S.R. Kottegoda

Is vasoactive intestinal polypeptide the principal transmitter involved in human penile erection

Previous work from this laboratory reported on the effects of several autacoids and other agents on strips of human corpus cavernosum (cc) muscle. These investigations indicated the presence in the cc muscle of a) atropine-sensitive cholinoceptors, b) alpha- and beta-adrenoceptors and c) a non-adrenergic non-cholinergic mechanism. Several recent publications have presented evidence in support of the possibility that vasoactive intestinal polypeptide (VIP) is an important, or the chief, transmitter in human penile erection. This paper describes the actions of VIP and other compounds on the cc muscle and the effect of intracavernous injection of VIP in volunteers. Among the agents tested, VIP was the most potent relaxant of the cc muscle. This effect, which was seen at a dose as low as 0.03 nM, was suppressed by VIP antiserum. The response of the isolated penile vasculature to VIP was similar. VIP antiserum had no effect on the relaxation of the cc muscle produced by field stimulation. In five of the seven subjects given intracavernous VIP (1.0 micrograms.) some degree of penile enlargement was evident, but none had an erection. It is suggested that local release of VIP, withdrawal of the alpha-adrenoceptor mediated tonic supply to the penis and the activation of the latters beta-adrenoceptors are all probably involved in penile erection in man.

Complications of Beta-Mimetic Therapy in Preterm Labour

EDITORIAL COMMENT: This careful review of the reported complications of beta‐mimetic drugs may properly cause obstetricians to have ‘second thoughts on stopping labour’ (Anderson, 1981: 53), in many patients, especially when there is premature rupture of the membranes and the possibility of intrauterine infection.

Inhibition of platelet aggegation and reversal of vasopressin-induced ECG changes by a carboprostacyclin analogue, ono 41483, in primates

15-cyclopentyl-omega-pentanor-5(E)-carbacyclin (ONO 41483), a chemically stable carboprostacyclin analogue, was 3.3 times less active than prostacyclin but was 2.6 times more active than carboprostacyclin in inhibiting aggregation of ADP-induced baboon platelet in vitro. On human platelets in vitro, ONO 41483 was 9.4 times less active than prostacyclin and 12.7 times more active than carboprostacyclin. ONO 41483 was 3.7 times less active than prostacyclin but was 2.2 times more active than carboprostacyclin in producing a fall in arterial blood pressure in anaesthetised baboons. Intravenous and oral administration of ONO 41483 in baboons produced ex vivo inhibition of ADP-induced platelet aggregation at doses that did not affect blood pressure or heart rate. In addition, bolus intravenous doses (3 to 10 micrograms/kg) of ONO 41483 reversed vasopressin-induced ECG changes in the monkey, suggesting an ability of the compound to relieve coronary spasm.

A comparison of some pharmacological actions of prostaglandin E1, 6-OXO-PGE1 and PGI2

Some pharmacological actions of prostaglandin E1 (PGE1), 6-oxo-PGE1 and PGI2 have been studied. 6-oxo-PGE1 and PGE1 relaxed guinea-pig tracheal muscle in vitro and increased nasal patency in normal volunteers and in subjects with vasomotor rhinitis whereas PGI2 produced opposite effects. All three compounds produced bronchodilatation in the anaesthetised guinea-pig and relaxed human respiratory tract muscle in vitro. PGI2 was several times more potent than either 6-oxo-PGE1 or PGE1 against ADP-induced aggregation of human and baboon platelets in vitro. Intravenous 6-oxo-PGE1 in the baboon caused an ex vivo inhibition of platelet aggregation, but the EC50 was 7.7 times that of PGI2. As a vasodepressor in the baboon 6-oxo-PGE1 and PGI2 were equipotent. Thus with the exception of the vasodepressor effect, the actions of 6-oxo-PGE1 qualitatively and quantitatively resembled those of the structurally related PGE1 rather than those of PGI2.

Plasma levels of 13,14-dihydro-15-keto PGE2 after vaginal application of a new PGE2 film.

To determine the release and absorption profile of prostaglandin E2 from a new vaginal film formulation containing 850 micrograms PGE2, serial plasma levels of 13,14-dihydro-15-keto PGE2 were measured by radioimmunoassay in pregnant women between 16 and 18 weeks gestation. A control group, using placebo vaginal film was included in the study. There was a somewhat uniform increase in the plasma levels of the PGE2 metabolite, reaching peak levels between 4 and 6 hours after application of the film. The findings suggest that this drug formulation could be used clinically when slow constant release of the prostaglandin is required over a period of hours such as in pre-induction cervical ripening of term pregnancy.

Comparison of AFP And β-hCG Levels in Infiltrating Duct Mammary Carcinoma at Different Stages of Malignancy

&NA; In order to assess the likely clinical value of AFP and β‐hCG levels as markers of the extent of spread of infiltrating duct mammary carcinoma, we compared (Mann‐Whitney U test) the immunoreactive tumour tissue concentrations of the respective antigens, measured by specific RIA, after mastectomy in Chinese women at stages I (n = 9), II (n = 13) and III (n = 7) with that of normal breast tissue (n = 11). Elevated concentrations of the oncofetal antigens were found at all stages of malignancy. The discovery of an hCG‐like material in the extract of normal breast tissues indicates limited value of β‐hCG assay in mammary tumours. However, our findings generally suggest that measurement of the tumour tissue AFP levels warrant consideration as a useful biochemical marker for in‐vitro evaluation of tumour spread at all stages of malignancy.

Another look at initiation of human parturition.

Summary: Despite our moderate understanding of the physiology of the initiation of labour in various animal species, notably ruminants and rodents, the mechanism in man remains enigmatic. In the initiation process in the human the major role is apparently taken by the placental and fetal membranes, while the fetus may modulate the timing of labour. This review sets out to examine current knowledge of the process of initiating and maintaining parturition in the human.

Multimolecular forms of oxytocinase activity in the human uterus and their inhibition by prostaglandins and cyclic GMP

Oxytocinase (EC 3.4.11.3) activity was measured in uterine homogenates from pregnant and non-pregnant women using S-benzyl-L-cysteine-p-nitroanilide (BCN) and L-leucine-p-nitroanilide (LN) separately as substrates. There was no significant difference between the specific activity of the enzyme in the pregnant and non-pregnant uterus. The uterine homogenates were also subjected to gel filtration on Ultrogel AcA 22 column and two hydrolyzing activity peaks from the pregnant uterus (PUI, PUII) and three from the non-pregnant uterus (UI, UII, UIII) were obtained. Although the pattern of hydrolysis of the two substrates by the enzyme peaks was similar, the hydrolysis of LN was greater than that of BCN. PUII, UII and UIII showed higher affinity for the substrates than PUI and UI, and the affinity of all isoenzymes was significantly greater for LN than BCN. These uterine oxytocinases appeared to be metallo-aminopeptidases and were potently inhibited by Cu2+, Zn2+ and prostaglandins (PGs). Cyclic GMP (cGMP) and its 8-bromo derivative, however, inhibited only PUI and UI. The divalent cations and PGs were equipotent against the hydrolysis of both substrates, but cGMPs were more effective against BCN hydrolysis. All of these inhibitions depended on the pH of the incubation medium and types of the inhibition by PGs and cGMPs were mixed and uncompetitive respectively. The implications of these findings in relation to human parturition have been discussed.

Selective inhibition of multimolecular forms of human serum and placental oxytocinase activity by prostaglandins and cyclic GMP

Ultrogel acrylamide-agarose chromatography was employed for fractionation of oxytocinase isoenzymes from serum of pregnant women and from human placenta. Using S-benzyl-L-cysteine-p-nitroanilide ( BCN ) and L-leucine-p-nitroanilide (LN) as substrates, three activity peaks (PI, PII, PIII) from placenta, and one peak (SI) from serum were identified. SI coincided with PII, and with all isoenzymes the hydrolysis of LN was greater than that of BCN . Prostaglandins E1, E2 and F2 alpha inhibited all oxytocinases , more potently the hydrolysis of LN than BCN and at pH 6.2 than at pH 6.8. Although cyclic GMP and its 8-bromo derivative similarly inhibited these isoenzymes except PIII, they were considerably more effective against the hydrolysis of BCN than LN.

Altered Hypothalamic‐Pituitary‐Testicular Function in Incomplete Testicular Feminization Syndrome

Summary: An 18‐year‐old 46 XY patient with the syndrome of incomplete testicular feminization was investigated. The clinical phenotypic features were distinctive and typical of the 4 46 XY cases previously reported. The findings of elevated plasma T4 with evidence of incomplete development of female secondary sex characteristics suggest partial end organ insensitivity to the androgen at the target tissues. This possibility is substantiated by the high plasma LH level, presumably the consequence of the relative inability of the hypothalamic‐pituitary unit to respond to testosterone in the feedback regulation of LH secretion. It is therefore suggested that, compared to normal males, the patient had an altered hypothalamic‐pituitary‐testicular function.