Mohammad Fatehi

Effects of 17β-Estradiol on Neuronal Cell Excitability and Neurotransmission in the Suprachiasmatic Nucleus of Rat

17β-Estradiol receptors have been found in several brain nuclei including the suprachiasmatic nucleus (SCN) of mammalian species. The SCN is believed to act as brain clock regulating circadian and circannual biological rhythms, such as body temperature, sleep, and mood. Here, we examined whether 17β-estradiol (E2) could affect cell excitability and synaptic transmission in the SCN. Bath application of E2 (0.03–3 μM) increased the spontaneous firing frequency and depolarized cell membrane of the SCN neurons significantly. Furthermore, E2 (0.03–3 μM) increased (by about 25–150% of control) frequency of the miniature excitatory postsynaptic currents. Amplitude of the evoked excitatory postsynaptic currents was enhanced (by about 32% of control) after exposure to 1 μM E2. The paired-pulse ratio was reduced by E2. These effects were prevented by the estrogen receptor antagonist, ICI 182780. Exposure to the biologically inactive 17α-estradiol did not cause any significant changes in the parameters mentioned above. These findings are in favor of an implication of estrogen in modulation of neuronal activity in SCN and possibly regulating circadian rhythms.

THE BENEFICIAL EFFECTS OF PROTEIN TYROSINE KINASE INHIBITION ON THE CIRCULATORY FAILURE INDUCED BY ENDOTOXIN IN THE RAT

Implication of enhanced activity of tyrosine kinases has been established in the pathophysiology of many diseases associated with local (e.g., atherosclerosis) or systemic (e.g., septic shock) inflammation. The main objective of this study was to elucidate whether tyrosine kinase and nitric oxide were involved in endotoxin-induced impairment of vascular responses to sympathetic nerve stimulation (SNS) in rat isolated mesenteric bed. Therefore, the effects of genistein, an inhibitor of protein tyrosine kinase, and L-NAME (N-nitro-L-arginine methyl ester), an inhibitor of nitric oxide synthase, on endotoxin-induced shock were investigated in the thiopental-anesthetized rats. We also studied the effects of endotoxin on the vasoconstrictor responses to SNS in the rat isolated perfused mesenteric bed. Endotoxin injection (10 mg kg−1, i.p.) produced a marked hypotension and a reduction of the pressor responses elicited by phenylephrine (0.1, 0.3, and 3 &mgr;g kg−1, i.v.). Pretreatment of the rats with either genistein (10 mg kg−1 i.p., 2 h before endotoxin injection), L-NAME (0.1 mg kg−1, i.p., 30 min before endotoxin injection), or a combination of both attenuated the hypotension caused by endotoxin. SNS in the rat isolated perfused mesenteric bed caused a frequency-dependent vasoconstrictor response, which was abolished by tetrodotoxin (10−7 M), prazoscin (10−7 M), and guanethidine (10−7M). In mesenteric vascular beds removed from rats injected with endotoxin, the vasoconstrictor responses to SNS were markedly impaired. Although genistein and L-NAME pretreatment attenuated the vascular hyporeactivity to phenylephrine, they did not improve the impaired SNS response of the isolated vascular bed of endotoxin-treated animals. These results indicate that genistein and L-NAME pretreatment prevent the hypotension and the delayed hyporeactivity to phenylephrine induced by endotoxin, but they failed to restore the vascular hyporeactivity to SNS.

Soy-diet has beneficial effects on cardiovascular parameters that are independent of its lipid effect in male hypercholesterolemic rats.

Diet‐induced atherosclerosis is lower in animals fed soy protein. The effects of various soy components have been extensively studied; however, little is known about the effect of crude soybean feeding on hypercholesterolemia‐induced cardiovascular changes. This study investigated the effect of soy feeding on cardiovascular parameters in hypercholesterolemic male rats. Total cholesterol (TC), low density lipoprotein (LDL) and high density lipoprotein cholesterol (HDL), and triglyceride (TG) were measured. Rats were randomly assigned to control, high cholesterol (HC, 2% cholesterol) or HC + soy (HC+S) diets. In the HC+S group, rats received HC diet for 10 weeks followed by 2 weeks of soybean feeding. Arterial blood pressure, TC, TG, LDL and HDL were measured. TC, TG and LDL were higher in HC rats and were not significantly reduced by soybean feeding. Soy feeding reversed the HC‐induced increase in arterial blood pressure and also restored the impaired vascular responses to acetylcholine in isolated aortic rings. Pre‐incubation of HC+S aortic rings with L‐NAME (10−5 M for 20 min) partially reduced the effects of soy on acetylcholine responses, indicating that the beneficial vascular effects of dietary soy are partially mediated via nitric oxide pathway. Copyright

Effects of Echis carinatus Venom on the Haemodynamy and Contractility of Vascular and Visceral Smooth Muscle of Rats

Abstract Echis carinatus is considered to be one of the most dangerous snakes in the world because of its venom toxicity and high population densities in rural agriculture areas. However, little information is available on the pharmacological effects of venom from this snake on haemodynamy and vasculature smooth muscle contractility. The haemodynamic alterations induced by the intravenous administration of Echis carinatus venom was investigated in anaesthetized rats. Injection of several doses of venom (1, 3, 5, and 7 μ g kg − 1) decreased the arterial blood pressure. For instance, injection of 3 μ g kg−1 of Echis carinatus venom reduced the mean arterial blood pressure from 107 ± 4 to 71 ± 4 mmHg (p < 0.05). Exposure of the rat isolated vas deferens preparations to Echis carinatus venom (1 μ g ml−1) significantly reduced the contractile responses to epinephrine (10 μ g ml− 1) without changing the response to KCl (50 mM). To investigate the effects of venom on peripheral vascular resistance, mesenteric bed was removed and perfused with Krebs solution. Addition of different concentrations of venom (1, 3, and 10 μ g ml−1) to the precontracted mesenteric bed (with phenylephrine, 5 × 10− 4 M) decreased the contraction in a concentration-dependent manner. However, preincubation of mesenteric bed with atropine (0.1 μ M), L-NAME (10 −5 M) or indomethacin (10−5 M) prevented this effect of the venom. These results may suggest that the inhibitory effect of the venom on nonvascular smooth muscle (such as vas deferens) contractions is a postsynaptic phenomenon. Furthermore, it could be suggested that the cardiovascular effects of Echis carinatus venom are mediated through multiple mechanisms such as activation of muscarinic receptors as well as production of nitric oxide and prostaglandins.