The effect of K(atp)channel activation on myocardial cationic and energetic status during ischemia and reperfusion: role in cardioprotection.

The role of cation and cellular energy homeostasis in ATP-sensitive K(+)(K(ATP)) channel-induced cardioprotection is poorly understood. To evaluate this, rapidly interleaved(23)Na and(31)P NMR spectra were acquired from isolated rat hearts exposed to direct K(ATP)channel activation from nicorandil or pinacidil. Nicorandil attenuated ATP depletion and intracellular Na(+)(Na(+)(i)) accumulation, delayed the progression of acidosis during zero-flow ischemia and prevented ischemic contracture. The K(ATP)channel inhibitor 5-hydroxydecanoate abolished these effects. Pinacidil did not alter Na(+)(i)accumulation, ATP depletion or pH during ischemia under the conditions employed. Both agonists greatly improved the post-ischemic functional recovery. Both agonists also dramatically improved the rate and extent of the reperfusion recoveries of Na(+)(i), PCr and ATP. The Na(+)(i)and PCr reperfusion recovery rates were tightly correlated, suggesting a causal relationship. Separate atomic absorption tissue Ca(2+)measurements revealed a marked reperfusion Ca(2+)uptake, which was reduced two-fold by pinacidil. In conclusion, these results clearly indicate that while K(ATP)channel-induced metabolic alterations can vary, the functional cardioprotection resulting from this form of pharmacological preconditioning does not require attenuation of acidosis, cellular energy depletion, or Na(+)(i)accumulation during ischemia. Rather than preservation of cationic/energetic status during ischemia, the cardioprotective processes may involve a preserved capability for its rapid restoration during reperfusion. The enhanced reperfusion Na(+)(i)recovery may be enabled by the improved reperfusion cellular energy state. This accelerated Na(+)(i)recovery could play an important cardioprotective role via a potential causal relationship with the reduction of reperfusion tissue Ca(2+)uptake and resultant reperfusion injury.

Controlled postcardioplegia reperfusion: mechanism for attenuation of reperfusion injury.

OBJECTIVE: Controlled reperfusion and secondary cardioplegia are used to minimize reperfusion injury. The mechanisms for their benefit are incompletely defined and may include attenuation of myocyte sodium uptake. METHODS: Pigs had 1 hour of cardioplegic arrest followed by reperfusion with blood (control) or warm cardioplegic solution followed by blood (test). Reperfusion injury in the control and test groups was quantified by measuring changes of intramyocyte ion content with atomic absorption spectrometry and by analyzing electrophysiologic recovery from recordings of reperfusion arrhythmias. RESULTS: Control animals had an increase in intramyocyte sodium content at 5 minutes after initiating reperfusion (+20.2 micromol/g dry weight, P <.04), whereas the test group had an insignificant decrease (-14.0 micromol/g dry weight, P =.33). The first rhythm after initiating reperfusion was more often ventricular fibrillation in the control group (100% vs 50%, P <.02), and the control group required more defibrillations to establish a nonfibrillating rhythm (4.5 +/- 1.2 vs 1.1 +/- 0.3, P <.03). CONCLUSIONS: Controlled reperfusion eliminated the increase in intramyocyte sodium that was observed in the control group at 5 minutes after cardioplegic arrest. This improvement in myocyte ion homeostasis during postcardioplegia reperfusion was associated with fewer reperfusion arrhythmias. These data support the hypothesis that attenuation of myocyte sodium gain during postischemic reperfusion is a mechanism by which controlled reperfusion and secondary cardioplegia are beneficial.

Novel methods to evaluate controlled reperfusion techniques in cardiac surgery.

BACKGROUND: This manuscript describes two novel techniques that may be useful for comparing methods to reperfuse the heart during cardiac operations. These techniques are based on measurements of intra-myocyte ion content and the analysis of reperfusion arrhythmias. METHODS: Myocyte ion content was measured in normal porcine hearts before and after ischemia (cardioplegic arrest, CP arrest) using atomic absorption spectroscopy. A cobalt-EDTA complex served as the extra-cellular marker. Cobalt-EDTA was infused into the aorta together with blood or cardioplegia (CP) solution. Myocardial biopsies were taken prior to CP arrest and upon successful defibrillation 5 min after initiating reperfusion. Ventricular fibrillation (VF) was recorded prior to ischemia, and then during reperfusion. VF wavefront (WF) morphology and propagation patterns were analyzed using computer algorithms. Electrophysiologic variables for measuring VF included the multiplicity index (a descriptor of VF organization), the number of WFs detected (nwaves/s) and the mean peak first derivative of electrogram voltage with respect to time (mp d V/dt). RESULTS: Intra-cellular sodium content increased, while intra-cellular magnesium content decreased between control and reperfusion measurements (p < 0.05). Electrophysiologic recovery was characterized by increasingly rapid depolarization (i.e. more negative mp d V/dt) and an increasing nwaves/s during the first minute of post-CP reperfusion. CONCLUSIONS: Atomic absorption spectroscopy and computer-based analysis of reperfusion VF successfully measured metabolic and electrophysiologic events that occurred during controlled reperfusion. These methods may be useful for comparing controlled reperfusion techniques.

The Arthus reaction in rodents: species-specific requirement of complement.

We induced reverse passive Arthus (RPA) reactions in the skin of rodents and found that the contribution of complement to immune complex-mediated inflammation is species specific. Complement was found to be necessary in rats and guinea pigs but not in C57BL/6J mice. In rats, within 4 h after initiation of an RPA reaction, serum alternative pathway hemolytic titers decreased significantly below basal levels, whereas classical pathway titers were unchanged. Thus the dermal reaction proceeds coincident with systemic activation of complement. The serine protease inhibitor BCX 1470, which blocks the esterolytic and hemolytic activities of the complement enzymes Cls and factor D in vitro, also blocked development of RPA-induced edema in the rat. These data support the proposal that complement-mediated processes are of major importance in the Arthus reaction in rats and guinea pigs, and suggest that BCX 1470 will be useful as an anti-inflammatory agent in diseases where complement activation is known to be detrimental.

23Na NMR shift reagents enhance cardiac staircase effect in isolated perfused rat hearts.

The effects of the currently used (23)Na NMR shift reagents, dysprosium bis-triphosphate [Dy(PPP)(2)], dysprosium triethylenetriamine hexaacetate [Dy(TTHA)] and thulium 1,4,7, 10-tetraazacyclododecane-N,N',N",N"'-tetra(methylenephosphonate) [Tm(DOTP)] were studied in the rat heart cardiac staircase model. Rat hearts were perfused with low or normal extracellular free calcium ([Ca(o)](f)). At low [Ca(o)](f) (0.34 +/- 0.05 mM), hearts were perfused with Dy(PPP)(2) (group I), Dy(TTHA) (group II) or no shift reagent (group III), while at normal [Ca(o)](f) (1.25 +/- 0.15 mM), hearts were perfused with Tm(DOTP) (group IV), Dy(TTHA) (group V) or no shift reagent (group VI). Left ventricular developed pressure (LVDP) values in group I were significantly higher than in groups II and III (p < 0.01), while no significant differences were found between groups II and III. LVDP values in group IV were significantly higher than in groups V and VI (p < 0.05), while the LVDP values in groups V and VI were almost identical. Also, a positive correlation between pacing rate and intracellular sodium ([Na(i)]) was evident. The [Na(i)] values at high [Ca(o)](f) were significantly lower than at low [Ca(o)](f) at each pacing level (p <0.01), indicating a negative correlation between [Na(i)] and [Ca(o)](f). No statistical differences were found in [Na(i)] between groups I vs II and IV vs V, showing that determination of [Na(i)] is not affected by any of these shift reagents. Thus the different LVDP responses in groups I vs II and IV vs V were not mirrored in [Na(i)] changes. We hypothesize that a direct, sarcolemmal Ca-Dy(PPP)(2)-, or Ca-Tm(DOTP)-induced positive inotropic effect could be responsible for these Na(i)-independent LVDP increases in groups I and IV.

Peroxynitrite irreversibly decreases diastolic and systolic function in cardiac muscle.

Much of the damaging action of nitric oxide in heart may be due to its diffusion-limited reaction with superoxide to form peroxynitrite. Direct infusion of peroxynitrite into isolated perfused hearts fails to model the effects of in situ formation because the bulk of peroxynitrite decomposes before reaching the myocytes. To examine the direct effects of peroxynitrite on the contractile apparatus of the heart, we exposed intact and skinned rat papillary muscles to a steady state concentration of 4-microM peroxynitrite for 5 min, followed by a 30-min recovery period to monitor irreversible effects. In intact muscles developed force fell immediately to 26% of initial force, recovering to 43% by 30 min. Resting tension increased by 600% immediately, and was still elevated 500% by 30 min. Nitrotyrosine immunochemistry showed that peroxynitrite can induce tyrosine nitration at low concentrations and is capable of penetrating 200-380 microm into the papillary muscle after a 5-min infusion. Decomposed peroxynitrite had no effect on either intact or skinned muscle developed force or resting tension. Our results show that peroxynitrite directly damages both developed force and resting tension of isolated heart muscle, which can be extrapolated to systolic and diastolic injury in intact hearts.

MDL-28170, a membrane-permeant calpain inhibitor, attenuates stunning and PKC epsilon proteolysis in reperfused ferret hearts.

OBJECTIVES: This paper tests the hypothesis that calpains are activated in the ischemic (I)/reperfused (R) heart and contribute to myocardial stunning. METHODS: Isolated ferret hearts were Langendorff perfused isovolumically, and subjected to 20 min of global I followed by 30 min of R in the presence or absence of 0.2 microM MDL-28170, a membrane-permeant calpain inhibitor. Right trabeculae then were isolated from these hearts, skinned chemically, and pCa(2+)-force curves obtained. Samples of left ventricle were extracted subjected to SDS-PAGE, and Western analyzed for PKC epsilon and PKM epsilon. RESULTS: Perfused ferret hearts exhibit a 43% decline in left ventricular developed pressure during R. Pre-treatment of hearts with MDL-28170 prior to I significantly improves function during R. Trabecular myofilaments from normal hearts have a KD for Ca2+ of 6.27 +/- 0.06; I/R decreased the KD to 6.09 +/- 0.04; trabeculae from I/R hearts pre-treated with MDL-28170 have a KD of 6.28 +/- 0.04. Western analysis shows ferret hearts to contain a single approximately equal to 96 kDa species of PKC epsilon. I/R hearts contain the native PKC epsilon and a approximately equal to 25 kDa smaller species of PKC epsilon which corresponds to PKM epsilon, the calpain proteolyzed form of PKC epsilon. Pre-treatment of I/R hearts with MDL-28170 markedly diminishes PKM epsilon in reperfused hearts. CONCLUSIONS: Mechanical stunning during R is sensitive to MDL-28170. Depressed mechanical function is reflected in a hyposensitization of trabecular myofilaments to Ca2+. Western analysis shows that PKM epsilon is present in R hearts.

Effect of hemoglobin concentration on oxyhemoglobin dissociation during hypothermic blood cardioplegic arrest.

BACKGROUND: This study compares oxyhemoglobin dissociation during the nonperfused periods of hypothermic cardioplegic arrest in two blood cardioplegic solutions with different hemoglobin concentrations. The hypothesis is that more oxygen will dissociate from hemoglobin in a blood cardioplegic solution with a higher hemoglobin content than from a cardioplegic solution with a lower hemoglobin content. However, the increment in the volume of oxygen that dissociates from hemoglobin will be less than anticipated by a ratio of hemoglobin concentrations in the cardioplegic solution. METHODS AND RESULTS: Pigs (n = 22) were supported by bypass and subjected to 60 minutes of hypothermic cardioplegic arrest with either a high-hemoglobin (n = 10) or low-hemoglobin (n = 12) blood cardioplegic solution. Aortic root and coronary sinus blood samples were obtained before bypass and 5 seconds after the start of cardioplegic infusions at 20, 40, and 60 minutes of cardioplegic arrest. Oxyhemoglobin dissociation occurred in both experimental groups during the ischemic intervals of cardioplegic arrest. However, there were no significant differences between the high- and low-hemoglobin groups in the arterial-venous oxygen content differences for samples taken after each of the three ischemic intervals (p values: control = 0.78; cardioplegia interval 1 = 0.95; interval 2 = 0.56; and interval 3 = 0.12). CONCLUSIONS: The present study emphasizes the inherent limitations of unmodified erythrocyte hemoglobin as an oxygen source in hypothermic alkalotic cardioplegic solutions. These limitations may be obviated by methods that increase the dissolved oxygen content of the cardioplegic solution or methods that decrease the affinity of hemoglobin for oxygen under conditions of hypothermia and alkalosis.

Effect of postcardioplegia reperfusion rhythm on myocardial blood flow.

This study compared myocardial blood flow during postcardioplegia reperfusion asystole and ventricular fibrillation. Pigs (n = 20) were placed on cardiopulmonary bypass and blood cardioplegic solution at 38 degrees C was then infused. A preischemia microsphere injection was given in asystolic hearts. All animals then had 1 hour of hypothermic cardioplegic arrest and underwent reperfusion with high-dose (n = 10) or low-dose (n = 10) 38 degrees C blood cardioplegia. At 30 seconds after reperfusion, all hearts were asystolic. The second microsphere injection was then given. At 3 and 6 minutes after reperfusion, the animals' hearts were either in asystole (n = 10) or ventricular fibrillation (n = 10), and the third and fourth microsphere injections were then given. At 10 minutes after reperfusion, all hearts were beating and the final (fifth) microsphere injection was given. There was an initial increase in the global myocardial blood flow during reperfusion versus the preischemic control value. However, later, during reperfusion (ie, at the third and fourth injections), there was a significant (p < 0.05) decrease in the global myocardial blood flow. There was no discernible response in either the global myocardial blood flow or regional myocardial blood flow distribution to electromechanical activity (ie, ventricular fibrillation) for the third and fourth injections, suggesting that coronary autoregulation was abnormal. Postcardioplegia reperfusion ventricular fibrillation imposes metabolic demands that may cause reperfusion injury, especially in hearts affected by hypertrophy, ventricular distention, or coronary obstruction.

Preischemic glycogen reduction or glycolytic inhibition improves postischemic recovery of hypertrophied rat hearts.

The purpose of this study was to determine whether metabolites produced by glycolysis during ischemia significantly contribute to myocardial injury of hypertrophied hearts. The accumulation of glycolytic metabolites during ischemia was reduced by means of glycogen reduction or by treatment with the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG) before ischemia. Hearts from aortic-banded (Band) and sham-operated (Sham) rats (8 wk postop) were isolated, perfused with Krebs buffer, and had a left ventricular (LV) balloon to measure developed pressure. A 15-min perfusion with hypoxic buffer (glycogen reduction, GR) or a 10-min perfusion with 10 mM 2-DG (glycolytic inhibition) was followed by 25 min global, normothermic, no-flow ischemia and 30 min normoxic reperfusion. Heart weights were greater in Band than Sham [2.76 +/- 0.06 vs. 1.5 +/- 0.04 (mean +/- SE) g; P < 0.001]. GR and 2-DG each resulted in reduced ATP levels measured at the beginning of ischemia in both Band and Sham groups compared with untreated groups, but there were no differences among groups after 25 min of ischemia. Myocardial lactate levels at the end of ischemia were significantly reduced in both Band and Sham hearts with GR or 2-DG compared with untreated controls. Recovery of LV function after ischemia and reperfusion was significantly improved in Band after GR (206% increase) and after 2-DG treatment (126% increase) compared with their respective untreated controls. Diastolic dysfunction during reperfusion was ameliorated in Band by preischemic GR but not by 2-DG treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxyhemoglobin dissociation during hypothermic blood cardioplegia arrest.

BACKGROUND: Coronary sinus effluent contains desaturated blood during the first few seconds of hypothermic cardioplegia infusion in humans. This occurs despite the high affinity of hemoglobin for oxygen at a low temperature and alkaline pH. The present study quantitates oxyhemoglobin dissociation during hypothermic cardioplegic arrest. METHODS AND RESULTS: Three infusions of a 4 degrees C alkalotic blood cardioplegia solution were given into the cross-clamped aortic root during 1 hour of cardioplegic arrest. Paired aortic root and coronary sinus blood samples were obtained before and shortly after initiating cardiopulmonary bypass and at t = 5 seconds and 30 seconds during each cardioplegia infusion. Throughout the study, the hemoglobin saturation in the aortic root samples was 100%. The mean coronary sinus hemoglobin saturation at t = 5 seconds during hypothermic cardioplegia infusion ranged from 63.0% to 66.5% (p < 0.05 coronary sinus compared with aortic root samples). The coronary sinus hemoglobin saturation approximated the aortic root hemoglobin saturation at t = 30 seconds during hypothermic cardioplegia infusion. The mean PO2 of the aortic root samples ranged from 214 to 307 mm Hg during hypothermic cardioplegia infusion. The mean PO2 of the t = 5 seconds coronary sinus samples ranged from 31 to 39 mm Hg, whereas the mean PO2 of the t = 30 seconds coronary sinus samples ranged from 85 to 119 mm Hg during cardioplegia infusion (p < 0.05 coronary sinus compared with aortic root samples). CONCLUSIONS: Oxygen dissociates from hemoglobin contained in a hypothermic, alkalotic blood cardioplegia solution during the nonperfused phase of cardioplegic arrest. However, the only oxygen delivered to the myocardium during the infusion of a hypothermic alkalotic blood cardioplegia solution is oxygen physically dissolved in the solution.

The response to ischemia in blood perfused vs. crystalloid perfused isolated rat heart preparations.

With a research hypothesis that the behavior of blood perfused hearts was different from that of crystalloid perfused hearts, we tested the null hypothesis that the functional and metabolic status of blood-perfused (paracorporeal oxygenation) and Krebs-Henseleit (bubble oxygenation) perfused Langendorff isolated rat hearts is the same before, during and after global myocardial ischemia. Thirty isolated rat hearts were studied under identical conditions except that in equal numbers they were randomly assigned to either blood or crystalloid perfusion. In the blood perfused and crystalloid perfused hearts subjected to 22 min of normothermic ischemia and 30 min of reperfusion, mean systolic recovery was 72 +/- 3.9% (S.E.) and 20 +/- 10% (P = 0.001), respectively; coronary resistance increased 21 +/- 16% and 158 +/- 27% (P = 0.0003) (unadjusted for viscosity); mean water content after reperfusion was 82.0 +/- 0.43% and 86.7 +/- 0.42% (P < 0.0001), ATP content was 8.4 +/- 1.9 and 4.3 +/- 0.5 mumol/g dry wt (P = 0.08), and energy charge was 0.74 +/- 0.114 and 0.59 +/- 0.048 (P = 0.3). A major qualitative difference during reperfusion was spontaneous relaxation of contracture and rapid resumption of sinus rhythm in blood perfused hearts, in contrast to continued contracture and rise in intraventricular pressure in 9 of 10 crystalloid perfused hearts. One crystalloid perfused heart did not develop contracture, and its phenomena during reperfusion were similar to those of blood perfused hearts. The data support the research hypothesis, and suggest caution in extrapolating to blood perfused systems inferences from crystalloid perfused models. Better preservation of reactive hyperemia early in reperfusion may explain the better performance of blood perfused hearts.

31P NMR spectroscopy in chronic adriamycin cardiotoxicity.

Abnormal cardiac energy metabolism has been postulated as a mechanism for adriamycin induced cardiotoxicity. This study was designed to determine high energy phosphate stores at rest and with hemodynamic stress in perfused rat hearts after animals had been chronically exposed to adriamycin (2 mg/kg weekly for 14 weeks). Morphologic and hemodynamic changes were mild in this model. Phosphorus-31 NMR determined intracellular pH and levels of inorganic phosphate (Pi) and ATP were comparable in treated and control hearts. Phosphocreatine (PCr) levels were markedly decreased in treated hearts (0.89 +/- 0.07 units/g versus 1.7 +/- 0.13 units/g, p less than 0.001). The PCr/Pi ratio decreased in both groups during hemodynamic stress. It recovered earlier in controls and there was a marked over-shoot after cessation of rapid pacing in this group which was not present in adriamycin treated hearts. These results suggest that metabolic regulation in response to hemodynamic stress is impaired after chronic adriamycin exposure. PCr depletion and delayed metabolic recovery after hemodynamic stress appear to be potentially useful markers for the effect of adriamycin on the heart.

Increased ischemic injury but decreased hypoxic injury in hypertrophied rat hearts.

The purpose of this study was to compare the degree of ischemic and hypoxic injury in normal versus hypertrophied rat hearts to investigate basic mechanisms responsible for irreversible myocardial ischemic injury. Hearts from rats with bands placed on the aortic arch at 23 days of age (BAND) and sham-operated rats (SHAM, 8 weeks postoperative) were isolated, perfused with Krebs buffer, and had a left ventricular balloon to measure developed pressure. Hearts were made globally ischemic until they developed peak ischemic contracture and were reperfused for 30 minutes. Additional hearts were perfused for 15 minutes with glucose-free hypoxic buffer followed by 20 minutes of oxygenated perfusion. There was an 87% increase in heart weight of BAND compared with SHAM (p less than 0.01). During ischemia, lactate levels increased faster in BAND compared with SHAM, ischemic contracture occurred earlier in BAND than in SHAM despite no difference in ATP levels, and postischemic recovery of left ventricular pressure was less in BAND (26.8 +/- 5.6% of control left ventricular pressure, mean +/- SEM) compared with SHAM (40 +/- 4.6%, p less than 0.05). During hypoxic perfusion, lactate release was greater in BAND than in SHAM (48.8 +/- 1.2 versus 26.6 +/- 0.97 mumols/g, p less than 0.01), and with reoxygenation, lactate dehydrogenase release was less in BAND than in SHAM (13.2 +/- 0.7 versus 19.5 +/- 0.2 IU/g, p less than 0.01). After hypoxia and reoxygenation, left ventricular pressure recovery was greater in BAND than in SHAM (93 +/- 8.4% versus 66 +/- 5.3%, p less than 0.01). Thus, this study suggests that hypertrophied hearts have a greater potential for glycolytic metabolism, resulting in an increased rate of by-product accumulation during ischemia, which may be responsible for the increased susceptibility of hypertrophied hearts to ischemic injury.

Controlled initial hyperkalemic reperfusion after cardiac transplantation: coronary vascular resistance and blood flow.

The coronary vascular response to controlled initial hyperkalemic reperfusion after global ischemia during cardiac transplantation was studied in 11 patients. The mean global ischemic time was 206 minutes (range, 143 to 245 minutes). All donor hearts received initial hyperkalemic crystalloid cardioplegia and subsequent oxygenated crystalloid cardioplegia during implantation. Coronary blood flow was highest during the first one to two minutes of controlled reperfusion but remained normal throughout the first ten minutes of reperfusion. Coronary vascular resistance was less than normal throughout the first ten minutes of controlled reperfusion, but there was a gradual increase throughout this period. Systemic vascular resistance remained within normal limits. The time to effective contraction was highly variable, but a greater potassium load during initial reperfusion was generally associated with a longer time to effective contraction.

Use of the isolated perfused heart for evaluation of cardiac toxicity.

The isolated perfused rat heart model can be used to evaluate cardiotoxicity, and is especially useful in distinguishing direct vs indirect cardiac injury. Various perfusion systems can be used to characterize the pathophysiologic as well as morphologic changes induced by drugs or chemicals of interest. The isolated perfused heart was used in the studies described herein to characterize the mechanism of allylamine cardiotoxicity. Rat hearts were perfused with Krebs-Henseleit buffer containing 10 mM allylamine and a latex balloon was inserted into the left ventricle to monitor pressure. Coronary flow in hearts perfused with 10 mM allylamine was similar to control hearts at 5, 10, and 30 min, but was reduced by 1 hr (11.5 +/- 0.6 ml/min/g wet heart weight vs 16.0 +/- 0.7, p less than 0.01). Peak left ventricular systolic pressure increased in hearts perfused with allylamine for 5 min (156 +/- 8 mm Hg vs 103 +/- 9, p less than 0.01), but by 2 hr was decreased compared to controls (89 +/- 6 vs 105 +/- 5, p less than 0.05). End diastolic pressure was markedly increased at 2 hr (58 +/- 3 vs 4 +/- 0.8, p less than 0.01). Morphologically, allylamine perfused hearts exhibited significant contraction band changes as well as numerous cells with marked swelling of the sarcoplasmic reticulum. The findings in this study suggest that allylamine produces direct myocardial damage that appears to be independent of coronary flow. These studies demonstrate that the isolated perfused rat heart model can be used to evaluate mechanisms of acute cardiotoxicity.

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.

Coronary and systemic vascular resistance during reperfusion after global myocardial ischemia.

During controlled aortic root reperfusion after global myocardial ischemia for the performance of coronary artery bypass grafting (N = 16), coronary blood flow was the highest during the first 1 minute to 2 minutes even though the aortic root pressure was controlled at about 40 mm Hg. Even during the period of controlled low pressure, flow began to decline, and the decline continued during the period in which the pressure was controlled at 75 mm Hg. Calculated coronary vascular resistance rose steadily from an initially low value to one well above the normal value for beating hearts. A transient fall in resistance resulted from the administration of a bolus of nitroglycerin into the aortic root. When the initial reperfusate was normokalemic, coronary flow was less and coronary vascular resistance higher during the initial phase of reperfusion. The systemic arterial pressure and resistance fell during the first 1 minute to 3 minutes of reperfusion and in 25% of patients, remained low. The greater the potassium load delivered during the initially hyperkalemic phase, the longer the interval between the beginning of reperfusion and the resumption of cardiac systole.