Endogenous nitric oxide attenuates beta-adrenoceptor-mediated relaxation in rat aorta

1. Divergent evidence suggests that the intracellular signalling pathways for beta-adrenoceptor-mediated vascular relaxation involves either cAMP/protein kinase (PK) A or endothelial nitric oxide (NO) release and subsequent activation of cGMP/PKG. The present study identifies the relative roles of NO and cAMP, as well as dependence on the endothelium for beta-adrenoceptor-mediated relaxation of rat isolated aortas. 2. Cumulative concentration-response curves to isoprenaline (0.01-3 mu mol/L) in phenylephrine (0.1 mu mol/L)-preconstricted endothelium-intact and -denuded aortas were constructed. Isoprenaline-mediated relaxation was partially reduced by endothelium removal and the presence of the NO synthase inhibitor N-G-monomethyl-L-arginine (0.1 mmol/L), but not by the cAMP antagonist (Rp)-cyclic adenosine-3',5'-monophosphorothioate (Rp-cAMPS; 0.5 mmol/L). 3. In contrast, in endothelium-denuded aortas, the isoprenaline-mediated relaxation was inhibited by Rp-cAMPS and this inhibition was lost in the presence of the NO donor sodium nitroprusside (1 nmol/L)

Endogenous imidazoline receptor ligands relax rat aorta by an endothelium-dependent mechanism

The definitive version is available at www.blackwell-synergy.comAgmatine and harmane have been proposed as endogenous ligands of imidazoline receptors. Agmatine has been reported to activate nitric oxide synthetase (NOS) in endothelial cells, so we sought to determine if agmatine or harmane and an analogue of harmane, propyl harmane, produced vasodilatation through an endothelium-dependent mechanism. The experiments were performed in endothelium-denuded and intact rat aortic rings preconstricted with phenylephrine (0.1 mM). Agmatine (0.3–1000 mM), harmane, and propyl harmane (0.3–100 mM) relaxed endothelium-intact rings in a concentration-dependent manner. Removal of endothelium inhibited the relaxant effect of agmatine, harmane, and propyl harmane. The NOS inhibitor L-NIO (100 mM) inhibited the relaxant effect of agmatine and harmane. The I₁-receptor antagonist AGN (100 mM) partly inhibited the effect of harmane but not that of agmatine. These results suggest that the endogenous imidazoline ligands are capable of stimulating NOS largely by an I₁-receptor-independent mechanism.Ian F. Musgrave, Andrea Van Der Zypp, Mathew Grigg, Colin J. Barro

A role for cyclooxygenase in aging-related changes of beta-adrenoceptor-mediated relaxation in rat aortas

beta-Adrenoceptor-mediated vasorelaxation decreases with age in various vascular beds. The present study investigated the roles of cyclooxygenase (COX) on beta-adrenoceptor vasorelaxation by isoprenaline in 8- and 54-week-old rat aortas. The vasorelaxation responses by isoprenaline (0.03-3 mu M) were significantly reduced in 54-week-old aortas compared to 8-week. Addition of the non-selective COX inhibitors indomethacin (10 mu M) or aspirin (10 mu M) restored isoprenaline vasorelaxation of 54-week-old aortas to levels found in 8-week-old aortas. This suggests the involvement of COX prostanoids in the age-related reduction of beta-adrenoceptor vasorelaxation. Immunohistochemistry revealed greater levels of COX-1 and COX-2 staining in 54-week-old aortas compared to 8-week with expression located mainly in medial smooth muscle. An age-linked increase in COX-1 and COX-2 protein was found in cremaster arterioles of 54-week-old rats (compared to 8-week) mainly in the endothelial layer. The age-related increase in COX-1 and COX-2 protein led to elevation of prostacyclin (measured as 6-keto prostagladin F-1 alpha) and thromboxane A(2) (measured as thromboxane B-2) in 54-week compared to 8-week-old aortas. Endothelium removal in 54-week aortas markedly reduced the 6-keto prostaglandin F-1 alpha level, thus suggesting an endothelial source for elevated prostacyclin. These findings in combination with the effects of COX inhibitors suggest that the age-related decrease in beta-adrenoceptor vasorelaxation by isoprenaline is due to an age-linked increase in COX expression, which elevates production of COX-derived vasoactive prostanoids

Age-related changes in monocyte and platelet cycloxxygenase expression in healthy male humans and rats

Cyclooxygenase (COX) catalyses the formation of prostanoids that are crucial in maintaining hemostasis and important in inflammation. Animal studies reveal that COX-1 and COX-2 expression increase in some cell types during aging. This study determined age-related changes in COX expression in platelets and monocytes. Platelets and mononuclear cells were isolated from healthy male human volunteers from 18 to 28 and from 55 to 65 years of age, as well as male rats 8 and 54 weeks old for comparison. Western blot analysis was performed using selective antibodies against COX-1 and COX-2, followed by densitometrical analysis. In humans, an age-related increase in COX-2 expression in mononuclear cells was observed, with a 70% increase in the older age group. In rat studies, a 50% increase of COX-2 protein occurred in mononuclear cells of 54-week-old rats, compared with 8-week-old rats. For COX-1, an age-related increase of 50% occurred in rat platelets, but no difference occurred in the platelets' COX-1 levels between young and elderly human age groups. The increased COX-2 in monocytes of older humans, which is mirrored in rats, may have downstream implications in atherosclerosis and cardiovascular risk as mononuclear prostanoids are implicated in atherosclerotic plaque stability

Dapson in heterocyclic chemistry, part VIII: synthesis, molecular docking and anticancer activity of some novel sulfonylbiscompounds carrying biologically active 1,3-dihydropyridine, chromene and chromenopyridine moieties

<p>Abstract</p> <p>Several new sulfonebiscompounds having a biologically active 1,2-dihydropyridine-2-one 3–19, acrylamide 20, chromene 21, 22 and chromenopyridine 23, 24 moieties were synthesized and evaluated as potential anticancer agents. The structures of the products were confirmed via elemental analyses and spectral data. The screening tests showed that many of the biscompounds obtained exhibited good anticancer activity against human breast cell line (MCF7) comparable to doxorubicin which was used as reference drug. Compounds 11, 17 and 24 showed IC₅₀ values 35.40 μM, 29.86 μM and 30.99 μM, respectively. In order to elucidate the mechanism of action of the synthesized compounds as anticancer agents, docking on the active site of farnesyltransferase and arginine methyltransferase was also performed and good results were obtained.</p

Exercício físico, receptores &#946;-adrenérgicos e resposta vascular Physical exercise, &#946;-adrenergic receptors, and vascular response

O exercício aeróbio promove efeitos benéficos na prevenção e tratamento de doenças como hipertensão arterial, aterosclerose, insuficiência venosa e doença arterial periférica. Os receptores &#946;-adrenérgicos estão presentes em várias células. No sistema cardiovascular, promovem inotropismo e cronotropismo positivo cardíaco e relaxamento vascular. Embora os efeitos do exercício tenham sido investigados em receptores cardíacos, estudos focados nos vasos são escassos e controversos. Esta revisão abordará os efeitos do exercício físico sobre os receptores &#946;-adrenérgicos vasculares em modelos animais e humanos e os mecanismos celulares envolvidos na resposta relaxante. Em geral, os estudos mostram resultantes conflitantes, onde observam diminuição, aumento ou nenhum efeito do exercício físico sobre a resposta relaxante. Assim, os efeitos do exercício na sensibilidade &#946;-adrenérgica vascular merecem maior atenção, e os resultados mostram que a área de fisiopatologia vascular é um campo aberto para a descoberta de novos compostos e avanços na prática clínica.<br>Aerobic exercise promotes beneficial effects on the prevention and treatment of diseases such as arterial hypertension, atherosclerosis, venous insufficiency, and peripheral arterial disease. &#946;-adrenergic receptors are present in a variety of cells. In the cardiovascular system, &#946;-adrenergic receptors promote positive inotropic and chronotropic response and vasorelaxation. Although the effect of exercise training has been largely studied in the cardiac tissue, studies focused on the vascular tissue are rare and controversial. This review examines the data from studies using animal and human models to determine the effect of physical exercise on the relaxing response mediated by &#946;-adrenergic receptors as well as the cellular mechanisms involved in this response. Studies have shown reduction, increase, or no effect of physical exercise on the relaxing response mediated by &#946;-adrenergic receptors. Thus, the effects of exercise on the vascular &#946;-adrenergic sensitivity should be more deeply investigated. Furthermore, the physiopathology of the vascular system is an open field for the discovery of new compounds and advances in the clinical practice