Paul M. Vanhoutte

University of Hong Kong

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Aimin Xu

University of Hong Kong

J. T. Shepherd

Mayo Clinic

Michel Félétou

Servier (France)

Nicholas A. Flavahan

Johns Hopkins University

Thomas F. Lüscher

Royal Brompton & Harefield NHS Foundation Trust

Chantal M. Boulanger

Paris Cardiovascular Research Center

Hiroaki Shimokawa

International University of Health and Welfare

Yu Wang

University of Hong Kong

Tony J. Verbeuren

Servier (France)

Weiping Jia

Shanghai Sixth People's Hospital

Cooperative Institutions

University of Hong Kong

163

Chinese University of Hong Kong

129

Inserm

Hong Kong College of Technology

Mayo Clinic

University of Zurich

Chinese Academy of Sciences

Sociedad Española de Cardiología

Servier (France)

Sun Yat-sen University

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John A. Bevan, MD

Journal of Cardiovascular Pharmacology (2007)

Bill Halpern Michael J. Mulvany Paul M. Vanhoutte

FIGURE: John A. Bevan (1930-2007)John Bevan, one of the pioneers of vascular pharmacology, passed away on February 14, 2007, following an illness that he bore valiantly. John had a dedicated scientific career, building an international reputation that spanned a half-century. His experimental studies of the vascular system encompassed myriad aspects of the human and animal vascular networks and the mechanisms that control them. He took a broad-spectrum approach, integrative in nature, to examine neurogenic, developmental, hemodynamic, humoral, and therapeutic aspects. John, born in 1930, grew up in Britain and, following a degree in pharmacology and physiology, he did his medical training at the University of London, receiving his MD and other medical qualifications in 1953, followed by medical duty in the Royal Air Force. During their medical studies, John and his wife Rosemary developed their lifelong fascination for science. Britain, still a country of austerity after World War II, offered limited research possibilities. John was tempted “across the pond” to UCLA, where he was offered a faculty position in 1957. This gave him the opportunity he needed, and he began working on the morphological and pharmacological characterization of pulmonary arterial nerve endings. He rose to the rank of full professor in 1967. John's experiments using classical methods to examine large vessels provided him with numerous insights, but he was nevertheless one of the first to recognize that an understanding of cardiovascular control required the investigation of isolated small vessels. At that time, the idea of doing in vitro experiments on vessels almost too small to see appeared impossible. In 1972 John, together with John Osher, showed that it was feasible to mount such vessels in a myograph, allowing isometric responses to be obtained. This myograph proved to be the prototype for the later development of myography. Vermont became one of the centers of myography, and perhaps for this reason in 1983, after 25 years in California, John and Rosemary accepted appointments to the University of Vermont, where John became chair of the Department of Pharmacology. John played a major role in further developing the myograph technique, and established the Vermont Center for Vascular Research. His interests broadened to studies of myogenic tone, the vasoactive effects of flow, the endothelium, and the control of the human brain circulation. An important theme of John's work was to extend the extensive experimental knowledge of blood vessels to the study of isolated human blood vessels. To this end, he and Rosemary established the Totman Laboratory for Human Cerebrovascular Research, which they directed until John retired from the Department of Pharmacology and became Emeritus. John's work is recorded in more than 400 articles and book chapters. At the time of his death, John was working on a book treating the cerebrovascular circulation as it was seen from ancient times to the present. Apart from his laboratory interests, John used his organizational skills to play a major international role in establishing the field of vascular pharmacology. John held the first Vascular Neuroeffector Mechanism Symposium in 1970, a symposium series that has continued regularly ever since. In 1975 he took over the editorship of Blood Vessels (now the Journal of Vascular Research) and with his love of literary and scientific precision succeeded in making this a respected journal; indeed, for many, it is the leading journal in the field. Although the scientific attractions of UVM weighed heavily, John and Rosemary were surely attracted by the natural delights of Vermont, where they decided to set up house on the slopes of Mount Philo, with its magnificent views of Lake Champlain. He often explored its shores in his sailboat. This location was an added incentive for his 4 children and their families to visit. John was an avid hiker here and abroad and enjoyed traveling to maintain long-term contacts with his scientific colleagues. Above all, he was a wonderful human being. It was a privilege to know him. He will be sorely missed and never forgotten.

Wife

10.1097/fjc.0b013e318154c833

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Citations (1)

Thrombin Prevents the Expression of Inducible Nitric Oxide Synthase in Vascular Smooth Muscle Cells by a Proteolytically-Activated Thrombin Receptor

Thrombosis and Haemostasis (1995)

Valérie B. Schini‐Kerth Beate Fißithaler Thomas T. Andersen John W. Fenton Paul M. Vanhoutte

Proteolytically active forms of thrombin ( alpha- and gamma-thrombin) and thrombin receptor peptides inhibited the release of nitrite, a stable endproduct of nitric oxide, evoked by interleukin-1 beta (IL-1 beta ) in cultured vascular smooth muscle cells while proteolytically inactive forms [D-Phe-Pro-Arg chloromethyl ketone-alpha-thrombin (PPACK-alpha-thrombin) and diisopropylphosphoryl-alpha-thrombin (DIP-alpha-thrombin)] had either no or only minimal inhibitory effects. Under bioassay conditions, perfusates from columns containing IL-1 beta-activated vascular smooth muscle cells or cells treated with IL-1 beta plus PPACK-alpha-thrombin relaxed detector blood vessels. These relaxations were abolished by the inhibitor of nitric oxide synthesis, NG-nitro-L-arginine. No relaxations were obtained with untreated cells or IL-1 beta-treated cells in the presence of alpha-thrombin. The expression of inducible nitric oxide synthase mRNA and protein in vascular smooth muscle cells by IL-1 beta was impaired by alpha-thrombin. These results demonstrate that thrombin regulates the expression of the inducible nitric oxide synthase at a transcriptional level via the proteolytic activation of the thrombin receptor in vascular smooth muscle cells.

Thrombin receptor

10.1055/s-0038-1649859

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Citations (8)

Effect of Hypoxia on Reactivity of Cutaneous and Mesenteric Veins of the Dog

Springer eBooks (1972)

Paul M. Vanhoutte I Leusen

Hypoxia

Mesenteric Vein

10.1007/978-3-642-65327-8_69

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Citations (3)

Regulation of Adhesion Molecules: A New Target for the Treatment of Chronic Venous Insufficiency

Microcirculation (2000)

Tony J. Verbeuren Eliete Bouskela Richard A. Cohen Paul M. Vanhoutte

ABSTRACT As more insight into the mechanisms leading to chronic venous insufficiency (CVI) is gained, novel targets for drug treatment of the disease, or of its complications, become available. Studies using chemical entities capable of inhibiting leukocyte adhesion in postcapillary venules have led to the discovery of selective inhibitors of cell adhesion mechanisms. The aim of the current review is to describe the pharmacology, biochemistry, and molecular biology studies performed with some new inhibitors of adhesion molecule expression. Compounds such as hydroxy triallyl farnisine (S 17834) may offer new and efficient treatment of the microcirculatory complications that accompany chronic venous disease.

Chronic Venous Insufficiency

10.1111/j.1549-8719.2000.tb00150.x

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Citations (8)

Hypercholesterolemia causes generalized impairment of endothelium-dependent relaxation to aggregating platelets in porcine arteries

Journal of the American College of Cardiology (1989)

Hiroaki Shimokawa Paul M. Vanhoutte

Apyrase

Ketanserin

Coronary arteries

Adenosine diphosphate

10.1016/0735-1097(89)90318-5

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Citations (93)

Oxidative Stress and Pathological Changes After Coronary Artery Interventions

Journal of the American College of Cardiology (2013)

Rio P. Juni Henricus J. Duckers Paul M. Vanhoutte Renu Virmani An L. Moens

Endothelial Dysfunction

10.1016/j.jacc.2012.11.068

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Citations (105)

Prostacyclin releases endothelium‐derived relaxing factor and potentiates its action in coronary arteries of the pig

British Journal of Pharmacology (1988)

Hiroaki Shimokawa Nicholas A. Flavahan Robert R. Lorenz Paul M. Vanhoutte

The possible interactions between prostacyclin and endothelium‐derived relaxing factor were examined, in isolated coronary arteries of the pig treated with indomethacin (10 −5 m ). In organ chamber experiments, prostacyclin caused relaxations, which were potentiated in the presence of the endothelium; the potentiation was abolished by oxyhaemoglobin. In bioassay experiments, prostacyclin caused minimal relaxations of bioassay rings without endothelium; these relaxations were potentiated when the bioassay ring was exposed to basally‐released endothelium‐derived relaxing factor (interaction between prostacyclin and basal endothelium‐derived relaxing factor) and further augmented when the endothelial cells were exposed to the prostanoid (stimulated release of endothelium‐derived relaxing factor). The endothelium‐dependent, but not the direct effects of prostacyclin were augmented by superoxide dismutase plus catalase and abolished by oxyhaemoglobin. Forskolin, a direct activator of adenylate cyclase, caused relaxations of rings without endothelium, which were augmented by the presence of the endothelium. The relaxations induced by prostacyclin or forskolin also had an endothelium‐dependent component in basilar and femoral arteries and in jugular veins of the pig. The endothelium‐dependent actions of prostacyclin probably reflect activation of adenylate cyclase.

Endothelium-derived relaxing factor

10.1111/j.1476-5381.1988.tb11756.x

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Citations (156)

PDE and sGC hand in hand to see the light

Proceedings of the National Academy of Sciences (2014)

Paul M. Vanhoutte

In PNAS, Sikka et al. (1) suggest that melanopsin, a non–image-forming opsin (opsin4, Opn4), may play a physiological role in the regulation of vascular tone by mediating photorelaxation. The authors conclude that the response to light is due to hyperpolarization of the vascular smooth muscle cells resulting from the activation of soluble guanylyl cyclase (sGC), but does not involve protein kinase G (PKG). This study not only provides an intriguing molecular explanation for a phenomenon (photorelaxation) that has puzzled vascular biologists for more than half a century (2), but also forces us to rethink the fate of the products generated by sGC.

Melanopsin

Soluble guanylyl cyclase

Opsin

Vascular tone

Hyperpolarization

cGMP-dependent protein kinase

Second messenger system

10.1073/pnas.1421161111

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Citations (1)

Further investigations into the endothelium‐dependent hyperpolarizing effects of bradykinin and substance P in porcine coronary artery

British Journal of Pharmacology (2001)

G. Edwards Michel Félétou M J Gardener Colin D. Glen Gillian R. Richards

In porcine coronary arteries, smooth muscle hyperpolarizations produced by the nitric oxide donor, NOR‐1, and the prostacyclin analogue, iloprost, were compared with those induced by substance P and bradykinin and attributed to the endothelium‐derived hyperpolarizing factor (EDHF). In the presence of 300 μ M L ‐nitroarginine and 10 μ M indomethacin, iloprost‐induced hyperpolarizations were partially inhibited by 10 μ M glibenclamide whereas those to NOR‐1, substance P and bradykinin were unaffected. Hyperpolarizations produced by maximally‐effective concentrations of NOR‐1 and NS1619 were identical (to −65 mV). They were significantly less than those generated by either substance P or bradykinin (to approximately −80 mV) and were abolished by iberiotoxin 100 n M , a concentration which had essentially no effect on responses to substance P or bradykinin. Incubation of segments of intact arteries for 16–22 h in bicarbonate‐buffered Krebs solution had little effect on EDHF responses to substance P or bradykinin. In contrast, after incubation for this period of time in HEPES‐buffered Tyrode solution or Krebs containing 10 m M HEPES the EDHF response to substance P was abolished and that to bradykinin was markedly reduced. The residual bradykinin‐induced hyperpolarization following incubation in Tyrode solution was inhibited by iberiotoxin and by 10 μ M 17‐octadecynoic acid. We conclude that substance P activates only the EDHF pathway in the presence of nitric oxide synthase and cyclo‐oxygenase inhibitors. Incubation in HEPES‐buffered Tyrode solution abolishes the EDHF responses to substance P and bradykinin to reveal an additional hyperpolarizing mechanism, associated with the opening of K + channels, activated only by bradykinin. British Journal of Pharmacology (2001) 133 , 1145–1153; doi: 10.1038/sj.bjp.0704157

Endothelium-derived hyperpolarizing factor

Hyperpolarization

Calphostin C

10.1038/sj.bjp.0704157

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Citations (41)

The induction of nitric oxide synthase activity is inhibited by TGF-β1, PDGFAB and PDGFBB in vascular smooth muscle cells

European Journal of Pharmacology (1992)

Valérie B. Schini William Durante E Elizondo Timothy Scott‐Burden Didier Junquéro

BETA (programming language)

Platelet-derived growth factor

Endothelium-derived relaxing factor

10.1016/0014-2999(92)90434-6

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Citations (97)