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SUMMARY This paper addresses some issues in palliative-care work that emerged in a short-term staff-support group, and shows that work with terminally-ill cancer patients had an impact on the staff and team as a whole. In dealing with distressing and disturbing feelings related to work with dying patients, the staff used manic defences and denial of differences within the team.

Background and Aims. Intracellular calcium regulation in endothelial cells depends on transient receptor potential channels (TRPs). Canonical TRPs (TRPCs) are now recognized as the most important Ca2+-permeable cation channels in vascular endothelium and TRPC3 channel is reported to play a role in vasodilation in animal vessels. However, little is known about the role of TRPCs in human arteries. We therefore tested the hypothesis that TRPCs play a role in human arteries. Methods. Cumulative concentration-relaxation curves to acetylcholine (-11 to -4.5 log M) were established in the human internal mammary artery (IMA) rings (n = 42) taken from 28 patients undergoing coronary artery bypass grafting in precontraction induced by U46619 (-8 log M) in the absence or presence of SKF96365 (10 mu mol/L) or Pyr3 (3 mu mol/L). Protein expressions of TRPC3 were determined by Western blot and immunohistochemistry staining. Results. The maximal relaxation induced by acetylcholine was significantly attenuated by the nonspecific cation channels inhibitor, SKF96365 (48.2 +/- 3.7 vs. 66.0 +/- 0.9% in control, p lt 0.01) or the selective TRPC3 blocker, Pyr3 (58.4 +/- 2.3% vs. 67.7 +/- 1.1% in control, p lt 0.01). Protein expression of TRPC3 was detected in human 1MA. Conclusions. TRPC3 exists and plays a role in the acetylcholine-induced endothelium-dependent relaxation in the human IMA. This study suggests that TRPC3 may be a potential new target in endothelial protection in patients with endothelial dysfunction such as in patients with coronary artery disease in order to improve the long-term patency of the grafting vessels.

The drug nicorandil is a vasodilator approved for the treatment of angina. In addition to its well-known effect on the opening of ATP-sensitive K (KATP) channels, nicorandil-induced vasorelaxation also involves the opening of Ca-activated K channels. The aim of this study was to investigate the effects of nicorandil on the isolated human internal mammary artery (HIMA) and the human saphenous vein (HSV) and to define the contribution of different K channel subtypes in the nicorandil action on these arterial and venous grafts. Our results show that nicorandil induced a concentration-dependent relaxation of HSV and HIMA rings precontracted by phenylephrine. Glibenclamide, a selective KATP channels inhibitor, partially inhibited the response to nicorandil in both HSV and HIMA. Iberiotoxin, a most selective blocker of large-conductance Ca-activated K (BKCa) channels, partly antagonized relaxation of HIMA. A nonselective blocker of voltage-gated K channels, 4-aminopyridine caused partial inhibition of the nicorandil-induced relaxation of HSV but did not antagonize relaxation of HIMA induced by nicorandil. Margatoxin, a potent inhibitor of KV1.3 channels, did not abolish the effect of nicorandil on HSV and HIMA. Our results showed that nicorandil induced strong endothelium-independent relaxation of HSV and HIMA contracted by phenylephrine. It seems that KATP and 4-aminopyridine-sensitive K channels located in the smooth muscle of HSV mediated relaxation induced by nicorandil. In addition, KATP and BKCa channels are probably involved in the nicorandil action on HIMA.

The ATP-sensitive K(+) channels opener (K(ATP)CO), P1075 [N-cyano-N'-(1,1-dimethylpropyl)-N″-3-pyridylguanidine], has been shown to cause relaxation of various isolated animal and human blood vessels by opening of vascular smooth muscle ATP-sensitive K(+) (K(ATP)) channels. In addition to the well-known effect on the opening of K(ATP) channels, it has been reported that vasorelaxation induced by some of the K(ATP)COs includes some other K(+) channel subtypes. Given that there is still no information on other types of K(+) channels possibly involved in the mechanism of relaxation induced by P1075, this study was designed to examine the effects of P1075 on the rat renal artery with endothelium and with denuded endothelium and to define the contribution of different K(+) channel subtypes in the P1075 action on this blood vessel. Our results show that P1075 induced a concentration-dependent relaxation of rat renal artery rings pre-contracted by phenylephrine. Glibenclamide, a selective K(ATP) channels inhibitor, partly antagonized the relaxation of rat renal artery induced by P1075. Tetraethylammonium (TEA), a non-selective inhibitor of Ca(2+)-activated K(+) channels, as well as iberiotoxin, a most selective blocker of large-conductance Ca(2+) -activated K(+) (BK(Ca)) channels, did not abolish the effect of P1075 on rat renal artery. In contrast, a non-selective blocker of voltage-gated K(+) (K(V)) channels, 4-aminopyridine (4-AP), as well as margatoxin, a potent inhibitor of K(V)1.3 channels, caused partial inhibition of the P1075-induced relaxation of rat renal artery. In addition, in this study, P1075 relaxed contractions induced by 20 mM K(+) , but had no effect on contractions induced by 80 mM K(+). Our results showed that P1075 induced strong endothelium-independent relaxation of rat renal artery. It seems that K(ATP), 4-AP- and margatoxin-sensitive K(+) channels located in vascular smooth muscle mediated the relaxation of rat renal artery induced by P1075.

Because adrenergic contractions can contribute to the development of life-threatening spasm of coronary artery bypass graft, this study was performed to investigate the effect of adenosine 3-phosphate (ATP)-sensitive K+ channel (KATP) opener P1075 on contractions of isolated human saphenous vein (HSV) and human internal mammary artery (HIMA). Phasic contractions were evoked by electric field stimulation (20 Hz) and noradrenaline. The sustained contractions were evoked by phenylephrine. The presence of pore-forming Kir6.1 and Kir6.2 subunits of the KATP channels in the HIMA and only Kir6.2 in the HSV was confirmed immunomorphologically. P1075 inhibited in the HSV only, the electrical field stimulation contractions more strongly than noradrenaline contractions. In addition, the phenylephrine contractions of HSV were more sensitive to P1075 in comparison to those of HIMA. Glibenclamide, a KATP channel blocker antagonized the vasodilatation produced by P1075 in both grafts differently, because its effect was more prominent on the P1075-induced inhibition of contractions of HSV than of HIMA. We conclude that P1075 has a vasorelaxant effect and inhibited adrenergic contractions of the tested grafts. This effect is graft and vasoconstrictor selective and seems to be mediated by Kir6.1- and/or Kir6.2-containing KATP channels. Thus, P1075 can be considered as a potential drug in the prevention of graft spasm.

Recently it has been suggested that resveratrol relaxes different isolated arteries. The present study addressed the question whether different ion channels are involved in the endothelium-independent mechanism of vasodilatation induced by resveratrol. For that purpose, we tested the action of resveratrol on the rat mesenteric artery without endothelium. Resveratrol induced concentration-dependent relaxation of rat mesenteric artery. Among the K+-channel blockers, 4-amynopiridine (4-AP) moderately antagonized the resveratrol-induced relaxation, while glibenclamide, tetraethylammonium chloride, charybdotoxin, margatoxin, and barium chloride did not inhibit resveratrol-induced vasorelaxation. In rings, precontracted with 100 mM K+, the relaxant responses to resveratrol were highly significantly shifted to the right compared to those obtained in rings precontracted with phenylephrine, but resveratrol-induced maximal relaxation was only slightly affected. In order to minimize the influence of K+ channels and voltage-gated Ca2+ channels (VGCCs) in vascular smooth muscle, the third contraction was made by 100 mM K+ in the presence of nifedipine. The relaxant response to resveratrol was abolished. Thus, the mechanism of vasorelaxation induced by resveratrol probably involves activation of 4-AP-sensitive K+ channels. Its ability to completely relax the mesenteric artery precontracted with K+-rich solution suggests that K+ channel–independent mechanism(s) are involved in its vasorelaxant effect. It seems that interaction with VGCCs plays a part in this K+ channel–independent effect of resveratrol. Keywords:: resveratrol, rat mesenteric artery, ion channel, vasorelaxation, K+ channel

77th Congress of the European Atherosclerosis Society 26-29 April 2008 • Istanbul, Turkey

s / Atherosclerosis 241 (2015) e32ee71 e50 EAS-0759. EPICATECHIN INDUCED VASORELAXATION OF HUMAN INTERNAL MAMMARY ARTERY A. Novakovic , M. Marinko , A. Vranic , G. Jankovic , I. Stojanovic , P. Milojevic , N. Ugresic , V. Kanjuh , Q. Yang , G.W. He . Department of Pharmacology, Faculty of Pharmacy University of Belgrade, Belgrade, Serbia; Department of Surgery, 1) Faculty of Medicine University of Belgrade 2) Institute for Cardiovascular Diseases “Dedinje”, Belgrade, Serbia; Department of Pharmacology, Academy of Sciences and Arts, Belgrade, Serbia; Department of Surgery, The Chinese University of Hong Kong, Hong Kong, Hong Kong China; 5 TEDA International Cardiovascular Hospital, Medical College Nankai University, Tianjin, China Aim: Epicatechin is a flavanol abundantly present in grapes, cocoa and tea. Different biological actions of flavanol-rich foods support their potential cardioprotective effects including vasodilation, as well as reduction of oxidative stress, early event in development of atherosclerosis. Because the exact mechanisms by which epicatechin causes vasodilation are unclear, we aimed to investigate relaxant effect of epicatechin on the isolated human internal mammary artery (HIMA) and its underlying mechanisms. Methods: Discarded segments of HIMA were collected from patients undergoing coronary artery bypass grafting and studied in organ baths. Results: Epicatechin induced a concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Among the K+ channel blockers, 4-aminopyridine and margatoxin, blockers of voltage-gated K+ (KV) channels, and glibenclamide, a selective ATP-sensitive K+ (KATP) channels blocker, partly inhibited the epicatechin-induced relaxation of HIMA, while iberiotoxin, a most selective blocker of large conductance Ca2+-activated K+ channels (BKCa), almost completely inhibited the relaxation. In rings pre-contracted by 80 mM K+, epicatechin induced partial relaxation of HIMA, whereas in Ca2+-free medium, epicatechin completely relaxed HIMA rings pre-contracted by phenylephrine and caffeine. Finally, thapsigargin, a sarcoplasmic reticulum Ca2+-ATPase inhibitor, slightly antagonized epicatechin-induced relaxation of HIMA pre-contracted by phenylephrine. Conclusions: These results suggest that epicatechin induces strong endothelium-independent relaxation of HIMA pre-contracted by phenylephrinewhilst 4-aminopyridineandmargatoxin-sensitive KV channels, as well as BKCa and KATP channels, located in vascular smooth muscle, mediate this relaxation. In addition, it seems that epicatechin could inhibit influx of extracellular Ca2+, interfere with intracellular Ca2+ release and reuptake by the sarcoplasmic reticulum. CV risk factors and atherosclerosis II EAS-0052. INFANT BIRTH WEIGHT AND RISK FACTORS FOR ADULT CARDIOVASCULAR DISEASE INCLUDING BODY MASS INDEX IN THE LIFEWAYS CROSS-GENERATION COHORT STUDY OF A THOUSAND FAMILIES S. McKey, M. Heinen, R. Segurado, J.O.H.N. Mehegan, C. Murrin, C. Kelleher. School of Public Health Physiotherapy and Population Science, University College Dublin, Dublin, Ireland Background: Infant birth-weight predicts risk of adult chronic disease and more recently studies have reported on cross-generation transmission of risk patterns. The Lifeways study is highly novel, with information on three generations of the same families. Aim: To examine whether adults' birth-weights were associated with measures of own health status, or social position and to relate these also to infant birth-weights (BW) of index child or grandchild. Methods: Participants were 1083 children and 934 adult cohort members, mothers, fathers and grandparents, recruited in 2001, followed prospectively until 2014. At baseline adults reported own birth weight (RBW) by questionnaire. Child's birth-weight was from hospital records. At descriptive uni-variate level, categorical chi2 and Pearson's correlations were performed. A multi-level mixed effects linear regression model with adults' body mass index as the outcome variable was also undertaken. Results: Male adults' RBW were significantly higher than females' (p1⁄40.001). There was a u-shaped association with education in that those adults with highest education were least likely to be in either the highest or lowest tertile for RBW (p1⁄40.004). Child's BW was correlated positively with that of mother for both sexes (r 1⁄4 0.168, p1⁄40.001). Paternal grandfather's RBW was inversely associated with child's BW (r1⁄4-0.424, p1⁄40.039). In the multi-level model, adults' BMI was positively associated with age (p1⁄40.000), index child's BW (p1⁄40.001), educational status (p1⁄40.001), group (0.011) but not RBW, adjusting for family ID. Conclusion: Cross-generational associations for birth-weight and BMI are confirmed in the Lifeways cohort, consistent with the developmental origins of disease hypothesis. EAS-0100. RELATIONS BETWEEN RETINAL ARTERIOLES ANATOMY AND LARGE ARTERY GEOMTRY AND FUNCTION AND PERIPHERAL RESISTANCE IN HYPERTENSIVES D. Rosenbaum, N. Kachenoura , E. Koch , M. Paques , P. Cluzel , E. Brucket , A. Redheuil , X. Girerd . Cardiovascular prevention, GH Piti eSalpetri ere, Paris, France; 2 laboratoire d'imagerie biom edicale, INSERM U1166, Paris, France; CIC des 15/20, Institut de la vision, Paris, France; Cardiovascular imaging department, GH Piti e Salpetri ere, Paris, France; 5 cardiovascular prevention unit, GH Piti e Salpetri ere, Paris, France Background: Microvascular remodeling and large artery stiffness are key determinants of blood pressure (BP) yet they are difficult to study noninvasively in humans. Our objective was to study relationships between retinal arterioles anatomy and total peripheral resistance (TPR) as well as with large artery geometry and function in hypertension. Methods and results: Demographics, ambulatory home and central BP were assessed in 80 subjects (age 52±13 years; 53% male): 23 normotensives, 28 treated and controlled hypertensives and 29 treated and uncontrolled hypertensives. Retinal arteriolar wall-to-lumen ratio (WLR) was assessed non-invasively using an Adaptive Optic camera. Carotido-femoral pulse wave velocity (Cf-PWV) was assessed along with cardiovascular MRI ascending aorta distensibility (AAD), geometry and ultrasound carotid intima media thickness (IMT). TPR was calculated using central BP and CMR-derived aortic flow. WLR, IMT and TPR were significantly higher and AAD lower in hypertensives, compared to normotensives. In univariate analysis, WLR correlated positively with central BP (p

Resveratrol, a phenolic substance present in grapes and a variety of medical plants, has been reported to induce vasorelaxation, however the mechanisms are uncertain. In this paper we investigate the possible participation of K(+) channels in the endothelium-independent vasodilatation of rat aorta induced by resveratrol. Resveratrol induced concentration-dependent relaxation of rings with endothelium and without endothelium. We used different potassium channel inhibitors to determine whether the K(+) channels mediated endothelium-independent relaxation of rat aorta induced by resveratrol. Highly selective blocker of ATP-sensitive K(+) channels, glibenclamide, as well as non-selective blockers of K(+) channels, tetraethylammonium, did not block resveratrol-induced relaxation of rat aortic rings. Charybdotoxin, a blocker of calcium-sensitive K(+) channels did not affect the resveratrol-induced relaxation. 4-Aminopiridine, non-selective blocker of voltage-gated K(+) (Kv) channels, and margatoxin that inhibits Kv1 channels abolished relaxation of rat aortic rings induced by resveratrol. In conclusion, we have shown that resveratrol potently relaxed rat aortic rings with denuded endothelium. It seems that 4-aminopiridine and margatoxin-sensitive K(+) channels located in the smooth muscle of rat aorta mediated this relaxation.

Resveratrol, a stilbene polyphenol found in grapes and red wine, produces vasorelaxation in both endothelium-dependent and endothelium-independent manners. The mechanisms by which resveratrol causes vasodilatation are uncertain. The aim of this study was to investigate the mechanism(s) of endothelium-independent resveratrol-induced vasorelaxation in human internal mammary artery (HIMA) obtained from male patients undergoing coronary artery bypass surgery and to clarify the contribution of different K+ channel subtypes in resveratrol action in this blood vessel. HIMA rings without endothelium were precontracted with phenylephrine. Resveratrol induced a concentration-dependent relaxation of the HIMA. A highly selective blocker of ATP-sensitive K+ channels, glibenclamide, as well as nonselective blockers of Ca2+-sensitive K+ channels, tetraethylammonium and charybdotoxin, did not block resveratrol-induced relaxation of HIMA rings. 4-Aminopyridine (4-AP), non selective blocker of voltage-gated K+ (KV) channels, and margatoxin that inhibits KV1.2, KV1.3, and KV1.6 channels abolished relaxation of HIMA rings induced by resveratrol. In conclusion, we have shown that resveratrol potently relaxed HIMA rings with denuded endothelium. It seems that 4-AP- and margatoxin-sensitive K+ channels located in smooth muscle of HIMA mediated this relaxation. Keywords:: resveratrol, vasorelaxation, human internal mammary artery, K+ channel

Nutrition and nutraceuticals

2013 e47 PP098—NICORANDIL INDUCED ENDOTHELIUMINDEPENDENT RELAXATION OF ARTERIAL BYPASS GRAFT M. Marinko; A. Novakovic; I. Stojanovic; P. Milojevic; M. Jovic; D. Nenezic; N. Ugresic; V. Kanjuh; Q. Yang; and G.-W. He Department of Pharmacology, Faculty of Pharmacy, University of Belgrade; Faculty of Medicine, University of Belgrade; Institute for Cardiovascular Diseases “Dedinje”; Academy of Sciences and Arts, Belgrade, Serbia; Department of Surgery, Chinese University of Hong Kong, Hong Kong, Hong Kong; TEDA International Cardiovascular Hospital, Medical College, Nankai University, Tianjin, China; and Providence Heart & Vascular Institute, Albert Starr Academic Center, Department of Surgery, Oregon Health and Science University, Portland, Oregon Introduction: Spasm of the human internal mammary artery (HIMA) is a rare but life-threatening complication after coronary artery bypass grafting (CABG). The reversal of this vasospasm is often challenging, and the most effective therapy is not well defined. The present study was aimed to investigate vasorelaxant effect of nicorandil, K+ channel opener, on the HIMA and to define the role of different K+ channel subtypes in nicorandil action on this blood vessel. Patients (or Materials) and Methods: Discarded segments of HIMA were collected from patients undergoing CABG and studied in organ baths. HIMA rings were precontracted with phenylephrine (10 μM) followed by cumulatively adding increasing doses of nicorandil. The endothelium was removed mechanically. Results: Nicorandil (0.001 μM–300 μM) induced a concentrationdependent relaxation of HIMA rings precontracted by phenylephrine. Glibenclamide (10 μ M), a highly selective blocker of ATP-sensitive K+ (K ATP ) channels, partially inhibited relaxation of HIMA induced by nicorandil. Tetraethylammonium (TEA, 1 mM), a nonselective blocker of Ca 2+ -activated K+ (K Ca ) channels, as well as iberiotoxin (100 nM), a most selective blocker of large-conductance K Ca (BK Ca ) channels, partly antagonized relaxation of HIMA. A nonselective blocker of voltage-gated K+ (K V ) channels, 4-aminopyridine (4-AP, 0.5 mM), as well as margatoxin (10 nM), a potent inhibitor of K V 1.3 channels, did not significantly modify the nicorandil-induced relaxation of HIMA. Conclusion: The results from our study demonstrate that, in HIMA, nicorandil has a potent vasorelaxant effect which is endotheliumindependent. It seems that mechanism of this relaxation includes KATP and 4-AP-sensitive K+ channels located in the smooth muscle of HIMA. Disclosure of Interest: None declared.