Professor Martin Wilkins

Khoo JP, Zhao L, Alp NJ, Bendall JK, Nicoli T, Rockett K, Wilkins MR, Channon KMet al., 2005, Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension, CIRCULATION, Vol: 111, Pages: 2126-2133, ISSN: 0009-7322

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• Citations: 122

Phillips PG, Long L, Wilkins MR, Morrell NWet al., 2005, cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodeling, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 288, Pages: L103-L115, ISSN: 1040-0605

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• Citations: 74

Wilkins MR, 2004, Selective or nonselective endothelin receptor blockade in pulmonary arterial hypertension, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 169, Pages: 433-434, ISSN: 1073-449X

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• Citations: 9

Sebkhi A, Strange JW, Phillips SC, Wharton J, Wilkins MRet al., 2003, Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension, CIRCULATION, Vol: 107, Pages: 3230-3235, ISSN: 0009-7322

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• Citations: 194

Zhao L, Mason NA, Strange JW, Walker H, Wilkins MRet al., 2003, Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic peptide activity, CIRCULATION, Vol: 107, Pages: 234-237, ISSN: 0009-7322

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• Citations: 80

Gibbs JSR, Wharton J, Wilkins M, 2003, Pulmonary hypertension and the vasoconstrictive factor: is there still a role for vasodilator testing?, Eur Heart J, Vol: 24, Pages: 297-298

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Aldashev AA, Sarybaev AS, Sydykov AS, Kalmyrzaev BB, Kim EV, Mamanova LB, Maripov R, Kojonazarov BK, Mirrakhimov MM, Wilkins MR, Morrell NWet al., 2002, Characterization of high-altitude pulmonary hypertension in the Kyrgyz: Association with angiotensin-converting enzyme genotype, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 166, Pages: 1396-1402, ISSN: 1073-449X

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• Citations: 98

Wilkins MR, Møller GMO, Ren X, Wharton Jet al., 2002, Developments in therapeutics for pulmonary arterial hypertension., Minerva Cardioangiol, Vol: 50, Pages: 175-187, ISSN: 0026-4725

For many years, the management of pulmonary hypertension has been frustrated by an inadequate understanding of its pathology and limited therapeutic options, but this is changing rapidly. Recently, novel insight into the pathogenesis of primary pulmonary hypertension (PPH) has been provided by the demonstration of mutations in BMPR2 and ALK-1 genes in a significant number of patients with the condition. These genes encode members of the TGF-b receptor superfamily and their integrity is important in the maintenance of normal pulmonary vascular structure and function. At the same time, there has been a major advance in the treatment of the condition due to development of 2 orally active pharmacological agents, bosentan and sildenafil, which demonstrate some selectivity for the pulmonary vasculature. This review examines how the management of PPH and severe pulmonary hypertension in associated diseases has changed and looks at exciting future developments.

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Wilkins MR, Aldashev A, Morrell NW, 2002, Nitric oxide, phosphodiesterase inhibition, and adaption to hypoxic conditions, LANCET, Vol: 359, Pages: 1539-1540, ISSN: 0140-6736

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• Citations: 20

King L, Wilkins MR, 2002, Natriuretic peptide receptors and the heart, HEART, Vol: 87, Pages: 314-315, ISSN: 1355-6037

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• Citations: 18

Strange JW, Wharton J, Phillips PG, Wilkins MRet al., 2002, Recent insights into the pathogenesis and therapeutics of pulmonary hypertension, CLINICAL SCIENCE, Vol: 102, Pages: 253-268, ISSN: 0143-5221

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• Citations: 25

Abdelkarim Sebkhi, Peter G Phillips, Julian Strange, John Wharton, Martin R Wilkinset al., 2002, Phosphodiesterase Inhibition in the Treatment of Pulmonary Hypertension, Cardiovasc Rev Rep, Vol: 23, Pages: 274-279

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Wilkins MR, Wharton J, 2001, Progress in, and future prospects for, the treatment of primary pulmonary hypertension, HEART, Vol: 86, Pages: 603-604, ISSN: 1355-6037

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• Citations: 3

Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov MM, Aldashev A, Wilkins MRet al., 2001, Sildenafil inhibits hypoxia-induced pulmonary hypertension, CIRCULATION, Vol: 104, Pages: 424-428, ISSN: 0009-7322

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• Citations: 367

Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov MM, Aldashev A, Wilkins MRet al., 2001, Sildenafil inhibits hypoxia-induced pulmonary hypertension., Circulation, Vol: 104, Pages: 424-428

BACKGROUND: This study investigated the effect of the phosphodiesterase 5 inhibitor sildenafil on the pulmonary vascular response to hypoxia in humans and mice. METHODS AND RESULTS: In a randomized, double-blind study, sildenafil 100 mg or placebo was given orally to 10 healthy volunteers 1 hour before breathing 11% O(2) for 30 minutes. Pulmonary artery pressure (PAP) was measured with an indwelling right heart catheter. The acute 56% increase in mean PAP produced by hypoxia during placebo treatment (mean PAP [mean+/-SD mm Hg]: normoxia 16.0+/-2.1 versus hypoxia 25.0+/-4.8) was almost abolished by sildenafil (normoxia 16.0+/-2.1 versus hypoxia 18.0+/-3.6), with no significant effect on systemic blood pressure. In the isolated perfused lung of wild-type and endothelial nitric oxide synthase (eNOS)-deficient mice, sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction. Wild-type mice dosed orally with the drug (25 mg. kg(-1). d(-1)) throughout 3 weeks of exposure to hypoxia (10% O(2)) exhibited a significant reduction in right ventricular systolic pressure (placebo versus sildenafil: 43.3+/-9.9 versus 29.9+/-9.7 mm Hg, P<0.05) coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodeling. In eNOS mutant mice, sildenafil attenuated the increase in right ventricular systolic pressure but without a significant effect on right ventricular hypertrophy or vascular remodeling. CONCLUSIONS: Sildenafil attenuates hypoxia-induced pulmonary hypertension in humans and mice and offers a novel approach to the treatment of this condition. The eNOS-NO-cGMP pathway contributes to the response to sildenafil, but other biochemical sources of cGMP also play a role. Sildenafil has beneficial pulmonary hemodynamic effects even when eNOS activity is impaired.

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Jourdan KB, Mason NA, Long L, Philips PG, Wilkins MR, Morrell NWet al., 2001, Characterization of adenylyl cyclase isoforms in rat peripheral pulmonary arteries, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 280, Pages: L1359-L1369, ISSN: 1040-0605

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• Citations: 28

Morrell NW, Wilkins MR, 2001, Genetic and molecular mechanisms of pulmonary hypertension, CLINICAL MEDICINE, Vol: 1, Pages: 138-145, ISSN: 1470-2118

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• Citations: 5

Zhao L, Sebkhi A, Nunez DJR, Long L, Haley CS, Szpirer J, Szpirer C, Williams AJ, Wilkins MRet al., 2001, Right ventricular hypertrophy secondary to pulmonary hypertension is linked to rat chromosome 17 - Evaluation of cardiac ryanodine Ryr2 receptor as a candidate, CIRCULATION, Vol: 103, Pages: 442-447, ISSN: 0009-7322

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• Citations: 23

Wilkins MR, Gibbs JSR, Shovlin CL, 2000, A gene for primary pulmonary hypertension, LANCET, Vol: 356, Pages: 1207-1208, ISSN: 0140-6736

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• Citations: 12

Wilkins MR, Roses AD, Clifford CP, 2000, Pharmacogenetics and the treatment of cardiovascular disease, HEART, Vol: 84, Pages: 353-354, ISSN: 1355-6037

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• Citations: 8

Aguirre JI, Morrell NW, Long L, Clift P, Upton PD, Polak JM, Wilkins MRet al., 2000, Vascular remodeling and ET-1 expression in rat strains with different responses to chronic hypoxia, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 278, Pages: L981-L987, ISSN: 1040-0605

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• Citations: 48

Sebkhi A, Zhao L, Lu L, Haley CS, Nunez DJ, Wilkins MRet al., 1999, Genetic determination of cardiac mass in normotensive rats: results from an F344xWKY cross., Hypertension, Vol: 33, Pages: 949-953, ISSN: 0194-911X

Genetic determinants affect adult cardiac mass and the predisposition to develop cardiac hypertrophy. The aim of this study was to identify quantitative trait loci (QTL) that control heart and left ventricular (LV) weight by use of normotensive inbred rat strains that differ in their adult cardiac mass phenotype. We studied 126 male F2 rats derived from a cross of normotensive Wistar-Kyoto and Fischer 344 rats. At 12 weeks of age, total heart weight and LV weight were measured. Genomic DNA from these animals was screened by use of polymorphic microsatellite markers across the whole genome (excluding the sex chromosomes). In this cross, the genetic contribution to total heart weight variation was 56%, and the genetic contribution for LV weight was 55%. Using the Mapmaker/QTL computer package, we identified a significant QTL on chromosome 3 with a log10 likelihood (LOD) score of 4.8, which accounted for 16.5% of the total variance of LV weight. This QTL was centered close to the marker D3Rat29. The QTL was also found to be significantly linked with total heart weight (LOD=4.4). These data provide the first demonstration of a QTL on chromosome 3 that plays a role in determining the difference in LV mass between normotensive Fischer 344 and Wistar- Kyoto inbred rat strains. The prostaglandin synthase 1 gene is located within the QTL.

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Zhao L, Long L, Morrell NW, Wilkins MRet al., 1999, NPR-A-deficient mice show increased susceptibility to hypoxia-induced pulmonary hypertension, CIRCULATION, Vol: 99, Pages: 605-607, ISSN: 0009-7322

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• Citations: 73

Redondo J, Bishop JE, Wilkins MR, 1998, Effect of atrial natriuretic peptide and cyclic GMP phosphodiesterase inhibition on collagen synthesis by adult cardiac fibroblasts, British Journal of Pharmacology, Vol: 124, Pages: 1455-1462

* Cardiac fibroblasts play an important role in the pathophysiology of cardiac remodelling induced by hypertension and myocardial infarction by undergoing proliferation and depositing extracellular matrix proteins such as collagen. We have examined the effects of atrial natriuretic peptide (ANP) on proliferation and collagen synthesis by adult rat and human cardiac fibroblasts in culture. * In cells from both species radioligand studies using 125I-ANP suggested that the majority of binding sites (>85%) were non-guanylyl cyclase-linked (NPR-C subtype). Nonetheless ANP (10−9 to 10−6 M), in the presence of zaprinast, an inhibitor of phosphodiesterase 5 (PDE5), increased fibroblast cyclic GMP levels 3–5 fold in a concentration-dependent manner (P<0.05). * ANP (10−11 to 10−6 M), a NPR-C ligand, C-ANF4-23 (10−11 to 10−6 M) and zaprinast alone had no significant effect on either basal or serum-stimulated DNA synthesis or fibroblast number. In combination with zaprinast (10−5 M), however, ANP (10−9 to 10−6 M) but not C-ANF4-23 (10−7 M) inhibited markedly both basal and stimulated fibroblast mitogenesis, an effect reproduced by 8-bromo-cyclic GMP (10−5 to 10−3 M). * Collagen synthesis, determined by measuring hydroxyproline levels, was stimulated with transforming growth factor-β1 (40 pM), angiotensin II (10−7 M) or 2% foetal bovine serum. The increase in collagen production, normalised by cell number, was reduced dramatically (to at or near basal production) by ANP (10−9 to 10−7 M) but not C-ANF4-23 (10−7 M) in the presence of zaprinast. Again 8-bromo-cyclic GMP (10−5 to 10−3 M) reproduced the effect. * ANP is capable of inhibiting collagen synthesis in adult rat and human cardiac fibroblasts via cyclic GMP, a property unmasked and enhanced by inhibition of PDE5.

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Brown LA, Rutherford RAD, Nunez DJR, Wharton J, Lowe DG, Wilkins MRet al., 1997, Downregulation of natriuretic peptide C-receptor protein in the hypertrophied ventricle of the aortovenocaval fistula rat, CARDIOVASCULAR RESEARCH, Vol: 36, Pages: 363-371, ISSN: 0008-6363

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• Citations: 10

Brown LA, RAD R, Nunez DJ, Wharton J, Lowe DG, Wilkins MRet al., 1997, Downregulation of natriuretic peptide C-receptor protein in the hypertrophied ventricle of the aortovenocaval fistula rat, Vol: 36, Pages: 363-371

Objectives: This study examined the expression of the C-type receptor for the natriuretic peptide family (NPR-C) in the ventricles of normal and aortovenocaval (AV)-fistula rats, the latter a model of cardiac volume overload producing hypertrophy of both ventricles. Methods: Western blotting with a rabbit anti-NPR-C antibody was used to quantify NPR-C levels in ventricular membranes. NPR-C expression was localised anatomically and measured in frozen sections of cardiac tissue by histochemistry and in vitro autoradiography. Results: Western blot analysis revealed a single band (∼120 kDa) in ventricular membranes which was reduced to ∼60 kDa after treatment with β-mercaptoethanol. NPR-C immunoreactivity and [125I]rat ANP1–28 binding (displaceable by the NPR-C-specific ligand C-ANP 4–23) were localised to the endocardium. NPR-C protein levels, as measured by all three techniques, were reduced significantly in the hypertrophied ventricles of AV-fistula rats compared to sham-operated animals. Conclusions: Volume-induced cardiac hypertrophy in the AV-fistula rat is associated with downregulation of endocardial NPR-C. This may be one mechanism by which the endocardium regulates the myocardial response to changes in haemodynamic load.

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Clifford CP, Adams DA, Murray S, Taylor GW, Wilkins MR, Boobis AR, Davies DSet al., 1997, The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice, EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, Vol: 52, Pages: 311-315, ISSN: 0031-6970

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• Citations: 49

Clifford CP, Adams DA, Murray S, Taylor GW, Wilkins MR, Boobis AR, Davies DSet al., 1997, The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice, European Journal of Clinical Pharmacology, Vol: 52, Pages: 311-315, ISSN: 0031-6970

Objective: To determine whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by the concomitant administration of grapefruit juice.Methods: Six healthy volunteers were recruited for a balanced cross-over study. Each volunteer received 120 mg terfenadine 30 min after drinking 300 ml of either water or freshly squeezed grapefruit juice. The alternative treatment was administered on the second study day 2 weeks later. Measurements of the area under the terfenadine plasma concentration-time curve (AUC), maximum terfenadine concentration (Cmax) and the time to maximum concentration (tmax) were made, and the corrected QT (QTc) interval was measured from the surface electrocardiogram.Results: Terfenadine was quantifiable in plasma in all 6 subjects on both study days for up to 24 h post-dosing. The AUC of terfenadine was significantly increased by concomitant grapefruit administration (median values 40.6 vs 16.3 ng · ml−1 · h), as was the Cmax (median values 7.2 vs 2.1 ng · ml−1). The tmax was not significantly increased and there was no significant change in the median QTc interval despite the increased terfenadine levels. The 95% confidence interval for the difference in the change in QTc interval at Cmax was −13 to +38 ms.Conclusion: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in terfenadine bioavailability, but the increase observed in this study did not lead to significant cardiotoxicity in normal subjects. However, this does not exclude the risk of cardiotoxicity in high-risk subjects given greater doses of grapefruit juice over longer periods of time.

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Zhao L, Al-Tubuly R, Sebkhi A, Owji AA, DJR N, Wilkins MRet al., 1996, Angiotensin II receptor expression and inhibition in the chronically hypoxic rat lung, British Journal of Pharmacology, Vol: 119, Pages: 1217-1222

1. Angiotensin II (AII) binding density and the effect of chronic AII receptor blockade were examined in the rat model of hypoxia-induced pulmonary hypertension. 2. [125I]-[Sar1,Ile2]AII binding capacity was increased in lung membranes from rats exposed to hypoxia (10% fractional inspired O2) for 7 days compared to normal rats (Bmax 108 +/- 12 vs 77 +/- 3 fmol mg-1 protein; P < 0.05), with no significant change in dissociation constant. Competition with specific AII receptor subtype antagonists demonstrated that AT1 is the predominant subtype in both normal and hypoxic lung. 3. Rats treated intravenously with the AT1 antagonist, GR138950C, 1 mg kg-1 day-1 rather than saline alone during 7 days of exposure to hypoxia developed less pulmonary hypertension (pulmonary arterial pressure: 21.3 +/- 1.7 vs 28.3 +/- 1.1 mmHg; P < 0.05), right ventricular hypertrophy (right/left ventricle weight ratio: 0.35 +/- 0.01 vs 0.45 +/- 0.01; P < 0.05) and pulmonary artery remodelling (abundance of thick-walled pulmonary vessels: 9.6 +/- 1.4% vs 20.1 +/- 0.9%; P < 0.05). 4. The reduction in cardiac hypertrophy and pulmonary remodelling with the AT1 antagonist was greater than that achieved by a dose of sodium nitroprusside (SNP) that produced a comparable attenuation of the rise in pulmonary arterial pressure during hypoxia. 5. The data suggest that AII, via the AT1 receptor, has a role in the early pathogenesis of hypoxia-induced pulmonary hypertension in the rat.

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Zhao L, Brown LA, Owji AA, Nunez DJR, Smith DM, Ghatei MA, Bloom SR, Wilkins MRet al., 1996, Adrenomedullin activity in chronically hypoxic rat lungs, American Journal of Physiology - Heart and Circulatory Physiology, Vol: 40, ISSN: 0363-6135

Adrenomedullin (AM) is a novel vasodilator with structural similarities to calcitonin gene-related peptide (CGRP). This study investigated AM activity in the rat lung during hypoxia-induced pulmonary hypertension. Both rat AM (0.2-10 nmol) and α-CGRP (0.2-2 nmol) produced dose-related reductions in pulmonary artery pressure in the isolated perfused lung ventilated with 2% O 2 . Pretreatment with α-CGRP, which demonstrated tachyphylaxis, or its antagonist, CGRP-(8-37), reduced the hypotensive response to AM, suggesting that part of the response to AM is mediated by CGRP receptors. 125 I-labeled AM and 125 I-labeled CGRP binding was significantly increased in lung membranes from 7-day hypoxic animals (AM from 1.94 ± 0.3 to 3.36 ± 0.4 and CGRP from 0.06 ± 0.01 to 0.12 ± 0.02 pmol/mg protein), with no change in dissociation constant. Moreover, the hypotensive response to both peptides was increased in the lungs of 7-day hypoxic rats. There was no significant change in lung immunoreactive AM concentrations (hypoxic 5.04 ± 0.48 vs. control 6.28 ± 0.76 pmol/g wet wt of tissue) or steady-state AM mRNA levels in 7-day hypoxic rats. Nonetheless, AM may be useful for the acute pharmacological manipulation of pulmonary artery pressure in hypoxiainduced pulmonary hypertension. Copyright © 1996 the American Physiological Society.

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• Citations: 11