Systolic and diastolic dysfunction in diabetes have frequently been associated with abnormal calc... more Systolic and diastolic dysfunction in diabetes have frequently been associated with abnormal calcium (Ca2+) regulation. However, there is emerging evidence that Ca2+ mishandling alone is insufficient to fully explain diabetic heart dysfunction, with focus shifting to the properties of the myofilament proteins. Our aim was to examine the effects of diabetes on myofilament Ca2+ sensitivity and Ca2+ handling in left ventricular tissues isolated from the same type 2 diabetic rat hearts. We measured the force-pCa relationship in skinned left ventricular cardiomyocytes isolated from 20-week-old type 2 diabetic and non-diabetic rats. Myofilament Ca2+ sensitivity was greater in the diabetic relative to non-diabetic cardiomyocytes, and this corresponded with lower phosphorylation of cardiac troponin I (cTnI) at ser23/24 in the diabetic left ventricular tissues. Protein expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), phosphorylation of phospholamban (PLB) at Ser16, and SERCA/PL...
Confocal studies show that positively charged oCOms, like oCOm-58, release CO in mitochondria pre... more Confocal studies show that positively charged oCOms, like oCOm-58, release CO in mitochondria preserving their energetics.
Background —Heat shock protein 70 (HSP70) gene transfection has been shown to enhance myocardial ... more Background —Heat shock protein 70 (HSP70) gene transfection has been shown to enhance myocardial tolerance after normothermic ischemia-reperfusion. We investigated the effect of HSP70 gene transfection on mechanical and endothelial function in a protocol mimicking clinical heart preservation. Methods and Results —Rat hearts were infused ex vivo with Hemagglutinating Virus of Japan–liposome complex containing HSP70 gene (HSP, n=8) or no gene (CON, n=8), and heterotopically transplanted into recipient rats. Four days after surgery, transfected hearts were perfused on a Langendorff apparatus for 45 minutes, arrested with St Thomas’ No. 1 cardioplegia for 4 hours at 4°C, and reperfused for 1 hour. Mechanical and endothelial function was studied before and after ischemia. Creatine kinase was measured in reperfusion effluent. Hearts underwent Western blotting and immunohistochemistry to confirm HSP70 overexpression. Postischemic recovery of mechanical function (% preischemic±SEM) was grea...
semi-quantitatively. Results: Absolute albumin excretion was significantly greater in diabetic co... more semi-quantitatively. Results: Absolute albumin excretion was significantly greater in diabetic compared to NG sham operated TGRs (0.5±0.07 NG vs 2.9±0.7mg/24hr diabetic, p<0.01); the effect of BRD in diabetic TGR resulted in a significantly lower rates of albumin excretion compared to the intact innervated group (2.9±0.7 innervated vs 1.3±0.3mg/ 24hr denervated, p<0.05). Plasma urate levels in diabetic innervated rats were also high compared to NG innervated rats (6.5±0.8 NG vs 9.3±1.2mg/dL diabetic, p=0.08); BRD in diabetic TGRs resulted in a significantly reduced plasma urate level compared to the innervated TGRs (9.3±1.2 innervated vs 5.2±0.9mg/dL denervated, p<0.05). Microscopic examination confirmed the presence of glomerular basement membrane thickening and mesangial expansion in the diabetic kidneys. This morphological appearnce was markedly reduced by BRD intervention. Immunohistochemistry showed significantly higher expression of type I collagen (1.8-fold, p<0.0...
Cardiorenal syndrome, de novo renal pathology arising secondary to cardiac insufficiency, is clin... more Cardiorenal syndrome, de novo renal pathology arising secondary to cardiac insufficiency, is clinically recognised but poorly characterised. This study establishes and characterises a valid model representative of Type 2 cardiorenal syndrome. Extensive permanent left ventricular infarction, induced by ligation of the left anterior descending coronary artery in Lewis rats, was confirmed by plasma cardiac troponin I, histology and cardiac haemodynamics. Renal function and morphology was assessed 90-days post-ligation when heart failure had developed. The involvement of the paraventricular nucleus was investigated using markers of inflammation, apoptosis, reactive oxygen species and of angiotensin II involvement. An extensive left ventricular infarct was confirmed following coronary artery ligation, resulting in increased left ventricular weight and compromised left ventricular diastolic function and developed pressure. Glomerular filtration was significantly decreased, fractional excr...
Bilateral renal denervation (BRD) has been shown to normalise blood pressure in clinical and expe... more Bilateral renal denervation (BRD) has been shown to normalise blood pressure in clinical and experimental studies of hypertension by reducing systemic sympathetic output. This study determined the effect of BRD on cardiac β-adrenoceptor (AR) responsiveness in a diabetic model with underlying hypertension using the transgenic (mRen-2)27 rat. BRD or sham surgeries were conducted repeatedly at 3, 6 and 9 weeks in Ren-2 rats with or without streptozotocin (STZ)-induced diabetes (4 x n = 7); Sprague Dawley rats (n = 6) served as control. Cardiac function was determined in isolated hearts at 18 weeks of age. Normalised left ventricular developed pressure and relaxation was recorded in response to incrementing concentrations of the β-AR agonist isoproterenol (10(-10) to 10(-7 ) M) or the β3 -AR agonist BRL37344 (10(-13) to 10(-6 ) M). Expression levels of β1 -AR were determined by Western blot. Both inotropic and lusitropic β-AR responsiveness was reduced in the hypertensive diabetic heart...
We report the synthesis and characterisation of a photoactive nitric oxide (NO) releasing nanopar... more We report the synthesis and characterisation of a photoactive nitric oxide (NO) releasing nanoparticle (NP) by encapsulation of the NO donor tert-dodecane s-nitrosothiol (tDodSNO) into a co-polymer of styrene and maleic acid (SMA) to afford SMA-tDodSNO. Encapsulation did not affect tDodSNO's stability or NO release profile, but imparted water solubility and protection from degradation reactions with glutathione. Under photoactivation the NP acted as a potent NO donor, with photoactivation acting as a switch to induce localized vasodilation in aortic rings (EC 660nM at 2,700W/m) and cause vascular hyperpermeability in mesenteric beds (8-fold increase in dye uptake at 1µM SMA-tDodSNO with 460W/m photoactivation). The NP was markedly superior as a photoactive NO donor in comparison to the s-nitrosothiols GSNO and SNAP, which are commonly used in experimental studies, as well as sodium nitroprusside, a clinically used vasodilator. Future development of this NP may find wide ranging ...
Hypertension is a leading risk factor for cardiovascular and chronic kidney disease. A new rodent... more Hypertension is a leading risk factor for cardiovascular and chronic kidney disease. A new rodent model (transgenic maleCyp1a1-Ren2 rats) provides reversible induction of hypertension through the addition of indole-3-carbinol (I3C) to the diet,without the need for surgical intervention, thus giving researchers control over both the onset of hypertension and its magnitude(I3C dose-dependency). We here report the breeding performance and productivity of Cyp1a1-Ren2 rats. Despite beingtransgenic, these animals proved to be efficient breeders. In addition to confirming inducible and reversible dose-dependenthypertension (by using I3C doses of 0.125%, 0.167%, and 0.25% [w/w] in the diet for 14 d, followed by normal chow for 4 d),we demonstrated that hypertension can be sustained chronically (14 wk) by continuous dosing with I3C (0.167% [w/w]) inthe diet. In chronically dosed male rats, systolic blood pressure continued to rise, from 173 ± 11 mm Hg after 1 mo to 196 ±19 mm Hg after 3 mo, ...
Altered autonomic activity has been implicated in the development of cardiac dysfunction during s... more Altered autonomic activity has been implicated in the development of cardiac dysfunction during seizures. This study investigates whether intervening in seizure progression with diazepam will reduce seizure-induced cardiomyopathy. Second, this study examines the hypothesis that combining atenolol with diazepam, as an intervention after seizure onset, will combat cardiac injury during status epilepticus. Male Sprague-Dawley rats were implanted with electroencephalographic/electrocardiographic electrodes to allow simultaneous recordings during seizures induced by intrahippocampal (2 nmol, 1 μL) kainic acid (KA). Subcutaneous saline, atenolol (5 mg·kg), diazepam (5 mg·kg), or atenolol and diazepam (n = 12/group) were administered at 60 minutes post-KA and daily for 7 days, at which point echocardiography, susceptibility to aconitine-induced arrhythmias, and histology were evaluated. Seizure activity was associated with immediately increased heart rate, QTc interval, and blood pressure ...
A prodrug strategy for the release of the gasotransmitter carbon monoxide (CO) at physiological p... more A prodrug strategy for the release of the gasotransmitter carbon monoxide (CO) at physiological pH, based upon 3a-bromo-norborn-2-en-7-one Diels–Alder cycloadducts has been developed.
Systolic and diastolic dysfunction in diabetes have frequently been associated with abnormal calc... more Systolic and diastolic dysfunction in diabetes have frequently been associated with abnormal calcium (Ca2+) regulation. However, there is emerging evidence that Ca2+ mishandling alone is insufficient to fully explain diabetic heart dysfunction, with focus shifting to the properties of the myofilament proteins. Our aim was to examine the effects of diabetes on myofilament Ca2+ sensitivity and Ca2+ handling in left ventricular tissues isolated from the same type 2 diabetic rat hearts. We measured the force-pCa relationship in skinned left ventricular cardiomyocytes isolated from 20-week-old type 2 diabetic and non-diabetic rats. Myofilament Ca2+ sensitivity was greater in the diabetic relative to non-diabetic cardiomyocytes, and this corresponded with lower phosphorylation of cardiac troponin I (cTnI) at ser23/24 in the diabetic left ventricular tissues. Protein expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), phosphorylation of phospholamban (PLB) at Ser16, and SERCA/PL...
Confocal studies show that positively charged oCOms, like oCOm-58, release CO in mitochondria pre... more Confocal studies show that positively charged oCOms, like oCOm-58, release CO in mitochondria preserving their energetics.
Background —Heat shock protein 70 (HSP70) gene transfection has been shown to enhance myocardial ... more Background —Heat shock protein 70 (HSP70) gene transfection has been shown to enhance myocardial tolerance after normothermic ischemia-reperfusion. We investigated the effect of HSP70 gene transfection on mechanical and endothelial function in a protocol mimicking clinical heart preservation. Methods and Results —Rat hearts were infused ex vivo with Hemagglutinating Virus of Japan–liposome complex containing HSP70 gene (HSP, n=8) or no gene (CON, n=8), and heterotopically transplanted into recipient rats. Four days after surgery, transfected hearts were perfused on a Langendorff apparatus for 45 minutes, arrested with St Thomas’ No. 1 cardioplegia for 4 hours at 4°C, and reperfused for 1 hour. Mechanical and endothelial function was studied before and after ischemia. Creatine kinase was measured in reperfusion effluent. Hearts underwent Western blotting and immunohistochemistry to confirm HSP70 overexpression. Postischemic recovery of mechanical function (% preischemic±SEM) was grea...
semi-quantitatively. Results: Absolute albumin excretion was significantly greater in diabetic co... more semi-quantitatively. Results: Absolute albumin excretion was significantly greater in diabetic compared to NG sham operated TGRs (0.5±0.07 NG vs 2.9±0.7mg/24hr diabetic, p<0.01); the effect of BRD in diabetic TGR resulted in a significantly lower rates of albumin excretion compared to the intact innervated group (2.9±0.7 innervated vs 1.3±0.3mg/ 24hr denervated, p<0.05). Plasma urate levels in diabetic innervated rats were also high compared to NG innervated rats (6.5±0.8 NG vs 9.3±1.2mg/dL diabetic, p=0.08); BRD in diabetic TGRs resulted in a significantly reduced plasma urate level compared to the innervated TGRs (9.3±1.2 innervated vs 5.2±0.9mg/dL denervated, p<0.05). Microscopic examination confirmed the presence of glomerular basement membrane thickening and mesangial expansion in the diabetic kidneys. This morphological appearnce was markedly reduced by BRD intervention. Immunohistochemistry showed significantly higher expression of type I collagen (1.8-fold, p<0.0...
Cardiorenal syndrome, de novo renal pathology arising secondary to cardiac insufficiency, is clin... more Cardiorenal syndrome, de novo renal pathology arising secondary to cardiac insufficiency, is clinically recognised but poorly characterised. This study establishes and characterises a valid model representative of Type 2 cardiorenal syndrome. Extensive permanent left ventricular infarction, induced by ligation of the left anterior descending coronary artery in Lewis rats, was confirmed by plasma cardiac troponin I, histology and cardiac haemodynamics. Renal function and morphology was assessed 90-days post-ligation when heart failure had developed. The involvement of the paraventricular nucleus was investigated using markers of inflammation, apoptosis, reactive oxygen species and of angiotensin II involvement. An extensive left ventricular infarct was confirmed following coronary artery ligation, resulting in increased left ventricular weight and compromised left ventricular diastolic function and developed pressure. Glomerular filtration was significantly decreased, fractional excr...
Bilateral renal denervation (BRD) has been shown to normalise blood pressure in clinical and expe... more Bilateral renal denervation (BRD) has been shown to normalise blood pressure in clinical and experimental studies of hypertension by reducing systemic sympathetic output. This study determined the effect of BRD on cardiac β-adrenoceptor (AR) responsiveness in a diabetic model with underlying hypertension using the transgenic (mRen-2)27 rat. BRD or sham surgeries were conducted repeatedly at 3, 6 and 9 weeks in Ren-2 rats with or without streptozotocin (STZ)-induced diabetes (4 x n = 7); Sprague Dawley rats (n = 6) served as control. Cardiac function was determined in isolated hearts at 18 weeks of age. Normalised left ventricular developed pressure and relaxation was recorded in response to incrementing concentrations of the β-AR agonist isoproterenol (10(-10) to 10(-7 ) M) or the β3 -AR agonist BRL37344 (10(-13) to 10(-6 ) M). Expression levels of β1 -AR were determined by Western blot. Both inotropic and lusitropic β-AR responsiveness was reduced in the hypertensive diabetic heart...
We report the synthesis and characterisation of a photoactive nitric oxide (NO) releasing nanopar... more We report the synthesis and characterisation of a photoactive nitric oxide (NO) releasing nanoparticle (NP) by encapsulation of the NO donor tert-dodecane s-nitrosothiol (tDodSNO) into a co-polymer of styrene and maleic acid (SMA) to afford SMA-tDodSNO. Encapsulation did not affect tDodSNO's stability or NO release profile, but imparted water solubility and protection from degradation reactions with glutathione. Under photoactivation the NP acted as a potent NO donor, with photoactivation acting as a switch to induce localized vasodilation in aortic rings (EC 660nM at 2,700W/m) and cause vascular hyperpermeability in mesenteric beds (8-fold increase in dye uptake at 1µM SMA-tDodSNO with 460W/m photoactivation). The NP was markedly superior as a photoactive NO donor in comparison to the s-nitrosothiols GSNO and SNAP, which are commonly used in experimental studies, as well as sodium nitroprusside, a clinically used vasodilator. Future development of this NP may find wide ranging ...
Hypertension is a leading risk factor for cardiovascular and chronic kidney disease. A new rodent... more Hypertension is a leading risk factor for cardiovascular and chronic kidney disease. A new rodent model (transgenic maleCyp1a1-Ren2 rats) provides reversible induction of hypertension through the addition of indole-3-carbinol (I3C) to the diet,without the need for surgical intervention, thus giving researchers control over both the onset of hypertension and its magnitude(I3C dose-dependency). We here report the breeding performance and productivity of Cyp1a1-Ren2 rats. Despite beingtransgenic, these animals proved to be efficient breeders. In addition to confirming inducible and reversible dose-dependenthypertension (by using I3C doses of 0.125%, 0.167%, and 0.25% [w/w] in the diet for 14 d, followed by normal chow for 4 d),we demonstrated that hypertension can be sustained chronically (14 wk) by continuous dosing with I3C (0.167% [w/w]) inthe diet. In chronically dosed male rats, systolic blood pressure continued to rise, from 173 ± 11 mm Hg after 1 mo to 196 ±19 mm Hg after 3 mo, ...
Altered autonomic activity has been implicated in the development of cardiac dysfunction during s... more Altered autonomic activity has been implicated in the development of cardiac dysfunction during seizures. This study investigates whether intervening in seizure progression with diazepam will reduce seizure-induced cardiomyopathy. Second, this study examines the hypothesis that combining atenolol with diazepam, as an intervention after seizure onset, will combat cardiac injury during status epilepticus. Male Sprague-Dawley rats were implanted with electroencephalographic/electrocardiographic electrodes to allow simultaneous recordings during seizures induced by intrahippocampal (2 nmol, 1 μL) kainic acid (KA). Subcutaneous saline, atenolol (5 mg·kg), diazepam (5 mg·kg), or atenolol and diazepam (n = 12/group) were administered at 60 minutes post-KA and daily for 7 days, at which point echocardiography, susceptibility to aconitine-induced arrhythmias, and histology were evaluated. Seizure activity was associated with immediately increased heart rate, QTc interval, and blood pressure ...
A prodrug strategy for the release of the gasotransmitter carbon monoxide (CO) at physiological p... more A prodrug strategy for the release of the gasotransmitter carbon monoxide (CO) at physiological pH, based upon 3a-bromo-norborn-2-en-7-one Diels–Alder cycloadducts has been developed.
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