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Biomedical subjects

S C Cunnane

Publications and source records attributed to S C Cunnane.

159 records · Page 9Linked to original sources
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

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↗
PubMedDate not supplied

Dietary carbohydrate influences tissue fatty acid and lipid composition in the copper-deficient rat.

Fructose and copper have been shown independently to influence long chain fatty acid metabolism. Since fructose feeding exacerbates copper deficiency, their possible interaction with respect to tissue long chain fatty acid and lipid composition was studied. Weanling male Sprague-Dawley rats were given diets containing 0.6 or 6 mg/kg copper. The carbohydrate source (627 g/kg) was either fructose or corn starch. After 3 wk, fatty acid profiles and total lipids in heart and liver were analyzed. Copper-deficient rats fed fructose had more severe signs of copper deficiency than those fed starch, according to heart/body wt ratio, hematocrit, and liver copper content. The fatty acid composition of heart and liver triacylglycerol was significantly different between groups, but the changes did not correlate with the severity of copper deficiency. In heart, phosphatidylinositol and phosphatidylserine, arachidonic acid and docosapentaenoic acid (n-6) were increased 193 and 217%, respectively, p less than 0.05) in rats given the copper-deficient diet containing fructose. Changes in the long chain fatty acids in heart phospholipids may be related to the higher mortality commonly observed in rats fed a copper-deficient diet containing fructose.

Animals↗
PubMedDate not supplied

Carbon recycling into de novo lipogenesis is a major pathway in neonatal metabolism of linoleate and alpha-linolenate.

Recent reports indicate that recycling of the beta-oxidized carbon skeleton of linoleate and alpha-linolenate into newly synthesized cholesterol and fatty acids in the brain is quantitatively significant in both suckling rats and pre- and postnatally in rhesus monkeys. The recycling appears to occur via ketones which are not only readily produced from these 18 carbon polyunsaturates but are also the main lipogenic precursors for the developing mammalian brain. Since the neonatal rat brain appears not to acquire cholesterol or long chain saturated or monounsaturated fatty acids from the circulation, ketones and ketogenic precursors seem to be crucial for normal brain synthesis of these lipids. Cholesterol is plentiful in brain membranes and it has also been discovered to be the essential lipid adduct of the 'hedgehog' family of proteins, the appropriate expression of which determines normal embryonic tissue patterning and neurological development. Insufficient cholesterol or inappropriate expression of 'sonic hedgehog' has major adverse neurodevelopmental consequences typified in humans by Smith-Lemli-Optiz syndrome. Hence, we propose that the importance of alpha-linolenate and linoleate for normal neural development arises not only from being precursors to longer chain polyunsaturates incorporated into neuronal membranes but, perhaps equally importantly, by being ketogenic precursors needed for in situ brain lipid synthesis.

Animals↗
PubMedDate not supplied

Potential role of polyunsaturates in seizure protection achieved with the ketogenic diet.

Epilepsy is a serious neurological disease that responds to two very different treatments involving lipids. Clinically, it responds to a state of ketosis induced by a very high-fat 'ketogenic' diet. Experimentally, in vitro and in vivo models demonstrate that injection or infusion of free (non-esterified) polyunsaturates such as arachidonate and docosahexaenoate also reduces seizure susceptibility. In our experience, rats on a very high-fat ketogenic diet not only have mild-to-moderate ketosis, but also have raised serum free fatty acids. Some polyunsaturates, particularly linoleate and alpha-linolenate, are relatively easily beta-oxidized and are therefore ketogenic. We conclude that raised levels of free plasma polyunsaturates could contribute to the beneficial effect of the ketogenic diet in refractory epilepsy not only by helping sustain ketosis, but also by their own direct (though poorly defined) antiseizure effects.

Adipose Tissue↗
PubMedDate not supplied

Low zinc intake increases apparent oxidation of linoleic and alpha-linolenic acids in the pregnant rat.

Dietary zinc deficiency impairs desaturation and elongation of linoleic acid, but nothing is so far known about its effects on net whole-body utilization of linoleic or alpha-linolenic acids. By measuring intake, whole-body accumulation, and excretion of linoleic and alpha-linolenic acids, together with accumulation of their long-chain products, we hypothesized that a quantitative estimate could be obtained of their whole-body disappearance (apparent oxidation). This was evaluated in pregnant and non-pregnant rats given a low-zinc diet (3.4 vs. 34 mg zinc/kg diet in zinc-adequate controls). In the nonpregnant controls, low zinc intake did not significantly affect food intake or weight gain but did reduce whole-body accumulation of desaturated and (or) elongated products of linoleic and alpha-linolenic acids. In pregnant rats, low zinc intake reduced food intake and weight gain and doubled whole-body disappearance of linoleic and alpha-linolenic acids relative to that in the zinc-adequate controls. In contrast to the maternal fatty acid changes, low zinc intake had no significant effect on linoleic acid accumulation in the fetuses. We conclude that low zinc intake during pregnancy prevents the normal accumulation of long-chain fatty acids and differentially depletes maternal whole-body stores of linoleic and alpha-linolenic acids.

Animals↗
PubMedDate not supplied

NMR and isotope ratio mass spectrometry studies of in vivo uptake and metabolism of polyunsaturates by the developing rat brain.

This article describes the application of in vivo 13C-nuclear magnetic resonance (NMR) spectroscopy and gas chromatography (GC)-combustion-isotope ratio mass spectrometry to the study of brain uptake and metabolism of polyunsaturated fatty acids in the suckling rat model. NMR spectroscopy is uniquely suited to the non-invasive detection of nonradioactive metabolites in living animals. We applied this approach to the noninvasive detection of 13C-arachidonate in brain and liver of living suckling rats but found that technical limitations in our model, mainly poor signal-to-noise, largely prevent useful results at this time. However, in a tracer study using simultaneous doses of 13C-gamma-linolenate and 13C-arachidonate, 13C-NMR of tissue lipid extracts quantitatively demonstrated a 10-fold greater (liver) or 17-fold greater (brain) accumulation of pre-formed vs newly synthesized arachidonate. GC-combustion-isotope ratio mass spectrometry was used to trace the utilization of [U-13C]-alpha-linolenate into three products in the brain: docosahexaenoate, cholesterol, and palmitate. The rationale was that although alpha-linolenate is used in de novo lipogenesis, the quantitative importance of this pathway is unknown. Our results in the suckling rat show that 2-13% of carbon from [U-13C]-alpha-linolenate appearing in brain lipids is in docosahexaenoate while the rest is in brain lipids synthesized de novo. Overall, these results indicate that the suckling rat brain prefers pre-formed to newly synthesized arachidonate and that alpha-linolenate is readily utilized in brain lipid synthesis. These methods are suited to comparative studies of the metabolism of polyunsaturates and they support previous observations that the metabolism of some polyunsaturates such as alpha-linolenate extends well beyond the traditional desaturation-chain elongation pathway.

Animals↗
PubMedDate not supplied

The vascular response to zinc varies seasonally: effect of pinealectomy and melatonin.

The effect of physiological concentrations of zinc on the in vitro pressor responses of male Wistar rat mesenteric preparations to norepinephrine was systematically studied over a 2-year period. A marked seasonal variation in the response of the preparations was observed over a range of zinc concentrations from 3.5 X 10(-11) to 3.5 X 10(-6) M. All concentrations of zinc inhibited pressor responses during the winter (November to March), but during the spring months (April to May) zinc became very much less effective and low concentrations of zinc potentiated the response. Inhibition of the pressor response at this time only occurred at zinc concentrations above 3.5 X 10(-7) M. In the summer months. (June to September) the zinc effect shifted back towards the winter situation with lower concentration of zinc potentiating and higher concentrations inhibiting vasoconstriction. Pinealectomy of the rats a week prior to preparation of the mesenteric beds very significantly enchanced pressor responses to norepinephrine in the winter months but had much less effect in the summer. The seasonal variation noted in preparations from control rats was maintained following pinealectomy but the amplitude was reduced. Perfusion of melatonin (4.3 X 10(-10) M through preparations from pinealectomized rats enhanced the inhibitory effect of zinc compared to the response to zinc from similarly perfused preparations from control rats. Thus, the rat mesenteric vascular bed is an in vitro model of seasonal variation in vascular reactivity which is sensitive to physiological concentrations of zinc. The origin of the seasonal rhythmicity remains speculative particularly in view of the fact that the rats were maintained under constant photoperiod. That the pineal may modulate the seasonal effect of zinc is suggested by the shift in response to zinc following pinealectomy. Melatonin reversed the effect of pinealectomy on this preparation implicating it as a possible mediator of normal vascular reactivity to zinc. A possible influence of magnetic radiation in evaluating the occurrence of seasonally varying phenomena in vitro should be considered.

Animals↗
PubMedDate not supplied

Response of individual serum free fatty acids to oral and intravenous glucose: relation to adipose tissue composition.

The rate of oral glucose delivery determines whether serum total free fatty acids remain low (glucose sipping over 210 min) or rebound 120-180 min after initial suppression (via glucose bolus), but the response of individual serum free fatty acids to glucose ingestion is largely unknown. In this study, we measured the changes over 240 min in the levels of individual serum free and esterified fatty acids after bolus or sipped glucose ingestion and determined the extent to which the changes are related to abdominal subcutaneous adipose tissue composition. In eight healthy volunteers, 74% of the prolonged suppression of total serum free fatty acids resulting from sipping 50 g glucose over 210 min was caused by a decrease in free linoleic and oleic acids, whereas 92% of the rebound in total free fatty acids 240 min after consuming 50 g of glucose as a bolus was caused by increases in free oleic and linoleic acids. Two hundred forty minutes after the oral glucose, slower intravenous clearance of 5 g glucose was directly correlated to higher total serum free fatty acids and free stearic acid and higher oleic but lower linoleic acid in adipose tissue. We conclude that the net response of serum free fatty acids to an oral glucose load is mediated primarily by oleic and linoleic acids in a manner largely unrelated to adipose tissue composition.

Abdomen↗