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Biomedical subjects

R D Rakhit

Publications and source records attributed to R D Rakhit.

13 recordsLinked to original sources
PubMed2001

Role of G proteins and modulation of p38 MAPK activation in the protection by nitric oxide against ischemia-reoxygenation injury.

Protein kinase C (PKC)-mediated regulation of the mitogen-activated protein kinases (MAPK) may play a role in the protection afforded by ischemic preconditioning (PC). Nitric oxide (NO) can influence MAPK activation via interaction with PKC or farnesylation of low-molecular-weight (LMWT) G proteins. However, we have recently reported the mechanism of NO-induced cardioprotection to be a PKC-independent process. Therefore, we investigated the role of LMWT G proteins and MAPK signaling in NO-induced cardioprotection against simulated ischemia-reoxygenation (SI-R) injury. Neonatal rat cardiomyocytes treated for 90 min with the NO donor S-nitroso-N-acetyl-l,l-penicillamine (SNAP) 1 mM were protected against 6 h of SI (hypoxic conditions at 37 degrees C with 20 mM lactate, 16 mM KCl at pH 6.2) and 24 h reoxygenation under normal culture conditions. NO-induced protection was blocked by the G protein inhibitor alpha-hydroxyfarnesylphosphonic acid (alphaHFP) 10 microM. We studied the time course of p42/44 and p38 MAPK dual-phosphorylation hourly during SI using phospho-specific antibodies. p38 was phosphorylated during SI and the peak phosphorylation was significantly delayed by SNAP pretreatment. The p38 inhibitor SB203580 1 microM, given during SI, protected against injury. Thus the delay in peak p38 activation may contribute to, rather than be the effect of, NO-induced cardioprotection. We have shown that p38beta does not contribute to the total p38 signal in our extracts. Thus there is no detectable beta isoform. We conclude that the main isoform present in these cells and thought to be responsible for the observed phenomenon, is the alpha isoform.

Adenoviridae↗
PubMed2001

Mitochondria as targets for nitric oxide-induced protection during simulated ischemia and reoxygenation in isolated neonatal cardiomyocytes.

BACKGROUND: As shown previously, exposure to NO donors initiates protective mechanisms in cardiomyocytes that persist after removal of the donor, a form of pharmacological preconditioning. Because NO also affects mitochondrial respiration, we studied the effect of NO on mitochondrial Ca(2+) uptake. METHODS AND RESULTS: Neonatal rat ventricular myocytes in primary culture were exposed to 1 hour of simulated ischemia and 1 hour of reoxygenation (sI/R). Pretreatment with the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) (1 mmol/L for 90 minutes), followed by washing and incubation for 10 to 30 minutes, reduced sI/R-induced cell death to 25.4% compared with control (propidium iodide exclusion assay, P<0.001). Short (10-second) exposures to SNAP reversibly suppressed mitochondrial respiration without a detectable change in mitochondrial potential. In contrast, treatment with SNAP for 90 minutes caused a modest but sustained mitochondrial depolarization, as judged by JC-1 fluorescence. SNAP pretreatment limited cellular Ca(2+) overload during ischemia (fura-2 ratio rose to 226+/-40% versus 516+/-170% of baseline, n=5, P<0.05) and prevented loss of cell membrane integrity during reoxygenation. SNAP pretreatment also significantly reduced the ability of mitochondria to accumulate Ca(2+) in the face of a similar cytosolic Ca(2+) load (peak rhod-2 fluorescence 133+/-4% versus 166+/-7% of baseline at similar fluo-3 levels, P=0.0004, n=52 and 25, respectively). CONCLUSIONS: Pretreatment with an NO donor induces a modest, sustained mitochondrial depolarization and protects cardiomyocytes from sI/R injury. The demonstrated reduction in mitochondrial Ca(2+) uptake possibly reduces cytosolic Ca(2+) overload, providing a likely mechanism for NO-induced protection.

Animals↗
PubMed2000

Nitric oxide-induced cardioprotection in cultured rat ventricular myocytes.

The aim of this study was to investigate the role of nitric oxide (NO) in a cellular model of early preconditioning (PC) in cultured neonatal rat ventricular myocytes. Cardiomyocytes "preconditioned" with 90 min of stimulated ischemia (SI) followed by 30 min reoxygenation in normal culture conditions were protected against subsequent 6 h of SI. PC was blocked by N(G)-monomethyl-L-arginine monoacetate but not by dexamethasone pretreatment. Inducible nitric oxide synthase (NOS) protein expression was not detected during PC ischemia. Pretreatment (90 min) with the NO donor S-nitroso-N-acetyl-L,L-penicillamine (SNAP) mimicked PC, resulting in significant protection. SNAP-triggered protection was completely abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) but was unaffected by chelerythrine or the presence of glibenclamide and 5-hydroxydecanoate. With the use of RIA, SNAP treatment increased cGMP levels, which were blocked by ODQ. Hence, NO is implicated as a trigger in this model of early PC via activation of a constitutive NOS isoform. After exposure to SNAP, the mechanism of cardioprotection is cGMP dependent but independent of protein kinase C or ATP-sensitive K(+) channels. This differs from the proposed mechanism of NO-induced cardioprotection in late PC.

Alkaloids↗
PubMed1999

Restrictive pericarditis.

BACKGROUND: Pericardial thickening is an uncommon complication of cardiac surgery. OBJECTIVES: To study pericardial thickening as the cause of severe postoperative venous congestion. SUBJECTS: Two men, one with severe aortic stenosis and single coronary artery disease, and one with coronary artery disease after an old inferior infarction. Both had coronary artery bypass grafting surgery. METHODS: Magnetic resonance imaging (MRI), Doppler echocardiography, and cardiac catheterisation. RESULTS: Venous pressure was raised in both patients. MRI showed mildly thickened pericardium, and cardiac catheterisation indicated diastolic equalization of pressures in the four chambers. Jugular venous pulse showed a dominant "Y" descent coinciding with early diastolic flow in the superior vena cava, and mitral and tricuspid Doppler forward flow proved restrictive physiology. The clinical background suggested pericardial disease so both patients had pericardiectomy. This proved the pericardium to be thickened; the extent of fibrosis also involved the epicardium. CONCLUSIONS: Although rare, restrictive pericarditis (restrictive ventricular physiology resulting from pericardial disease) should be considered to be a separate diagnostic entity because its pathological basis and treatment are different from intrinsic myocardial disease. This diagnosis may be confirmed by standard investigational techniques or may require diagnostic thoracotomy.

Aged↗
PubMed1996

An audit of lipid screening and management in patients undergoing diagnostic cardiac catheterization. Brompton House Officer Audit Group.

The aim of this study was to audit the management of hyperlipidaemia in a cohort of 206 consecutive patients, with known or suspected coronary artery disease, referred for diagnostic coronary angiography. The association of lipid subfraction values with the presence and extent of coronary artery disease was explored to identify the indices of greatest potential value to the hospital cardiologist, in the management of secondary prevention. Patients were questioned about previous lipid tests performed, advice received and treatment prescribed. Referral letters and hospital notes were reviewed to identify documentation of lipid results and treatment strategies. De novo fasting lipid estimations were obtained on 205 subjects at the time of catheterization. In only 46/206 (22%) cases was some form of lipid result recorded in the existing hospital notes or referral documentation. No patient was aware of the levels of the high or low density lipoprotein cholesterol subfractions (HDL, LDL) nor were these specifically recorded, or the subject of clinical comment, in any of the referral documentation. Patients who knew their total cholesterol (in mmol.1-1) result either as a value or as a "high' or "normal' categorization proved accurate witnesses. In keeping with other angiographic studies, we found that low values of HDL and high TC/HDL ratios were significantly associated with both disease presence and extent. Total cholesterol, calculated LDL and triglyceride levels had no such association. In the group as a whole and despite current therapy, 169/206 (82%) patients had a total cholesterol > 5.2 and 163/206 (79%) a TC/HDL ratio > 5. Only 22 (11%) patients were on drug therapy with a further 43 (21%) practising dietary modification. In the vast majority of subjects receiving some form of lipid intervention, target lipid levels had not been achieved. This study identifies the need for more intensive management of hyperlipidaemia in patients with coronary artery disease. Knowledge of HDL levels may be of value in guiding lipid secondary prevention management in the patient population evaluated at an angiographic centre.

Age Factors↗
PubMed1993

Sarcoid, amyloid and heart failure.

We report the case of an adult West Indian patient who presented with heart failure 20 years after an initial diagnosis of pulmonary sarcoidosis. Endomyocardial biopsy revealed AL type amyloid which was later found to be secondary to an underlying multiple myeloma.

Amyloid↗