Response of isolated perfused heart to ischemia after long-term treatment of spontaneously hypertensive rats with diltiazem

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.     

Cardiac Mechanical Dysfunction Induced by Ischemia‐reperfusion in Perfused Heart Isolated from Stroke‐prone Spontaneously Hypertensive Rats

We investigated the difference in mechanical function after ischemia and reperfusion between Wistar‐Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) or stroke‐prone SHR (SHRSP) using the isolated working heart model, in order to examine postischemic mechanical dysfunction in the severely hypertrophied heart. Systolic blood pressure of SHRSP was higher than that of SHR and WKY, and the left ventricular wall in SHRSP was thicker than in WKY. Mechanical dysfunction of the heart during reperfusion following ischemia (11 min) in SHRSP was severer than that in SHR and WKY, and recovery of the cardiac energy charge potential (ECP) level in SHRSP was lower than that in SHR and WKY. Twenty‐five, 12 and 11 min‐ischemia in WKY, SHR and SHRSP, respectively, caused a similar level of cardiac mechanical damage. Also, the ECP levels were almost equivalent among them at the end of 20 min reperfusion following each time of ischemia. Under each ischemic condition, a Ca^{2 +}‐channel blocker, diltiazem, and an adenosine potentiator, dilazep, produced a beneficial effect on the post‐ischemic dysfunction in SHR and WKY. However, neither cardioprotective drug led to recovery of the mechanical dysfunction of the heart during reperfusion following ischemia in SHRSP. Thus, the severely hypertrophied heart such as that in SHRSP was more susceptible to cardiac reperfusion dysfunction, than the moderately hypertrophied heart such as that in SHR. These results suggest that the cardioprotective effects of drugs may be deteriorated in severe hypertrophied hearts.     

Cardiac mechanical dysfunction induced by ischemia-reperfusion in perfused heart isolated from stroke-prone spontaneously hypertensive rats

We investigated the difference in mechanical function after ischemia and reperfusion between Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) or stroke-prone SHR (SHRSP) using the isolated working heart model, in order to examine postischemic mechanical dysfunction in the severely hypertrophied heart. Systolic blood pressure of SHRSP was higher than that of SHR and WKY, and the left ventricular wall in SHRSP was thicker than in WKY. Mechanical dysfunction of the heart during reperfusion following ischemia (11 min) in SHRSP was severer than that in SHR and WKY, and recovery of the cardiac energy charge potential (ECP) level in SHRSP was lower than that in SHR and WKY. Twenty-five, 12 and 11 min-ischemia in WKY, SHR and SHRSP, respectively, caused a similar level of cardiac mechanical damage. Also, the ECP levels were almost equivalent among them at the end of 20 min reperfusion following each time of ischemia. Under each ischemic condition, a Ca2+-channel blocker, diltiazem, and an adenosine potentiator, dilazep, produced a beneficial effect on the post-ischemic dysfunction in SHR and WKY. However, neither cardioprotective drug led to recovery of the mechanical dysfunction of the heart during reperfusion following ischemia in SHRSP. Thus, the severely hypertrophied heart such as that in SHRSP was more susceptible to cardiac reperfusion dysfunction, than the moderately hypertrophied heart such as that in SHR. These results suggest that the cardioprotective effects of drugs may be deteriorated in severe hypertrophied hearts.     

Functional and metabolic properties in hearts from aged spontaneously hypertensive rats

The effect of long-term pressure overload on myocardial functional and metabolic alterations was investigated in hearts from spontaneously hypertensive rats of 16 weeks (young SHR) and 44 weeks (aged SHR) and age matched normotensive Wistar Kyoto strain rats (young WKY, aged WKY). The hearts were perfused by working heart mode and whole heart ischemia was induced by one-way valve. Following 20 min of ischemia, the hearts were reperfused for 30 min. The heart-body weight ratio in both SHR groups was significantly higher than in the respective age-matched WKY groups. Coronary flow relative to heart weight in both SHR groups was significantly lower than that of the respective age-matched WKY during both preischemic and reperfused periods. There was no significant difference in the recovery rate of cardiac output between young and aged WKY, whereas the young and aged SHR revealed significantly less recovery than their respective age-matched WKY. Tissue creatine phosphate and energy charge in both aged groups were significantly lower than in the young groups. These results indicate that long-term pressure overload increases susceptibility to ischemia and decreases the myocardial reserve presumably resulting from relative ischemia, whereas deterioration was minimal in the normotensive aged rat heart.     

Functional and metabolic responses to ischemia in the perfused heart isolated from normotensive and spontaneously hypertensive rats

The difference between normotensive rats (WKY) and spontaneously hypertensive rats (SHR) in functional and metabolic responses to ischemia was studied. Systolic arterial blood pressure of SHR (171.2 +/- 2.9 mmHg) was significantly higher than that of WKY (135.3 +/- 1.2 mmHg), and the left ventricular mass of SHR was larger than that of WKY. Hearts isolated from either WKY or SHR were perfused by the working heart technique. Ischemia was induced by lowering the afterload pressure of the working heart. Ischemia produced cardiac arrest, and decreased the tissue levels of adenosine triphosphate and creatine phosphate in both WKY and SHR. Recovery of mechanical function of the heart during reperfusion following ischemia in SHR was better than that in WKY, while recovery of the high-energy phosphates level in SHR was less prominent than in WKY. It is postulated that hypertension has a deleterious effect on myocardial energy metabolism in ischemic heart, even when cardiac mechanical function is maintained.     

Effect of Nicorandil on Cardiac Dysfunction During Reperfusion in Normotensive and Spontaneously Hypertensive Rats

The cardioprotective effect of nicorandil, an opener of ATP-sensitive potassium channels, was studied in the isolated perfused hearts of the spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto (WKY) rat. The hearts were subjected to 30 min of global ischemia followed by 30 min of reperfusion. Controls received no drug. In the nicorandil group, the hearts were treated with 0.03 to 0.3 mmol/L nicorandil for 15 min before ischemia. Left ventricular developed pressure (LVDP and end diastolic pressure (LVEDP) at 30 min of reperfusion were significantly lower and larger, respectively, in SHR than in WKY rats. Nicorandil improved LVDP and decreased LVEDP at 30 min of reperfusion in both SHR and WKY rats dose-dependently. The hypertensive heart in the early stage is already susceptible to reperfusion-cardiac dysfunction. Nicorandil has a beneficial effect on the post-ischemic dysfunction in both SHR and WKY rats.     

Effect of celiprolol on cardiac hypertrophy in hypertension.

The present study was undertaken to clarify whether celiprolol and atenolol, beta1-selective beta blockers with and without intrinsic sympathomimetic activity (ISA), respectively, might improve ischemic damage in the isolated perfused hearts of spontaneously hypertensive rats (SHR), and whether long-term treatment with celiprolol may reduce left ventricular hypertrophy (LVH) in patients with essential hypertension. Atenolol (50 mg/kg/day) or celiprolol (300 mg/kg/day) for 7 weeks significantly reduced the blood pressure in SHR to the same degree, and both drugs decreased the heart rate, but the magnitude of the fall in heart rate was significantly higher with atenolol treatment than with celiprolol treatment. Both treatments significantly reduced the ratio of LV weight to body weight in SHR and significantly improved the coronary reserve in SHR to the same extent. Both treatments significantly improved the extent of recovery of the pressure-rate product and the extent of percent recovery of the coronary flow after reperfusion following 30 min of ischemia in SHR. Celiprolol treatment in patients with essential hypertension for 12 months significantly decreased interventricular septal thickness (IVST)+LV posterior wall thickness (PWT) and LV mass index (LVMI), but there was no significant correlation between IVST+PWT or LVMI and blood pressure before and after treatment. IVST+PWT and LVMI were significantly decreased after 3 months of treatment and these LVH indices were significantly smaller after 6 and 12 months of treatment than after 3 months of treatment. In conclusion, both celiprolol and atenolol treatment reduced LVH and improved the ischemic damage in SHR. In essential hypertensive patients with LVH, celiprolol treatment effectively reduced blood pressure and achieved LVH regression.     

Functional and metabolic responses to ischemia in the isolated perfused hypothyroid rat heart.

It has been demonstrated that the V3 cardiac myosin isozyme has a higher efficiency and consumes less oxygen in doing mechanical work than the V1 myosin isozyme. The purpose of the present study is to investigate the functional and metabolic responses to ischemia following reperfusion of the hypothyroid heart, in which ventricular myosin isozyme is shifted from V1 predominance to V3 predominance. The heart was perfused by the working heart method for 15 min, and then global ischemia was induced for 10, 20 and 30 min with pacing at a rate of 320/min until cardiac cessation. The ischemic heart was reperfused for 30 min. The extent of recovery of pressure-rate product after reperfusion, following 20 min of ischemia in the hypothyroid heart, was higher than that in the control heart (p less than 0.01). The level of adenosine triphosphate (ATP) declined more slowly in the hypothyroid heart than in the control heart. The level of ATP and energy charge potential in the hypothyroid heart reperfused after 20 min of ischemia were higher than those in the reperfused control heart (p less than 0.01, p less than 0.05, respectively), though they did not differ from each other in preischemia. There were no significant differences in the levels of tissue lactate between the 2 hearts during ischemia and reperfusion. The recovery rate of the coronary flow of the 2 hearts did not differ from each other significantly. These data suggest that there is probability of the V3 predominant heart recovering from ischemic damage to the metabolism and cardiac function better than the V1 predominant heart because the transformation of myocardium, due to an increase in V3 into a slower but more efficiently working muscle results in conservation of tissue ATP during ischemia.     

Effects of a protocol of ischemic postconditioning and/or captopril in hearts of normotensive and hypertensive rats

Brief periods (a few seconds) of cyclic coronary occlusions applied early in reperfusion induce a cardioprotection against infarct size, called postconditioning (PostC) in which B₂-bradykinin receptors play a pivotal role. Since angiotensin-converting enzyme (ACE) inhibitors reduce degradation of kinins, we studied the effects of PostC on infarct size and postischemic myocardial dysfunction in both normotensive (WKY) and spontaneously hypertensive rats (SHR) acutely or chronically treated with the ACE inhibitor Captopril. Isolated hearts from SHR and WKY rats were subjected to the following protocols: (a) ischemia for 30- and 120-min reperfusion (I/R); (b) I/R + PostC protocol (5-cycles 10-s I/R); (c) pretreatment with Captopril for 4-weeks before to subject the hearts to I/R with or without PostC maneuvers. Some SHR hearts were treated with Captopril during the 20- or 40-min early reperfusion with or without PostC maneuvers. Cardiac function was assessed in vivo with echocardiography. Left ventricular pressure and infarct size were measured ex vivo. Chronic Captopril significantly reduced left ventricular hypertrophy in SHR, and reduced infarct size in both WKY and SHR hearts. PostC maneuvers significantly reduced infarct size in WKY, but not in SHR hearts. Yet, PostC slightly improved postischemic systolic function in untreated SHR. Captopril given in reperfusion was unable to limit I/R injury in SHR hearts. Data show that PostC protection against infarct size is blunted in SHR and that PostC is unable to add its protective effect to those of chronic Captopril, which per se reduces cardiac hypertrophy and heart susceptibility to I/R insult.     

Influence of 2,3-butanedione monoxime on heart energy metabolism

Summary The influence of 2,3-butanedione monoxime (BDM) on function and subcellular energy status in isolated perfused guinea pig hearts was examined during ischemia and reperfusion. For this purpose the mitochondrial and extramitochondrial contents of ATP, ADP, creatine phosphate (CrP) and creatine (Cr) were determined after fractionation of freeze-clamped heart tissue in non-aqueous solvents. Furthermore, the inhibitory action of this compound on isolated cardiac mitochondria and the actomyosin-ATPase was studied.BDM in the millimolar range inhibited both the actomyosin-ATPase in skinned-fibers (IC₅₀ 22 mM) and the electron transport chain in isolated mitochondria (IC₅₀ 28 mM).In normoxia at 35°C the contractile function of isolated guinea pig hearts was completely inhibited and oxygen consumption was markedly reduced (–60%) by 30 mM BDM. The mitochondrial and extramitochondrial contents of adenine nucleotides (sum of ATP+ADP) and total creatine (sum of CrP+Cr) as well as the extramitochondrial ATP/ADP- and CrP/Cr-ratios were decreased. Similar changes, significantly more pronounced, however, were found after 30 min of warm (35°C) ischemia.However, if hearts were exposed to BDM during cold ischemia, extramitochondrial ATP/ADP- and CrP/Cr-ratios were increased compared to BDM-free controls.If hearts were exposed to BDM during ischemia (at 35°C) and were then reperfused BDM-free, ATP/ADP- and CrP/Cr-ratios were decreased. However, if hearts were exposed to BDM during cold ischemia and were then reperfused BDM-free, extramitochondrial ATP/ADP- and CrP/Cr-ratios were unchanged.These results confirm earlier studies on the tissue protective action of BDM but point to the importance of low temperature exposure to BDM for its beneficial effect.     

A low concentration of nisoldipine reduces ischemic heart injury: enhanced reflow and recovery of contractile function without energy preservation during ischemia

Isolated working rat hearts which received no drug treatment had reduced ATP and creatine phosphate levels and increased lactate content during 20 min of ischemia. When subjected to 33 min of ischemia and 30 min of reperfusion, these hearts recovered low values of cardiac output (9.8 ml/min), heart rate, maximum developed pressure, pressure-rate product (72.9, 32.6, 27.5% of control, respectively), had low levels of tissue ATP, and reduced coronary flow upon reperfusion. Addition of nisoldipine (1 nM) 10 min before ischemia caused no decrease in cardiac output or heart rate, slightly decreased maximum developed pressure and pressure-rate product (93% of control), and did not reduce the degradation of ATP and creatine phosphate or the accumulation of lactate during 20 min of ischemia. When nisoldipine was included 10 min before ischemia, during ischemia (33 min) and reperfusion (30 min), however, the recovery of cardiac function and tissue ATP levels was significantly increased. This protective effect occurred when drug treated ischemic hearts were reperfused with control buffer, indicating residual effects. The beneficial effects of nisoldipine were not due to changes in afterload or preload (isolated perfused heart), collateral flow (zero flow model), energy preservation during ischemia (little contractile depression, ATP not enhanced during ischemia), or reduced lactate accumulation during ischemia. The beneficial effects were associated with increased coronary flow (31% higher than no drug) during reperfusion, indicating a reduction in the no-reflow phenomenon.     

Myocardial stretch induced by increased left ventricular diastolic pressure preconditions isolated perfused hearts of normotensive and spontaneously hypertensive rats

Objective: The aim of our study was to determine whether myocardial stretch (non-ischemic stress) could precondition isolated perfused hearts of both normotensive Wister-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR).Methods: The perfused hearts in Langendorff mode were subjected to 30 min of global no-flow ischemia followed by 30 min of reperfusion. Left ventricular developed pressure (LVDP) and end-diastolic pressure (LVEDP) were measured. In the control group, LVEDP was set at 10 mmHg. In the stretch group, LVEDP was increased to 30 or 60 mmHg for 5 min before 30 min of ischemia. In the ischemic preconditioning group, the hearts were exposed to two cycles of a 5-min period of ischemia before 30 min of ischemia. Myocardial lactate contents were measured at the baseline and at the end of the 60 mmHg stretch.Results: Hemodynamic parameters of LVDP and LVEDP at 30 min of reperfusion improved in the stretch group (LVEDP at 60 mmHg) and the ischemic preconditioning group. Coronary flow did not decrease during the stretch. Recovery of the coronary flow during reperfusion was better in the stretch and ischemic preconditioning groups. Postischemic contractile function was better in WKY rats than in SHR. Myocardial lactate contents at the end of 60 mmHg stretch were negligible. Conclusions: Myocardial stretch induced by increasing LVEDP preconditioned isolated perfused hearts of both WKY rats and SHR, via mechanisms not involving myocardial ischemia during stretch.     

Smoking accelerates the progression of hypertension-induced myocardial hypertrophy to heart failure in spontaneously hypertensive rats

OBJECTIVE: Myocardial hypertrophy often develops in response to hypertension, and it is causal to and an independent predictor of heart failure. Several risk factors modify the progression of hypertrophy, the associated progressive impairment of myocardial function, and eventually the transition to overt congestive heart failure. The aim of the present study was to investigate the effects of smoking on the progression of pressure-dependent myocardial hypertrophy. METHODS: Spontaneously hypertensive rats (SHR) were used as a model for pressure-dependent hypertrophy. SHR were exposed to mainstream smoke from the Kentucky reference cigarette 2R4F (450 microg total particulate matter/l) or to fresh air (control), 5 days a week, twice for 1 h per day with a 30-minute fresh air exposure break for 30, 60, or 90 days. Endpoints for hypertrophy-associated changes were heart weight to body weight ratio, ventricular expression of hypertrophy-associated genes, ischemic tolerance, and inotropic responsiveness to isoprenaline in post-ischemic hearts. RESULTS: Smoke-exposed SHR showed a significant elevation in heart weight to body weight ratio, increased mRNA expression of atrial natriuretic factor (ANF), transforming growth factor (TGF)-beta(1), ornithine decarboxylase (ODC), and parathyroid hormone-related protein in both ventricles compared to controls. Hearts from smoke-exposed SHR showed a reduced recovery after 30 min global ischemia during the first 5 min of reperfusion and loss of inotropic stimulation after 30 min reperfusion. Smoke cessation was sufficient to reverse most of these alterations. WKY exposed to smoke did not develop similar changes. CONCLUSION: Our data indicate that several aspects of myocardial hypertrophy are accelerated by smoking.     

Increase in G(i alpha) protein accompanies progression of post-infarction remodeling in hypertensive cardiomyopathy

Hypertensive cardiac hypertrophy and myocardial infarction (MI) are clinically relevant risk factors for heart failure. There is no specific information addressing signaling alterations in the sequence of hypertrophy and post-MI remodeling. To investigate alterations in beta-adrenergic receptor G-protein signaling in ventricular remodeling with pre-existing hypertrophy, MI was induced by coronary artery ligation in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Ten weeks after the induction of MI, the progression of left ventricular dysfunction and increases in plasma atrial natriuretic peptide (ANP) and cardiac ANP mRNA were more pronounced in SHR than WKY. In addition, the impaired contractile response to beta-adrenergic stimulation was observed in the noninfarcted papillary muscle isolated from SHR. Immunochemical G(s alpha) protein and beta-adrenoceptor density were not significantly altered by MI in both strains. However, immunochemical G(i alpha) was increased (1.5-fold) in the noninfarcted left ventricle of the SHR in which infarction had been induced when compared with that in SHR that underwent sham operation. This increase was observed especially in rats with a high plasma ANP level. Furthermore, there was a positive correlation between G(i alpha) and the extent of post-MI remodeling in WKY. A similar correlation between G(i alpha) and the extent of hypertensive hypertrophy was observed in SHR. In conclusion, the vulnerability of hypertrophied hearts to ischemic damage is greater than that of normotensive hearts. An increase in G(i alpha) could be one mechanism involved in the transition from cardiac hypertrophy to cardiac failure when chronic pressure overload and loss of contractile mass from ischemic heart disease coexist.     

Vascular remodeling and improvement of coronary reserve after hydralazine treatment in spontaneously hypertensive rats

The purpose of these studies was to evaluate cardiovascular structural and functional changes in a model of hypertension-induced myocardial hypertrophy in which vasodilator therapy decreased blood pressure to normal levels. Thus, we determined the separate contributions of hypertension and hypertrophy on myocardial and coronary vascular function and structure. Twelve-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with and without 12 weeks of vasodilator antihypertensive treatment (hydralazine) were studied using an isolated perfused rat heart model. Hydralazine treatment normalized blood pressure in SHR but did not cause regression of cardiac hypertrophy (heart weight to body weight ratio of SHR + hydralazine 4.33 +/- 0.098 vs. SHR 4.66 +/- 0.091; WKY 3.21 +/- 0.092 and WKY + hydralazine 3.38 +/- 0.152; mean +/- SEM). Coronary flow reserve, elicited by adenosine vasodilation in the perfused heart, was decreased in SHR (29%) compared with WKY (105%) and WKY + hydralazine (100%) and was significantly improved in SHR + hydralazine (75%). Morphometric evaluation of perfusion-fixed coronary arteries and arterioles (30-400 microns diameter) demonstrated a significant increase in the slope of the regression line comparing the square root of medial area versus outer diameter in SHR (0.444) compared with WKY (0.335) and WKY + hydralazine (0.336, p less than 0.05). Blood vessels from SHR + hydralazine were not different from control (0.338). Cardiac oxygen consumption was decreased in SHR (10.9 +/- 0.74 mumols oxygen/min/g/60 mm Hg left ventricular pressure) compared with WKY (22.4 +/- 1.47) and WKY + hydralazine (23.4 +/- 1.90; p less than 0.01), while SHR + hydralazine was intermediate (16.0 +/- 1.60). These studies suggest that significant alterations in myocardial and coronary vascular structure and function occur in hypertension-induced cardiac hypertrophy. The coronary vasculature is responsive to blood pressure, independent of cardiac hypertrophy, although moderate coronary deficits do remain after chronic antihypertensive therapy.     

Changes in myocardial nonesterified fatty acids during ischemia and reperfusion in isolated,perfused, working rat hearts

Summary The time course of changes in the myocardial levels of nonesterified fatty acids (NEFA), adenosine triphosphate (ATP), creatine phosphate (CrP) and lactate, and those in the cardiac mechanical function during ischemia and reperfusion was investigated in the isolated, perfused, working rat heart. Ischemia was produced by lowering the afterload pressure from 60 to 0 mm Hg, and reperfusion resulted from raising the afterload pressure to 60 mm Hg. Ischemia stopped the heart beat, and increased the myocardial levels of unsaturated NEFA (such as arachidonic, palmitoleic, and linoleic acids) as a function of the ischemic period; it decreased the myocardial levels of ATP and CrP, and increased the myocardial level of lactate. The level of arachidonic acid increased when the myocardial level of ATP fell below 5 µmol/g dry weight. Reperfusion after ischemia started the heart beat, and restored the mechanical function which depended on the preceding ischemic period. Reperfusion also increased the levels of ATP and CrP and decreased the level of lactate, whereas it further increased the levels of the NEFA that had been elevated by ischemia. The recovery of mechanical function was inversely correlated with the myocardial level of arachidonic acid during ischemia and reperfusion. We concluded that changes in the myocardial levels of NEFA during ischemia and reperfusion are different from those of ATP, CrP, and lactate, and suggest that the myocardial level of arachidonic acid during ischemia and reperfusion can be a sensitive and suitable marker for the recovery of mechanical function during reperfusion.     

Myocardial function in normal and spontaneously hypertensive rats during reperfusion after a period of global ischaemia

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.     

Ischemic preconditioning prevents reperfusion heart injury in cardiac hypertrophy by activation of mitochondrial KATP channels

BACKGROUND: Cardiac hypertrophy has been demonstrated to decreases the ATP-sensitive potassium channels (K(ATP)), the major protective mechanism following the energy depletion, a common condition seen during the reperfusion after open heart surgery. In this study we have demonstrated the role of ischemic preconditioning (IP) in preventing the reperfusion injury of the hypertrophied heart by activation of the depleted K(ATP) channels. METHODS: Pressure overload left ventricular hypertrophy was induced in 6 weeks old male Wistar rats by supra renal transverse abdominal aortic constriction and the study was conducted 10-12 weeks later. Hypertrophied rats were subjected to IP protocols by four episodes of 3 min ischemia each being separated by 10 min reperfusion, followed by 30 min of sustained ischemia and 120 min of reperfusion with or without treating the rats with K(ATP) channel antagonists 5-hydroxydecanoic acid (10 mg/kg per i.v.) or glibenclamide (1 mg/kg per i.v.), 10 min before the sustained ischemia. RESULTS: IP resulted in (a) less incidence of ventricular arrhythmias (b) less area of myocardial infarction (9.3% vs. 48.1%, IP to control) (c) less tissue water content (76.5% vs. 94.8%, IP to control) (d) well preserved myocardial ATP content (P<0.001 from control) content and (e) much fewer apoptotic cells (4.7% vs. 13.2%, IP to control). Pre treating the rats with the K(ATP) channel inhibitors before sustained ischemia resulted in inhibition of these protective effects of IP on cardiac hypertrophy. CONCLUSION: The above results, therefore, suggest to us that IP by activation of K(ATP) channels can afford protection against the ischemia-reperfusion injury in the hypertrophied heart.     

Age-related decline of PCr/ATP-ratio in progressively hypertrophied hearts of spontaneously hypertensive rats

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 30 min at baseline conditions (low afterload), followed by another 30 min 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. Received: September 18, 2000 / Accepted January 5, 2001     

Effects of human superoxide dismutase on ischemic and reperfused myocardium in isolated perfused rat heart

The effect of human superoxide dismutase (h-SOD) on the ischemic heart was studied in the isolated perfused working rat heart. Myocardial mechanical function expressed as pressure-rate product decreased and completely stopped within 5 min after the onset of global ischemia, and never recovered after reperfusion following 20 min of ischemia. In the ischemic myocardium, the levels of ATP, ADP, and creatine phosphate decreased, and those of AMP and lactate increased. Reperfusion of the ischemic heart did not restore the level of ATP completely. When the heart was treated with h-SOD, the perfusion medium was switched from the buffer containing no h-SOD to that containing h-SOD at either 100, 300 or 1,000 units/ml 5 min before the onset of ischemia. The pressure-rate products of the heart treated with 100, 300, and 1,000 units/ml of h-SOD were restored by reperfusion to 22%, 59%, and 51% of the preischemic level, respectively. The levels of ATP and creatine phosphate in the reperfused heart with 300 and 1,000 units/ml of h-SOD were significantly higher than those without h-SOD. However, a dose-response relationship was not observed when h-SOD was used in concentrations greater than 300 units/ml. These results indicate that a certain amount of h-SOD has some beneficial effects on the ischemic myocardium.