Imperial College London
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ProfessorSianHarding

Faculty of Medicine, National Heart & Lung Institute

Emeritus Professor of Cardiac Pharmacology
 
 
 
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Contact

 

+44 (0)20 7594 3009sian.harding Website

 
 
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Location

 

435ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

464 results found

BRADY AJB, WARREN JB, POOLEWILSON PA, WILLIAMS TJ, HARDING SEet al., 1993, NITRIC-OXIDE ATTENUATES CARDIAC MYOCYTE CONTRACTION, AMERICAN JOURNAL OF PHYSIOLOGY, Vol: 265, Pages: H176-H182, ISSN: 0002-9513

Journal article

Brady AJB, Warren JB, Poole-Wilson PA, Williams TJ, Harding SEet al., 1993, Nitric oxide attenuates cardiac myocyte contraction, American Journal of Physiology - Heart and Circulatory Physiology, Vol: 265, ISSN: 0002-9513

Cardiac muscle fibers have microvessels in close proximity, the distance from the nearest capillary being no greater than 8 μm. We performed experiments on isolated, electrically stimulated, contracting guinea pig cardiac myocytes to test whether NO from endothelium or nitrovasodilators or directly superfused in solution might affect myocyte contractility. In endothelium-myocyte coculture experiments, 10-7 M bradykinin reduced myocyte shortening by 11 ± 3.5%. This effect was abolished in the presence of N(G)-nitro-L-arginine methyl ester and was unaffected by indomethacin. Sodium nitroprusside, but not organic nitrovasodilators, reduced myocyte contraction amplitude by 23% at 3 x 10-5 M. This effect was reversed by methylene blue. Superfusion with NO solution had an effect similar to sodium nitroprusside, as did exposure to 8-bromoguanosine 3',5'-cyclic monophosphate. Thus the present study shows that cardiac myocyte contraction is attenuated by NO, which appears to act via production of guanosine 3',5'- cyclic monophosphate within the myocytes. Because cardiac myocytes in vivo are in such close proximity to endothelium, the effects of endothelial products on cardiac myocyte contractility may be important in myocardial function.

Journal article

Brady AJ, Poole-Wilson PA, Harding SE, Warren JBet al., 1992, Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia., Am J Physiol, Vol: 263, Pages: H1963-H1966, ISSN: 0002-9513

We investigated whether increased nitric oxide (NO) synthase activity within cardiac myocytes contributes to the depressed cardiac contractility observed in endotoxic shock. Isolated ventricular myocytes were studied to examine the effects of substrates and inhibitors of NO synthase on myocyte contractility. When stimulated electrically, the resting length of myocytes from control animals shortened by 5.3 +/- 0.3% (means +/- SE, n = 32). Baseline contraction of myocytes from endotoxin-treated animals was reduced to 3.0 +/- 0.3% (n = 17, P < 0.001). The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) had no effect on myocytes from control animals, but it increased the contraction of myocytes from endotoxin-treated animals by 40% (fractional shortening increased to 4.3 +/- 0.4%, P < 0.01). Similar results were obtained with NG-methyl-L-arginine. The effect of L-NAME could be reversed by excess L-arginine, but not D-arginine. The effect of endotoxin was abolished by dexamethasone pretreatment. Methylene blue also reversed the effects of endotoxin but had toxic effects on myocytes. Agents that either prevent synthesis or the effects of NO reverse the depression of myocyte contraction seen following endotoxin treatment.

Journal article

BRADY AJB, POOLEWILSON PA, HARDING SE, WARREN JBet al., 1992, NITRIC-OXIDE PRODUCTION WITHIN CARDIAC MYOCYTES REDUCES THEIR CONTRACTILITY IN ENDOTOXEMIA, AMERICAN JOURNAL OF PHYSIOLOGY, Vol: 263, Pages: H1963-H1966, ISSN: 0002-9513

Journal article

HARDING SE, JONES SM, VESCOVO G, DELMONTE F, POOLEWILSON PAet al., 1992, REDUCED CONTRACTILE RESPONSES TO FORSKOLIN AND A CYCLIC-AMP ANALOG IN MYOCYTES FROM FAILING HUMAN VENTRICLE, EUROPEAN JOURNAL OF PHARMACOLOGY, Vol: 223, Pages: 39-48, ISSN: 0014-2999

Journal article

AMRANI M, OSHEA J, ALLEN NJ, HARDING SE, JAYAKUMAR J, PEPPER JR, MONCADA S, YACOUB MHet al., 1992, ROLE OF BASAL RELEASE OF NITRIC-OXIDE ON CORONARY FLOW AND MECHANICAL PERFORMANCE OF THE ISOLATED RAT-HEART, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 456, Pages: 681-687, ISSN: 0022-3751

Journal article

BROWN LA, HARDING SE, 1992, THE EFFECT OF PERTUSSIS TOXIN ON BETA-ADRENOCEPTOR RESPONSES IN ISOLATED CARDIAC MYOCYTES FROM NORADRENALINE-TREATED GUINEA-PIGS AND PATIENTS WITH CARDIAC-FAILURE, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 106, Pages: 115-122, ISSN: 0007-1188

Journal article

HARDING SE, JONES SM, OGARA P, DELMONTE F, VESCOVO G, POOLEWILSON PAet al., 1992, ISOLATED VENTRICULAR MYOCYTES FROM FAILING AND NONFAILING HUMAN HEART - THE RELATION OF AGE AND CLINICAL STATUS OF PATIENTS TO ISOPROTERENOL RESPONSE, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 24, Pages: 549-564, ISSN: 0022-2828

Journal article

Brady AJB, Poole-Wilson PA, Harding SE, Warren JBet al., 1992, Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia, American Journal of Physiology - Heart and Circulatory Physiology, Vol: 263, ISSN: 0002-9513

We investigated whether increased nitric oxide (NO) synthase activity within cardiac myocytes contributes to the depressed cardiac contractility observed in endotoxic shock. Isolated ventricular myocytes were studied to examine the effects of substrates and inhibitors of NO synthase on myocyte contractility. When stimulated electrically, the resting length of myocytes from control animals shortened by 5.3 ± 0.3% (means ± SE, n = 32). Baseline contraction of myocytes from endotoxin-treated animals was reduced to 3.0 ± 0.3% (n = 17, P < 0.001). The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10-4 M) had no effect on myocytes from control animals, but it increased the contraction of myocytes from endotoxin-treated animals by 40% (fractional shortening increased to 4.3 ± 0.4%, P < 0.01). Similar results were obtained with N(G)-methyl-L-arginine. The effect of L- NAME could be reversed by excess L-arginine, but not D-arginine. The effect of endotoxin was abolished by dexamethasone pretreatment. Methylene blue also reversed the effects of endotoxin but had toxic effects on myocytes. Agents that either prevent synthesis or the effects of NO reverse the depression of myocyte contraction seen following endotoxin treatment.

Journal article

MACLEOD KT, HARDING SE, 1991, EFFECTS OF PHORBOL ESTER ON CONTRACTION, INTRACELLULAR PH AND INTRACELLULAR CA2+ IN ISOLATED MAMMALIAN VENTRICULAR MYOCYTES, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 444, Pages: 481-498, ISSN: 0022-3751

Journal article

HARDING SE, MACLEOD KT, JONES SM, VESCOVO G, POOLEWILSON PAet al., 1991, CONTRACTILE RESPONSES OF MYOCYTES ISOLATED FROM PATIENTS WITH CARDIOMYOPATHY, EUROPEAN HEART JOURNAL, Vol: 12, Pages: 44-48, ISSN: 0195-668X

Journal article

HARDING SE, GURDEN JM, POOLEWILSON PA, 1991, A COMPARISON OF CONTRACTILE FUNCTION BETWEEN PAPILLARY-MUSCLES AND ISOLATED MYOCYTES FROM THE SAME HUMAN HEARTS, CARDIOSCIENCE, Vol: 2, Pages: 141-146, ISSN: 1015-5007

Journal article

del Monte F, Harding SE, Puddu PE, Poole-Wilson PAet al., 1991, [Isolated cardiac myocytes: preparation and use in experimental cardiology]., Cardiologia, Vol: 36, Pages: 319-329, ISSN: 0393-1978

Journal article

del Monte F, Harding SE, Puddu PE, Poole-Wilson PAet al., 1991, Isolated cardiac myocytes: preparation and use in experimental cardiology, Cardiologia (Rome, Italy), Vol: 36, Pages: 319-329, ISSN: 0393-1978

Journal article

Harding SE, MacLeod KT, Jones SM, Vescovo G, Poole-Wilson PAet al., 1991, Contractile responses of myocytes isolated from patients with cardiomyopathy, Pages: 44-48, ISSN: 0195-668X

Single cardiac myocytes isolated from failing and non-failing human ventricles were superfused at 32°C and electrically stimulated at 0.2 Hz. Their contraction amplitude and velocities of contraction and relaxation were continuously during challenge with isoprenaline or high extracellular calcium. Action potentials were monitored with intracellular microelectrodes, and calcium transients followed using the fluorescent dye fura-2. Changes in contractility were correlated with severity of disease, as defined by New York Heart Association class, dose of diuretics, left ventricular ejection fraction and left ventricular end-diastolic pressure. Beta-adrenoceptor desensitization was detected in these cells as a decreased response to isoprenaline relative to that of calcium in the same cell. Significant correlations were obtained between reduction of beta-adrenoceptor sensitivity and all four indicators of disease severity. No correlation between the maximum contraction amplitude in high extracellular calcium and severity of disease was observed, the same was true for contraction and relaxation velocity in high calcium. Some significant decline in contractility with age of the patient was noted. Analysis with respect to aetiology of disease showed a subpopulation with dilated or hypertrophic cardiomyopathy where relaxation of the single cells was impaired. This was related to a prolonged calcium transient and action potential. Isoprenaline accentuated the lengthened second phase of relaxation, whereas high extracellular calcium reduced it. These interventions had similar effects on action potential duration. The actions of isoprenaline and calcium were similar on cells from failing and non-failing human hearts and on normal guinea-pig myocytes. They are not, therefore, likely to be caused by the disease, but possible interactions between disease- and catecholamine-induced lengthening of the action potential are discussed.

Conference paper

ANAND IS, GURDEN J, WANDER GS, OGARA P, HARDING SE, FERRARI R, CORNACCHIARI A, PANZALI A, WAHI PL, POOLEWILSON PAet al., 1991, CARDIOVASCULAR AND HORMONAL EFFECTS OF CALCITONIN GENE-RELATED PEPTIDE IN CONGESTIVE-HEART-FAILURE, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 17, Pages: 208-217, ISSN: 0735-1097

Journal article

PAULETTO P, VESCOVO G, LIBERA LD, SCANNAPIECO G, PESSINA AC, DALPALU C, POOLEWILSON PA, HARDING SEet al., 1991, MOLECULAR AND CELLULAR-CHANGES IN VENTRICULAR HYPERTROPHY AND FAILURE, SYMP ON THE CONTINUUM OF HEART FAILURE, Publisher: BUTTERWORTH-HEINEMANN, Pages: 133-155

Conference paper

JONES SM, HUNT NA, DELMONTE F, HARDING SEet al., 1990, CONTRACTION OF CARDIAC MYOCYTES FROM NORADRENALINE-TREATED RATS IN RESPONSE TO ISOPRENALINE, FORSKOLIN AND DIBUTYRYL CAMP, EUROPEAN JOURNAL OF PHARMACOLOGY, Vol: 191, Pages: 129-140, ISSN: 0014-2999

Journal article

BROWN LA, HUMPHREY SM, HARDING SE, 1990, THE ANTIADRENERGIC EFFECT OF ADENOSINE AND ITS BLOCKADE BY PERTUSSIS TOXIN - A COMPARATIVE-STUDY IN MYOCYTES ISOLATED FROM GUINEA-PIG, RAT AND FAILING HUMAN HEARTS, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 101, Pages: 484-488, ISSN: 0007-1188

Journal article

JONES SM, KIRBY MS, HARDING SE, VESCOVA G, WANLESS RB, LIBERA LD, POOLEWILSON PAet al., 1990, ADRIAMYCIN CARDIOMYOPATHY IN THE RABBIT - ALTERATIONS IN CONTRACTILE PROTEINS AND MYOCYTE FUNCTION, CARDIOVASCULAR RESEARCH, Vol: 24, Pages: 834-842, ISSN: 0008-6363

Journal article

HARDING SE, JONES SM, OGARA P, VESCOVO G, POOLEWILSON PAet al., 1990, REDUCED BETA-AGONIST SENSITIVITY IN SINGLE ATRIAL CELLS FROM FAILING HUMAN HEARTS, AMERICAN JOURNAL OF PHYSIOLOGY, Vol: 259, Pages: H1009-H1014, ISSN: 0002-9513

Journal article

MOODY CJ, DASHWOOD MR, SYKES RM, CHESTER M, JONES SM, YACOUB MH, HARDING SEet al., 1990, FUNCTIONAL AND AUTORADIOGRAPHIC EVIDENCE FOR ENDOTHELIN-1 RECEPTORS ON HUMAN AND RAT CARDIAC MYOCYTES - COMPARISON WITH SINGLE SMOOTH-MUSCLE CELLS, CIRCULATION RESEARCH, Vol: 67, Pages: 764-769, ISSN: 0009-7330

Journal article

GAILIS L, NAYLER WG, HARDING SE, 1990, REVERSIBLE ELIMINATION OF MYOFIBRILLAR CA-2+ SENSITIVITY BY DIAMIDE AND OTHER SULFHYDRYL-REAGENTS - COMPARISON WITH REVERSIBLE CONTRACTURE PRODUCED IN INTACT-CELLS, CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, Vol: 68, Pages: 1170-1175, ISSN: 0008-4212

Journal article

HARDING SE, OGARA P, JONES SM, BROWN LA, VESCOVO G, POOLEWILSON PAet al., 1990, SPECIES DEPENDENCE OF CONTRACTION VELOCITY IN SINGLE ISOLATED CARDIAC MYOCYTES, CARDIOSCIENCE, Vol: 1, Pages: 49-53, ISSN: 1015-5007

Journal article

Harding SE, Jones SM, O'Gara P, Vescovo G, Poole-Wilson PAet al., 1990, Reduced β-agonist sensitivity in single atrial cells from failing human hearts, American Journal of Physiology - Heart and Circulatory Physiology, Vol: 259, ISSN: 0002-9513

Human myocytes were isolated from right atrial appendage, and contractile responses to inotropic agents were studied. Responses to inotropic agents of cells isolated from patients with mild heart disease [New York Heart Association (NYHA) classes I and II] were compared with those of myocytes from rabbit aorta. Maximally effective concentrations of calcium, forskolin, and isoproterenol increased contraction amplitude to a similar extent (11.9, 11.5, and 11.3% change in cell length, respectively), but histamine produced a smaller effect (7.1%). The maximum responses of rabbit atrial cells to calcium (18.5%) and isoproterenol (15.0%) were significantly greater than human. In human cells, the velocity of contraction or relaxation was accelerated more by isoproterenol (P < 0.05) or forskolin (P < 0.01) than by high calcium. Only relaxation velocity was increased by isoproterenol in rabbit cells (P < 0.05). Rabbit myocytes contracted and relaxed 10-30% faster than human (P < 0.05). Cells from the atria of patients with New York Heart Association (NYHA) heart failure class III or IV were less responsive to isoproterenol than those from class I or II (P < 0.01). Omitting data from patients who had been taking calcium-channel blockers or β-adrenoceptor agonist or antagonist drugs did not affect the conclusions. Analysis of variance revealed a significantly greater between-patient than within-patient variation (P < 0.001), indicating that cells from the same patient have a tendency to respond in a similar way. Responses to high calcium did not differ among NYHA classes. The effect of forskolin was not reduced in NYHA class III, although there was a decreased response in cells from two patients in NYHA class IV. The β-adrenoceptor subsensitivity that has been reported for whole tissue from failing human hearts can therefore be detected in single cells. The normal response to high calcium suggests that there is no major cellular defect of excitation

Journal article

VESCOVO G, HARDING SE, JONES M, LIBERA LD, PESSINA AC, POOLEWILSON PAet al., 1989, CONTRACTILE ABNORMALITIES OF SINGLE RIGHT VENTRICULAR MYOCYTES ISOLATED FROM RATS WITH RIGHT VENTRICULAR HYPERTROPHY, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 21, Pages: 103-111, ISSN: 0022-2828

Journal article

CHIN TK, HARDING SE, EAGLES PAM, 1989, CHARACTERIZATION OF 2 PROTEOLYTICALLY DERIVED SOLUBLE POLYPEPTIDES FROM THE NEUROFILAMENT TRIPLET COMPONENTS NFM AND NFH, BIOCHEMICAL JOURNAL, Vol: 264, Pages: 53-60, ISSN: 0264-6021

Journal article

HARDING SE, VESCOVO G, JONES SM, BENNETT G, YACOUB M, POOLEWILSON PAet al., 1989, MORPHOLOGICAL AND FUNCTIONAL-CHARACTERISTICS OF MYOCYTES ISOLATED FROM HUMAN LEFT-VENTRICULAR ANEURYSMS, JOURNAL OF PATHOLOGY, Vol: 159, Pages: 191-196, ISSN: 0022-3417

Journal article

VESCOVO G, JONES SM, HARDING SE, POOLEWILSON PAet al., 1989, ISOPROTERENOL SENSITIVITY OF ISOLATED CARDIAC MYOCYTES FROM RATS WITH MONOCROTALINE-INDUCED RIGHT-SIDED HYPERTROPHY AND HEART-FAILURE, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 21, Pages: 1047-1061, ISSN: 0022-2828

Journal article

VESCOVO G, HARDING SE, JONES SM, LIBERA LD, PESSINA AC, POOLEWILSON PAet al., 1989, COMPARISON BETWEEN ISOMYOSIN PATTERN AND CONTRACTILITY OF RIGHT VENTRICULAR MYOCYTES ISOLATED FROM RATS WITH RIGHT CARDIAC-HYPERTROPHY, BASIC RESEARCH IN CARDIOLOGY, Vol: 84, Pages: 536-543, ISSN: 0300-8428

Journal article

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