Naunyn-Schmiedebergs Archiv für Pharmakologie und experimentelle Pathologie

Hyperlipidemia is regarded as independent risk factor in the development of ischemic heart disease, and it can increase the myocardial susceptibility to ischemia-/reperfusion (I/R)-induced injury. Hyperlipidemia attenuates the cardioprotective response of ischemic preconditioning (IPC). The present study investigated the effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat hearts. Hyperlipidemia was induced in rat by feeding high-fat diet (HFD) for 6 weeks then the serum lipid profile was observed. In experiment, the isolated Langendorff rat heart preparation was subjected to 4 cycles of ischemic preconditioning (IPC), then 30 min of ischemia followed by 120 min of reperfusion. Myocardial infarct size was elaborated morphologically by triphenyltetrazolium chloride (TTC) staining and biochemically by lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) release from coronary effluent and left ventricular collagen content. However, the effect of zinc supplement, i.e., zinc pyrithione (10 μM) perfused during reperfusion for 120 min, significantly abrogated the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart whereas administration of chelator of this zinc ionophore, i.e., N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylene diamine (TPEN; 10 μM), perfused during reperfusion 2 min before the perfusion of zinc pyrithione abrogated the cardioprotective effect of zinc supplement during experiment in hyperlipidemic rat heart. Thus, the administration of zinc supplements limits the infarct size, LDH, and CK-MB and enhanced the collagen level which suggests that the attenuated cardioprotective effect of IPC in hyperlipidemic rat is due to zinc loss during reperfusion caused by ischemia/reperfusion.

The aim of the present study was to assess the effect of diethylcarbamazine (DEC), siver nanoparticles (AgNPs), nitazoxanide (NTZ), and a combination of nitazoxanide with silver nanoparticle (NTZ+AgNPs) against the microfilariae of Setaria cervi in experimentally infected albino rats. The NTZ+AgNPs was synthesized and subsequently characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), UV-visible absorption Spectra (UV-VIS), Fourier transforms infrared spectroscopy (FTIR), and energy dispersive X-ray (EDX) spectra. Twenty male albino rats were divided into 5 groups. Groups I, II, III, and IV were treated with DEC, AgNPs, NTZ, and NTZ+AgNPs, while group V was taken as untreated infected control. After the establishment of infection, microfilaraemic rats were treated with aforesaid drugs for 6 days at 100 mg/kg body weight. Efficacy of drugs was observed by counting the microfilariae in the blood of albino rats every 3rd day till microfilariae disappeared. Blood was taken at every 10 days interval till 40 days for biochemical studies to assess the level of antioxidant enzymes. NTZ+AgNPs proved to be the most effective drug which cleared the microfilariae within 18 days of infection when compared with DEC, AgNPs and NTZ where microfilariae persisted up to 24, 36, and 33 days, respectively. Oxidative stress is common inflammatory process associated with many diseases including filariasis. An enhanced antioxidant activity of NTZ+AgNPs was observed in the infected rats which was evident by quick disappearance of microfilariae due to increased oxidative stress. It clearly indicated positive contribution of the NTZ+AgNPs to the host together with harmful effect on the parasite. Hence, AgNPs improved the NTZ efficacy against S. cervi infection in albino rats and proved as a successful synergistic combination.

The role of the cardiac energy status in the potassium-evoked exocytosis of both noradrenaline and the sympathetic co-transmitter neuropeptide Y (NPY) was investigated in the guinea-pig perfused heart. The transmitter release was stimulated by potassium depolarization (10–80 mmol/l) during normoxic perfusion (pO2 > 100 mmHg) in the presence of glucose (11 mmol/l) and at various periods (5–40 min) of cardiac energy depletion. Energy depletion was induced either by anoxia (pO2 < 5 mmHg) or by cyanide intoxication (1 mmol/l), both in combination with glucose-free perfusion. Endogenous noradrenaline and NPY were determined in the coronary venous overflow by high-pressure liquid chromatography combined with electrochemical detection and by radioimmunoassay, respectively. Under normoxic conditions potassium depolarization evoked a co-release of both transmitters [molar ratio 862 (noradrenaline) :1 (NPY)] at a threshold concentration of 40 mmol/l potassium. This transmitter overflow was characterized by its dependence on extracellular calcium and calcium influx through voltage-dependent neuronal calcium channels of the N-type. Cardiac energy depletion was accompanied by an acceleration and an enhancement of the potassium-evoked transmitter overflow. In comparison to normoxia, a 10-fold increased transmitter overflow with a comparable molar ratio [709 noradrenaline :1 (NPY)] was evoked by 40 mmol/l potassium after 10 min of either anoxia or cyanide intoxication. This sensitization to potassium depolarization reached a peak after 10 min of energy depletion and was characterized by a markedly reduced threshold concentration (10 mmol/l potassium). The enhanced sympathetic transmitter overflow in anoxia was suppressed by addition of glucose (11 mmol/l) to the perfusion buffer, suggesting that the sensitization of the overflow of noradrenaline and NPY to potassium depolarization requires a cessation of energy metabolism. The sensitization of the potassium-evoked (20 mmol/l) sympathetic transmitter overflow by energy depletion was further characterized: Consistent with an exocytotic release mechanism, the overflow was calcium-dependent. In contrast to normoxia, however, blockade of neuronal N-type calcium channels by either co-conotoxin (100 nmol/1) or cadmium chloride (50 μmol/l) failed to reduce the potassium-evoked overflow of noradrenaline and NPY. In anoxia blockade of sodium-proton exchange by amiloride (1 mmol/l) or more specifically by ethylisopropylamiloride (1 μmol/l) markedly attenuated the potassium-evoked transmitter overflow. Likewise, suppression of the potassium-evoked overflow of noradrenaline and NPY from the energy-depleted heart was achieved by extracellular acidosis (pH 6.0). In contrast, during normoxia blockade of sodium-proton exchange by either ethylisopropylamiloride (1 μmol/l) or by extracellular acidosis (pH 6.0) did not affect the potassium-evoked (80 mmol/l) transmitter overflow. These findings suggest that the sensitization of sympathetic nerve endings to potassium depolarization, caused by cardiac energy depletion, requires sodium entry into the sympathetic nerve ending via sodium-proton exchange. The results of the present study indicate, that the threshold concentration for the potassium-evoked exocytotic release of noradrenaline and NPY from the guinea-pig isolated perfused heart is intimately coupled to the energy status of cardiac sympathetic nerve fibres. The energy status not only determines the quantity of the transmitters released but also the mode of sodium and calcium entry triggering the depolarization-evoked transmitter overflow. Preliminary findings were reported at the 63rd Scientific Sessions of the American Heart Association, Dallas/USA (Haass et al., 1990b) and at the Annual Meeting of the European Section of the International Society for Heart Research, Leuwen/Belgium (Haass et al. 1991b)