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Chronic Inhibition (chronic + inhibition)
Selected AbstractsChronic inhibition of standing behaviour alters baroreceptor reflex function in ratsACTA PHYSIOLOGICA, Issue 3 2009H. Waki Abstract Aim:, To investigate whether daily orthostatic stress during development is an important factor affecting arterial baroreceptor reflex function, we examined the effect of chronic inhibition of upright standing behaviour on the baroreceptor reflex function in rats. Methods:, Upright standing behaviour was chronically inhibited during the developmental period between 3 and 8 weeks of age in Sprague,Dawley rats and heart rate (HR) and aortic nerve activity in response to increased and decreased mean arterial pressure (MAP) was measured after the treatment period. Results:, The baroreceptor cardiac gain in the rats grown without standing behaviour was significantly lower than the control rats grown in a normal commercial cage (1.0 ± 0.1 beats min,1 mmHg,1 vs. 1.6 ± 0.2 beatsmin,1 mmHg,1, P < 0.05). The range of HR change in the MAP,HR functional curve was also lowered by chronic inhibition of orthostatic behaviour (56.2 ± 5.9 beats min,1) compared with that of the control rats (76.8 ± 6.9 beats min,1, P < 0.05). However the aortic afferent function remained normal after the treatment period, indicating that the attenuated baroreceptor reflex function may be due to other mechanisms involving functional alterations in the cardiovascular centres, efferents and/or peripheral organs. Body weight and adrenal weight were not affected by the inhibition of orthostatic behaviour, suggesting that the animals were not exposed to specific stress by this treatment. Conclusion:, These results indicate that active haemodynamic changes induced by orthostatic behaviour are an important factor for setting the basal level of reflex function during development. Moreover, our experimental model may be useful for studying mechanisms of attenuated baroreceptor reflex observed after exposure to a chronic inactive condition. [source] Chronic inhibition of nitric-oxide synthase induces hypertension and erectile dysfunction in the rat that is not reversed by sildenafilBJU INTERNATIONAL, Issue 1 2010Serap Gur Study Type , Aetiology (case control) Level of Evidence 3b OBJECTIVE To evaluate the effect of N(G)-nitro- l -arginine methyl ester (L-NAME)-induced hypertension (HT) on erectile function in the rat and determine if the phosphodiesterase (PDE)-5 inhibitor, sildenafil, can reverse the effects of nitric oxide (NO) deficiency, as HT is a risk factor for erectile dysfunction (ED) and the NO synthase (NOS) inhibitor L-NAME induces NO-deficient HT. MATERIALS AND METHODS Thirty-six adult Sprague-Dawley male rats were divided into three groups, i.e. a control, L-NAME-HT (40 mg/rat/day in the drinking water for 4 weeks), and sildenafil-treated L-NAME-HT (1.5 mg/rat/day sildenafil, by oral gavage concomitantly with L-NAME). The erectile response expressed as a ratio of intracavernosal pressure (ICP)/mean arterial pressure (MAP), evaluated after electrical stimulation of the right cavernous nerve. The isometric tension of corpus cavernosum smooth muscle (CCSM) was measured in organ-bath experiments. NOS expression was determined immunohistochemically for neuronal (n)NOS and by Western blot analysis for endothelial (e) and inducible (i) NOS protein. cGMP levels were evaluated by enzyme-linked immunosorbent assay. RESULTS The erectile response was diminished in the HT group. Nitrergic and endothelium-dependent relaxation was reduced, while the relaxation response to sodium nitroprusside and contractile response to phenylephrine were not altered in CCSM from L-NAME-treated rats. HT rats showed decreased expression of nNOS, whereas eNOS and iNOS protein expression was increased. Sildenafil partly restored endothelial and molecular changes in CCSM from HT rats, but did not reverse the decreased erectile response, even as cGMP levels returned to normal levels. CONCLUSIONS Sildenafil treatment did not correct the ED in L-NAME-treated HT rats. Under sustained high blood pressure, up-regulation of PDE5 expression failed to reverse the depletion of neuronal NO and/or impaired nNOS activity. However, endothelium-dependent relaxation was restored. Drug targeting of neuronal dysfunction might delay the onset of ED in HT. [source] Chronic inhibition of standing behaviour alters baroreceptor reflex function in ratsACTA PHYSIOLOGICA, Issue 3 2009H. Waki Abstract Aim:, To investigate whether daily orthostatic stress during development is an important factor affecting arterial baroreceptor reflex function, we examined the effect of chronic inhibition of upright standing behaviour on the baroreceptor reflex function in rats. Methods:, Upright standing behaviour was chronically inhibited during the developmental period between 3 and 8 weeks of age in Sprague,Dawley rats and heart rate (HR) and aortic nerve activity in response to increased and decreased mean arterial pressure (MAP) was measured after the treatment period. Results:, The baroreceptor cardiac gain in the rats grown without standing behaviour was significantly lower than the control rats grown in a normal commercial cage (1.0 ± 0.1 beats min,1 mmHg,1 vs. 1.6 ± 0.2 beatsmin,1 mmHg,1, P < 0.05). The range of HR change in the MAP,HR functional curve was also lowered by chronic inhibition of orthostatic behaviour (56.2 ± 5.9 beats min,1) compared with that of the control rats (76.8 ± 6.9 beats min,1, P < 0.05). However the aortic afferent function remained normal after the treatment period, indicating that the attenuated baroreceptor reflex function may be due to other mechanisms involving functional alterations in the cardiovascular centres, efferents and/or peripheral organs. Body weight and adrenal weight were not affected by the inhibition of orthostatic behaviour, suggesting that the animals were not exposed to specific stress by this treatment. Conclusion:, These results indicate that active haemodynamic changes induced by orthostatic behaviour are an important factor for setting the basal level of reflex function during development. Moreover, our experimental model may be useful for studying mechanisms of attenuated baroreceptor reflex observed after exposure to a chronic inactive condition. [source] Orbofiban: An orally active GPIIb/IIIa platelet receptor antagonistMEDICINAL RESEARCH REVIEWS, Issue 3 2001Nancy S. Nicholson Abstract A key role has been established for platelet activation and thrombus formation in the pathogenesis of acute coronary syndromes, and restenosis after percutaneous interventions. Antiplatelet agents that have a wider spectrum of activity than aspirin, and clopidogrel would be expected to provide improved antithrombotic protection. Preclinical studies were used to predict clinical efficacy of orally active GPIIb/IIIa antagonists such as xemilofiban, sibrafiban, lefradafiban, and orbofiban. While clinical trials have shown potent and sustained platelet inhibition, outcomes of trials with these first generation GPIIb/IIIa compounds have been disappointing. The active moiety of orbofiban is a potent and specific inhibitor of fibrinogen binding to GPIIb/IIIa, leading to inhibition of platelet aggregation to a wide variety of agonists. Studies comparing inhibition of aggregation and bleeding suggest that chronic inhibition of platelet aggregation can be achieved without major bleeding side effects. Thrombus formation is prevented in canine models of thrombosis. Orbofiban is approximately 28% bioavailable with a t1/2 of 18,hr. The high bioavailability, long half-life, and potential safety suggest orbofiban would be suitable for chronic oral administration. Clinical data demonstrate that orally administered orbofiban has the desired pharmacodynamic effect of inhibiting platelet aggregation but does not demonstrate clinical benefit when examined in large-scale trials. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 3, 211,226, 2001 [source] Thymoquinone supplementation attenuates hypertension and renal damage in nitric oxide deficient hypertensive ratsPHYTOTHERAPY RESEARCH, Issue 5 2007Mahmoud M. Khattab Abstract The present study was undertaken to evaluate the protective effect of thymoquinone (TQ), the main constituent of the volatile oil from Nigellasativa seeds, in rats after chronic inhibition of nitric oxide synthesis with N, -nitro- l -arginine methyl esters (l -NAME). Rats were divided randomly into different treatment groups: control, l -NAME, TQ and l -NAME + TQ. Hypertension was induced by 4 weeks administration of l -NAME (50 mg/kg/day p.o.). TQ was administered alone or in combination with l -NAME and continued for 4 weeks. The animals were killed, and the serum and kidney tissues were isolated for the determination of creatinine and glutathione (GSH), respectively. Rats receiving l -NAME showed a progressive increase in systolic blood pressure compared with control rats. Concomitant treatment with TQ (0.5 and 1 mg/kg/day p.o.) reduced the increase in systolic blood pressure induced by l -NAME in a dose dependent manner. Kidney injury was demonstrated by a significant increase in serum creatinine and a decrease in GSH in kidney tissue from l -NAME treated rats. Treatment of rats with TQ decreased the elevated creatinine and increased GSH to normal levels. TQ inhibited the in vitro production of superoxide radical in enzymatic and non-enzymatic systems. In conclusion, TQ is effective in protecting rats against l -NAME-induced hypertension and renal damage possibly via antioxidant activity. Copyright © 2007 John Wiley & Sons, Ltd. [source] Effects of mood stabilizers on the inhibition of adenylate cyclase via dopamine D2 -like receptorsBIPOLAR DISORDERS, Issue 3 2007Liliana P Montezinho Objective:, The mood stabilizing drugs lithium, carbamazepine and valproate modulate brain adenosine monophosphate (cAMP) levels, which are assumed to be elevated in bipolar disorder patients. The aim of this work was to investigate how these three mood stabilizing agents affect the regulation of cAMP levels by dopamine D2 -like receptors in vitro in rat cortical neurons in culture and in vivo in the rat prefrontal cortex. Methods:, The production of cAMP was measured in the cultured cortical neurons or in microdialysis samples collected from the prefrontal cortex of freely moving rats using the [8- 3H] and [125I] radioimmunoassay kits. Results:,In vitro and in vivo data showed that the treatment with the mood stabilizing drugs had no effect on basal cAMP levels in vitro, but had differential effects in vivo. Direct stimulation of adenylate cyclase (AC) with forskolin increased cAMP levels both in vitro and in vivo, and this effect was significantly inhibited by all three mood stabilizers. Activation of dopamine D2 -like receptors with quinpirole partially inhibited forskolin-induced increase in cAMP in untreated cultures, but no effect was observed in cortical neuron cultures treated with the mood stabilizing drugs. Similar results were obtained by chronic treatment with lithium and valproate in the prefrontal cortex in vivo. However, surprisingly, in carbamazepine-treated rats the activation of dopamine D2 -like receptors enhanced the responsiveness of AC to subsequent activation by forskolin, possibly as a consequence of chronic inhibition of the activity of the enzyme. Conclusions:, It was shown that each of these drugs affects basal- and forskolin-evoked cAMP levels in a distinct way, resulting in differential responses to dopamine D2 -like receptors activation. [source] Phosphoinositide 3-kinase mediated signalling contributes to development of diabetes-induced abnormal vascular reactivity of rat carotid arteryCELL BIOCHEMISTRY AND FUNCTION, Issue 1 2006Mariam H. M. Yousif Abstract Diabetes mellitus is associated with vascular complications, including an impairment of vascular function and alterations in the reactivity of blood vessels to vasoactive agents. Phosphatidylinositol 3-kinase (PI3K) is a signalling enzyme that plays key roles in vascular growth, proliferation and cellular apoptosis and is implicated in modulating vascular smooth muscle contractility. The aim of this study was to determine whether PI3K plays a role in development of diabetes-induced altered vascular reactivity to selected vasoconstrictors and vasodilators. The effect of 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a selective PI3K inhibitor, on isolated segments of carotid arteries from streptozotocin (STZ)-diabetic rats was investigated. Ring segments of the isolated carotid arteries were mounted in organ baths to measure changes in isometric tension. Our results showed that STZ treatment produced an increase in the vasoconstrictor response to norepinephrine (NE), angiotensin II (Ang II) and endothelin-1 (ET-1) and an attenuated vasodilator response to carbachol and histamine in the isolated carotid arteries from STZ-diabetic animals. Diabetes-induced impaired vascular responsiveness to the vasoactive agonists was prevented by chronic inhibition of PI3K by LY294002 even though blood glucose levels remained high. This is the first study to show that selective inhibition of PI3K can attenuate the development of diabetes-induced abnormal vascular reactivity in the isolated carotid arteries of diabetic rats. Copyright © 2005 John Wiley & Sons, Ltd. [source] | |||||||||||||