Imperial College London

Professor Martin Wilkins

Faculty of MedicineDepartment of Medicine

Head of the Department of Medicine
 
 
 
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Contact

 

+44 (0)20 3313 2049m.wilkins

 
 
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Location

 

NIHR / Wellcome Trust Clinical Research FacilityICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

180 results found

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

JOURNAL ARTICLE

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

JOURNAL ARTICLE

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

JOURNAL ARTICLE

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

JOURNAL ARTICLE

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

JOURNAL ARTICLE

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, Vol: 278, ISSN: 0002-9513

Chronic hypoxia leads to a greater degree of pulmonary hypertension in the Wistar-Kyoto (WKY) rat than in the Fischer 344 (F-344) rat. We questioned whether this difference is associated with baseline differences in pulmonary artery anatomy, a greater degree of hypoxia-induced pulmonary vascular remodeling in the WKY rat, and/or differences in expression of endothelin (ET)-1. Male F-344 and WKY rats were maintained in normoxia or normobaric hypoxia for 21 days. Morphometry revealed that baseline pulmonary artery anatomy was similar in the two strains. However, during chronic hypoxia, the WKY rats developed a greater degree of muscularization of small pulmonary arteries. Baseline plasma and lung immunoreactive ET-1 levels were similar in the WKY and F-344 rats and increased significantly during hypoxia in the WKY rats. Northern analysis demonstrated increased lung preproET-1 mRNA during hypoxia in both strains, with a greater increase in WKY rats. Immunostaining demonstrated increased ET-1 in bronchial epithelium and peripheral pulmonary arteries during hypoxia, although to a greater degree in the WKY rats. We conclude that the WKY strain demonstrates increased susceptibility to hypoxia-induced pulmonary vascular remodeling compared with the F-344 strain and that increased lung and circulating ET-1 levels during hypoxia may partly explain this difference. Copyright © 2000 the American Physiological Society.

JOURNAL ARTICLE

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

JOURNAL ARTICLE

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

JOURNAL ARTICLE

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.

JOURNAL ARTICLE

Sebkhi A, Zhao L, Lu L, Haley CS, Nunez DJR, Wilkins MRet al., 1999, Genetic determination of cardiac mass in normotensive rats - Results from an F344 x WKY cross, HYPERTENSION, Vol: 33, Pages: 949-953, ISSN: 0194-911X

JOURNAL ARTICLE

Sebkhi A, Zhao L, Nunez DR, Haley C, Wilkins MRet al., 1999, Genetic determination of cardiac mass in normotensive rats: results from an F344 x WKY cross, Hypertension, Vol: 33, Pages: 949-953

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

JOURNAL ARTICLE

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

JOURNAL ARTICLE

Aguirre JI, Morrell N, Marron K, Long L, Wilkins M, Polak JMet al., 1998, A comparative study of pulmonary artery remodelling in pulmonary hypertension between Wistar Kyoto and F344 rats., Publisher: JOHN WILEY & SONS LTD, Pages: 42A-42A, ISSN: 0022-3417

CONFERENCE PAPER

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, ISSN: 0007-1188

JOURNAL ARTICLE

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.

JOURNAL ARTICLE

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

JOURNAL ARTICLE

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

JOURNAL ARTICLE

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.

JOURNAL ARTICLE

Clifford CP, Adams DA, Murray S, Taylor GW, Wilkins MR, Boobis AR, Davies DSet al., 1996, Pharmacokinetic and cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice, Clinical Pharmacology Section of the Joint Meeting with the Pharmacological-Society-of-Canada / Canadian-Society-for-Clinical-Pharmacology, Publisher: BLACKWELL SCIENCE LTD, Pages: P662-P662, ISSN: 0306-5251

CONFERENCE PAPER

Kirk JE, Wilkins, 1996, Renal effects of concurrent E-24.11 and ACE inhibition in the aortovenocaval fistula rat, Vol: 119, Pages: 943-948

JOURNAL ARTICLE

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.

JOURNAL ARTICLE

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: 271, Pages: H622-H629, ISSN: 0363-6135

JOURNAL ARTICLE

BROWN LA, NUNEZ DJ, BROOKES CIO, WILKINS MRet al., 1995, SELECTIVE INCREASE IN ENDOTHELIN-1 AND ENDOTHELIN-A RECEPTOR SUBTYPE IN THE HYPERTROPHIED MYOCARDIUM OF THE AORTO-VENACAVAL FISTULA RAT, CARDIOVASCULAR RESEARCH, Vol: 29, Pages: 768-774, ISSN: 0008-6363

JOURNAL ARTICLE

Brown LA, Nunez DJ, CIO B, Wilkins MRet al., 1995, Selective increase in endothelin-1 and endothelin-A receptor subtype during cardiac hypertrophy in the rat, Cardiovascular Research, Vol: 29, Pages: 768-774

JOURNAL ARTICLE

GOOD JM, PETERS M, WILKINS M, JACKSON N, OAKLEY CM, CLELAND JGFet al., 1995, RENAL RESPONSE TO CANDOXATRILAT IN PATIENTS WITH HEART-FAILURE, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 25, Pages: 1273-1281, ISSN: 0735-1097

JOURNAL ARTICLE

Hirokawa K, O'Shaughnessy K, Moore K, Ramrakha P, Wilkins MRet al., 1994, Induction of nitric oxide synthase in cultured vascular smooth muscle cells: the role of cyclic AMP, British Journal of Pharmacology, Vol: 112, Pages: 396-402

JOURNAL ARTICLE

Hirokawa K, O'Shaughnessy KM, Ramrakha P, Wilkins MRet al., 1994, Inhibition of nitric oxide synthase in vascular smooth muscle by retinoids, British Journal of Pharmacology, Vol: 113, Pages: 1448-1454

JOURNAL ARTICLE

RAD R, Matsuda Y, Wilkins MR, Polak JM, Wharton Jet al., 1994, Identification of renal natriuretic peptide receptor subpopulations by use of the non-peptide antagonist, HS-142-1, British Journal of Pharmacology, Vol: 113, Pages: 931-939

JOURNAL ARTICLE

RUTHERFORD RAD, MATSUDA Y, WILKINS MR, POLAK JM, WHARTON Jet al., 1994, IDENTIFICATION OF RENAL NATRIURETIC PEPTIDE RECEPTOR SUBPOPULATIONS BY USE OF THE NONPEPTIDE ANTAGONIST, HS-142-1, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 113, Pages: 931-939, ISSN: 0007-1188

JOURNAL ARTICLE

BROWN LA, NUNEZ DJR, WILKINS MR, 1993, DIFFERENTIAL REGULATION OF NATRIURETIC PEPTIDE RECEPTOR MESSENGER-RNAS DURING THE DEVELOPMENT OF CARDIAC-HYPERTROPHY IN THE RAT, JOURNAL OF CLINICAL INVESTIGATION, Vol: 92, Pages: 2702-2712, ISSN: 0021-9738

JOURNAL ARTICLE

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