Biomedical subjects

C S Apstein

Publications and source records attributed to C S Apstein.

At least 73 records · Page 4Linked to original sources

PubMed1990

Tolerance of the hypertrophic heart to ischemia. Studies in compensated and failing dog hearts with pressure overload hypertrophy.

Tolerance of the canine heart to prolonged ischemic arrest was studied in 10 hearts from normal control dogs and 15 hearts from dogs with left ventricular hypertrophy (LVH); experiments were performed 1 year after banding the aorta in 8-week-old puppies. At 1 year, hemodynamic studies revealed decreased left ventricular (LV) fiber shortening and elevated end-diastolic pressure (EDP) in five dogs (group with LVH failure); 10 dogs exhibited normal shortening and normal EDP (group with LVH compensation). The left ventricle-to-body weight ratio (g/kg) was 4.4 +/- 0.8 in the control group of dogs, 7.7 +/- 1.0 in the group with LVH compensation, and 10 +/- 2.5 in the group with LVH failure. The tolerance to 60 minutes of global ischemia (37 degrees C) followed by 90 minutes of reperfusion was studied in an isolated blood-perfused heart apparatus (isovolumic left ventricle, coronary perfusion pressure of 100 mm Hg). In the baseline (preischemic) state, coronary blood flow, myocardial oxygen consumption, lactate extraction, and myocardial high-energy phosphate content were essentially equal in the three groups; with LV volume adjusted to produce a systolic pressure of 100 mm Hg, there were no significant differences in LVEDP among the three groups. During ischemia, the diastolic (asystolic) pressure increased from 11 +/- 3 to 28 +/- 16 mm Hg (p less than 0.05) in the group with LVH failure; however, it did not increase in the control or the LVH compensation groups. Myocardial ATP levels declined equally in all three groups. During early reperfusion, lactate washout was lowest in the group with LVH failure. By 90 minutes of reperfusion, there were no significant differences in coronary blood flow, myocardial oxygen consumption, lactate extraction, or high-energy phosphate levels. High diastolic pressure persisted at 90 minutes of reperfusion in the LVH failure group (EDP was 34 +/- 19 mm Hg); however, there was no significant change in EDP during reperfusion in the control or with LVH compensation groups. After 90 minutes of reperfusion, developed pressures in the control (54 +/- 9 mm Hg), the LVH compensation (49 +/- 18 mm Hg), and the LVH failure (67 +/- 17 mm Hg) groups were not significantly different. These data indicate that hearts with compensated LVH do not exhibit an impaired tolerance to ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗

PubMed1990

Influence of glucose and insulin on the exaggerated diastolic and systolic dysfunction of hypertrophied rat hearts during hypoxia.

Myocardial hypertrophy can result in increased sensitivity toward the development of mechanical dysfunction during hypoxia. Alterations in glycolytic metabolism may contribute to this. We studied the response to 15 minutes of hypoxia in hypertrophied (deoxycorticosterone-salt hypertension model) and nonhypertrophied rat hearts and examined the influence of a high glucose (27.5 mM) and insulin (100 mU/ml) concentration. In response to hypoxia in the presence of a normal glucose concentration (5.5 mM), left ventricular end-diastolic pressure was higher in hypertrophied than in nonhypertrophied hearts (65 +/- 6 vs. 44 +/- 4 mm Hg; p less than 0.05). Perfusion with high glucose and insulin blunted the rise in left ventricular end-diastolic pressure in both hypertrophied and nonhypertrophied hearts and abolished the difference in diastolic dysfunction between groups during hypoxia (26 +/- 2 vs. 32 +/- 4 mm Hg, respectively; p = NS). At end hypoxia in the presence of a normal glucose concentration, developed pressure was more depressed in hypertrophied than in nonhypertrophied hearts (11 +/- 1 vs. 18 +/- 1% of baseline, respectively; p less than 0.05). Perfusion with high glucose and insulin resulted in improved function in both groups during hypoxia such that a greater impairment of developed pressure was no longer present in the hypertrophied versus nonhypertrophied hearts (21 +/- 1 vs. 24 +/- 2% of baseline, respectively; p = NS). At the end of hypoxic perfusion in the presence of a normal glucose concentration, hypertrophied hearts were producing 38% less lactate than nonhypertrophied hearts. Perfusion with high glucose and insulin increased lactate production in both groups and equalized lactate production between groups. Thus, the greater deterioration in hemodynamic function in hypertrophied hearts compared with nonhypertrophied hearts during hypoxia is associated with lower lactate production. Both the exaggerated hemodynamic dysfunction and deficient lactate production can be ameliorated by perfusion with a high glucose concentration and insulin.

Animals↗

PubMed1990

Contribution of endothelial cells to calcium-dependent fluorescence transients in rabbit hearts loaded with indo 1.

In studies that attempt to measure intracellular calcium [( Ca2+]i) in the intact heart with the calcium indicator indo 1-AM, a fundamental assumption is that the signals report changes in myocyte [Ca2+]i. We studied isolated perfused rabbit hearts loaded with the calcium probe indo 1-AM and recorded surface fluorescence of the left ventricle during continuous excitation at 360 nm. In cells containing indo 1, an increase in [Ca2+]i is associated with an increase in fluorescence intensity at 400 nm, a decrease in intensity at 500 nm, and an increase in the 400:500 nm ratio. Beat-to-beat fluorescence transients were recorded from the surface of the heart coincident with contraction, indicating that a component of the fluorescence signals is derived from beating myocytes. To evaluate the potential contribution of endothelial cells, we compared the response to increases in [Ca2+]o or bradykinin (10(-5) M). In response to an increase of the [Ca2+] in the perfusate from 0.6 to 3.0 mM, left ventricular developed pressure and +dP/dt increased with a simultaneous increase in the [Ca2+]i-sensitive 400:500 nm ratio. Perfusion with the endothelial cell agonist bradykinin caused no change in left ventricular isovolumic peak systolic pressure or left ventricular dP/dt, whereas bradykinin evoked an immediate elevation in both the diastolic and systolic levels of the [Ca2+]i-sensitive 400:500 nm ratio. In additional experiments with indo 1-loaded isolated beating myocytes, superfusion with bradykinin had no effect on either the fluorescence [Ca2+]i transients or contractility. In contrast, superfusion of indo 1-loaded cultured endothelial cells with bradykinin caused the elevation of [Ca2+]i within seconds. Fluorescence microscopy of unstained frozen tissue sections from indo 1-loaded hearts also suggested the presence of more intense microvascular endothelial cell indo 1 fluorescence relative to that observed in myocytes. These experiments provide evidence that a component of [Ca2+]i-sensitive fluorescence of whole hearts loaded with indo 1 is contributed by nonmyocyte sources, including endothelial cells. These results also raise the caution that the abrupt rise of [Ca2+]i that has been observed during the initial phase of ischemia in whole hearts loaded with indo 1 may be partly derived from endothelial cells rather than myocytes.

Animals↗

PubMed1990

Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. Effects on coronary resistance, contractility, and relaxation.

We compared the activity and physiologic effects of cardiac angiotensin converting enzyme (ACE) using isovolumic hearts from male Wistar rats with left ventricular hypertrophy due to chronic experimental aortic stenosis and from control rats. In response to the infusion of 3.5 X 10(-8) M angiotensin I in the isolated buffer perfused beating hearts, the intracardiac fractional conversion to angiotensin II was higher in the hypertrophied hearts compared with the controls (17.3 +/- 4.1% vs 6.8 +/- 1.3%, P less than 0.01). ACE activity was also significantly increased in the free wall, septum, and apex of the hypertrophied left ventricle, whereas ACE activity from the nonhypertrophied right ventricle of the aortic stenosis rats was not different from that of the control rats. Northern blot analyses of poly(A)+ purified RNA demonstrated the expression of ACE mRNA, which was increased fourfold in left ventricular tissue obtained from the hearts with left ventricular hypertrophy compared with the controls. In both groups, the intracardiac conversion of angiotensin I to angiotensin II caused a comparable dose-dependent increase in coronary resistance. In the control hearts, angiotensin II activation had no significant effect on systolic or diastolic function; however, it was associated with a dose-dependent depression of left ventricular diastolic relaxation in the hypertrophied hearts. These novel observations suggest that cardiac ACE is induced in hearts with left ventricular hypertrophy, and that the resultant intracardiac activation of angiotensin II may have differential effects on myocardial relaxation in hypertrophied hearts relative to controls.

Angiotensin I↗

PubMed1989

Leakage of heart fatty acid binding protein with ischemia and reperfusion in the rat.

Fatty acids and their metabolites have been implicated as a cause of myocardial damage during ischemia. Fatty acid binding protein (FABP), an abundant low molecular weight protein present in the cytosol of myocytes, has been postulated to be a key fatty acid carrier protein in the myocardium. Postulating that loss of FABP during ischemia could cause an increase in unbound intracellular fatty acids contributing to myocardial damage, we measured plasma FABP levels during 60 min of myocardial ischemia followed by 60 min of reperfusion in the rat. Peak levels were seen 15 min after reperfusion. Plasma levels were higher with larger areas of myocardial ischemia (1720 +/- 528 ng/ml vs. 216 +/- 76 ng/ml with smaller areas, P less than 0.02). Tissue levels after 60 min of ischemia and 60 min of reperfusion were decreased by over 50%, (1.0 +/- 0.3 mg FABP/g wet wt compared with 2.9 +/- 0.4 mg FABP/g wet wt in normal myocardium, P less than 0.005). The data is consistent with the proposal that loss of FABP contributes to the myocardial damage associated with ischemia and reperfusion. Additional studies are needed to determine the exact role of FABP in the regulation of fatty acid metabolism in the heart.

Animals↗

PubMed1989

Deleterious effect of ouabain on myocardial function during hypoxia.

The effect of cardiac glycosides on myocardial function during hypoxia is controversial. Accordingly, we studied left ventricular performance during hypoxia and reoxygenation in the presence of a mildly inotropic, nontoxic dose of ouabain using isolated, isovolumic, buffer-perfused rabbit hearts. After 15 min of hypoxia, left ventricular developed pressure was less in the ouabain-treated group than in controls (35 +/- 4 vs. 55 +/- 3 mmHg, P less than 0.025). Left ventricular end-diastolic pressure (LVEDP) increased more during hypoxia in the presence of ouabain (9 +/- 1 to 32 +/- 7 with ouabain vs. 9 +/- 1 to 14 +/- 3 mmHg without ouabain, P less than 0.005) despite comparable degrees of coronary vasodilatation and myocardial lactate production in the two groups. When coronary flow was abruptly reduced to zero to eliminate the coronary turgor contribution to diastolic pressure, LVEDP after 15 min of hypoxia in the presence of ouabain was greater than that in control hearts that did not receive ouabain (13 +/- 4 vs. 4 +/- 1 mmHg, P less than 0.05), implicating greater diastolic myocardial fiber tension in the ouabain group during hypoxia. With reoxygenation, recovery of developed pressure was less and end-diastolic pressure remained elevated in the ouabain-treated group when compared with controls. We conclude that a modestly inotropic dose of ouabain exacerbates the decrease in diastolic ventricular distensibility induced by hypoxia, worsens the decline in developed pressure during hypoxia, and impairs recovery during reoxygenation.

Animals↗

PubMed1989

Effect of coronary occlusion and reperfusion on myocardial blood flow during infarct healing.

Coronary occlusion (CO) of 1 h or longer causes transmural myocardial infarction (MI) in the rabbit. We studied how reperfusion of an infarct affected myocardial blood flow (MBF) acutely and after 3 wk of healing. CO was performed in rabbits for 60 or 180 min (n = 22) followed by reperfusion, and MBF to normal and infarcted zones was determined by radioactive microspheres. In a separate series (n = 23), MBF was measured at 21-25 days post-CO in three groups that had either permanent CO or reperfusion after 60 or 180 min of CO. MBF to the infarct was approximately 8 +/- 3% (+/-SE) of normal MBF (3.8 +/- 0.5 ml.min-1.g-1) during 60-180 min of CO but 3 wk later had increased to 33 +/- 6% of normal MBF (P less than 0.005). Reperfusion after 60 or 180 min of CO resulted in 74 +/- 6% and 41 +/- 5% return of normal MBF, respectively, but 3 wk later, MBF had decreased to 25 +/- 5% (P less than 0.001) and 24 +/- 4% (P less than 0.025) of normal MBF, respectively. Thus after 3 wk of postinfarction healing, MBF to the permanently occluded infarcts increased fourfold, whereas MBF decreased by 50% in the reperfused infarcts so that MBF to the scar tissue was comparable among the three groups and was not influenced by acute post-MI reperfusion.

Animals↗

PubMed1989

Stress-shortening relations and myocardial blood flow in compensated and failing canine hearts with pressure-overload hypertrophy.

Serial changes in left ventricular (LV) size and function during the adaptation to chronic pressure overload and the transition to pump failure were studied in 16 conscious dogs (aortic bands placed at 8 weeks of age). Echocardiographic data at baseline and at 3, 6, 9, and 12 months after banding revealed a progressive increase in LV mass in all dogs. In six dogs with LV pump failure, there was a progressive decline in circumferential fiber shortening (29 +/- 4% at 12 months); this was significantly less than that seen in five littermate controls (38 +/- 3%, p less than 0.05). The average LV to body weight ratio in this group was 9.8 +/- 2.7 g/kg. In 10 dogs without pump failure (compensated LVH group), shortening exceeded that seen in the controls (43 +/- 4%, p less than 0.05); the LV to body weight ratio was 7.7 +/- 1.0 g/kg. At 12 months (cardiac catheterization), the LV end-diastolic pressure was higher in the failure (25 +/- 15 mm Hg) than in the compensated group (8 +/- 5 mm Hg, p less than 0.05); mean systolic stress was also higher in the failure group (313 +/- 67 g/cm2) than in the compensated group (202 +/- 53 g/cm2, p less than 0.05). The transmural distribution of myocardial blood flow was measured (at 12 months) with the radioactive microsphere technique; flow data were then related to an index of demand (a stress-time index). There was preferential blood flow to the subendocardial layers in the control (endo/epi = 1.28) and compensated hearts (endo/epi = 1.10), but in the failure group there was a relative decrease in subendocardial flow (endo/epi = 0.92). However, the absolute values for subendocardial flow in the normal, compensated, and failure groups were 77 +/- 54, 125 +/- 48, and 113 +/- 64 ml/min/100 g; the stress-time indexes in the subendocardial shell were 38 +/- 11, 74 +/- 19, and 93 +/- 34 g sec.10(2)/cm2/min. Despite what appears to be a marginal balance between blood flow and the stress time index in the failure group, the myocardial high energy phosphates were not depleted and the inoptropic state was not depressed. In this model of LV hypertrophy, the observed differences in fiber shortening can be explained on the basis of the inverse afterload-shortening relation; pump failure was due to an inadequate LV hypertrophy with afterload excess.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗

PubMed1989

Influence of hypertension with minimal hypertrophy on diastolic function during demand ischemia.

Hearts with advanced pressure-overload hypertrophy from systemic hypertension have been shown to have an increased susceptibility to the development of diastolic dysfunction in response to tissue hypoxia and ischemia. It is not known if this propensity to develop diastolic dysfunction in response to ischemia is dependent on the presence of a substantial increase in left ventricular mass, or alternatively, is characteristic of hearts subjected to mild chronic hypertension early in the development of cardiac hypertrophy. We tested the hypothesis that systemic hypertension associated with mild left ventricular hypertrophy increases the susceptibility to the development of diastolic dysfunction in response to demand ischemia. The effects of demand ischemia (6 minutes) were studied in hearts from New Zealand white rabbits with chronic systemic hypertension produced by the one-kidney, one-wrap method (n = 15) and compared with age-matched, sham-operated control rabbits (n = 11) with similar left ventricular mass (5.4 +/- 0.2 vs. 5.4 +/- 0.3 g, respectively). The hearts were studied using an isolated, isovolumic (balloon in left ventricle) preparation with absent pericardium that was perfused with fresh whole blood. At baseline, coronary perfusion pressure was 100 mm Hg with comparable coronary flow per gram left ventricular weight; the hearts were paced at a physiological rate of 3 Hz, and the left ventricular balloon volume was adjusted to achieve a left ventricular end-diastolic pressure of 15 mm Hg in both groups. Left ventricular balloon volume was similar in both groups and volume was thereafter held constant. At baseline, left ventricular systolic pressure (114 +/- 4 vs. 95 +/- 3 mm Hg, p less than 0.001) and developed pressure (18.9 +/- 1.2 vs. 15.1 +/- 0.9 mm Hg/g, p less than 0.05) were higher in the hearts from the hypertensive group in comparison with the control group. During the first minute of global ischemia produced by reducing coronary perfusion pressure from 100 to 20 mm Hg, there was an immediate fall in left ventricular systolic pressure in both groups without an increase in diastolic pressure. In response to the superimposition of pacing tachycardia (heart rate, 6 Hz) during the remaining 5 minutes of the period of ischemia, left ventricular developed pressure was comparable. However, isovolumic left ventricular end-diastolic pressure (measured during long diastoles obtained with transient cessation of pacing) rose to a significantly higher level in the hearts from hypertensive rabbits than in those from the control rabbits (29 +/- 3 vs. 18 +/- 2 mm Hg, p less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

Coronary hypertension and diastolic compliance in isolated rabbit hearts.

Acute pulmonary edema during hypertensive crisis has been attributed to acute left ventricular systolic failure secondary to increased afterload. We tested the hypothesis that the increase in coronary artery perfusion pressure associated with systemic hypertension could also contribute to increased left ventricular filling pressures by acutely increasing coronary intravascular volume and decreasing left ventricular diastolic compliance. Isolated isovolumic (balloon in left ventricle) normal rabbit hearts (n = 13) with pericardium removed and right ventricle vented were blood perfused at an initial coronary artery perfusion pressure of 100 mm Hg; left ventricular balloon volume was adjusted to produce an initial left ventricular end-diastolic pressure of 15 +/- 1 mm Hg; left ventricular systolic pressure was 102 +/- 3 mm Hg. When coronary perfusion pressure was increased to 130 +/- 1 mm Hg to simulate a hypertensive crisis, coronary flow increased from 2.0 +/- 0.2 to 3.0 +/- 0.2 ml/min/g left ventricle (p less than 0.001), left ventricular systolic pressure increased to 116 +/- 4 mm Hg, and isovolumic left ventricular end-diastolic pressure increased to 21 +/- 1 mm Hg (p less than 0.001), which indicated a decrease in left ventricular diastolic compliance. When coronary perfusion pressure was decreased to a physiological level of 70 mm Hg, coronary flow rate decreased to 1.4 +/- 0.1 ml/min/g left ventricle (p less than 0.001), left ventricular systolic pressure fell to 82 +/- 4 mm Hg, and left ventricular end-diastolic pressure fell to 14 +/- 1 mm Hg (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Contrast effects of isoproterenol and ouabain on left ventricular diastolic relaxation dysfunction in isolated, blood-perfused rabbit hearts.

We studied the influence of inotropic agents on prompt and transient left ventricular (LV) diastolic relaxation dysfunction produced by superimposition of pacing tachycardia on low-flow ischemia, using an isolated, blood-perfused and isovolumic (balloon-in-LV) rabbit heart preparation. The LV balloon volume was adjusted to produce an LV end-diastolic pressure (EDP) of 15 mmHg and was held constant thereafter. Coronary perfusion pressure was adjusted to 100 mmHg during baseline and to 20 mmHg during low-flow ischemia of 6 min. At baseline, isoproterenol and ouabain were administered to cause moderate and similar rises (14 +/- 3 and 16 +/- 4% above baseline values, respectively) in maximum + dp/dt of LVP with no change in LVEDP. In control hearts which received no drug, superimposition of 5-min pacing tachycardia on low-flow ischemia produced a significant and transient increase in LVEDP under constant LV volume (from 13.4 +/- 0.4 to 24.7 +/- 3.3 mmHg, p less than 0.01). In the hearts which received isoproterenol it did not change LVEDP (from 14.0 +/- 0.4 to 16.2 +/- 1.0 mmHg, NS). In contrast, the ouabain hearts showed a further increase in LVEDP (from 13.7 +/- 0.8 to 29.9 +/- 4.6 mmHg, p less than 0.01). LV developed pressure, myocardial oxygen consumption or myocardial lactate production during pacing tachycardia superimposed on the low-flow ischemia did not differ significantly among the 3 groups. Thus, isoproterenol markedly improved transient LV relaxation dysfunction produced by superimposition of pacing tachycardia on low-flow ischemia, in which an equipotent inotropic dose of ouabain exaggerated the relaxation dysfunction. These results suggest that calcium overload rather than ATP depletion per se contributes to transiently impaired diastolic relaxation by pacing tachycardia and low-flow ischemia.

Animals↗

PubMed1989

Comparison of three cardioplegic solutions during hypothermic ischemic arrest in neonatal blood-perfused rabbit hearts.

Inadequate myocardial preservation continues to be an important cause of postoperative morbidity and mortality after pediatric cardiac operations. To investigate methods of improving preservation in neonatal myocardium, we compared three cardioplegic solutions with topical hypothermia during 120 minutes of ischemic arrest in isolated, blood-perfused, neonatal rabbit hearts. Topical hypothermia (15 degrees C) without cardioplegia resulted in 71% +/- 5% recovery of preischemic contractile function. A high potassium (30 mEq/L) cardioplegic solution resulted in a 76% +/- 6% recovery of function, not significantly different from that obtained with hypothermia alone. In contrast, the St. Thomas' Hospital and Hôpital Lariboisiere cardioplegic solutions resulted in recoveries of 89% +/- 6% and 88% +/- 7%, respectively, both of which were significantly greater (p less than 0.001) than recoveries obtained with the high potassium solution or hypothermia alone. Thus the cardioplegic solutions used at St. Thomas' Hospital and Hôpital Lariboisiere provided excellent protection during 2 hours of hypothermic ischemic arrest in neonatal rabbit hearts and resulted in functional recovery superior to that achieved with hypothermia alone or with the high potassium cardioplegic solution.

Animals↗

PubMed1989

Studies of the mechanism of the vasoconstrictor activity of stroma-free hemoglobin in the isolated perfused rat kidney and rabbit heart.

We have found that DBBF-Hb and Hb Ao have significantly less vasoconstrictor activity than unmodified Hb in the rabbit heart. In striking contrast to these findings, DBBF-Hb and unmodified Hb have comparable hemodynamic effects in the isolated kidney. We have demonstrated that lipophilic contamination of fraction V BSA causes vasoconstriction in the coronary vasculature and speculate that similar contaminants may contribute to the vasoconstrictor activity of SFH solutions. Finally, we have shown that renal vasoconstriction induced by DBBF-Hb is reversed by acetylcholine as well as nitroprusside. These studies suggest that renal vasoconstriction induced by DBBF-Hb is not related to inhibition of EDRF. These studies make it clear that SFH solutions have different effects on the heart and kidney vasculature. The use of both heart and kidney models should provide important information on the mechanisms by which SFH causes vasoconstriction in these two organs.

Acetylcholine↗

PubMed1988

The physiological basis of left ventricular diastolic dysfunction.

Overall cardiac pump function requires adequate ventricular diastolic filling as well as normal systolic ejection. Abnormalities of the rate or extent of myocardial relaxation (diastolic dysfunction) have been described in a large variety of clinical conditions, including hypertrophy, ischemia, and after cardiac surgery. Diastolic and systolic dysfunction can be readily distinguished by analysis of pressure volume loops and utilization of echocardiography or nuclear cardiology gated blood pool scans. The mechanisms by which diastolic dysfunction can occur may be structural (hypertrophy, fibrosis) or dynamic (hypoxia, ischemia, alteration of diastolic cytosolic calcium levels). Hypertrophied myocardium is particularly susceptible to diastolic dysfunction by virtue of both structural changes (increased LV mass and interstitial fibrosis) and greater susceptibility to develop impaired myocardial relaxation during hypoxia or ischemia than nonhypertrophied myocardium.

Cardiomegaly↗

PubMed1988

Enhanced sensitivity to hypoxia-induced diastolic dysfunction in pressure-overload left ventricular hypertrophy in the rat: role of high-energy phosphate depletion.

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 400 WORDS)

Adenosine Triphosphate↗

PubMed1988

Effects of alloxan-induced diabetes on ischemia-reperfusion injury in rabbit hearts.

Hearts from rabbits with 8-16 weeks of alloxan-diabetes were compared with hearts from normal rabbits to determine whether diabetic myocardium is more sensitive to ischemic injury. In isolated buffer-perfused hearts, left ventricular developed pressure, diastolic pressure, time to peak pressure (TTPP), time to half-maximal relaxation (RT1/2), and positive and negative dP/dt were measured during generation of left ventricular filling curves before and after 90 minutes of low-flow ischemia. Hearts from diabetic rabbits (blood glucose, 384 +/- 28 mg/dl, mean +/- 95% confidence limits) had left ventricular developed and diastolic pressures similar to normal hearts but exhibited significant increases in TTPP and RT1/2 with decreased positive and negative dP/dt. Left ventricular chamber volume relative to heart mass was greater in diabetic than in normal hearts. Recovery of developed pressure after ischemia was similar in normal (41 +/- 16%) and diabetic hearts (47 +/- 13%). In diabetic hearts during recovery from ischemia, TTPP and R1/2 remained increased compared with normal hearts, with positive and negative dP/dt decreased compared with normal hearts, in proportion to the preischemic differences. After ischemia, high-energy phosphates were depleted to the same extent in normal and diabetic rabbits. In coronary ligation experiments, histochemically determined infarct size in diabetic rabbits after 30 minutes occlusion and 24 hours reperfusion was similar to that in normal rabbits when adjusted for a significantly smaller heart weight and a correspondingly smaller anatomic risk region in the diabetic animals. Thus, despite characteristic abnormalities of mechanical function in diabetic hearts, the severity of injury after ischemia with reperfusion was normal for diabetic hearts.

Animals↗

PubMed1988

Effects of ouabain and isoproterenol on left ventricular diastolic function during low-flow ischemia in isolated, blood-perfused rabbit hearts.

Myocardial ischemia causes both systolic and diastolic dysfunction. A variety of positive inotropic agents with different subcellular mechanisms may be used clinically in an attempt to reverse ischemic contractile failure. We tested the hypothesis that two inotropic agents, isoproterenol (a beta-adrenergic agonist) and ouabain (a sodium pump inhibitor), might have different effects on left ventricular (LV) diastolic function during ischemic failure despite an equivalent inotropic effect. Isolated isovolumic (balloon-in-LV) blood perfused rabbit hearts were paced at constant physiological heart rate (4 Hz), given either no drug (controls, n = 7), isoproterenol (n = 7), or ouabain (n = 7), and then subjected to 6 minutes of low flow ischemia (75% reduction of baseline coronary flow). The doses of isoproterenol and ouabain were selected to produce equivalent modest inotropic effects (15% increase in LV + dP/dt) in each heart during baseline perfusion conditions. During the ischemic period, there was a marked decrease in contractility, and neither isoproterenol nor ouabain demonstrated a positive inotropic effect relative to the control group. However, these agents had markedly different effects on diastolic chamber distensibility (assessed by end-diastolic pressure at constant LV volume) during ischemia. In the control and isoproterenol groups, diastolic chamber distensibility did not change during the ischemic period. In contrast, ouabain treatment resulted in a marked decrease in diastolic chamber distensibility during ischemia; this change was not completely reversible during the 10-minute reperfusion period. The mechanism by which ouabain decreased diastolic chamber distensibility relative to isoproterenol was assessed indirectly. The ouabain and isoproterenol groups were subjected to equivalent degrees of ischemia as assessed by oxygen supply/demand imbalance; during ischemia, each drug group did not differ with regard to myocardial perfusion rates, determinants of myocardial oxygen demand (heart rate, LV developed pressure, LV + dP/dt), myocardial oxygen consumption, lactate production, and ATP and creatine phosphate content. We therefore inferred that the greater decrease in diastolic distensibility in the ouabain group was not due to a greater metabolic severity of ischemia. These observations are consistent with a mechanism of cytosolic calcium overload induced by ouabain, resulting in persistent active myofilament tension development throughout diastole, to cause the observed decrease in diastolic chamber distensibility during ischemia in the ouabain group.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1988

Effects of stroma-free hemoglobin solutions on isolated perfused rabbit hearts and isolated perfused rat kidneys.

"Stroma-free" hemoglobin solutions (SFH) cause hemodynamic alterations indicative of vasoconstriction. We studied vasoconstrictor activity in isolated rabbit hearts and rat kidneys of unmodified SFH and of SFH modified by pyridoxylation or glyoxylation, with or without glutaraldehyde cross-linking. The purity and chemical composition of the solutions, all prepared by other laboratories, were not characterized by us. In isolated hearts SFH prepared by conventional methods had potent vasoconstrictor activity. Pyridoxylation or purification by ion exchange chromatography did not alter the constrictor activity. Decreased constrictor activity was observed with human SFH cross-linked by glutaraldehyde treatment, or purified by affinity chromatography, and with bovine SFH purified by ultrafiltration and preparative HPLC. In isolated kidneys modified and unmodified SFH increased renal vascular resistance and decreased glomerular filtration rate with no morphologic evidence of tubular damage.

Animals↗