phosphocreatine and Hypertension

The creatine kinase system, the central regulatory system of cellular energy metabolism, provides ATP in situ at ATP-ases involved in ion transport and muscle contraction. Furthermore, the enzyme system provides relative protection from tissue ischaemia and acidosis. The system could therefore be a target for pharmacologic intervention.. To systematically evaluate evidence regarding the effectiveness of interventions directly targeting the creatine kinase system as compared to placebo control in adult patients with essential hypertension or cardiovascular disease.. Electronic databases searched: Medline (1950 - Feb 2011), Embase (up to Feb 2011), the Cochrane Controlled Trials Register (issue 3, Aug 2009), Latin-American/Caribbean databank Lilacs; references from textbooks and reviews; contact with experts and pharmaceutical companies; and searching the Internet. There was no language restriction.. Randomized controlled trials comparing creatine, creatine phosphate, or cyclocreatine (any route, dose or duration of treatment) with placebo; in adult patients with essential hypertension, heart failure, or myocardial infarction. We did not include papers on the short-term use of creatine during cardiac surgery.. The outcomes assessed were death, total myocardial infarction (fatal or non-fatal), hospitalizations for congestive heart failure, change in ejection fraction, and changes in diastolic and systolic blood pressure in mm Hg or as percent change.. Full reports or abstracts from 1164 papers were reviewed, yielding 11 trials considering treatment with creatine or creatine analogues in 1474 patients with heart failure, ischemic heart disease or myocardial infarction. No trial in patients with hypertension was identified. Eleven trials (1474 patients, 35 years or older) comparing add-on therapy of the creatine-based drug on standard treatment to placebo control in patients with heart failure (6 trials in 1226 / 1474 patients ), or acute myocardial infarction (4 trials in 220 / 1474 patients) or 1 in ischemic heart disease (28 / 1474 patients) were identified. The drugs used were either creatine, creatine phosphate (orally, intravenously, or intramuscular) or phosphocreatinine. In the trials considering heart failure all three different compounds were studied; creatine orally (Gordon 1995, Kuethe 2006), creatine phosphate via intravenous infusion (Ferraro 1996, Grazioli 1992), and phosphocreatinine orally (Carmenini 1994, Maggi 1990). In contrast, the acute myocardial infarction trials studied intravenous creatine phosphate only. In the ischemic heart disease trial (Pedone 1984) creatine phosphate was given twice daily through an intramuscular injection to outpatients and through an intravenous infusion to inpatients. The duration of the study intervention was shorter for the acute patients, from a two hour intravenous infusion of creatine phosphate in acute myocardial infarction (Ruda 1988, Samarenko 1987), to six months in patients with heart failure on oral phosphocreatinine therapy (Carmenini 1994). In the acute myocardial infarction patients the follow-up period varied from the acute treatment period (Ruda 1988) to 28 days after start of the symptoms (Samarenko 1987) or end of the hospitalization period (Zochowski 1994). In the other trials there was no follow-up after discontinuation of treatment, except for Gordon 1995 which followed the patients until four days after stopping the intervention.Only two out of four trials in patients with acute myocardial infarction reported mortality outcomes, with no significant effect of creatine or creatine analogues (RR 0.73, CI: 0.22 - 2.45). In addition, there was no significance on the progression of myocardial infarction or improvement on ejection fraction. The main effect of the interventions seems to be on improvement of dysrhythmia.. This review found inconclusive evidence to decide on the use of creatine analogues in clinical practice. In particular, it is not clear whether there is an effect on mortality, progression of myocardial infarction and ejection fraction, while there is some evidence that dysrhythmia and dyspnoea might improve. However, it is not clear which analogue, dose, route of administration, and duration of therapy is most effective. Moreover, given the small sample size of the discussed trials and the heterogeneity of the population included in these reports, larger clinical studies are needed to confirm these observations.

Topics: Cardiovascular Diseases; Creatine; Creatine Kinase; Heart Failure; Humans; Hypertension; Molecular Targeted Therapy; Myocardial Infarction; Myocardial Ischemia; Phosphocreatine

Gradual alterations in cardiac energy balance, as assessed by the myocardial PCr/ATP-ratio, are frequently associated with the development of cardiac disease. Despite great interest for the follow-up of myocardial PCr and ATP content, cardiac MR-spectroscopy in rat models in vivo is challenged by sensitivity issues and cross-contamination from other organs.. Here we combined MR-Imaging and MR-Spectroscopy (Bruker BioSpec 9.4T) to follow-up for the first time in vivo the cardiac energy balance in the SHR, a genetic rat model of cardiac hypertrophy known to develop early disturbances in cytosolic calcium dynamics.. We obtained consistent 31P-spectra with high signal/noise ratio from the left ventricle in vivo by using a double-tuned (31P/1H) surface coil. Reasonable acquisition time (<3.2min) allowed assessing the PCr/ATP-ratio comparatively in SHR and age-matched control rats (WKY): i) weekly from 12 to 21 weeks of age; ii) in response to a bolus injection of the ß-adrenoreceptor agonist isoproterenol at age 21 weeks.. Along weeks, the cardiac PCr/ATP-ratio was highly reproducible, steady and similar (2.35±0.06) in SHR and WKY, in spite of detectable ventricular hypertrophy in SHR. At the age 21 weeks, PCr/ATP dropped more markedly (-17.1%±0.8% vs. -3,5%±1.4%, P<0.001) after isoproterenol injection in SHR and recovered slowly thereafter (time constant 21.2min vs. 6.6min, P<0.05) despite similar profiles of tachycardia among rats.. The exacerbated PCr/ATP drop under ß-adrenergic stimulation indicates a defect in cardiac energy regulation possibly due to calcium-mediated abnormalities in the SHR heart. Of note, defects in energy regulation were present before detectable abnormalities in cardiac energy balance at rest.

Topics: Adenosine Triphosphate; Adrenergic beta-Agonists; Animals; Energy Metabolism; Follow-Up Studies; Heart; Hypertension; Isoproterenol; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Myocardium; Phosphocreatine; Phosphorus; Rats; Rats, Inbred SHR; Rats, Inbred WKY

We studied the effect of phosphocreatine and ethylmethylhydroxypyridine succinate on the expression of Bax and Bcl-2 proteins in left-ventricular cardiomyocytes of spontaneously hypertensive rats (SHR). Both drugs have no effect on the expression of Bcl-2, but significantly reduce the level of Bax protein (phosphocreatine produces more pronounced effect). These data attest to an important role of energy deficit and oxidative stress in the induction of cardiomyocyte apoptosis in genetically determined arterial hypertension.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Gene Expression Regulation; Heart Ventricles; Hypertension; Male; Myocytes, Cardiac; Phosphocreatine; Picolines; Proto-Oncogene Proteins c-bcl-2; Pyridines; Rats; Rats, Inbred SHR

Primary systemic carnitine deficiency is an autosomal recessive disorder caused by a decreased renal reabsorption of carnitine because of mutations of the carnitine transporter OCTN2 gene, and hypertrophic cardiomyopathy is a common clinical feature of homozygotes. Although heterozygotes for OCTN2 mutations are generally healthy with normal cardiac performance, heterozygotes may be at risk for cardiomyopathy in the presence of additional risk factors, such as hypertension. To test this hypothesis, we investigated the effects of surgically induced pressure overload on the hearts of heterozygous mutants of a murine model of OCTN2 mutation, juvenile visceral steatosis mouse (jvs/+). Eleven-week-old jvs/+ mice and age-matched wild-type mice were used. At baseline, there were no differences in physical characteristics between wild-type and jvs/+ mice. However, plasma and myocardial total carnitine levels in jvs/+ mice were lower than in wild-type mice. Both wild-type and jvs/+ mice were subjected to ascending aortic constriction with or without 1% l-carnitine supplementation for 4 weeks. At 4 weeks after ascending aortic constriction, jvs/+ mice showed an exaggeration of cardiac hypertrophy and pulmonary congestion, further increased gene expression of atrial natriuretic peptide in the left ventricles, further deterioration of left ventricular fractional shortening, reduced myocardial phosphocreatine:adenosine triphosphate ratio, and increased mortality compared with wild-type mice; l-carnitine supplementation prevented these changes in jvs/+ mice subjected to ascending aortic constriction. In conclusion, cardiomyopathy and heart failure with energy depletion may be induced by pressure overload in heterozygotes for OCTN2 mutations and could be prevented by l-carnitine supplementation.

Topics: Adenosine Triphosphate; Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Cardiomyopathies; Carnitine; Constriction; Echocardiography; Genetic Predisposition to Disease; Heterozygote; Hypertension; Lung; Male; Mice; Mice, Mutant Strains; Mutation; Myocardium; Organ Size; Organic Cation Transport Proteins; Phosphocreatine; RNA, Messenger; Solute Carrier Family 22 Member 5

Compared with normal hearts, those with pathology (hypertrophy) are less tolerant of metabolic stresses such as ischemia. Pharmacologic intervention administered prior to such stress could provide significant protection. This study determined, firstly, whether the pentose sugar ribose, previously shown to improve postischemic recovery of energy stores and function, protects against ischemia when administered as a pretreatment. Secondly, the efficacy of this same pretreatment protocol was determined in hearts with pathology (hypertrophy). For study 1, Sprague-Dawley rats received equal volumes of either vehicle (bolus i.v. saline) or ribose (100 mg/kg) before global myocardial ischemia. In study 2, spontaneously hypertensive rats (SHR; blood pressure approximately 200/130) with myocardial hypertrophy underwent the same treatment protocol and assessments. In vivo left ventricular function was measured and myocardial metabolites and tolerance to ischemia were assessed. In normal hearts, ribose pretreatment significantly elevated the heart's energy stores (glycogen), and delayed the onset of irreversible ischemic injury by 25%. However, in vivo ventricular relaxation was reduced by 41% in the ribose group. In SHR, ribose pretreatment did not produce significant elevations in the heart's energy or improvements in tolerance to global ischemia, but significantly improved ventricular function (maximal rate of pressure rise (+dP/dt(max)), 25%; normalized contractility ((+dP/dt)/P), 13%) despite no change in hemodynamics. Thus, administration of ribose in advance of global myocardial ischemia does provide metabolic benefit in normal hearts. However, in hypertrophied hearts, ribose did not affect ischemic tolerance but improved ventricular function.

Topics: Adenosine Triphosphate; Anaerobic Threshold; Animals; Cardiotonic Agents; Disease Models, Animal; Drug Administration Schedule; Glycogen; Hypertension; Hypertrophy, Left Ventricular; Injections, Intravenous; Male; Myocardial Ischemia; Myocardium; Phosphocreatine; Rats; Rats, Sprague-Dawley; Ribose; Structure-Activity Relationship; Ventricular Function, Left; Ventricular Function, Right

The purpose of the present study was to measure absolute concentrations of phosphocreatine (PCr) and adenosine triphosphate (ATP) in normal, hypertrophied, and failing human heart.. Conflicting evidence exists on the extent of changes of high-energy phosphate metabolites in hypertrophied and failing human heart. Previous reports using phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) have quantified metabolites in relative terms only. However, this analysis cannot detect simultaneous reductions.. Four groups of subjects (n = 10 each), were studied: volunteers and patients with hypertensive heart disease (HHD), aortic stenosis, and dilated cardiomyopathy (DCM). Left ventricular (LV) function and mass were measured by cine magnetic resonance imaging. Absolute and relative concentrations of PCr and ATP were determined by (31)P-MRS with spatial localization with optimum point spread function.. Left ventricular ejection fraction remained normal in HHD and aortic stenosis, but was severely reduced to 18% in DCM; LV mass was increased by 55%, 79%, and 68% respectively. In volunteers, PCr and ATP concentrations were 8.82 +/- 1.30 mmol/kg wet weight and 5.69 +/- 1.02 mmol/kg wet weight, and the PCr/ATP ratio was 1.59 +/- 0.33. High-energy phosphate levels were unaltered in HHD. In aortic stenosis, PCr was decreased by 28%, whereas ATP remained constant. In DCM, PCr was reduced by 51%, ATP by 35%, and reduction of the PCr/ATP ratio by 25% was of borderline significance (p = 0.06). Significant correlations were observed among energetic and functional variables, with the closest relations for PCr.. In human heart failure due to DCM, both PCr and ATP are significantly reduced. Ratios of PCr to ATP underestimate changes of high-energy phosphate levels.

Topics: Adenosine Triphosphate; Adult; Aged; Aged, 80 and over; Aortic Valve Stenosis; Bias; Cardiomyopathy, Dilated; Case-Control Studies; Energy Metabolism; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myocardium; Phosphocreatine; Phosphorus Isotopes; Stroke Volume; Ventricular Function, Left

Topics: Adenosine Triphosphate; Aortic Valve Stenosis; Cardiomyopathy, Dilated; Humans; Hypertension; Hypertrophy, Left Ventricular; Myocardium; Phosphates; Phosphocreatine

Although the ultimate cause for the myocardial dysfunction of hypertensive heart disease is still unclear, a crucial role of the myocardial energy metabolism has been suggested. Therefore, the aim of the present study was to investigate whether age-related myocardial dysfunction in hearts of spontaneously hypertensive rats (SHR) is associated with an impaired myocardial energy metabolism. Isolated hearts of SHR and Wistar Kyoto rats (WKY) aged about 40, 60, and 80 weeks, respectively (each n = 4-5), were perfused according to the working heart technique. Cardiac work and coronary flow were monitored online. Myocardial energy metabolism was evaluated by calculating the ratio of phosphocreatine (PCr) and adenosine triphosphate (ATP) which were measured by nuclear magnetic resonance (31P-NMR) spectroscopy. All hearts were subjected to work for 30min at baseline conditions (low afterload), followed by another 30min under a moderate pressure load (high afterload). Each SHR group showed a higher heart weight/body weight ratio than the age-matched WKY controls. The SHR showed a progressive age-dependent reduction of cardiac work (40 weeks = 5.1+/-0.3, 60 weeks = 4.0+/-0.3, 80 weeks = 3.8+/-0.2 (mW/g) at baseline conditions) and PCr/ATP-ratio (40 weeks = 1.82+/-0.06, 60 weeks = 1.69+/-0.05, 80 weeks = 1.59+/-0.09 (PCr/ATP) at baseline conditions). Similar results were found for hearts of SHR at high afterload. In WKY no significant decline in cardiac work or PCr/ATP-ratio was found under either low or under high afterload. The cardiac work capacity of hearts of SHR progressively decreases with increasing age and left ventricular hypertrophy. This myocardial dysfunction is closely associated with an impaired PCr/ATP-ratio, suggesting a decreased energy reserve.

Topics: Adenosine Triphosphate; Age Factors; Animals; Disease Progression; Energy Metabolism; Hypertension; Hypertrophy, Left Ventricular; Linear Models; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Rats; Rats, Inbred SHR

Hypertension is an important clinical problem and is often accompanied by left ventricular (LV) hypertrophy and dysfunction. Whether the myocardial high-energy phosphate (HEP) metabolism is altered in human hypertensive heart disease and whether this is associated with LV dysfunction is not known.. Eleven patients with hypertension and 13 age-matched healthy subjects were studied with magnetic resonance imaging at rest and with phosphorus-31 magnetic resonance spectroscopy at rest and during high-dose atropine-dobutamine stress. Hypertensive patients showed higher LV mass (98+/-28 g/m2) than healthy control subjects (73+/-13 g/m2, P<0.01). LV filling was impaired in patients, reflected by a decreased peak rate of wall thinning (PRWThn), E/A ratio, early peak filling rate, and early deceleration peak (all P<0. 05), whereas systolic function was still normal. The myocardial phosphocreatine (PCr)/ATP ratio determined in patients at rest (1. 20+/-0.18) and during stress (0.95+/-0.25) was lower than corresponding values obtained from healthy control subjects at rest (1.39+/-0.17, P<0.05) and during stress (1.16+/-0.18, P<0.05). The PCr/ATP ratio correlated significantly with PRWThn (r=-0.55, P<0.01), early deceleration peak (r=-0.56, P<0.01), and with the rate-pressure product (r=-0.53, P<0.001).. Myocardial HEP metabolism is altered in patients with hypertensive heart disease. In addition, there is an association between impaired LV diastolic function and altered myocardial HEP metabolism in humans. The level of myocardial PCr/ATP is most likely determined by the level of cardiac work load.

Topics: Adenosine Triphosphate; Adult; Aged; Diastole; Humans; Hypertension; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Phosphocreatine; Ventricular Dysfunction, Left

The effect of induced hypertension treatment on cerebral ischemia is still controversial. We investigated the preferred blood pressure manipulation level and pressor agent required to reduce cerebral ischemic injury following transient forebrain ischemia induced by bilateral occlusion of the common carotid arteries in anesthetized gerbils. Following 60-min cerebral ischemia, we evaluated the preferred blood pressure manipulation level and pressor agent required to treat cerebral ischemic injury after reperfusion by examining the effects of different levels of mean arterial blood pressure (MABP), increased with phenylephrine or angiotensin II or decreased by blood withdrawal, on cerebral blood flow (CBF), survival ratio, cerebral edema, and brain energy metabolism following transient forebrain ischemia in gerbils. Mild phenylephrine-induced hypertension treatment (21+/-4 mmHg) during post-cerebral ischemia-reperfusion improved the survival ratio and reduced cerebral edema, which was also associated with an increase in local CBF and a recovery of brain energy metabolism. However, intense phenylephrine-induced hypertension, angiotensin II-induced hypertension, or hypotension worsen the survival rate and produced extra cerebral edema, that were also associated with deterioration of brain energy metabolism. These results demonstrate that a mild induced hypertension with phenylephrine (21+/-4 mmHg above the baseline level) results in reduction of the cerebral edema and improves the survival ratio and brain energy metabolism. Furthermore, angiotensin II may have neurotoxic effect to use as the pressor agent for induced hypertension after cerebral ischemia.

Topics: Adenosine Triphosphate; Analysis of Variance; Angiotensin II; Animals; Blood Pressure; Brain Edema; Cerebrovascular Circulation; Energy Metabolism; Gerbillinae; Hypertension; Ischemic Attack, Transient; Male; Phenylephrine; Phosphocreatine; Prosencephalon; Reperfusion Injury; Survival Rate

A quantitative 31P-MR-spectroscopic technique was used to assess the energy metabolism in healthy and diseased myocardium.. 31P spectra were acquired on a 1.5 T scanner using a 3D-chemical shift imaging technique. Based on the anatomical information provided by 1H images, SLOOP (Spatial Localization with Optimal Pointspread Function) allows to obtain spectra from defined compartments. With SLOOP a free voxel shape with adaption to anatomic structures, e.g. the myocardium, is possible. Absolute values for phosphocreatine (PCr) and adenosine triphosphate (ATP) were determined using an external standard.. 31P-spectra showed only minimal contamination by surrounding tissue. The standard deviation for the determined values of healthy volunteers was low. Compared to healthy volunteers, reduced PCr and ATP concentrations were seen for dilative cardiomyopathies and coronary artery disease and unchanged concentrations were observed for hypertensive heart disease.. 31P-MR spectroscopy with SLOOP allows a non-invasive, quantitative analysis of cardiac energy metabolism.

Topics: Adenosine Triphosphate; Cardiomyopathy, Dilated; Electrocardiography; Energy Metabolism; Humans; Hypertension; Hypertrophy, Left Ventricular; Magnetic Resonance Spectroscopy; Myocardial Ischemia; Myocardium; Phosphates; Phosphocreatine

The contents of adenine nucleotides (ATP, ADP, AMP), phosphocreatine (PCr) and creatine (Cr) in the heart, skeletal muscle, liver and spleen in spontaneously hypertensive (SHR) and normotensive (WKY) rats. The ATP/ADP ratio in cardiac tissue was lower in SHR compared with WKY, while myocardial contents of adenine nucleotides, PCr and Cr did not differ significantly between the groups. A lower ATP/ADP ratio in the skeletal muscle SHR of was accompanied by a reduction of PCr content comparing with these indices in WKY rats. The liver and spleen of SHR exhibited lower ATP contents and higher ADP and AMP levels compared with those ones in WKY rats, despite of the close values of adenine nucleotide pools (sigma AN = ATP + ADP + AMP). This redistribution of tissue adenine nucleotides was corresponded to lower energy charges (EC = (ATP + 0.5 ADP)/sigma AN) and ATP/ADP ratios in SHR group. The reduction of the energy state of tissues in SHR rats increased in the following rank: heart > skeletal muscle > liver > spleen, thus, reflecting progressive decrease of intensity of oxidative metabolism. The results suggest changes in the balance of rates of ATP formation and hydrolysis occur at the system level in primary hypertension. Probably, consequences of such rearrangement in energy metabolism are functional disturbances of plasma membrane and sacroplasmic reticulum well-documented in a number of experimental and clinical studies.

Topics: Adenine Nucleotides; Animals; Creatine; Energy Metabolism; Hypertension; Liver; Male; Muscle, Skeletal; Myocardium; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Spleen

Although both aging and hypertrophy are extremely important factors for cardiac performance, their influence on cardiac metabolism, especially that of high-energy phosphates, has not been fully elucidated as yet. Quantitative measurements of high-energy phosphates were attempted by comparing myocardial 31P NMR spectra with an external reference using depth-resolved surface-coil spectroscopy. The voxel size of the region of interest (ROI) was disk-shaped with 15-cm diameter and 25-mm thickness, but the left ventricular weight actually involved in the ROI was estimated to be between 22 and 66 g using MRI. Myocardial phosphocreatine (PCr) content and adenosine triphosphate (ATP) content for the 30 normal volunteers showed significant age dependence since both decreased in relation to increasing age. Myocardial PCr content and ATP content in patients with hypertension did not differ significantly from the age-matched control group. PCr content (6.1 +/- 2.2 micromol/g wet tissue, n = 10) and ATP content (4.1 +/- 1.3 micromol/g wet tissue) in patients with hypertrophic cardiomyopathy were less than the age-matched control group (n = 15; PCr: 9.7 +/- 2.5 micromol/g wet tissue, P < 0.01; ATP: 6.4 +/- 1.8 micromol/g wet tissue, P < 0.05), respectively. These results indicate that quantitative 31P MRS may be valuable in the assessment of changes in high-energy phosphate metabolism caused by aging or hypertrophy.

Topics: Adenosine Triphosphate; Adult; Aged; Aged, 80 and over; Aging; Cardiomyopathy, Hypertrophic; Case-Control Studies; Electrocardiography; Exercise Test; Female; Humans; Hypertension; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myocardium; Phosphocreatine

Topics: Adenosine Triphosphate; Aortic Valve Insufficiency; Aortic Valve Stenosis; Diastole; Heart; Humans; Hypertension; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Male; Myocardium; Nuclear Magnetic Resonance, Biomolecular; Phosphocreatine; Phosphorus; Physical Fitness; Systole; Ventricular Function, Left

This study tested the hypothesis that 31P nuclear magnetic resonance (NMR)-detectable 2-deoxyglucose (2DG) uptake is increased in chronically pressure-overloaded hypertrophied left ventricular myocardium.. 31P NMR spectroscopy was used to determine the transmural distribution of high-energy phosphate levels and 2-deoxyglucose-6-phosphate (2DGP) accumulation during intracoronary infusion of 2DG (15 mumol.kg body wt-1.min-1) in eight normal dogs and in eight dogs with severe left ventricular hypertrophy (LVH) produced by ascending aortic banding. The ratio of LV weight to body weight was 8.25 +/- 0.65 g/kg in the LVH group compared with 4.35 +/- 0.11 g/kg in the normal group (P < .01). Myocardial ATP content was decreased by approximately 40% and phosphocreatine (PCr) by approximately 60% in LVH hearts. ATP values were transmurally uniform in LVH and normal hearts, whereas PCr was lower in the subendocardium (Endo) than the subepicardium (Epi) of both groups. The PCr/ATP ratio was lower in LVH hearts (1.72 +/- 0.05, 1.64 +/- 0.07, and 1.53 +/- 0.10 in Epi, midwall, and Endo, respectively) compared with normal hearts (2.36 +/- 0.05, 2.09 +/- 0.06, and 1.96 +/- 0.06; each P < .01 normal versus LVH). Arterial blood levels of glucose, insulin, and free fatty acids were comparable between groups, whereas arterial lactate and norepinephrine levels were significantly higher in the LVH group. 2DG infusion did not affect systemic hemodynamics or myocardial high-energy phosphate or inorganic phosphate levels in either group. At the end of 60 minutes of 2DG infusion, there was no detectable accumulation of 2DGP in the normal hearts. However, seven of the eight LVH hearts showed time-dependent accumulation of 2DGP, which was linearly related to the severity of hypertrophy (r = .90 for subendocardial 2DGP versus LV weight/body weight). A transmural gradient of 2DGP was present, with greatest accumulation in the subendocardium (3.3 +/- 1.6, 5.8 +/- 2.3, and 7.9 +/- 2.2 mumol/g in Epi, midwall, and Endo of the LVH hearts, respectively; P < .05 Epi versus Endo).. The pressure-overloaded hypertrophied left ventricle demonstrated increased accumulation of 2DGP detected with 31P NMR spectroscopy. Accumulation of 2DGP was positively correlated with the degree of hypertrophy and was most marked in the subendocardium.

Topics: Adenosine Triphosphate; Animals; Coronary Circulation; Deoxyglucose; Dogs; Energy Metabolism; Glucose-6-Phosphate; Glucosephosphates; Hypertension; Hypertrophy, Left Ventricular; Magnetic Resonance Spectroscopy; Myocardium; Phosphocreatine; Ventricular Pressure

Myocardium reperfused following ischemia may contain regions that are adequately perfused but temporarily dysfunctional or metabolically abnormal, and regions that are persistently ischemic. By examining heterogeneity in the inorganic phosphate (Pi) resonance in 31P NMR spectra obtained for isolated perfused young v old hypertensive rat hearts made globally ischemic and then reperfused, areas of persistent intracellular acidosis (pHi about 6) were distinguished from recovering tissue (pHi about 7). The extent of persistent regional acidosis reported by Pi heterogeneity in the 31P NMR spectrum of the reperfused heart correlates well with (1) whole heart flow deficit measured as coronary flow, (2) the decrease in extracellular (primarily vascular) 23Na NMR resonance area measured using 23Na NMR and shift reagent, and (3) regional flow deficits identified using perfusate-borne dye markers. Persistent intracellular acidosis during reperfusion was observed only in the hearts of aged hypertensive rats, confirming that the vasculature of these animals is more susceptible to ischemic injury than both younger hypertensive rats and age-matched controls. The portion of the heart that is reperfused following only 16 min of global ischemia is metabolically abnormal, showing incomplete recovery of ATP and pH.

Topics: Adenosine Triphosphate; Aging; Animals; Energy Metabolism; Heart; Hydrogen-Ion Concentration; Hypertension; Magnetic Resonance Spectroscopy; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Phosphates; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The effect of chronic low- and high-dose treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril (0.01 and 1 mg/kg per day) on the development of hypertension and left ventricular hypertrophy as well as on functional and biochemical alterations of the heart was studied in stroke-prone spontaneously hypertensive rats treated prenatally and subsequently up to the age of 20 weeks. The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment of rats with the bradykinin B2-receptor antagonist Hoe 140 (500 micrograms/kg per day SC) from 6 to 20 weeks of age. High- but not low-dose ACE inhibitor treatment prevented the development of hypertension and left ventricular hypertrophy. Chronic bradykinin receptor blockade did not attenuate the antihypertensive and antihypertrophic actions of ramipril. High-dose ramipril treatment improved cardiac function, as demonstrated by an increase in left ventricular pressure (29.9%), dP/dtmax (34.9%), and coronary flow (22.1%), without a change in heart rate. The activities of lactate dehydrogenase and creatine kinase and lactate concentration in the coronary effluent were reduced by 39.3%, 55.5%, and 66.7%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 31.3%, 39.9%, and 73.7%, respectively, whereas lactate was decreased by 20.8%. Chronic low-dose ACE inhibitor treatment led to a pattern of changes in cardiodynamics and cardiac metabolism similar to that observed with the high dose. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by chronic bradykinin receptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Administration, Oral; Animals; Bradykinin; Cerebrovascular Disorders; Coronary Circulation; Creatine Kinase; Dose-Response Relationship, Drug; Female; Glycogen; Heart; Hypertension; Hypertrophy, Left Ventricular; L-Lactate Dehydrogenase; Lactates; Male; Myocardium; Phosphocreatine; Pregnancy; Ramipril; Rats; Rats, Inbred SHR; Rats, Wistar; Ventricular Pressure

The involvement of adenosine 3',5'-cyclic monophosphate (cAMP) in the stimulation of ventricular protein synthesis by aortic hypertension or adrenergic agonists in the adult rat heart was investigated. In either the retrogradely or anterogradely perfused heart, aortic hypertension increased protein synthesis rates by up to 19%. However, no changes in cAMP concentrations or in cAMP-dependent protein kinase activity ratios could be detected either at early (< 5 min) or late (90 min) time points. Although isoproterenol, 3-isobutyl-1-methylxanthine, or forskolin raised cAMP concentrations (by up to 4.5-fold) and cAMP-dependent protein kinase ratios (by up to 4-fold), protein synthesis rates were not increased; however, under some perfusion conditions, glucagon did stimulate protein synthesis by 25%. Epinephrine stimulated protein synthesis by up to 32%, an effect that was not prevented by propranolol. Phenylephrine also stimulated protein synthesis, an effect that was prevented by prazosin but was unaffected by yohimbine. These findings implicate the alpha 1-adrenoceptor in the regulation of cardiac protein synthesis. Because changes in adenine nucleotide concentrations were similar in hearts perfused with epinephrine or with the agents that raised cAMP, it is unlikely that adenine nucleotide depletion is responsible for the failure to observe effects of the latter group of agents on protein synthesis. Although isoproterenol or forskolin raised cAMP concentrations in isolated ventricular cardiomyocytes where ATP depletion was minimal, neither stimulated protein synthesis. alpha 1-Adrenergic agonists stimulate phosphoinositide hydrolysis in the heart (Brown, J. H., I. L. Buxton, and L. L. Brunton. Circ. Res. 57:532-537, 1985). Aortic hypertension doubled the rate of phosphoinositide hydrolysis in the perfused heart. We suggest that the phosphoinositide-linked signal transduction pathway is more likely to be involved in stimulation of cardiac protein synthesis by hypertension or adrenergic agonism than the adenylyl cyclase/cAMP-linked pathway.

Topics: 1-Methyl-3-isobutylxanthine; Adenine Nucleotides; Animals; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Energy Metabolism; Epinephrine; Glucagon; Heart; Hypertension; In Vitro Techniques; Isoproterenol; Kinetics; Male; Myocardium; Perfusion; Phenylephrine; Phosphocreatine; Prazosin; Propranolol; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Yohimbine

The effect of different chronic blood pressure levels on cardiac energy metabolism was studied by 31P-NMR spectroscopy in perfused hearts from the Lyon strains of hypertensive (LH), normotensive (LN) and hypotensive (LL) rats at the ages of 12 and 21 weeks. The in vivo assessment of haemodynamic parameters measured at 21 weeks in anaesthetized rats with an ultraminiature catheter pressure transducer confirmed that left ventricular systolic pressure and mean aortic pressure were significantly greater (+25%) in LH rats than in LN and LL rats. In the LL animals, left ventricular systolic pressure was slightly reduced (-10%) and cardiac contractility (estimated by LV dP/dtmax) showed a 24% decreased compared to normotensive animals. The energy state of the cardiomyocytes was characterized at different work levels of isolated rat hearts, by determining the concentration of the free phosphorylated compounds at each work level. Changes in workload were induced by varying the calcium concentration in the perfusion fluid. Increasing extracellular calcium concentration resulted in a similar increase in left ventricular developed pressure (LVDP) in all groups studied. Intracellular pH was not influenced by either the age of the animals or the level of cardiac work, in the three groups of animals. ATP content of the LN and LL rats remained constant during the whole perfusion period while the 12 week-old LH rats showed a decreased ATP content with increasing cardiac work. In the older LH rats, ATP content was decreased at the highest work level (corresponding to 2 mM calcium). In response to the increase in work, phosphocreatine (PCr) content diminished and inorganic phosphate (Pi) content increased in both LN, LH and LL animals. PCr degradation and Pi accumulation were higher in the LH rats and less in LL rats compared to the LN. These changes were more important in the younger than in the older hypertensive animals. The relationship between LVDP and [Pi]/[PCr] indicates that oxidative metabolism is maximally activated in the young hypertensive rats and suggests that this maximal activation represents an adaptive phase to the increase in blood pressure. Since the difference between the metabolic pattern of the 21 week-old LH rats and age-matched LN rats was less pronounced, it is likely that a compensatory stage has been reached at that age.

Topics: Animals; Energy Metabolism; Heart; Hemodynamics; Hypertension; In Vitro Techniques; Magnetic Resonance Spectroscopy; Male; Myocardium; Organ Size; Phosphates; Phosphocreatine; Rats

The aim was to examine differences between the postischaemic functional and biochemical recovery of adult and aged hypertrophied hearts.. Isolated hypertrophied hearts of adult and aged spontaneously hypertensive rats (SHRadult; SHRaged) and normal hearts of age matched Wistar-Kyoto rats (WKYadult; WKYaged) were perfused in an ejecting heart preparation. Haemodynamic function was monitored before and after 45 min of ischaemia. Coronary effluent samples and tissue biopsies were taken for biochemical analysis.. After ischaemia, in SHRadult and WKYadult the maximum positive first derivative of the left ventricular pressure (dP/dtmax) was restored to 105% and 97% respectively of the preischaemic values. Left ventricular developed pressure recovered to 80% (SHRadult) and 97% (WKYadult), while cardiac output reached 71% (SHRadult) and 99% (WKYadult) of preischaemic levels. In SHRaged and WKYaged the dP/dtmax recovered to 26% and 60% respectively (both p < 0.05 compared to the preischaemic values). The left ventricular developed pressure recovered to 36% in SHRaged and to 73% in WKYaged (both p < 0.05), while cardiac output was restored to 6% in SHRaged and 38% in WKYaged (both p < 0.05). Throughout reperfusion, left ventricular end diastolic pressure remained significantly elevated in SHRaged, and was associated with a prominent subendocardial underperfusion, suggesting an impaired diastolic functional recovery. Overall haemodynamic recovery was significantly better in the WKYaged than in the SHRaged. The preischaemic total adenine nucleotides content was comparable in all groups, but creatine phosphate levels were significantly lower in both aged groups than in adult groups. In all but the WKYadult, the total adenine nucleotides were depressed upon reperfusion, while creatine phosphate normalised, except in SHRaged. SHRaged lost more lactate dehydrogenase and tended to lose more xanthine and uric acid than other groups.. The aged hypertrophied heart shows a higher vulnerability to ischaemic damage than the adult hypertrophied heart. This phenomenon is associated with subendocardial underperfusion, increased membrane damage and inadequate recovery of creatine phosphate levels.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Aging; Animals; Cardiomegaly; Heart; Hypertension; Myocardial Ischemia; Myocardium; Perfusion; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

1. An analysis of the recovery kinetics of intracellular pH and phosphocreatine concentration after exercise in skeletal muscle was developed to calculate the rate of proton efflux in vivo. 2. Recovery of rat leg muscle pH after sciatic nerve stimulation was faster in spontaneously hypertensive rats than in Wistar-Kyoto controls (both n = 5). 3. Analysis of these data showed that the rate of proton efflux depends on intracellular pH, being greater at lower pH. 4. The early rate of proton efflux was greater in spontaneously hypertensive rats [measured over the first 0.8 min, 12.5 mmol min-1 kg-1 (SEM 1.8) in spontaneously hypertensive rats compared with 7.6 mmol min-1 kg-1 (SEM 0.4) in Wistar-Kyoto rats, P less than 0.05], even though pH at the start of recovery was higher [6.30 (SEM 0.03) in spontaneously hypertensive rats compared with 6.17 (SEM 0.01) in Wistar-Kyoto rats, P less than 0.01]. 5. This novel analysis provides a quantitative estimate of the rate of proton efflux in vivo, and demonstrates directly that this is increased in spontaneously hypertensive rats, as has previously been inferred from pH changes during exercise and studies of cultured muscle cells in vitro.

Topics: Animals; Hydrogen-Ion Concentration; Hypertension; Kinetics; Muscle Contraction; Muscles; Phosphocreatine; Physical Conditioning, Animal; Protons; Rats; Rats, Inbred SHR; Rats, Inbred WKY

1. Angiotensin converting enzyme (ACE)-inhibitors have been demonstrated to be effective in the treatment of cardiac hypertrophy when used in antihypertensive doses. The aim of our one year study with an ACE-inhibitor in rats was to separate local cardiac effects produced by a non-antihypertensive dose from those on systemic blood pressure when an antihypertensive dose was used. 2. Rats made hypertensive by aortic banding were subjected to chronic oral treatment for one year with an antihypertensive dose of the ACE inhibitor, ramipril 1 mg kg-1 daily, (RA 1 mg) or received a low dose of 10 micrograms kg-1 daily (RA 10 micrograms) which did not affect high blood pressure. 3. Chronic treatment with the ACE-inhibitor prevented left ventricular hypertrophy in the antihypertensive rats as did the low dose which had no effects on blood pressure. Similar effects were observed on myocardial fibrosis. Plasma ACE activity was inhibited in the RA 1 mg but not in the RA 10 micrograms group although conversion of angiotensin (Ang) I to Ang II in isolated aortic strips was suppressed in both treated groups. Plasma catecholamines were increased in the untreated control group, but treatment with either dose of ramipril normalized the values. The myocardial phosphocreatine to ATP ratio (an indicator of the energy state in the heart) was reduced in the vehicle control group whereas the hearts from treated animals showed a normal ratio comparable to hearts from sham-operated animals. 4. After one year, five animals were separated from each group, treatment withdrawn, and housed for additional six months. In the RA 1 mg group, blood pressure did not reach the value of the control vehicle group and surprisingly, left ventricular hypertrophy and myocardial fibrosis did not recur in animals during withdrawal of treatment.5. These data show that long term ACE inhibitor treatment with ramipril in antihypertensive and non-antihypertensive doses prevented cardiac hypertrophy and myocardial fibrosis. This protective effect was still present after 6 months treatment withdrawal.

Topics: Adenosine Triphosphate; Angiotensins; Animals; Aorta, Thoracic; Blood Pressure; Cardiomegaly; Catecholamines; Cyclic GMP; Endomyocardial Fibrosis; Hypertension; Male; Myocardium; Peptidyl-Dipeptidase A; Phosphocreatine; Radioimmunoassay; Ramipril; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley

We report studies on the isolated hearts of rats treated with triiodothyronine (0.2 mg/kg daily) for 14 days, on spontaneously hypertensive rats (12 and 21 weeks old, Lyon strain) and on their respective controls. A 30% increase in cardiac weight was developed with triiodothyronine and a 40% increase in heart weight in the presence of spontaneous hypertension. The hearts were perfused in the presence of 2 mM pyruvate and the intracellular content of phosphocreatine, inorganic phosphate and ATP measured by nuclear magnetic resonance spectroscopy with 31P. The left ventricular developed pressure was measured with an intraventricular balloon. Changes in contractile strength were induced by stepwise modifications of the extracellular concentration of calcium from 0.5 mM to 1.0, 1.5 and 2.0 mM. In all experimental groups, each increase in the extracellular calcium induced an increase in the developed pressure, together with a decrease in phosphocreatine and an increase in inorganic phosphate; the ATP level remained unchanged. These metabolic changes increased progressively with the increase in developed pressure. In the hearts of animals treated with triiodothyronine and of the 21 weeks old hypertensive rats, the extent of changes in phosphocreatine and inorganic phosphate was the same as in the controls; but, in the hearts of 12 weeks old hypertensive rats, the changes were significantly greater than in their controls. These observations suggest that, during the development of cardiac hypertrophy from spontaneous hypertension, there is a transitory deficiency in the capacity for aerobic ATP production relative to the rate of hydrolysis of ATP induced by an inotropic effect.

Topics: Adenosine Triphosphate; Animals; Calcium; Cardiomegaly; Energy Metabolism; Female; Hypertension; In Vitro Techniques; Magnetic Resonance Spectroscopy; Myocardium; Phosphates; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Triiodothyronine; Ventricular Function, Left

The aim of the present study was to define the protective effects of verapamil and nifedipine on mechanical performance and energy and substrate metabolism of the postischemically reperfused myocardium in a chronic pressure overload cardiac hypertrophy model. The isolated beating rat heart preparation was used and left ventricular pressures and high-energy phosphates were continuously monitored during 30 min of global ischemia and reperfusion, respectively. Recovery of mechanical performance and high-energy phosphate and sugar monophosphate metabolism was significantly impaired in untreated hypertrophied hearts compared with normal control hearts and hypertrophied hearts treated with calcium antagonists. In hypertrophied hearts with chronic verapamil treatment, recovery was significantly improved compared to acute verapamil treatment, nifedipine treatment, and normal control hearts. Thus, verapamil and nifedipine exerted a protective effect on the postischemic recovery of the hypertrophied myocardium that was most prominent following long-term pretreatment with verapamil. Prolonged maintenance of adequate plasma levels and tissue distribution of calcium antagonists before an ischemic event may improve the postischemic prognosis in the presence of pressure-induced myocardial hypertrophy.

Topics: Adenosine Triphosphate; Animals; Calcium Channel Blockers; Cardiomegaly; Energy Metabolism; Hypertension; Myocardial Reperfusion Injury; Myocardium; Nifedipine; Phosphocreatine; Rats; Rats, Inbred Strains; Verapamil

The effects of long-term treatment with diltiazem on the heart in normotensive (WKY) and spontaneously hypertensive rats (SHR) were studied. Diltiazem was added to the drinking fluid (900 mg/liter) and given ad libitum from 19 to 26 weeks of age, whereas tap water was given to the control animals. Although diltiazem did not decrease blood pressure in SHR, it decelerated the increase in their left ventricular weight (p less than 0.01). Hearts were removed and perfused by the working heart technique for 15 min, and then global ischemia was induced for either 10 or 30 min. The ischemic heart was reperfused for 30 min. The extent of recovery of coronary flow after reperfusion, following 30 min of ischemia in the diltiazem-treated SHR, was higher than that in the control SHR (p less than 0.01). The levels of adenosine triphosphate (ATP), creatine phosphate (CrP), and energy charge potential in the SHR heart reperfused after 30 min of ischemia were lower than those in the reperfused WKY heart (p less than 0.01, respectively). Diltiazem improved the restoration of ATP and CrP and prevented the decrease in energy charge potential in SHR after reperfusion following 30 min of ischemia (p less than 0.01, respectively). In conclusion, long-term treatment of SHR with diltiazem may protect the myocardium when myocardial ischemia occurs.

Topics: Adenine Nucleotides; Animals; Blood Pressure; Cardiomegaly; Coronary Circulation; Coronary Disease; Diltiazem; Energy Metabolism; Heart; Hypertension; In Vitro Techniques; Male; Myocardium; Perfusion; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Isolated buffer-perfused rat hearts with pressure-overload hypertrophy develop a greater decrease in left ventricular (LV) diastolic distensibility and a greater impairment in extent of LV relaxation in response to hypoxia than do normal hearts. Using 31P-NMR spectroscopy, we tested the hypothesis that the enhanced susceptibility of hypertrophied hearts to develop hypoxia-induced diastolic dysfunction is due to an accelerated rate of ATP and/or creatine phosphate depletion. Twelve minutes of hypoxia were imposed on isolated isovolumic (balloon-in-left-ventricle) buffer-perfused hearts from 14 rats with pressure-overload hypertrophy (LVH; LV/body wt ratio = 3.43 +/- 17) secondary to hypertension induced by uninephrectomy plus deoxycorticosterone and salt treatment and from 17 age-matched controls (LV/body wt ratio = 2.22 +/- 0.12, p less than 0.001). Coronary artery flow per gram left ventricle was matched in the LVH and control groups during baseline oxygenated conditions and held constant thereafter. Balloon volume was held constant throughout the experiment so that an increase in LV end-diastolic pressure during hypoxia represented a decrease in LV diastolic distensibility. LV systolic pressure was 165 +/- 9 mm Hg in the LVH group compared with 120 +/- 5 mm Hg in the controls during baseline aerobic perfusion (p less than 0.001). LV end-diastolic pressure rose significantly more in response to 12 minutes of hypoxia in the LVH group (12 +/- 1 to 44 +/- 10 mm Hg) than in the controls (12 +/- 1 to 20 +/- 3 mm Hg, p = 0.04). During baseline aerobic conditions, ATP content was the same in the LVH (17.1 +/- 0.5 mumol/g dry LV wt, n = 4) and control (18.8 +/- 0.6 mumol/g dry LV wt, n = 4, p = NS) groups. During hypoxia, ATP declined at the same rate in the LVH and control groups (3.2 +/- 0.5 versus 3.0 +/- 0.5%/min, p = NS) despite the greater rise in end-diastolic pressure in the LVH group. Creatine phosphate content during baseline aerobic perfusion was 14% lower in the LVH group compared with controls, but the rate of creatine phosphate depletion during 12 minutes of hypoxia was the same. During hypoxia, intracellular pH declined modestly and to the same degree in both groups. Thus, the greater susceptibility to hypoxia-induced diastolic dysfunction observed in isolated buffer-perfused hypertrophied rat hearts cannot be explained by an initially lower total ATP content or by an accelerated rate of decline of ATP or creatine phosphate.(ABSTRACT TRUNCATED AT

Topics: Adenosine Triphosphate; Animals; Cardiomegaly; Diastole; Energy Metabolism; Heart; Hypertension; Hypoxia; In Vitro Techniques; Magnetic Resonance Spectroscopy; Myocardial Contraction; Myocardium; Phosphates; Phosphocreatine; Rats; Rats, Inbred WKY; Systole

Myocardial mechanics and high-energy phosphate content [ATP and creatine phosphate (CrP)] of isolated left ventricular papillary muscle preparations from male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were compared at 6 and 18 mo of age. In comparison with oxygenated (95% O2-5% CO2) glucose-supplied (5.5 mM) papillary muscles from hearts of WKY rats, papillary muscles from hypertrophied hearts of the 18-mo-old SHR exhibited a prolonged time to peak tension, electromechanical delay time, and an increase in resting tension measured at the apex of the length-tension curve. Adenine nucleotide (ATP and ADP) contents of oxygenated papillary muscles were not significantly different between SHR and WKY strains at 6 or 18 mo of age, but CrP content of hearts from adult WKY and SHR were higher than for aged WKY and SHR rats. For up to 30 min of hypoxia (95% N2-5% CO2), muscles from the 18-mo-old SHR and WKY rats demonstrated improved tolerance to hypoxia compared with muscles from younger animals. However, at 60 min of hypoxia the 18-mo-old SHR demonstrated lower active tension and adenylate energy charge [(1/2 ADP + ATP)/(ATP + ADP + AMP)]. At higher glucose concentrations (22 mM), both 18-mo-old WKY and SHR demonstrated improved tolerance to hypoxia; moreover, the differences between strains were no longer evident. Following reoxygenation with 5.5 mM glucose, contracture tension and CrP content recovered to near prehypoxic control levels, whereas developed tension and ATP content remained moderately depressed for all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Aging; Animals; Body Weight; Glucose; Heart; Hypertension; Hypoxia; Isometric Contraction; Organ Size; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Isolated working hearts of 16 month old spontaneously hypertensive rats (SHR, n = 8) and age matched Wistar-Kyoto (WKY, n = 8) rats were exposed to 30 min global normothermic ischaemia followed by 60 min reperfusion. The hearts were routinely perfused at an afterload level of 13.3 kPa and a preload level of 1.0 kPa. The control values of left ventricular pressure, its maximal positive first derivative (dP1v/dtmax), coronary flow per gram heart tissue, and release of lactate and enzymes such as lactate dehydrogenase and aspartate aminotransferase were comparable in both groups. WKY rat hearts ejected almost twice as much perfusate per gram heart weight as the SHR hearts. In pressure-flow curves, obtained during the control period in SHR hearts, cardiac output was independent of changes in afterload, varying between 10.7 and 18.7 kPa. In contrast, in WKY rat hearts increases in afterload resulted in a progressive decrease in cardiac output. Reperfusion of the SHR hearts after 30 min of global normothermic ischaemia resulted in a poor recovery of cardiac output (13% of the control values) and dP1v/dtmax (32%) compared with the values in the WKY rat hearts (66% and 91% of the control values respectively). Reactive hyperaemia was prominent in the WKY rat hearts but completely absent in the SHR hearts. During one hour reperfusion, SHR hearts lost 3.5 times more lactate dehydrogenase and 2.5 times more aspartate aminotransferase than the WKY rat hearts. Pressure-flow curves, obtained during the reperfusion period, showed modest recovery of myocardial function of the WKY rat hearts at the lowest afterload level tested but completely depressed myocardial function of the SHR hearts at all afterload levels. Heart tissue contents of adenosine triphosphate and creatine phosphate after one hour of reperfusion were lower in the SHR than in the WKY rats, but compared with native values a comparable percentage decrease was seen in both groups of rats.

Topics: Adenosine Triphosphate; Animals; Aspartate Aminotransferases; Cardiac Output; Cardiomegaly; Coronary Vessels; Heart; Hypertension; Ischemia; L-Lactate Dehydrogenase; Myocardium; Perfusion; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

We quantified high-energy phosphate metabolites in hypertensive hypertrophied and normal myocardium and monitored temporal changes using the non-invasive 31P nuclear magnetic resonance (NMR) spectroscopy. Hearts from 18 month spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY) were perfused with a phosphate-free buffer at 10 cc/min per g and paced at 240 beats/min on a modified Langendorff apparatus. Perfusion pressure, left ventricular pressure (LVP) and dP/dt were recorded and successive 31P NMR spectra were collected during a 24-min baseline period (oxygenated buffer), anoxia (N2-bubbled and glucose-free buffer) until a 70% fall in LVP occurred, and recovery. An aminomethylphosphonate standard, located within the LVP balloon, permitted absolute quantification of myocardial phosphate moieties (including inorganic phosphate (Pi), creatine phosphate (CP) and ATP). During perfusion, SHR hearts demonstrated higher coronary resistance but no significant differences in LVP or dP/dt. Spontaneously hypertensive rat hearts had lower CP, ATP and CP/Pi ratio and showed a faster fall in cardiac function during anoxia, associated with parallel rates of changes in the phosphate moieties.

Topics: Animals; Energy Metabolism; Heart; Hypertension; Hypoxia; Magnetic Resonance Spectroscopy; Male; Phosphates; Phosphocreatine; Phosphorus; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Arterial tissue has been analysed by 31P-, 13C-, 23Na- and 1H-NMR spectroscopy. Rabbit thoracic aortas were mounted on a system with perfusate circulation and studied in basal conditions. Phosphorus spectra remained stable for hours and showed low levels of phosphocreatine (PCr) compared to skeletal, cardiac or even to nonvascular smooth muscle. Significant levels of sugar-phosphates (SP), phosphodiesters (PDE) were detected, as well as occasionnally a peak in the diphosphodiester region. Experiments with phosphate-free perfusate demonstrated a very low level of intracellular inorganic phosphate. As expected from previous data, free ADP levels in tonic arterial tissue were found much higher than in any other muscle. Addition of norepinephrine into the perfusate induced transient decrease in ATP and PCr levels, associated with an increased production of phosphorylated intermediates. At the early stage of renovascular hypertension, aortic energetic pattern was characterized by an increased ADP/ATP ratio. Natural abundant 13C spectra were recorded from dog aortic fragments and showed mainly resonances attributed to fatty components. After addition of a shift-reagent, dysprosium tripolyphosphate, 23Na-NMR allowed separation of intra- and extracellular Na of perfused rabbits aortas. Proton NMR of lyophilized aortic fragments revealed several peaks originating from biologically relevant molecules, lactate, creatine, taurine... These preliminary data demonstrate the feasability of multinuclear NMR spectroscopy of vascular tissue and are suggestive of the potential of the method when it will be combined with monitoring of functional parameters.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Aorta, Thoracic; Dogs; Dysprosium; Hypertension; In Vitro Techniques; Magnetic Resonance Spectroscopy; Myocardium; Norepinephrine; Phosphates; Phosphocreatine; Rabbits; Rats; Sugar Phosphates

The purpose of this study was to determine whether repeated exposure to high sustained +Gz (HS + Gz) stress induced persistent changes in the functional state of the cardiovascular system. Three groups of rabbits--centrifuged, restrained, and control--were studied. After being placed in the restraining system of the centrifuge, the animals were submitted three times in a row to 8-9 +Gz sustained for 40 s. This exposure was repeated three times a week for 3-6 weeks. Restrained animals were not exposed to HS + Gz. Control animals were not restrained. The two types of stress (centrifuge + restraint; restraint alone) determined the appearance of two types of arterial hypertension. Systolic arterial pressure (AP) and left ventricular pressure (LVP) significantly increased in restrained animals. The function of the cardiovascular system was more perturbed in centrifuged rabbits since the significant changes affected not only systolic AP and LVP but alos systemic diastolic AP and the maximum rate of rise of LVP. The myocardium of rabbits repeatedly subjected to HS + Gz exposures, except for those that suffered a fracture of the lumbar spine, was significantly glycogen-depleted.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Aerospace Medicine; Animals; Blood Pressure; Glycogen; Gravitation; Heart Rate; Hypertension; Male; Myocardial Contraction; Myocardium; Phosphocreatine; Rabbits

Muscle biopsies from the vastus muscle were taken at rest and immediately after upright bicycle exercise at 50% of the individual VO2max, before and during 6 wk of alprenolol treatment (200 to 400 mg twice daily) in 6 untrained patients with essential hypertension. Resting muscle concentrations (mmole - kg-1 - wet weight) of glycogen, glucose, lactate, and high-energy phosphates [adenosine triphosphate (ATP) and creatine phosphate (CP)] were not affected by alprenolol treatment, but after 10 min after exercise the glycogenolysis increased and depletion of ATP and CP was enhanced. The relationship between blood and muscle lactate was altered by alprenolol, indicating that alprenolol prevents lactate translocation from the muscle to the blood. The results show that during moderate exercise, leg muscle metabolism is influenced by long-term antihypertensive therapy.

Topics: Adenosine Triphosphate; Adult; Alprenolol; Blood Pressure; Glucose; Glycogen; Heart Rate; Humans; Hypertension; Lactates; Male; Muscles; Phosphocreatine; Physical Exertion

Using experimental models of various disease states, the ability of the isolated perfused working rat heart to withstand and recover from a period of severe ischemia was investigated. The results revealed that the coexistence of a diabetic state, obesity, or left ventricular hypertrophy increased the susceptibility of the hearts to ischemic damage and reduced the rate or the extent of postischemic recovery. In contrast, hearts obtained from moderately hypertensive rats exhibited a greater resistance to, and a superior recovery from, ischemia than did hearts obtained from normotensive controls.

Topics: Adenosine Triphosphate; Animals; Cardiac Output; Cardiomegaly; Coronary Circulation; Coronary Disease; Diabetes Mellitus, Experimental; Disease Models, Animal; Electrolytes; Heart Arrest, Induced; Hypertension; Male; Myocardial Contraction; Myocardium; Obesity; Phosphocreatine; Procaine; Rats; Triglycerides

Topics: Adenosine Triphosphate; Adrenalectomy; Animals; Bradycardia; Catecholamines; Epinephrine; Glycogen; Hypertension; Hypoxia; Lactates; Methods; Myocardium; Nitrogen; Phosphocreatine; Rabbits; Statistics as Topic; Sympatholytics