems to be related to the "anti-stress" effect which was first demonstrated by Hecht and co-workers [5] and Oehme and co-workers [12]. Interaction of SP with opioid peptides could be the common reason of both the "anti-stress" effect and the hyperalgesic activity of SP.

[Substituted picolinic acids as DBH inhibitors. Inhibition of dopamine beta-hydroxylase and antihypertensive action]. / Substituierte Picolinsäuren als DBH-Inhibitoren. Hemmung der Dopamin-beta-Hydroxylase und antihypertensive Wirkung.

The authors determined the dissociation constant, the constant of copper complex formation, the inhibitory action on the catecholamine biosynthesis enzyme dopamine beta-hydroxylase (DBH; copper glycoprotein), as well as the antihypertensive effect on spontaneously hypertensive rats of a series of substituted picolinic or fusaric acids (FA; 5-n-butylpicolinic acids). The substances investigated may be characterized as weak to medium-strong acids which form stable copper(II) complexes in solution and in the solid state. The concentrations required for a 50% inhibition of DBH range between 10(-6) and 10(-5) mol/l. The picolinic acid structure is of greater importance to enzyme inhibition than the butylpyridine structure. From the inhibition type of FA it may be deduced that the mechanism of inhibition cannot be explained only by the complex formation of the enzyme copper. Most of these derivatives are of hypotensive activity; some others exert a hypertensive effect. A quantitative correlation between the action on blood pressure and the enzyme inhibition cannot be established without calculation (quantitative structure-activity analysis). The hypotensive activity is above all due to DBH inhibition in the angiovascular region and in the suprarenal gland.

[Dipeptidyl peptidase activities in various organs of the Wistar rat]. / Dipeptidyl-Peptidase-Aktivitäten in verschiedenen Organen der Wistarratte.

Using Gly-Pro-pNa as a substrate, the authors photometrically determined the dipeptidyl peptidase activity in organic homogenates and serum of Wistar rats at two pH values. The activity of the serine peptidase DP IV was measured at pH = 7.6; a mixed activity (DP MA) which is composed of the activities of several dipeptidyl peptidases, at pH = 5.0. Particularly high DP IV activities were determined in the kidney, lung, adrenal gland, liver and aortic arch, the differences among the enzyme activities measured in the single organic homogenates at pH = 5.0 being smaller. The DP IV activities and the values found for DP MA in the structures of the nervous system were in general lower. Maximum DP IV values were measured in the spinal ganglion, cerebral cortex and spinal bulb; and maximum DP MA values, in the hypothalamus, cerebellum and cerebral cortex. The results obtained are discussed from the aspects of the participation of these enzymes in peptidergic regulatory mechanisms and of a possible relation to blood-pressure regulation.