Edibe Karasu

Comparison of the vasodilatory effect of nadroparin, enoxaparin, dalteparin, and unfractioned heparin in human internal mammary artery.

The aim of this study was to investigate whether the low-molecular-weight heparins (LMWHs) (eg, nadroparin, enoxaparin, and dalteparin) cause a vasodilatory effect in human internal mammary artery (IMA) and to further compare its effect with unfractioned heparin (UFH). Samples of redundant IMA obtained from 20 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. LMWHs (0.5-6 U/mL) caused a concentration-dependent relaxation in the endothelium-intact human IMA rings, which were precontracted with Phe (10−6 M) (P < 0.05). The vasodilator potency of LMWHs seems to be nearly similar while the maximal effect produced by LMWHs was less pronounced compared with that produced by UFH. Removal of endothelium totally abolished the responses of human IMA to LMWHs as well as UFH (P < 0.05). LMWHs-induced vasodilator effect was significantly attenuated by Nω-nitro-L-arginine methyl ester (L-NAME, 10−4 M) but not indomethacin (10−5 M). Our results have shown that LMWHs cause a dose-dependent relaxation in human IMA but are less effective than that produced by UFH. The vasorelaxant effects induced by each of LMWH are nearly similar and seem to be via endothelium-dependent mechanisms, including generation of nitric oxide.

Unfractioned heparin produces vasodilatory action on human internal mammary artery by endothelium-dependent mechanisms

The aim of this study was to investigate whether unfractioned heparin produces a direct vasodilatory effect on the human internal mammary artery (IMA) and the possible underlying mechanisms. Samples of redundant IMA were obtained from 20 patients undergoing coronary artery bypass graft surgery, and concentration-response curves to unfractioned heparin were constructed. Unfractioned heparin (0.5-6 U/mL) caused a concentration-dependent relaxation in the endothelium-intact human IMA rings precontracted with phenylephrine (10−6 M). Removal of endothelium significantly inhibited the responses of human IMA to unfractioned heparin (P < 0.05). Nω-Nitro-L-arginine methyl ester (L-NAME, 10−4 M), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10−5 M) and L-NAME (10−4 M) plus ODQ (10−5 M) partially reduced unfractioned heparin-induced vasodilatory response in endothelium-intact rings, whereas indomethacin alone had no effect. The vasodilatory effect of unfractioned heparin was completely inhibited by 40 mM KCl in the presence of L-NAME, ODQ, and indomethacin. These results clearly demonstrated that unfractioned heparin causes a concentration-dependent vasodilatation in human internal mammary artery, and this action seems to be via endothelium-dependent mechanisms, including generation of nitric oxide and endothelium-derived hyperpolarizing factor.

Endothelial Dysfunction in the Human Umbilical Artery due to Preeclampsia Can Be Prevented by Sildenafil

Abstract Objectives. We aimed to determine the effects of sildenafil in human umbilical artery preparation taken from preeclamptic or normal pregnant women, also to investigate underlying mechanisms in these effects. Study design. Eighteen pregnant women with preeclampsia and 18 healthy pregnant women were involved. Relaxation responses of sildenafil in presence and absence of nitric oxide (NO) synthase inhibitor, N-[omega]-nitro-l-arginine methyl ester (l-NAME), and soluble guanylyl cyclase inhibitor, 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), were compared between the preeclampsia group and control group. Results. Sildenafil-induced relaxation responses were significantly attenuated in the presence of preeclampsia, l-NAME or ODQ, but not totally abolished. Interestingly, except with ODQ incubation, in all set of experiments maximal relaxation response was achieved by sildenafil. Conclusion. These data indicate that sildenafil might effect vascular responsiveness of human umbilical artery through the involvement of NO/cyclic guanosine monophosphate (cGMP)-dependent and -independent pathways. Further investigations are needed to clarify the exact mechanisms.

Changes in atrium and thoracic aorta reactivity to adenosinergic and adrenergic agonists in experimental hyperhomocysteinemia.

We prepared diet-induced hyperhomocysteinemia (hHcy) in adult male Wistar rats and investigated the effects of hHcy on the adenosinergic and adrenergic responses in vitro and in vivo. The responsiveness of right atria from hHcy rats to the negative chronotropic effects of adenosine (Ado) was found to be significantly greater in hHcy rats than in controls. The pD2 value and maximum effect of Ado were significantly increased in 12-week hHcy right atria when compared with those from age-matched controls. The vasodilatory effect of Ado on rat thoracic aorta was also increased in hHcy rats. In the presence of dipyridamole, an Ado uptake inhibitor, the negative chronotropic and vasodilatory effects of Ado were significantly potentiated in the hHcy rats much more than in the control rats. In anesthetized rats, Ado and dipyridamole, given as a rapid bolus into the femoral artery, led to reduction in mean blood pressure and heart rate. This effect was significantly pronounced in hHcy rats when compared with control animals. Otherwise, hHcy atria were found to have increased responsiveness to the positive chronotropic response to isoproterenol, an β-adrenoceptor agonist. However, there were no significant differences between two groups in the vasoconstrictor effects to phenylephrine, an α-adrenoceptor agonist. On the basis of these results, we concluded that hHcy rats were significantly more sensitive to the negative chronotropic and vasorelaxant effects of Ado, possibly because of accelerated cellular Ado uptake and/or a change in Ado receptor-G protein system. This change may be related with the increased responsiveness to β-adrenergic agonists in hHcy rats, and might contribute to the harmful cardiac effects of hHcy.

Effects of short-term exposure to homocysteine on vascular responsiveness of human internal mammary artery

Abstract: The aim of this study was to investigate the acute direct effects of homocysteine (Hcy) on the vascular responsiveness of human internal mammary artery (IMA) and to define the possible underlying mechanisms. The contractile response to both phenylephrine (Phe) (−36%) and KCl (−18%) was significantly reduced in arteries that were incubated with Hcy (10−4 M, 30 minutes), compared with controls (P < 0.05). Removal of endothelium did not significantly alter the responses of human IMA to Phe. Hcy (10−4 M) also caused a relaxation response in human IMA rings precontracted with Phe (10−6 M) and this effect was not inhibited by Nω-nitro-L-arginine methyl ester (L-NAME, 10−4 M), by l-NAME (10−4 M) + indomethacin (10−5 M), or by intimal rubbing. In addition, contractions induced by stepwise addition to calcium (Ca2+) to high KCl solution with no Ca2+ were significantly inhibited by Hcy incubation as well as contractions induced by Phe in the absence of extracellular Ca2+ (P < 0.05). On the other hand, Hcy (10−4 M, 30 minutes) did not significantly inhibit the relaxation responses to either acetylcholine (ACh) or sodium nitroprusside (SNP) (P > 0.05). These results demonstrated that short-term exposure to Hcy significantly decreased vascular responsiveness in human IMA without affecting endothelium-dependent and -independent vasorelaxation. This effect is not NO-, prostaglandin- or endothelium-dependent. The mechanism is uncertain but seems to depend on the interactions of Hcy with Ca2+ influxes and/or other undefined direct effects in this tissue.

Different effects of different phosphodiesterase type-5 inhibitors in pre-eclampsia

OBJECTIVES We aimed to determine the effects of sildenafil and vardenafil in human umbilical artery preparation taken from pre-eclamptic or normal pregnant women, and also to investigate the underlying mechanisms in these effects. STUDY DESIGN Fifteen pregnant women with pre-eclampsia and 15 healthy pregnant women were involved. Relaxation responses of sildenafil and vardenafil in the presence and absence of nitric oxide synthase inhibitor, N-[omega]-nitro-l-arginine methyl ester (l-NAME), and soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), were compared between the pre-eclampsia group and the control group. RESULTS Sildenafil induced relaxation responses were significantly attenuated in the presence of pre-eclampsia, l-NAME and QDO. Similarly, pre-eclampsia, l-NAME or ODQ incubation also shifted vardenafil-induced relaxation responses rightward. However, in all set of experiments a maximal relaxation response was achieved by vardenafil unlike sildenafil. In conclusion vardenafil seems to relax human umbilical artery stronger than sildenafil in both pre-eclamptic and normal pregnancies. CONCLUSION These data indicate that vardenafil might affect vascular responsiveness of human umbilical artery through the involvement of NO/cGMP-dependent and independent pathways while sildenafil-induced responses were seemed to be completely NO/cGMP-dependent. Further investigations are needed to clarify the mechanisms.

Klopidogrel direncine farmakogenetik yaklaşım: iki erkek kardeşde tekrarlayan stent trombozisi olgusu

Clopidogrel, is the antiplatelet treatment choice for prevention of thrombosis after coronary stent implantation.However, despite the use of clopidogrel, a considerable number of patients continue to have stent thrombosis.There is a growing degree of evidence that recurrence of ischemic complications may be attributed to poorresponse of clopidogrel. It is noteworthy to elucidate the mechanisms leading to poor clopidogrel effects.We reportrecurrent stent thrombosiswith possible clopidogrel resistanceand aimed to discuss the mechanismsof clopidogrel resistance in the light of the medical literature