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Fibromyalgia (FM) is often accompanied by chronic fatigue syndrome (CFS). It is a poorly understood disorder that mainly affects women and leads to chronic pain, fatigue, and insomnia, among other symptoms, which decrease quality of life. Due to the inefficiency of current pharmacological treatments, increasing interest is being directed towards non-pharmacological multicomponent therapies. However, nutrition and chronobiology are often overlooked when developing multicomponent therapies. This narrative and critical review explore the relevance of nutritional and chronobiological strategies in the therapeutic management of FM and the often-associated CFS. Reviewed literature offers scientific evidence for the association of dietary habits, nutrient levels, body composition, gut microbiota imbalance, chronobiological alterations, and their interrelation with the development and severity of symptoms. This review highlights the key role of nutrition and chronobiology as relevant and indispensable components in a multidisciplinary approach to FM and CFS.

The reactivity to methoxamine (Met) of atria isolated from the hearts of normal and from acutely streptozotocin-diabetic rats has been studied. Met (1 X 10(-6) M) increased the tension of both normal and diabetic atria, but in diabetic atria, the dose-response curve to Met was shifted to the left and the efficacy of Met was enhanced. Inhibitors of alpha-adrenoceptors blocked, in a competitive manner, the positive inotropic effect induced by Met in both types of atrial preparations. Inhibitors of the cyclo-oxygenase pathway for arachidonic acid metabolism blocked the atrial response to Met in non-diabetic as well as in diabetic atria. The inhibition of prostacyclin synthetase prevented the effect of Met in normal atria, while blockers of thromboxane generation inhibited it in diabetic ones. Agents that inhibit the activity of lipoxygenase(s) significantly reduced the positive inotropic action induced by Met in diabetic atria but failed to modify it in non-diabetic preparations. These results show that diabetic atria are more sensitive to Met than normal atria. In diabetes the response to alpha-adrenoceptor stimulation could be mediated by oxidative product generated via thromboxane synthetase and lipoxygenase(s) activities; whereas in normal preparations the action of Met may involve the release of prostacyclin.

The effects of a wide range of Prostacyclin (PGI2) concentrations on the Isometric Developed Tension (IDT) of isolated left auricles driven at different frequencies (0.8, 1.6 or 3.3 Hz) were explored. A comparison of the positive inotropism of PGI2, norepinephrine (NE), tyramine and phenylephrine (Phenyl) indicated that PGI2, NE and tyramine enhanced peak tension significantly less at slow (0.8 and 1.6 Hz) than at higher rates (3.3 Hz); whereas Phenyl augmented equally the IDT at all of these three driving frequencies. The positive inotropism evoked by PGI2 was inhibited by (-)-propranolol and also by a treatment with 6-OHDA. Cocaine, normetanephrine and U-0521, augmented the positive inotropic influence of PGI2 on atria paced at a slow rate (0.8 Hz) but not at a faster one (3.3 Hz). These results suggest that the action of PGI2 on atrial contractions is apparently indirect and mediated by the release of tissue catecholamines. In addition the effect of PGI2 and NE at slow and fast rates appears associated with a different relative relevance of the processes which terminate the action of added sympathomimetic agonists, namely, neuronal or extraneuronal uptake as well as metabolization via COMT. These mechanisms seen to be more prominent at slower driving frequencies and could explain the diminished effect of PGI2 and NE on slowly paced atria.

The effects of chagasic sera containing an antibody (EVI antibody) on "non toxic" and "toxic" actions of ouabain on isolated rat atria suspended in different media, were explored. Ouabain failed to evoke any significantly positive contractile effect on atria beating in EVI Positive Human Sera (EVI(+)S), and only produced "toxic" actions (arrhythmias, contracture enhanced frequency, reduced inotropism). On the contrary, atria beating in Krebs-Ringer-Bicarbonate (KRB) or in Normal Human Sera (NHS) reacted to added ouabain with a classical dose-dependent positive inotropic effect. The threshold concentration of ouabain required to elicit the onset of "toxic" effects was higher in KRB than in EVI(+)S. Decreasing the extracellular Ca2+ concentration or treating the auricles with verapamil, facilitated positive inotropic influence of ouabain and attenuated the "toxic" effects observed on atria beating in EVI(+)S. In addition, the combination of (--)-propranolol plus verapamil enhanced the facilitatory influence of verapamil induced on the positive inotropic effect of ouabain and reduced the "toxic" influences evoked on atria exposed to EVI(+)S. These findings support the notion that the overall "toxic" responses to ouabain on cardiac tissue immersed in an EVI(+)S containing solution may be related to a combined effect of the EVI antibody activating beta-adrenoceptors as well as to a rise in the tissue Ca2+ content.

Contractile responses to exogenous sodium arachidonate (NaA) were studied in auricles from normal and acutely diabetic (streptozotocin-treated) rats. NaA induced a concentration-dependent positive inotropic effect in atria from normal and diabetic rats but the magnitude of the contractile influence of the fatty acid was different in both types of auricles, i.e. diabetic atria had a greater responsiveness to NaA than normal preparations. Blockers of arachidonic acid (AA) metabolism via cyclo-oxygenase (indomethacin and acetylsalicylic acid), abolished the stimulatory influence of NaA in normal and in diabetic auricles. Moreover, incubation with tranylcipromine, a prostacyclin synthetase inhibitor, reduced the inotropic effect of NaA in normal atria, but failed to modify it in the diabetic atria. On the other hand, inhibitors of thromboxane (TX) synthetase (imidazole and L-8027) diminished the effect of NaA in diabetic preparations without altering the contractile responses in the controls. In the presence of lipoxygenase blocking agents (nordihydroguaiaretic acid and dithizone), the influence of NaA was reduced at normal values only in the atria from diabetic rats. Both atrial preparations (normal and diabetic) converted ([1-14C]arachidonic acid (AA) into PGI2 (assessed as 6-oxo-PGF1 alpha) and TXB2. Moreover, normal atria generated more PGI2 than TXB2 whereas TXB2 production was greater than that of PGI2 in diabetic atria. The foregoing results suggest that in non-diabetic atria the effect of exogenous NaA may be attributed to metabolites generated by the sequential action of cyclo-oxygenase and prostacyclin synthetase. On the other hand, the contractile action of exogenous NaA in diabetic atria may be ascribed to thromboxanes and lipoxygenase(s) metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of chagasic sera, containing an antibody (EVI antibody) which reacts with the plasma membrane of working myocardial cells, on "toxic" and "non-toxic" actions of ouabain upon isolated self beating or paced rat atria suspended in different media, were explored. Although ouabain produced a dose-dependent positive inotropic influence on atria suspended in Krebs-Ringer-bicarbonate (KRB) and in KRB plus normal human serum (KRB + NHS) it did not elicit any significant positive inotropic effect on atria beating in KRB plus EVI positive human chagasic serum (EVI(+)S). Additionally, EVI(+)S dose-response curves of classical signs of digitalis cardiac toxicity shifted to the left. The threshold concentration of ouabain required to elicit the onset of "toxic" effects was higher in control preparations (kept in KRB or KRB + NHS) than in EVI(+)S exposed preparations. (-)-Propranolol attenuated the overall toxic action of ouabain in EVI(+)S and facilitated its positive inotropic influence. In control media, the beta-adrenoceptor blocker failed to modify either the "non-toxic" or the "toxic" effect of ouabain. On the other hand, with control atria, subthreshold exogenous norepinephrine inhibited the positive inotropism of ouabain. The data suggest that an adrenergic mechanism is involved in the action of ouabain on cardiac tissue immersed in an EVI(+)S-containing solution. The foregoing results may explain the severe "toxic" effects observed with cardioactive glycosides when they are used in patients with Chagas' heart disease, even at low doses.

Contractile response to exogenous prostaglandin E2 (PGE2) was studied in auricles from normal and acutely-diabetic (streptozotocin-treated) rats. In normal atria, PGE2 induced a biphasic inotropic effect negative at low concentrations and positive at higher ones. In diabetic, PGE2 only elicited a positive inotropic action which was greater in efficacy and potency than in normal controls. Incubation of diabetic atrial preparations with alpha-adrenoceptor antagonists (phentolamine, phenoxybenzamine or Prazosin) diminished the prostaglandin effect. However, blockade of beta-adrenoceptors with propranolol did not modify the response. Blockers of arachidonic acid metabolism via cyclo-oxygenase (indomethacin and acetylsalicylic acid) or via lipoxygenase(s) (nordihydroguaiaretic acid and dithizone) were able to reduce the positive inotropism of PGE2. A significant blockade of the stimulant action of PGE2 was seen in the presence of inhibitors of thromboxane synthesis (L-8027 and imidazole). These results suggest that in diabetic atria PGE2 effect could be associated to an involvement of cardiac alpha-adrenergic stimulation which promotes endogenous arachidonic acid release with diversification of its metabolism towards cyclo- and lipoxygenase(s)- pathway and direct to an increased thromboxane formation which could account for the positive inotropic effect induced by PGE2.

Atrial contractile response to U-46619 was studied in auricles from normal and acutely diabetic rats. U-46619 induced an increment of dF/dt in diabetic atria, whereas nondiabetic auricles elicited a negative contractile effect. Blockers of arachidonic acid metabolism via cyclooxygenase inhibited the stimulatory action of U-46619. The stimulant action of the thromboxane A2 mimetic was attenuated when diabetic auricles were incubated with lipoxygenase(s) blocking agents. Results suggest that in diabetic atria, the abnormal inotropic effect induced by U-46619 may be associated with thromboxane formation and with lipoxygenase(s) metabolites.

The influences of different extracellular K+ concentrations and of blockers of potassium and calcium movements through cell membranes (perhexiline and SKF-525A) on the effects of ouabain on self beating isolated rat atria, both "non toxic" (positive inotropism without changes in contractile frequency or resting tension) and "toxic" (positive chronotropism, negative inotropism, contracture, arrhythmia), were explored. Decreasing extracellular K+ from 6 to 3 mM potentiated both the positive inotropic influences as well as the "toxic" effect of ouabain, whereas, increasing K+ from 6 to 8 mM delayed but potentiated the onset of the "non toxic" influences of the drug and abolished its "toxic" responses. Perhexiline and SKF-525A, sensitized the tissue to the "non toxic" effects of the glycoside, attenuated contracture but increased the positive chronotropic action. The aforementioned results suggest that factors which modify potassium environment (i.e., variable extracellular potassium concentration and ion-flux blocking agents) resulted in significant modification of the effect of ouabain on isolated rat myocardium.