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Biomedical subjects

M Karmazyn

Publications and source records attributed to M Karmazyn.

At least 127 records · Page 7Linked to original sources
PubMed1979

Thromboxane B2: a cardiodepressant of isolated rat hearts and inhibitor of sarcolemma Na+ - K+ stimulated ATPase activity.

The actions of thromboxane B2 on various parameters of cardiac performance were studied using the isolated perfused rat heart model. In concentrations from 100 pg/ml to 1 microgram/ml TXB2 significantly reduced the total generated myocardial contractile force. These changes were usually associated with an increase in the coronary perfusion pressure indicating an elevated coronary vascular resitance. Significant coronary pressure alterations were seen with TXB2 concentrations between 1 ng/ml and 1 microgram/ml. No significant changes were seen in either the resting tension or heart rate after TXB2 administration. However TXB2 (10 pg/ml to 10 ng/ml,, significantly reduced the amplitude of the electrical activity as observed in R wave changes of the surface electrocardiogram recording. In another series of experiments the action of TXB2 on rat heart sarcolemmal ATPase activity was studied. TXB2 significantly reduced the activity of the MG++ dependent - Na+ - K+ stimulated ATPase (Na+ - K+ ATPase) in these membrane preparations in concentrations from 10 ng/ml to 1 microgram/ml. Kinetic studies demonstrated that TXB2 reduced Vmax and increased the concentration required of ATP, Na+ and K+ for half-maximal enzyme activity. TXB2 did not inhibit either Ca++ or ouabain-induced depression of Na+ - K+ ATPase activity. The activity of either Mg++ or Ca++ - stimulated ATPase was not affected by TXB2. These results suggest possible important actions of TXB2 on rat heart activity which may be related to Na+ - K+ ATPase inhibition.

Animals↗
PubMed1979

The mechanism of coronary artery spasm: roles of oxygen, prostaglandins, sex hormones and smoking.

A reduced oxygen supply to the heart causes coronary vasodilatation in the first instance. But if the hypoxia is severe or prolonged, the dilatation passes off and coronary vasospasm develops leading to a vicious circle with a further reduction of myocardial oxygenation. The spasm is associated with increased outflow of prostaglandin (PG)-like material and can be prevented or reversed by inhibitors of PG synthesis such as indomethacin or antagonists of PG action such as chloroquine. The spasm does not appear to be caused by thromboxane (TX) A2 since selective inhibitors of TXA2 synthesis enhance the hypoxic spasm and by themselves can cause spasm even in oxygenated hearts. The mechanism may be related to loss of negative feedback control of the PG pathway by TXA2. Oxygen may enhance TXA2 production and reduce formation of vasoconstrictor PGs, while smoking, because of the formation of carboxyhaemoglobin, may have the opposite effect. Oestradiol and testosterone do not influence the hypoxic spasm but progesterone at physiological concentrations blocks it completely. Progesterone may be the protective female hormone and the increased susceptibility to myocardial infarction in women on oral contraceptives may be related to reduced formation of endogenous progesterone.

Coronary Circulation↗
PubMed1979

Thymic changes in muscular dystrophy and evidence for an abnormality related to prostaglandin synthesis or action.

In Bar Harbor 129 dystrophic mice, thymic development is abnormal. Before weaning, the thymus is slightly smaller than in phenotypically normal littermates; after weaning, however, the lymphoid elements undergo rapid atrophy. The epithelial elements, in contrast, display hyperlasia. Thymectomy has no influence on the course of the disease, and it is possible that the thymic changes are a reflection of a fundamental metabolic abnormality. Thymic lymphoid tissue development seems to require normal levels of PGE1. Levels that are either too high or too low both result in abnormalities. We have investigated the effects of PGE1 in smooth muscle and have demonstrated that while some PGE1 is required for both calcium release and calcium removal, high levels of PGE1 block both processes. We propose that the muscular dystrophies are related to defects in PG synthesis and action. Myotonic dystrophy may be due to PGE11 excess, whereas Duchenne dystrophy may in part be due to PGE1 deficiency.

Aging↗
PubMed1979

Copper inhibits pressor responses to noradrenaline but not potassium. Interactions with prostaglandins E1, E2, and I2 and penicillamine.

Low concentrations of copper inhibited responses to norepinephrine and angiotensin (IC50 3 X 10(-6) M) but not to potassium in rat mesenteric vascular preparations perfused either with buffer or indomethacin and prostaglandin (PGE2). The dose-response curve was not shifted by indomethacin, imidazole, or PGE2 but was moved to the right by 2.8 X 10(-11) M PGE1 and to the left by 2.8 X 10(-7) M PGE1. These effects of copper are similar to the effects of PGI2 in the preparation. Copper moved the PGI2 dose-response curve against noradrenaline in parallel to the left, suggesting that the two were interacting at some point. Penicillamine, which may stimulate PGE1 synthesis, had PGE1-like interactions with the copper effect, suggesting that its value in Wilson's disease may be partly due to antagonism of the biological action of copper as well as to its copper-chelating properties.

Animals↗
PubMed1979

Prolactin and zinc effects on rat vascular reactivity: possible relationship to dihomo-gamma-linolenic acid and to prostaglandin synthesis.

Ovine PRL at low concentrations potentiated pressor responses to norepinephrine and angiotensin in an isolated perfused rat mesenteric vascular preparation. Higher concentrations inhibited these pressor responses. Pressor responses to potassium which depend on extracellular calcium entry into the muscle were unaffected by PRL at any concentration. Either cortisol or lithium could completely block the PRL effect. Dihomo-gamma-linolenic acid (DHGL) and prostaglandin E1 had effects similar to those of PRL in that they potentiated norepinephrine responses at low concentrations, inhibited at high ones, and had no effect on potassium responses. Arachidonic acid and prostaglandin E2 potentiated both norepinephrine and potassium responses and had no inhibitory effects at high concentrations. Neither lithium nor cortisol blocked the effects of DHGL or arachidonic acid. Zinc had actions similar to those of PRL and DHGL, but which could be blocked only by lithium and not by cortisol. These results are consistent with the concept that PRL increases synthesis of the 1 series of prostaglandins by mobilizing DHGL. They provide further evidence that zinc may play a role in some actions of PRL.

8,11,14-Eicosatrienoic Acid↗
PubMed1978

Low prostaglandin concentrations cause cardiac rhythm disturbances. Effect reversed by low levels of copper or chloroquine.

In perfused male rat hearts concentrations of prostaglandins (PGs) E2 and F2alpha in the range 1 pg/ml to 10 ng/ml (2.8 X 10(-12) to 2.8 X 10(-8)M) consistently caused rhythm irregularities. Higher concentrations had no effect themselves and stabilized rhythm in hearts made unstable by lower concentrations. Copper ions (as the sulphate) at 2 X 10(-6)M stabilized hearts made unstable by PGs and when present prior to the PGs prevented PG induced disturbances. Chloroquine also reversed PG-induced rhythm changes.

Animals↗
PubMed1978

A defect in thromboxane A2 synthesis may be a factor predisposing to cancer.

A failure of thromboxane (TX) A2 synthesis may be a factor in cancer. Such a loss could explain the susceptibility to mutation, the excess prostaglandin production, the glycolytic mode of metabolism and the deranged calcium pumping characteristic of cancers. Ionising radiation and phorbols both have actions similar to inhibitors of TXA2 synthesis whereas colchicine and oxygen have actions consistent with stimulation of TXA2 synthesis. The concept accounts logically for hitherto unexplained features of cancer and suggests new strategies for the prevention and treatment of cancer.

Animals↗
PubMed1978

Ultra-violet radiation and 8-methoxypsoralen have actions similar to those of known inhibitors of thromboxane A2 synthesis in rat mesenteric blood vessels.

In the rat mesenteric vascular bed three structurally different agents (imidazole, benzydamine and N-0164) which have been reported to be inhibitors of thromboxane (TX) A2 synthesis at certain concentrations, all have a characteristic spectrum of action. They inhibit pressor responses to noradrenaline and angiotensin with equal potency and the inhibition can be reversed by exogenous PGE2: they do not inhibit responses to potassium. Ultra-violet (UV) radiation has a similar spectrum of action. The main difference between the action of imidazole and that of UV radiation is that the former is rapidly reversible while the latter is not. However, irradiation administered to preparations inhibited by imidazole has no irreversible effect provided that the radiation is switched off before the imidazole is removed. The imidazole protects against radiation damage suggesting that the drug may stabilize the site affected by UV light. 8-methoxypsoralen, a light sensitizing agent used in treatment of psoriasis also inhibited noradrenaline and angiotensin but not potassium responses and seemed to make the preparation more sensitive to radiation damage. It is possible that UV radiation and 8-methoxypsoralen may inhibit TXA2 synthesis but this requires confirmation by direct methods.

Angiotensin II↗
PubMed1978

Influence of agents which modulate thromboxane A2 synthesis or action on R3230AC mammary carcinoma.

The effects of agents which modulate thromboxane A2 synthesis or action, were tested in the R3230AC transplanted mammary tumour. Three different inhibitors of thromboxane A2 synthesis or action (copper, dipyridamole and diazepam) all caused an increase in tumour growth. Colchicine and melatonin, both stimulators of thromboxane A2 synthesis, inhibited the growth of the tumour significantly.

Animals↗
PubMed1978

Prostaglandins and schizophrenia: further discussion of the evidence.

It has been proposed that schizophrenia is a prostaglandin-deficiency disease and also that it is a disease of prostaglandin excess. New evidence is reviewed which suggests that 'classic' schizophrenia is due to a specific deficiency of prostaglandin E1 while certain toxic and vitamin-deficiency psychoses may be due to a broader spectrum of prostaglandin deficiency. There is also good evidence that a particular schizophrenic subgroup, which includes catatonic schizophrenia but may not be confirmed to it, is associated with an excess of prostaglandins. Part of the explanation may be that prostaglandin E1 has a 'bell-shaped' dose-response curve with high concentrations having effects similar to those of prostaglandin deficiency.

Animals↗
PubMed1978

Dantrolene blocks intracellular calcium release in smooth muscle: competitive antagonism of thromboxane A2.

Dantrolene sodium has been shown to block the release of intracellular calcium in skeletal muscle. It has been proposed that dantrolene blocks the movement and (or) action of a natural calcium ionophore. In a rat vascular preparation dantrolene was found to inhibit pressor responses to noradrenaline and angiotensin but not those to potassium with an IC50 concentration within the therapeutic levels in man. Imidazole, an inhibitor of thromboxane A2 (TXA2) synthesis, had similar actions to dantrolene. Interactions between imidazole and dantrolene suggested that dantrolene may be a competitive antagonist of TXA2 in muscle. We report the first demonstration of an effect of dantrolene sodium on smooth muscle contractility and suggest that TXA2 is an essential modulator of vascular reactivity. A similar role has been shown for TXA2 in platelets.

Angiotensin II↗
PubMed1978

Changes of vascular reactivity induced by low vasopressin concentrations: interactions with cortisol and lithium and possible involvement of prostaglandins.

Arginine vasopressin in physiological concentrations potentiated the vascular effects of various vasoconstrictor agents. By using the isolated rat mesenteric artery preparation, the pressor effects of norepinephrine, angiotensin II, and potassium chloride were all significantly increased when vasopressin was added to the perfusion buffer. Cortisol and lithium both inhibited the potentiating effect of vasopressin but had no effect on the control pressor response to norepinephrine. When the vascular effects of norepinephrine were first blocked with indomethacin and then restored by the addition of prostaglandin E2, the potentiation by vasopressin was almost completely prevented. This suggests that vasopressin may be acting by stimulating prostaglandin biosynthesis. Cortisol and lithium may exert their inhibitory effects by preventing the activation of prostaglandin synthesis by vasopressin. These findings may be of clinical significance because the phenomena occur well within the range of vasopressin levels found in human plasma.

Angiotensin II↗
PubMed1978

Regulation of cytoplasmic calcium: interactions between prostaglandins, prostacyclin, thromboxane A2, zinc, copper and taurine.

The regulation of cytoplasmic calcium is a key process in nerve tissue. Using a smooth muscle model we have shown that prostaglandin (PG) E2 probably regulates entry from extracellular fluid, whereas the release from intracellular stores depends on the interplay between thromboxane (TX) A2, PGEI and prostacyclin. Hormones and other agents interact with this system in the following ways: vasopressin, angiotensin and inositol mobilize arachidonic acid from membrane phospholipids and increase synthesis of PGE2 and TXA2, cortisol blocks this action. Prolactin and zinc mobilize dihomo-gamma-linolenic acid and increase synthesis of PGEI. These effects can be blocked by cortisol, lithium and taurine, three agents which on their own have no effect on basal PG production. Epileptogenic agents like penicillin and picrotoxin also stimulate PG synthesis, while diphenylhydantoin is a PG antagonist and diazepam is a TXA2 antagonist. The effects of all these agents occur at concentrations which are physiological in the case of the natural ones, and readily attained in human plasma in the case of the drgus. In view of recent evidence that calcium may be important in demyelination and considering the established role it plays in nerve conduction and synaptic transmission, we suggest that these observations may be of significance in understanding Friedreich's ataxia.

Animals↗