Nitric oxide regulates the apoptotic pathway in explanted failing human hearts.
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Journal Article↗
Biomedical subjects
S Mital
Publications and source records attributed to S Mital.
Left ventricular assist device implantation augments nitric oxide dependent control of mitochondrial respiration in failing human hearts.
OBJECTIVES: The objective of the study was to evaluate nitric oxide (NO) mediated regulation of mitochondrial respiration after implantation of a mechanical assist device in end-stage heart failure. BACKGROUND: Ventricular unloading using a left ventricular assist device (LVAD) can improve mitochondrial function in end-stage heart failure. Nitric oxide modulates the activity of the mitochondrial electron transport chain to regulate myocardial oxygen consumption (MVO2). METHODS: Myocardial oxygen consumption was measured polarographically using a Clark-type oxygen electrode in isolated left ventricular myocardium from 26 explanted failing human hearts obtained at the time of heart transplantation. RESULTS: The rate of decrease in oxygen concentration was expressed as a percentage of baseline. Results of the highest dose of drug are shown. Decrease in MVO2 was greater in LVAD hearts (n = 8) compared with heart failure controls (n = 18) in response to the following drugs: bradykinin (-34+/-3% vs. -24+/-5%), enalaprilat (-37+/-5% vs. -23+/-5%) and amlodipine (-43+/-13% vs. -16+/-5%; p<0.05 from controls). The decrease in MVO2 in LVAD hearts was not significantly different from controls in response to diltiazem (-22+/-5% in both groups) and exogenous NO donor, nitroglycerin (-33+/-7% vs. -30+/-3%). N(w)-nitro-L-arginine methyl ester, inhibitor of NO synthase, attenuated the response to bradykinin, enalaprilat and amlodipine. Reductions in MVO2 in response to diltiazem and nitroglycerin were not altered by inhibiting NO. CONCLUSIONS: Chronic LVAD support potentiates endogenous NO-mediated regulation of mitochondrial respiration. Use of medical or surgical interventions that augment NO bioavailability may promote myocardial recovery in end-stage heart failure.
Adolescent↗
Canine coronary microvessel NO production regulates oxygen consumption in ecNOS knockout mouse heart.
We have previously shown that NO production by tissues following stimulation with bradykinin or other agonists can regulate oxygen consumption in skeletal muscle, heart and kidney. From those studies and from those using agonists, which classically release NO from blood vessels and which are unable to regulate tissue oxygen consumption in heart from ecNOS knockout mice, we concluded that vascular NO production is capable of regulating tissue oxygen consumption. The goal of these studies was to directly address the concept that NO production by blood vessels can regulate tissue oxygen consumption using a classical transfer paradigm. Microvessels, capable of producing NO, were prepared from canine hearts using a sieving technique, cardiac tissue was taken from mice lacking the ability to produce NO from ecNOS (ecNOS -/- mice) and tissue oxygen consumption measured in vitro using a Clark type electrode in a sealed chamber. Bradykinin (10(-7)to 10(-4)M) had no effect on tissue oxygen consumption when administered to heart from ecNOS -/mice as expected and no effect on oxygen consumption by isolated canine coronary microvessels (0+/-5% at 10(-5)M). However when coronary microvessels were co-incubated with heart from ecNOS -/- mice, bradykinin caused a dose dependent reduction in tissue oxygen consumption reaching a maximum of 44+/-10% at 10(-4)M. The effects of bradykinin were entirely abolished by L -NAME. The calculated concentration range for NO in these studies was 2.9 to 293 n M, within estimated physiologic range for the activity of NO on cytochrome oxidase. These data indicate that coronary microvessels can regulate cardiac oxygen consumption through a NO dependent mechanism.
Animals↗
Impaired nitric oxide modulation of myocardial oxygen consumption in genetically cardiomyopathic hamsters.
We investigated the role of kinin and nitric oxide (NO) in the modulation of cardiac O(2)consumption in Syrian hamsters with overt heart failure (HF) and age-matched normal hamsters. Using echocardiography, the hamsters with heart failure had reduced ejection fraction [31(+/-8) v 76(+/-5)%] and LV dilation [4.9(+/-0. 2) v 5.7(+/-0.3) mm, both P<0.05 from normal]. O(2)consumption in the left ventricular free wall was measured using a Clark-type O(2)electrode in an air-tight chamber, containing Krebs solution buffered with Hepes (37 degrees C, pH 7.4). Concentration response curves to bradykinin (BK), ramiprilat (RAM), amlodipine (AMLO) and the NO donor, S -nitroso- N -acetyl-penicillamine (SNAP) were performed. Basal myocardial O(2)consumption was lower in the HF group compared to normal [316(+/-21) v 404(+/-36) nmol O(2)/min/g, respectively, P<0.05]. In the hearts from normal hamsters BK (10(-4)mol/l), RAM (10(-4)mol/l), and AMLO (10(-5)mol/l) all significantly reduced myocardial O(2)consumption by 42(+/-6)%, 29(+/-7)% and 27(+/-5)% respectively. This reduction was attenuated in the presence of N -nitro- l -arginine methyl ester (l -NAME) [BK: 3.3(+/-1.5)%, RAM: 3.3(+/-1.2)%, AMLO: 2.3(+/-1.2)%, P<0.05]. Interestingly in the hearts from HF group, BK, RAM and AMLO caused a significantly smaller reduction in myocardial O(2)consumption [10(+/-2)%, 2.5(+/-1.3)%, 6.3(+/-2.3)%, P<0.05]. In contrast, the NO donor SNAP reduced myocardial O(2)consumption in both groups and all those responses were not affected by l -NAME. These data indicate that endogenous NO production through the kinin-dependent mechanism is impaired at end-stage heart failure. The loss of kinin and NO control of mitochondrial respiration may contribute to the pathogenesis of heart failure.
Amlodipine↗
Simvastatin acts synergistically with ACE inhibitors or amlodipine to decrease oxygen consumption in rat hearts.
Statin drugs, which are cholesterol-lowering agents, can upregulate endothelial nitric oxide synthase (eNOS) in isolated endothelial cells independent of lipid lowering. We investigated the effect of short-term simvastatin administration on NO-mediated regulation of myocardial oxygen consumption (MV(O2)) in tissue from rat hearts. Male Wistar rats were divided into (a) control group (n = 14), and (b) simvastatin group (n = 10, 20 mg/kg/day by oral gavage). After 2 weeks, left ventricular myocardium was isolated to measure MV(O2) using a Clark-type oxygen electrode, and aortic plasma nitrates and nitrites (NOx) were measured. Baseline plasma NOx levels (19+/-2.6 in control vs. 20+/-2.5 microM/L in simvastatin) and baseline MV(O2) (288+/-23 in control vs. 252+/-11 nmol/g/min; p = 0.09) were not significantly different between the two groups. NO-dependent regulation of MV(O2) in response to bradykinin, ramipril, or amlodipine was augmented in simvastatin rats compared with controls (p < 0.05). Decrease of MV(O2) from baseline in response to highest doses in control versus simvastatin groups was as follows-bradykinin, -28+/-5% vs. -44+/-6%; ramipril, -35+/-5% vs. -50+/-8%; and amlodipine, -32+/-9% vs. -42+/-3%. Response to highest dose of NO donor S-nitroso N-acetyl penicillamine (SNAP) was not significantly different in the two groups (-55+/-5% vs. -52+/-7%). Treatment with Nw-nitro-L-arginine methyl ester, inhibitor of NO synthesis, attenuated the effect of bradykinin, ramipril, and amlodipine on MV(O2) (p < 0.05). In conclusion, short-term administration of simvastatin in rats potentiates the ability of angiotensin-converting enzyme (ACE) inhibitors and amlodipine to cause NO-mediated regulation of MV(O2).
Amlodipine↗
Simvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs.
Statin drugs can upregulate endothelial nitric oxide (NO) synthase (eNOS) in isolated endothelial cells independent of lipid-lowering effects. We investigated the effect of short-term simvastatin administration on coronary vascular eNOS and NO production in conscious dogs and canine tissues. Mongrel dogs were instrumented under general anesthesia to measure coronary blood flow (CBF). Simvastatin (20 mg. kg(-1). day(-1)) was administered orally for 2 wk; afterward, resting CBF was found to be higher compared with control (P < 0.05) and veratrine- (activator of reflex cholinergic NO-dependent coronary vasodilation) and ACh-mediated coronary vasodilation were enhanced (P < 0.05). Response to endothelium-independent vasodilators, adenosine and nitroglycerin, was not potentiated. After simvastatin administration, plasma nitrate and nitrite (NO(x)) levels increased from 5.22 +/- 1.2 to 7. 79 +/- 1.3 microM (P < 0.05); baseline and agonist-stimulated NO production in isolated coronary microvessels were augmented (P < 0.05); resting in vivo myocardial oxygen consumption (MVO(2)) decreased from 6.8 +/- 0.6 to 5.9 +/- 0.4 ml/min (P < 0.05); NO-dependent regulation of MVO(2) in response to NO agonists was augmented in isolated myocardial segments (P < 0.05); and eNOS protein increased 29% and eNOS mRNA decreased 50% in aortas and coronary vascular endothelium. Short-term administration of simvastatin in dogs increases coronary endothelial NO production to enhance NO-dependent coronary vasodilation and NO-mediated regulation of MVO(2).
Acetylcholine↗
Vascular potassium channels mediate oxygen-induced pulmonary vasodilation in fetal lambs.
The pulmonary vascular resistance decreases at birth secondary to release of endothelium-derived nitric oxide (EDNO). EDNO release is a calcium-dependent process, and endothelial potassium (K+) channels regulate intracellular calcium flux. We investigated the hypothesis that potassium channels mediate oxygen-induced pulmonary vasodilation and EDNO release in fetal lambs. We instrumented 18 near-term fetal lambs at 122-126 days of gestation to measure pulmonary pressures, flow, and resistance. We studied hemodynamic effects of (1) 100% oxygen; (2) pinacidil, an ATP-sensitive K+ (KATP) channel agonist, and (3) S-nitroso-N-acetylpenicillamine (SNAP), a NO donor. We studied the effects of glybenclamide, a K(ATP) channel antagonist, tetraethylammonium chloride (TEA), a preferential KCa channel antagonist, and nitro-L-arginine (NLA), an NO synthase inhibitor, on the response to some of the above agents. Oxygen-induced pulmonary vasodilation was inhibited by both glybenclamide and TEA, indicating that K(ATP) and K(Ca) channels mediate pulmonary vasodilator response to oxygen. Blocking NO synthesis with NLA inhibited pinacidil-mediated pulmonary vasodilation, indicating that K(ATP) channel activation stimulates NO release. SNAP-mediated pulmonary vasodilation was inhibited by TEA, but not glybenclamide, indicating that K(Ca) channels, but not K(ATP) channels, mediate effects of NO on vascular smooth muscle relaxation. In conclusion, K+ channels mediate oxygen-induced pulmonary vasodilation in fetal lambs. K(ATP) channels appear to mediate EDNO release, while K(Ca) channels probably mediate NO effects on vascular smooth muscle.
Animals↗
Adenosine and ATP cause nitric oxide-dependent pulmonary vasodilation in fetal lambs.
We investigated the hypothesis that the purine nucleotide ATP and its nucleoside adenosine cause pulmonary vasodilation in fetal lambs by the release of nitric oxide (NO). We also investigated the potential role of K(+)(ATP) channels in mediating the effects of ATP and adenosine on NO. We surgically prepared 28 fetal lambs to measure pulmonary and systemic pressures and pulmonary flow. We investigated the effects of glibenclamide and pinacidil (inhibitor and agonist, respectively, for K(+)(ATP) channels), N-nitro-L-arginine (N-LA) and its methyl ester, N-nitro-L-arginine methyl ester (L-NAME) (inhibitors of endothelium-derived NO synthesis), and U46619 (a thromboxane mimetic) on pulmonary vasodilation caused by adenosine and ATP. Adenosine decreased the pulmonary artery pressure and pulmonary vascular resistance (PVR) at doses of 0.08-2.5 microM/kg/min and increased the left pulmonary flow at doses of 0.3-2.5 microM/kg/min in control experiments. N-LA, L-NAME and glibenclamide attenuated the effects of adenosine at doses of < 2.5 microM/ kg/min and pinacidil potentiated its effects. ATP decreased the pulmonary artery pressure and PVR and increased the pulmonary flow at doses of 0.15-2.5 microM/kg/min in control experiments. N-LA and L-NAME attenuated the effects of ATP at doses of < 2.5 microM/kg/min, whereas glibenclamide and pinacidil had no effect on the response to ATP. U46619 increased the basal pulmonary vascular tone, but did not significantly alter the vasodilative responses to ATP and adenosine. In conclusion, adenosine and ATP cause NO-dependent pulmonary vasodilation in fetal lambs. The activation of K(+)(ATP) channels plays a role in adenosine-induced pulmonary vasodilation. The mechanism by which ATP causes NO release and pulmonary vasodilation requires further investigation.
Adenosine↗
Characterization of purine receptors in fetal lamb pulmonary circulation.
Activation of P1 purinergic receptors by adenosine and P2 receptors by ATP plays an important role in pulmonary vasodilation that occurs at birth in fetal lambs. Purine receptors occur in several subtypes, and the effects of their stimulation vary with the specific type involved. We characterized the subtypes of P1 receptors in fetal lamb pulmonary circulation at 128-132 d gestation by investigating the effects of the following adenosine analogs: N6-cyclopentyl adenosine (A1 selective), 2-phenylaminoadenosine (A2 selective), 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxamidoadenosine (A2A selective), N6-benzyl-5'-N-ethylcarboxamidoadenosine (A3 selective), and adenosine and 5'-N-ethylcarboxamidoadenosine (nonselective). We repeated the studies after treatment of animals with A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine or A2 antagonist 1,3-dipropyl-7-methylxanthine. Identification of P2 receptors was done by investigation of the effects of P2x agonist beta,gamma-methylene-L-ATP and P2x and P2y agonist ATP. The studies were repeated after the treatment of animals with P2x antagonist suramin and the P2y antagonist cibacron blue. N6-cyclopentyl adenosine caused a significant decrease in heart rate and did not change pulmonary blood flow or pulmonary vascular resistance (PVR). The effect of N6-cyclopentyl adenosine on heart rate was abolished by 1,3-dipropyl-8-cyclopentylxanthine but not by 1,3-dipropyl-7-methylxanthine. 2-Phenylaminoadenosine, 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine, 5'-N-ethylcarboxamidoadenosine, and adenosine caused significant increases in pulmonary flow and decreases in PVR, and their vasodilator effects were attenuated by the A2 antagonist 1,3-dipropyl-7-methylxanthine and not by 1,3-dipropyl-8-cyclopentylxanthine. N6-benzyl-5'-N-ethylcarboxamidoadenosine did not alter pulmonary flow or PVR. The P2x agonist beta,gamma-methylene-L-ATP caused a decrease in heart rate and had no effect on pulmonary flow and PVR. ATP caused a significant increase in pulmonary flow and decrease in PVR without affecting heart rate. The vasodilator effects of ATP were attenuated by cibacron blue and not by suramin. These data demonstrate that adenosine and ATP cause pulmonary vasodilation by activation of A2A and P2y receptors, respectively, in fetal lambs.
Animals↗
Nitric oxide modulates mitochondrial respiration in failing human heart.
Background-Our objective for this study was to investigate whether nitric oxide (NO) modulates tissue respiration in the failing human myocardium. Methods and Results-Left ventricular free wall and right ventricular tissue samples were taken from 14 failing explanted human hearts at the time of transplantation. Tissue oxygen consumption was measured with a Clark-type oxygen electrode in an airtight stirred bath containing Krebs solution buffered with HEPES at 37 degrees C (pH 7.4). Rate of decrease in oxygen concentration was expressed as a percentage of the baseline, and results of the highest dose are indicated. Bradykinin (10(-4) mol/L, -21+/-5%), amlodipine (10(-5) mol/L, -14+/-5%), the ACE inhibitor ramiprilat (10(-4) mol/L, -21+/-2%), and the neutral endopeptidase inhibitor thiorphan (10(-4) mol/L, -16+/-5%) all caused concentration-dependent decreases in tissue oxygen consumption. Responses to bradykinin (-2+/-6%), amlodipine (-2+/-4%), ramiprilat (-5+/-6%), and thiorphan (-4+/-7%) were significantly attenuated after NO synthase blockade with N-nitro-L-arginine methyl ester (10(-4) mol/L; all P<0.05). NO-releasing compounds S-nitroso-N-acetyl-penicillamine (10(-4) mol/L, -34+/-5%) and nitroglycerin (10(-4) mol/L, -21+/-5%), also decreased tissue oxygen consumption in a concentration-dependent manner. However, the reduction in tissue oxygen consumption in response to S-nitroso-N-acetyl-penicillamine (-35+/-7%) or nitroglycerin (-16+/-5%) was not significantly affected by N-nitro-L-arginine methyl ester. Conclusions-These results indicate that the modulation of oxygen consumption by both endogenous and exogenous NO is preserved in the failing human myocardium and that the inhibition of kinin degradation plays an important role in the regulation of mitochondrial respiration.
Amlodipine↗
Amlodipine promotes kinin-mediated nitric oxide production in coronary microvessels of failing human hearts.
Recently, we found that amlodipine can release nitric oxide (NO) from canine coronary microvessels, which raises the question of whether amlodipine can also promote coronary NO production in failing human hearts. The goal of this study was to define the effect of amlodipine on NO production in failing human hearts and to determine the role of kinins in the control of NO production induced by amlodipine. Six explanted human hearts with end-stage heart failure were obtained immediately at transplant surgery. Coronary microvessels were isolated as previously described, and nitrite, the stable metabolite of NO in aqueous solution, was measured using the Griess Reaction. Amlodipine (10(-10) to 10(-5) mol/L) significantly increased nitrite production in coronary microvessels in a dose-dependent manner. The increase in nitrite in response to the highest dose of amlodipine (79%) was similar in magnitude to either that of the angiotensin-converting enzyme inhibitor ramiprilat (74%) or the neutral endopeptidase inhibitors phosphoramidon (61%) and thiorphan (72%). Interestingly, the increase in nitrite production induced by amlodipine was entirely abolished by N(omega)-nitro-L-arginine methyl ester and also HOE-140 (a bradykinin-2 antagonist) and dichloroisocoumarin (a serine protease inhibitor that blocks kallikrein activity). These results indicate that amlodipine can promote coronary NO production in failing human hearts and that this effect is dependent on a kinin-mediated mechanism.
Amlodipine↗
Synergy of amlodipine and angiotensin-converting enzyme inhibitors in regulating myocardial oxygen consumption in normal canine and failing human hearts.
The production of endogenous nitric oxide, which regulates myocardial oxygen consumption, is decreased in heart failure. As with angiotensin-converting enzyme (ACE) inhibitors, amlodipine, a calcium antagonist, increases kinin-mediated nitric oxide production in coronary microvessels. We investigated the possibility of synergy between ACE inhibitors and amlodipine in regulating myocardial oxygen consumption. Left ventricular myocardium was isolated from 6 healthy dog hearts and 5 human hearts with end-stage heart failure at the time of orthotopic heart transplantation. Myocardial oxygen consumption was measured before and after administration of bradykinin, S-nitroso N-acetyl penicillamine (SNAP, a nitric oxide donor), ramiprilat (an ACE inhibitor), amlodipine, and the combination of a sub-threshold dose of ramiprilat (10(-8) md/L) + amlodipine. These experiments were repeated with L-nitro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthesis), dichloroisocoumarin (an inhibitor of kinin synthesis), and HOE 140 (a B2 kinin-receptor antagonist). Baseline myocardial oxygen consumption in canine hearts was 182 +/- 21 nmol/g/min. Bradykinin and SNAP caused dose-dependent reductions in myocardial oxygen consumption (p <0.05). Ramiprilat and amlodipine caused a 10 +/- 3.2% and 11 +/- 0.8% reduction in myocardial oxygen consumption, respectively, when used alone (p <0.05). In the presence of a subthreshold dose of ramiprilat, amlodipine caused a larger (15 +/- 1.7%) reduction in myocardial oxygen consumption compared with either drug used alone (p <0.05). In human hearts, baseline myocardial oxygen consumption was 248 +/- 57 nmol/g/min. Amlodipine caused a larger reduction in myocardial oxygen consumption when used with ramiprilat (22 +/- 3.2%) as compared with amlodipine alone (15 +/- 2.6%). The effect of both drugs was attenuated by L-NAME, dichloroisocoumarin, and HOE 140 (p <0.05). In conclusion, ACE inhibitors and amlodipine act synergistically to regulate myocardial oxygen consumption by modulating kinin-mediated nitric oxide release, and this combination of drugs may be useful in the treatment of heart failure.
Adolescent↗
Comparative left ventricular function following atrial, septal, and apical single chamber heart pacing in the young.
Ventricular pacing, typically initiated from a RV apical electrode, inherently causes abnormal biventricular activation, decrease LV function, and causes histopathological changes. Since pacing initiated in childhood can be expected to have a more protracted course compared with the adult, the consequences of this alteration in LV hemodynamics gain added significance among the young pacemaker recipient. The purpose of this study was to evaluate the potential of improving paced LV function by a septal electrode implant site. Acute alterations in cardiac index, LV pressure, and contraction indices, including dP/dt, Vmax, and Vpm, were compared among 22 patients (median age 10 years) with normal cardiac anatomy during intracardiac electrophysiological studies. LV hemodynamics were measured during intrinsic rhythms and following 15 minutes of atrial, RV apical, and septal pacing at an appropriate exercise rate for age of 150 ppm. Results showed a significant decrease in LV dP/dt, Vmax, and Vpm, and increase in LV end-diastolic pressure only with apical pacing. Septal pacing, in spite of loss of any atrial contribution to ventricular filling, maintained comparable indices with intrinsic and atrial paced rhythms. This study demonstrates that normalized LV function is maintained by septal and deteriorates with apical pacing acutely among young, nonischemic hearts. Continued evaluation of appropriate pacing electrode designs to permit septal implant is needed to ensure optimal chronically paced LV function.
Adolescent↗
Purine nucleotides contribute to pulmonary vasodilation caused by birth-related stimuli in the ovine fetus.
We investigated the hypothesis that the purine nucleotides ATP and adenosine mediate the pulmonary vasodilation that occurs at birth in fetal lambs. We instrumented 44 fetal lambs to measure left pulmonary arterial pressure and flow. In control studies, we investigated the effects of sequential ventilation with 10, 50, and 100% O2 on fetal pulmonary arterial pressure and flow and pulmonary vascular resistance (PVR). We also measured the blood and plasma ATP levels in the pulmonary artery and left atrium in the control studies. In three separate groups of studies, we investigated the effects of 8-phenyltheophylline, an adenosine-receptor antagonist, and cibacron blue, an inhibitor of ATP-sensitive P2y receptors, given alone or in combination, on the response of PVR to sequential ventilation. Fetal arterial PO2 increased during ventilation with 50 and 100% O2 but not with 10% O2. Ventilation with 10% O2 caused a 4-fold increase in pulmonary blood flow and a 10-fold decrease in PVR. Ventilation with 50 and 100% O2 caused a 7-fold increase in pulmonary blood flow and a 20-fold decrease in PVR. Blood and plasma ATP levels in the pulmonary artery and blood ATP levels in the left atrium increased significantly during ventilation with 50 and 100% O2 but not with 10% O2. Pretreatment of animals with 8-phenyltheophylline attenuated the increase in pulmonary flow and decrease in PVR caused by ventilation at all fractions of inspired O2 (FIO2 levels). Pretreatment of animals with cibacron blue attenuated pulmonary vasodilation at 50 and 100% FIO2. Combined treatment with 8-phenyltheophylline and cibacron blue caused complete inhibition of the decrease in PVR in response to ventilation at the three FIO2 levels. Incubation of fetal red blood cells in vitro with 100% O2 caused an increase in ATP production. An increase in arterial PO2 in the fetus causes an increase in blood ATP levels, and an inhibition of ATP receptors attenuates the O2-induced decrease in PVR. Adenosine-receptor inhibition attenuates both ventilation- and O2-induced changes in PVR. Increased synthesis and release of ATP plays a major role in causing pulmonary vasodilation in response to birth-related stimuli in the ovine fetus.
Adenosine↗
Synthesis and antibacterial activity of some new mesoionics.
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Anti-Bacterial Agents↗