Lithium Increases the α1-Adrenoceptor Mediated Inotropic Effect in Rat Heart

Abstract: The intracellular mechanisms activated by stimulation of myocardial α₁-adrenoceptors are not known. As in several other tissues, however, activation of α₁-adrenoceptors in heart has been related to breakdown of phosphoinositides resulting in production of putative intracellular messengers: different inositol phosphates and diacylglycerol. Lithium has been shown to inhibit enzymes hydrolyzing inositol phosphates. In the present paper we report studies on the effect of lithium upon the α₁-adrenoceptor mediated inotropic response elicited in electrically driven rat papillary muscles. While there was no shift of the horizontal positioning of the dose-response curve to α₁-adrenergic stimulation in the presence of lithium, the α₁-adrenoceptor mediated inotropic effect was increased in a concentration dependent manner (0.25 to 3.0 mmol/l lithium). For comparison, the effect of lithium upon the β-adrenoceptor mediated inotropic response was also studied. At 3.0 mmol/l lithium, the horizontal position of the dose-response curve to β-adrenoceptor stimulation was shifted significantly to the right (to higher agonist concentrations) and the maximal β-adrenoceptor mediated inotropic response was slightly although not significantly reduced. Thus the augmenting effect of lithium upon the α₁-adrenoceptor mediated response was specific for this receptor type. Although the effect of lithium may be complex, the data are compatible with the hypothesis that the inositol phosphates may be of functional importance during stimulation of myocardial α₁-adrenoceptors.     

Effects of 17β-Oestradiol on Rat Isolated Coronary and Mesenteric Artery Tone: Involvement of Nitric Oxide

Pre- and post-menopausal women receiving oestrogen replacement therapy have a significantly reduced risk of cardiovascular disorders. It has been suggested that this protection might be partly a result of a direct relaxant effect of oestrogens on coronary arteries. This study examines and directly compares the effects of 17β-oestradiol on rat isolated coronary and mesenteric vessels. The influence of nitric oxide on these responses was also investigated. 17β-Oestradiol caused similar concentration-dependent relaxation of isolated coronary and mesenteric resistance arteries pre-contracted with either KCl (60 mM) or 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin (U46619; 1 μM). The relaxation responses to 17β-oestradiol were significantly reduced, but not totally inhibited, in the presence of Nω-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase; they were not altered by indomethacin, an inhibitor of prostaglandin synthesis. The responses to 17β-oestradiol in the presence of L-NAME were not dependent on the vessel studied or the precontracting agent used. These results suggest that nitric oxide might contribute to the vasodilatory effects of 17β-oestradiol in rat isolated coronary and mesenteric resistance arteries.     

α‐Adrenoceptor‐Mediated Modulation of 5‐HT2 Receptor Agonist Induced Impulsive Responding in a 5‐Choice Serial Reaction Time Task

Abstract: The activation of 5‐HT_2A receptors has been shown to enhance the probability of premature responding, regarded as a form of motor impulsive behaviour. At the behavioural level, the interaction of α‐adrenoceptors and 5‐HT₂ receptors has been linked to head twitch behaviour, regarded as an experimental model of compulsive behaviour. The aim was to determine whether the probability of premature responding induced by an excess activation of 5‐HT_2A receptors can be modulated by the blockade of α₁‐ or α₂‐ adrenoceptors. In the experiments, the 5‐choice serial reaction time task was used to measure attention and response control of the rats. The experiments assessed the effects of (±)‐1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane hydrochloride (DOI) 0.1–0.2 mg/kg subcutaneously, a 5‐HT_2A/2C agonist, and prazosin, an α₁–adrenoceptor antagonist, alone or in combination, on the performance of rats. In an additional experiment to examine the possible role of the α₂–adrenoceptors, a potent, selective and specific α₂–adrenoceptor antagonist, atipamezole, was given alone or in combination with DOI. Results showed that DOI increased the probability of premature responses, but it did not affect the choice accuracy. Prazosin (0.1 or 0.3 mg/kg, subcutaneously), given on its own had no effects on probability of responding prematurely, but prazosin (0.3 mg/kg.) was able to attenuate the DOI‐induced responding. Atipamezole (0.1 mg/kg, s.c.) did not attenuate the effect of DOI on probability of premature responding. When given at lower doses, DOI (0.03 mg/kg) and atipamezole (0.03 mg/kg) synergistically increased the probability of premature responding, whereas a higher dose of atipamezole (0.3 mg/kg) on its own increased the probability of responding prematurely, but this effect was not additive to that of 0.1 mg/kg DOI. These data indicate that 5‐HT₂ receptor activation enhances impulsive responding and this effect can be diminished by the blockade of α₁‐adrenoceptors. Atipamezole, an α₂‐antagonist, enhances the probability of premature responding and shares the mechanism of action with the 5‐HT₂ agonist in this respect. These results provide evidence for an interaction between the serotonergic 5‐HT₂ receptors and α‐adrenoceptors in the modulation of response control to the motor impulsivity type of behaviour (premature responding) in addition to that of compulsory behaviour (head shakes) found previously.     

5‐Aminoimidazole‐4‐carboxamide‐1‐β‐d‐ribofuranoside Increases Myocardial Glucose Uptake during Reperfusion and Induces Late Pre‐conditioning: Potential Role of AMP‐Activated Protein Kinase

Abstract: Late pre‐conditioning protects against myocardial ischaemic‐reperfusion injury. AMP‐activated protein kinase (AMPK) is activated by exercise and 5‐aminoimidazole‐4‐carboxamide‐1‐β‐d ‐ribofuranoside (AICAR). Early pre‐conditioning involves AMPK activation and increased myocardial glucose uptake. The aim of the present study was to determine whether AICAR activates myocardial AMPK and induces late pre‐conditioning and whether myocardial glucose uptake during reperfusion was modulated. Twenty‐four hours after AICAR treatment or exercise, Wistar rats were subjected to ischaemia and reperfusion in a Langendorff model and compared to control rats. AMPK activity increased immediately 2.5‐fold in AICAR‐treated animals (P < 0.01) and twofold in exercised animals (P < 0.05). AICAR and exercise reduced infarct size by 60% and 50% (both P < 0.01), respectively, and increased myocardial glucose uptake during reperfusion (AICAR; 45%, P < 0.05, exercise; 40%, P < 0.05). In conclusion, AICAR induces late pre‐conditioning and increases myocardial glucose uptake during reperfusion in rat hearts. AICAR and exercise activate AMPK, suggesting a role of AMPK in the signalling mechanisms behind late pre‐conditioning.     

Peroxisome Proliferator‐Activated Receptor α Activation Suppresses Cytochrome P450 Induction Potential in Mice Treated with Gemfibrozil

Gemfibrozil, a peroxisome proliferator‐activated receptor α (PPARα) agonist, is widely used for hypertriglyceridaemia and mixed hyperlipidaemia. Drug–drug interaction of gemfibrozil and other PPARα agonists has been reported. However, the role of PPARα in cytochrome P450 (CYP) induction by fibrates is not well known. In this study, wild‐type mice were first fed gemfibrozil‐containing diets (0.375%, 0.75% and 1.5%) for 14 days to establish a dose–response relationship for CYP induction. Then, wild‐type mice and Pparα‐null mice were treated with a 0.75% gemfibrozil‐containing diet for 7 days. CYP3a, CYP2b and CYP2c were induced in a dose‐dependent manner by gemfibrozil. In Pparα‐null mice, their mRNA level, protein level and activity were induced more than those in wild‐type mice. So, gemfibrozil induced CYP, and this action was inhibited by activated PPARα. These data suggested that the induction potential of CYPs was suppressed by activated PPARα, showing a potential role of this receptor in drug–drug interactions and metabolic diseases treated with fibrates.