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Biomedical subjects

D F Horrobin

Publications and source records attributed to D F Horrobin.

At least 325 records · Page 18Linked to original sources
PubMed1977

Schizophrenia as a prostaglandin deficiency disease.

Evidence that schizophrenia may be a prostaglandin deficiency disease comes from three main sources: (1) all effective antischizophrenic drugs stimulate prolactin secretion and prolactin is a potent stimulator of prostaglandin synthesis; (2) schizophrenics are resistant to pain and inflammation and are free of rheumatoid arthritis and there is increasing evidence that prostaglandins play important roles in pain, inflammation, and rheumatoid arthritis; (3) high doses of drugs recently shown to be prostaglandin antagonists cause schizophrenia-like syndromes. The hypothesis is not necessarily inconsistent with current transmitter theories of schizophrenia since prostaglandins modify transmitter secretion and action. It does indicate radically new approaches to investigation, treatment, and drug design not suggested by the transmitter concepts.

Antipsychotic Agents↗
PubMed1977

Methyl xanthine phosphodiesterase inhibitors behave as prostaglandin antagonists in a perfused rat mesenteric artery preparation.

The methyl xanthines, theophylline, caffeine and 3-isobutyl-1 methyl xanthine (MIX) inhibited the pressure responses to noradrnealine, angiotensin II and potassium ions in the isolated perfused mesenteric vascular bed of the male rat. The ID50s for inhibition of responses to noradrenaline were 1.85 mug/ml (0.83 x 10(-5) M) for MIX, 18 mug/ml (1 x 10(-4)M) for theophylline and 133 mug/ml (6.8 x 10(-4) M) for caffeine. Similar ID50 concentrations were found for responses to angiotensin II and potassium. We have previously found that substances which inhibit the three pressor agents equally may be prostaglandin (PG) synthesis inhibitors or PG antagonists. Xanthine itself, cyclic AMP and dibutyrl cyclic AMP had no inhibitory effects on the preparation up to concentrations of 10-2 M. Partial inhibition of PG synthesis by indomethacin shifted the % inhibition/log concentration curve to the left, while addition of exogenous PGE2 shifted it to the right. In preparations completely inhibited by sufficient indomethacin added to the perfusate to block PG synthesis, and then restored by adding 1 or 5 ng/ml PGE2 in addition to the indomethacin, the methyl xanthines again inhibited responses suggesting that they were PG antagonists rather than inhibitors of synthesis or release. In preliminary experiments MIX also inhibited effects of PGF2alpha on rat uterus and PGE1 on guinea pig ileum. Effective concentrations of theophylline were similar to the therapeutic levels in human plasma. PG antagonists may be a major action of methyl xanthines requiring reinterpretation of many experiments which have attributed their effects to PDE inhibition. PGs may also be involved in regulating PDE action.

Angiotensin II↗
PubMed1977

Prostaglandin E1 modifies nerve conduction and interferes with local anaesthetic action.

Prostaglandin E1 (PGE1) altered both the amplitude and conduction velocity of the compound action potential in frog sciatic nerve. Concentrations up to 1 ng/ml increased both amplitude and conduction velocity but at higher concentrations both effects were reversed. Procaine, chloroquine, indomethacin and SC19220 all reduced action potential amplitude and conduction velocity. These local anaesthetic type actions could be partially or completely prevented by PGE1.

Action Potentials↗
PubMed1977

Adenosine as a natural prostaglandin antagonist in vascular smooth muscle.

Adenosine has actions on smooth muscle similar to those of prostaglandin (PG) antagonists. Like some PG antagonists it is a phosphodiesterase inhibitor and seems to interfere with calcium effects. It has agonist/antagonist interactions with theophylline, a PG antagonist. In rat mesenteric vascular smooth muscle adenosine blocked responses to noradrenaline which depend on release of intracellular calcium but not those to potassium ions which depend on calcium entry from extracellular fluid. Partial inhibition of endogenous PG synthesis by indomethacin enhanced the adenosine effect. In preparations in which vascular reactivity had been abolished by indomethacin and then partly restored by 1 or 5 ng/ml PG2, adenosine also inhibited responses to noradrenaline: the curve for the 5 ng/ml PG2 concentration was to the right of and parallel to the 1 ng/ml curve consistent with a competitive interaction between adenosine and PG2. Similar interactions between adenosine and PG2 were shown in human lymphocytes in which activation also depends on calcium release. These findings suggest how calcium-dependent metabolic responses may be controlled and indicate further reasons for caution in the interpretation of cyclic AMP experiments.

Adenosine↗
PubMed1977

Actions of the tricyclic antidepressant clomipramine on responses to pressor agents. Interactions with prostaglandin E2.

Clomipramine inhibited pressor responses to potassium ions and vasopressin in the rat mesenteric vascular bed with an ID50 of about 1.8 microgram/ml against both pressor agents and the actions of indomethacin and PG2 on the clomipramine effect suggested that the drug may have been antagonising the action of an endogenous PG. This was supported by the inhibitory action of clomipramine on PG2 actions on guinea-pig ileum. A lower concentration also inhibited pressor responses to noradrenaline and angiotensin (ID50 about 9 ng/ml): inhibition was increased by PG2 and reduced by indomethacin. In this preparation potassium and vasopressin act primarily by stimulating calcium entry from the extracellular fluid whereas noradrenaline and angiotensin act primarily by releasing calcium from intracellular or membrane-bound stores. Our results can be explained by two actions: 1. a PG-antagonist action of clomipramine at the cell membrane and 2. a selectve inhibitory effect on release of intracellular calcium. Clomipramine may prove useful in studying PG and calcium-dependent mechanisms.

Angiotensin II↗
PubMed1977

Effects of propranolol on the responses of the rat stomach strip to prostaglandin E2.

Propranolol is a local anaesthetic, membrane-stabilizing drug as well as a beta blocker. 2 mug/ml is added to many PG bioassay systems in order to inhibit beta adrenergic effects. This concentration inhibited responses of the rat stomach strip to PGE2 concentrations below 5 x 10(-7)M but potentiated responses to higher PGE2 concentrations. In calcium-free buffer only the potentiation was seen. Propranolol may not be a suitable drug for use in PG bioassay systems.

Animals↗
PubMed1977

Interactions between prostaglandins and calcium: the importance of bell-shaped dose-response curves.

Biological responses to PGs show two basic forms of dose/response relationship, plateau and bell-types. Although bell-shaped dose/response curves are well documented their possible occurrence is almost always ignored in the design and interpretation of experiments on PGs and related substances. This may lead to serious errors, several types of which are described. The ignoring of a well-documented phenomenon may take place because there is no accepted hypothesis which attempts to explain the bell-type curves. A hypothesis is proposed which accounts for both plateau and bell type responses. It is developed primarily with respect to PG-calcium interactions but may be applicable to some PG-cyclic nucleotide interactions as well. The model leads to precise predictions which can be experimentally tested in many systems.

Animals↗
PubMed1977

Effects of prostaglandins on baseline pressure and responses to noradrenaline in a perfused rat mesenteric artery preparation. PGE1 as an antagonist of PGE2.

Concentrations of PGE1, PGE2, PGA1, PGA2 and PGF2alpha ranging from 10 to 10(5) pg/ml (2.8 x 10(-11) to 2.8 x 10(-7)M) were perfused through a rat mesenteric vascular bed preparation and their effects on baseline pressure and responses to noradrenaline noted. PGs A2 and FEalpha elevated baseline pressure at concentrations of 100 pg/ml and above but the other three PGs had little or no effect. PGs E2, A1 and F2alpha markedly potentiated responses to noradrenaline at all concentrations studied. In contrast PGs E1 and A2 caused a clear potentiation at 10 pg/ml but at higher concentrations the effect disappeared and concentrations of above 10(4) pg/ml were actually inhibitiory. E1 could antagonize the vascular effects of E2. These results offer possible explanations for some of the confusing findings reported in the literature.

Animals↗
PubMed1977

Myo-inositol in physiological concentrations stimulates production of prostaglandin-like material.

In physiological concentrations myo-inositol stimulated production of prostaglandin (PG)-like material in a rat mesenteric vascular bed preparation. There were five lines of evidence: 1. Inositol potentiated pressor responses to both norepinephrine and potassium in a manner similar to PGE2. 2. Inositol had no potentiating effect in preparations in which endogenous PG production was blocked by indomethacin. 3. Inositol caused no further potentiation in preparations already potentiated by arachidonic acid, the PG precursor. 4. The inhibitory effect of the PG antagonist chloroquine was reduced in an apparently competitive manner by inositol. 5. As indicated by rat stomach bioassay inositol caused a three fold rise in the outflow of PG-like material from the preparation.

Animals↗
PubMed1977

Potentiation of pressor effects of noradrenaline and potassium ions in the rat mesenteric arteries by physiological concentrations of angiotensin II: effects of prostaglandin E2 and cortisol.

1. In the perfused rat mesenteric vascular bed, the effects of angiotensin II, cortisol and prostaglandin E2 on the vascular responses to noradrenaline or potassium chloride were studied. 2. Angiotensin II in subpressor concentrations potentiated the vasoconstrictor response to noradrenaline and potassium chloride. This effect of angiotensin II was inhibited in the presence of indomethacin and prostaglandin E2. 3. Cortisol in physiological concentrations inhibited the potentiating effect of angiotensin II. 4. Prostaglandin E2 enhanced the vasoconstrictor response to noradrenaline. This effect was not abolished by cortisol. 5. These results suggest that some actions of angiotensin II and cortisol in vivo are mediated by the regulation of prostaglandin synthesis or release.

Angiotensin II↗