Chronotropic Responses to GLP-1 Receptor Agonists and Sitagliptin in Atria From Diabetic Rats.

ABSTRACT: Type 2 diabetes mellitus increases the risk of cardiovascular diseases. Therefore, elucidation of the cardiovascular effects of antidiabetics is crucial. Incretin-based therapies are increasingly used for type 2 diabetes mellitus treatment as monotherapy and in combination. We aimed to study the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sitagliptin on beating rates in isolated atria from diabetic rats. The chronotropic responses to GLP-1 RAs and sitagliptin as monotherapy and in combinations with metformin, pioglitazone, and glimepiride in isolated atria from control and diabetic rats were determined. GLP-1 (7-36), GLP-1 (9-36), and exendin-4 (1-39) produced increases in beating rates in both control and diabetic rat atria. However, sitagliptin increased the beating frequency only in the diabetic group. Exendin (9-39), nitro- l -arginine methyl ester hydrochloride, and indomethacin blocked responses to GLP-1 RAs but not the response to sitagliptin. Glibenclamide, 4-aminopyridine, apamin, charybdotoxin, superoxide dismutase, and catalase incubations did not change responses to GLP-1 RAs and sitagliptin. GLP-1 RAs increase beating rates in isolated rat atrium through GLP-1 receptor, nitric oxide, and cyclooxygenase pathways but not potassium channels and reactive oxygen radicals.

The Functional Effects of Visfatin on Human Left Internal Mammary Artery.

ABSTRACT: Visfatin may play a role in vascular dysfunction in metabolic disorders. Apart from its insulin-mimetic actions, it has divergent actions in the cardiovascular system with discordant results in the literature. Thus, we aimed to study the effects of visfatin on vascular responses of the human left internal mammary artery. Sections of redundant human left internal mammary artery were cut into 3-mm wide rings and hung in 20-mL organ baths containing physiologic salt solution and attached to an isometric force transducer connected to a computer-based data acquisition system. Removing endothelium caused an increase in pD2 values for visfatin-induced relaxation responses (10 -12 -10 -7 M) (9.06 ± 0.21 and 11.08 ± 0.92, respectively). Nicotinamide phosphoribosyltransferase inhibitor FK866 (10 µM) reversed the visfatin-induced relaxations (10 -12 -10 -7 M) ( P = 0.024). Incubations with nitric oxide synthase inhibitor nitro- l -arginine methylester and guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) caused significant reductions in relaxation responses of visfatin ( P = 0.011 and 0.008, respectively). Visfatin incubations decreased relaxation responses to acetylcholine but not to sodium nitroprusside. Incubations with visfatin did not change contractile responses to angiotensin II, endothelin-1, noradrenalin, and phenylephrine. In this study, visfatin caused endothelium-dependent relaxations mediated by nitric oxide-cyclic guanosine monophosphate pathway and nicotinamide phosphoribosyltransferase activity. Furthermore, visfatin-induced decreases in relaxation responses were also related to endothelium-derived nitric oxide.

Effects of glucagon-like peptide-1 in diabetic rat small resistance arteries.

We investigated the functional effects of glucagon-like peptide-1 [GLP-1(7-36)] and GLP-1(9-36) and the mechanism(s) playing a role in the effects of these agents in isolated small resistance arteries from control and diabetic rats. Cumulative concentrations of GLP-1(7-36) and GLP-1(9-36) produced concentration-dependent relaxations in endothelium-intact but not endothelium-denuded arteries that were significantly decreased in diabetic rats. GLP-1 receptor antagonist exendin(9-39) significantly inhibited responses to GLP-1 analogs. Nitric oxide/cyclic guanosine monophosphate pathway blockers, but not indomethacin, significantly decreased responses to GLP-1(7-36) or GLP-1(9-36) in control and diabetic rats. 4-Aminopyridine or glibenclamide incubation did not alter relaxations to GLP-1 analogs. GLP-1(7-36)- and GLP-1(9-36)-induced relaxations were blunted significantly and to similar extends by charybdotoxin and apamin combination in control and diabetic rats. Catalase did not affect, whereas superoxide dismutase (SOD) caused a significant increase in relaxations to GLP-1 analogs only in diabetic rats. We provided evidence about the relaxant effects of GLP-1(7-36) and GLP-1(9-36) in resistance arteries that were reduced in diabetic rats. Both calcium-activated potassium channels and endothelium played a major role in relaxations. Increment in certain reactive oxygen species and/or reduction in superoxide dismutase function might play a role in reduced relaxant responses of resistance arteries to GLP-1(7-36) and GLP-1(9-36) in diabetic rats.

THE effect of P2X7 receptor activation on functional responses of human left internal mammary artery.

The Purinoreceptor 7 (P2X7R) has become a promising drug target in many cardiovascular diseases, including coronary artery disease, since prolonged activation of P2X7R could promote vascular dysfunction, atherosclerosis, and thrombosis. Thus, we aimed to study the effects of P2X7R activation on vascular relaxation responses of the human left internal mammary artery (LIMA). Sections of redundant human LIMA were cut into 3-mm wide rings,, suspended in 20-mL organ baths containing physiologic salt solution, and attached to an isometric force transducer connected to a computer-based data acquisition system. Long-term (60 min) incubation with specific P2X7R agonist Bz-ATP caused significant reductions in relaxation responses of LIMA to ATP and acetylcholine, which were reversed by selective P2X7R antagonists Brilliant Blue G or AZ11645373, whereas there were no changes in relaxation responses to endothelium-independent vasodilators isoprenaline, cAMP analog 8-Br-cAMP, and nitric oxide donor sodium nitroprusside. The impairment in relaxant responses of LIMA to endothelium-dependent vasodilators following activation of P2X7R for the long-term may contribute to postoperative LIMA vasospasm and hypertension. Modulation of P2X7R activity with selective agents may represent a new potential therapeutic approach in patients undergoing coronary artery bypass grafting surgery.

Can platelet activation markers predict preeclampsia and/or its severity?

OBJECTIVE: This study aimed to evaluate the value of platelet activation markers in predicting preeclampsia and its severity. Preeclampsia is a serious pregnancy complication that affects 3-5% of pregnancies and can lead to significant morbidity and mortality for both the mother and the fetus. METHODS: The study included 99 patients diagnosed with preeclampsia and 60 healthy pregnant women as a control group. Platelet activation markers such as mean platelet volume (MPV), platelet distribution width (PDW), platelet count, and plateletcrit were evaluated along with other clinical parameters. RESULTS: The results of the study showed that platelet activation markers, particularly PDW and MPV, are valuable in the diagnosis and follow-up of preeclampsia. However, they are not sufficient to predict the severity of the disease. CONCLUSION: The study suggests that platelet activation markers could aid in predicting, diagnosing, and managing preeclampsia. However, further research is needed to determine the role of these markers in predicting the severity of the disease. The findings of this study could contribute to the development of more effective strategies for the prevention and management of preeclampsia, which could ultimately improve maternal and fetal outcomes.

OBJETIVO: El estudio tuvo como objetivo determinar el valor de los marcadores de activación plaquetaria en la predicción de la preeclampsia y su gravedad. MÉTODO: Se incluyeron 99 pacientes diagnosticadas con preeclampsia, incluyendo 36 casos graves, y un grupo control de 60 mujeres embarazadas sanas. Se evaluaron diversas variables, como el volumen plaquetario medio, el recuento de plaquetas, el hematocrito plaquetario y la amplitud de distribución plaquetaria. RESULTADOS: Los resultados mostraron que el volumen plaquetario medio y la amplitud de distribución plaquetaria son parámetros valiosos en el diagnóstico y seguimiento de la preeclampsia, aunque no son suficientes para predecir su gravedad. El análisis estadístico reveló que la edad, el volumen plaquetario medio, la amplitud de distribución plaquetaria, la semana de gestación y los puntajes de Apgar al primer y quinto minuto fueron significativamente diferentes en el grupo de preeclampsia en comparación con el grupo control. CONCLUSIONES: En conclusión, estos resultados sugieren que los marcadores de activación plaquetaria pueden ser útiles para el diagnóstico y seguimiento de la preeclampsia, y que el volumen plaquetario medio y la amplitud de distribución plaquetaria, por ser parámetros económicos y accesibles, podrían ayudar a predecir, diagnosticar y manejar esta complicación durante el embarazo.

The effect of exercise training on the responsiveness of renal resistance arteries in rats.

Blood flow to several tissues changes during an acute bout of exercise. The kidney is one of the organs that are most affected by exercise-induced blood redistribution. The aim of the present study was to investigate possible exercise-induced vascular reactivity changes in renal resistance arteries in rats. Renal resistance arteries were isolated from rats that underwent 8 weeks of swimming and sedentary control rats, and the arteries were evaluated using wire myography. Similar dilation responses to acetylcholine, bradykinin, adenosine, isoproterenol, and sodium nitroprusside were observed in both groups. The vasoconstrictive agents vasopressin, endothelin-1, potassium chloride, and thromboxane A(2) also induced similar responses in both groups; however, the trained group had an increased constrictive response to norepinephrine compared to the control rats. The results of our study show that renal resistance arteries of trained rats behave differently than conduit-type renal arteries and exhibit an increased contractile response to sympathetic agonists. This finding provides supporting evidence that renal blood flow markedly decreases during exercise in trained individuals.

Functional effects of visfatin in isolated rat mesenteric small resistance arteries.

A new adipocytokine, visfatin is expressed in perivascular adipose tissue (PVAT) and exerts effects on vascular system in addition to its relationship with various pathological conditions. The present study aimed to investigate the functional effects of visfatin and the possible underlying mechanism(s) of the effects of visfatin in isolated rat mesenteric small resistance arteries. The study was conducted in small resistance arterial rings isolated from rat mesenteric vascular beds. While visfatin incubation did not produce significant alterations in contractile responses of mesenteric arterial rings to noradrenaline, relaxation responses to acetylcholine but not to sodium nitroprusside (SNP) were significantly reduced in endothelium-intact rings. The inhibitory effect of visfatin on responses to acetylcholine was not observed in endothelium-denuded preparations. Incubation of tissues with nicotinamide phosphoribosyl transferase (NAMPT) inhibitor FK866 or superoxide dismutase (SOD) reversed the inhibitory effects of visfatin on relaxation responses to acetylcholine. Co-incubation of visfatin with Nω-nitro-L-arginine methylester (L-NAME) did not produce a significant alteration in vascular responses to acetylcholine compared to L-NAME incubation alone. Mesenteric PVAT visfatin levels were significantly higher than and correlated positively with plasma visfatin levels. The results of our study indicated that visfatin-induced reductions in endothelium-dependent relaxations of rat isolated small resistance arteries are mediated by oxygen free radicals and a reduction in nitric oxide (NO) bioavailability. It was suggested that increment in systemic and/or local visfatin levels due to various pathologies including obesity and excessive weight gain may play a substantial role in initiation and/or propagation of vascular dysfunctions.

Chronic treatment with taurine ameliorates diabetes-induced dysfunction of nitric oxide-mediated neurogenic and endothelium-dependent corpus cavernosum relaxation in rats.

This study was aimed to examine the effect of chronic taurine treatment on corpus cavernosum dysfunction in diabetic rats and to investigate possible underlying mechanisms. Thirty male rats were randomized to three groups of 10 each, including control, diabetic, and taurine-treated diabetic. Diabetes was induced in rats by streptozotocin (STZ, single intraperitoneal dose of 50 mg/kg body weight). Taurine was administered orally for 12 weeks (1% w/v in drinking water) from the day on which STZ was injected. At the end of the 12th week, strips of corpus cavernosum were suspended in an organ bath system for functional studies. Nitric oxide (NO)-mediated endothelium-dependent and neurogenic corpus cavernosum relaxation were evaluated by acetylcholine (ACh, 0.1-100 µm) and electrical field stimulation (EFS, 30 V, 5 ms, 2-32 Hz), respectively. The expressions of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS) (Ser-1177), neuronal nitric oxide synthase (nNOS), NADPH oxidase subunit gp91(phox) , Rho A, and Rho kinase in corpus cavernosum were semi-quantitatively assessed by immunohistochemistry. Induction of diabetes resulted in significant inhibition of NO-mediated endothelium-dependent and neurogenic corpus cavernosum relaxation. Furthermore, eNOS, p-eNOS, and nNOS expressions decreased significantly in diabetic rats compared to controls, while gp91(phox) , RhoA and Rho kinase expressions increased significantly. The diminished relaxation response to ACh and EFS as well as diabetes-related changes in expressions of these proteins in corpus cavernosum of diabetic rats was significantly improved by taurine. Taurine treatment improves NO-mediated relaxations of corpus cavernosum in diabetic rats probably by inhibiting NADPH oxidase/Rho kinase pathways.

The role of nitric oxide and potassium channels in the effect of adrenomedullin in human internal thoracic arteries.

We investigated the effects of adrenomedullin (ADM) and the role(s) of cyclooxygenase, nitric oxide (NO) synthase and potassium channels in the effects of ADM in human internal thoracic artery (ITA) rings. Samples of redundant ITA rings were suspended in organ baths and isometric tension was continuously recorded. ADM (10(-10)-10(-7)M) produced concentration-dependent relaxation responses in ITA rings precontracted by phenylephrine. The relaxant responses to ADM were significantly higher in endothelium-intact than denuded preparations. Incubation of ITA rings with indomethacin (10(-5)M) did not cause a significant decrease in relaxant responses to ADM, while 10(-4)M of N(omega)-nitro-L-arginine methyl ester caused a significant decrease. Both specific guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (5x10(-5)M) and ADM receptor antagonist ADM((22-52)) (10(-7)M) also caused significant decreases in relaxant responses to ADM. Neither 4-aminopyridine (5mM) nor glibenclamide (10(-5)M) caused significant alterations in vasodilatory effect of ADM. ADM-induced relaxation was significantly blunted by both charybdotoxin and apamin. The present study provided pharmacological evidence about the functional relaxant effect of ADM in human ITA preparations. The findings suggested that both Ca(2+)-activated potassium channels and endothelium, through release of NO play a major role in ADM-induced relaxations in isolated human ITA preparations.

The effect of hydrogen peroxide in human internal thoracic arteries: role of potassium channels, nitric oxide and cyclooxygenase products.

INTRODUCTION: We investigated both the effect and the role(s) of potassium channels, nitric oxide (NO) and cyclooxygenase (COX) products in the effect of hydrogen peroxide (H(2)O(2)) in human internal thoracic artery (ITA) rings. MATERIALS AND METHODS: Samples of redundant ITA obtained from patients undergoing a coronary artery bypass graft surgery were cut into 3 mm wide rings and suspended in 20 ml organ baths. Isometric tension was continuously measured with an isometric force transducer connected to a computer-based data acquisition system. RESULTS: H(2)O(2) (10(-7)-10(-4) M) produced concentration-dependent relaxation responses in human ITA precontracted by phenylephrine. The relaxant responses to H(2)O(2) did not differ significantly between endothelium-intact and endothelium-denuded preparations. Incubation of human ITA rings with superoxide dismutase (50 U/ml) did not affect the relaxant responses to H(2)O(2), while 1,000 U/ml catalase caused a significant decrease. Incubation of endothelium-intact or endothelium-denuded human ITA rings with voltage-dependent potassium channel blocker 4-aminopyridine (5 mM) significantly inhibited the relaxant responses to H(2)O(2). COX inhibitor indomethacin (10(-5) M) also caused a significant inhibition. Incubation with ATP-dependent potassium channel blocker glibenclamide (10(-6) M) or Ca(2+)-activated potassium channel blocker iberiotoxin (10(-7) M) or NO synthase (NOS) blocker N(omega)-nitro-L: -arginine methyl ester (10(-4) M) did not alter relaxant responses of ITA rings to H(2)O(2). CONCLUSION: The findings of the present study suggested that H(2)O(2)-induced relaxation responses in human ITA were neither dependant on the endothelium nor blocked by NOS inhibition but they rather seem to depend on the activation of voltage-dependent potassium channels and COX.