ATP gated potassium channels in acute myocardial hibernation and reperfusion.

OBJECTIVE: ATP gated potassium (KATP) channels and adenosine are of crucial importance in coronary blood flow regulation and activation of KATP channels and adenosine receptor stimulation protect against infarction and development of stunning. The aim of this study was to test the hypothesis that opening of KATP channels and adenosine receptor stimulation are involved in perfusion-contraction matching, in acute hibernation, and in recovery after reperfusion. METHODS: 30 isolated piglet hearts (2-10 d old) and 20 isolated rabbit hearts were studied. The isolated piglet hearts were perfused with modified Krebs Henseleit (KH) solution enriched by washed human red blood cells; the isolated rabbit hearts were perfused with modified KH buffer. The effects of the KATP channel opener aprikalim (1 microM), the KATP channel antagonist glibenclamide (30 microM), and the adenosine receptor antagonist 8-(p-sulphophenyl)theophylline (SPT, 300 microM) on 2 h of low flow (10%) ischaemia and 1 h reperfusion were compared with saline in the piglet hearts. The effects of aprikalim (1 microM), glibenclamide (30 microM), and saline during 90 min of low flow (10%) ischaemia followed by 1 h reperfusion were also examined in the isolated rabbit hearts. RESULTS: At constant coronary flow aprikalim reduced perfusion pressure from 53(SEM 5) to 25(1) mm Hg (p < 0.001) in piglet hearts and from 55(5) to 39(5) mm Hg (p < 0.05) in rabbit hearts. Glibenclamide increased perfusion pressure from 47(5) to 61(6) mm Hg (p < 0.01) in piglet hearts and from 45(4) to 81(5) mm Hg (p < 0.001) in rabbit hearts. SPT increased perfusion pressure from 55(6) to 67(6) mm Hg (p < 0.05) in piglet hearts. Left ventricular systolic pressure remained unchanged in both models. During stepwise reductions in coronary flow a parallel stepwise reduction in left ventricular systolic pressure was observed in all groups. At 2 h of low flow ischaemia systolic pressure was 39(4)%, 37(5)%, 41(4)%, and 37(3)% of control for hearts treated with saline aprikalim, glibenclamide, and SPT, respectively. During the low flow period systolic pressure and MVO2 stabilised. An almost identical pattern occurred in rabbit hearts. After 30 min of recovery of piglet hearts left ventricular systolic pressure increased to 78(5)% (saline), 74(5)% (aprikalim), 84(5)% (glibenclamide), and 77(4)% (SPT) of control. The recovery as percentage of control in rabbit hearts was 63(11) (saline), 69(8) (aprikalim) and 56(13) (glibenclamide). CONCLUSION: Coronary vascular tone is highly responsive to KATP channel modulation and adenosine receptor blockade. KATP channels do not modulate either perfusion-contraction matching or acute hibernation and functional recovery during reperfusion in the red blood cell perfused piglet heart or the crystalloid perfused rabbit hearts. Moreover, adenosine receptor antagonism does not affect these phenomena in piglet hearts.

Pathophysiological correlates of thallium-201 myocardial uptake in experimental infarction.

The pathophysiological correlates of thallium-201 (201TI) myocardial uptake were studied in a 24-hour-old closed-chest canine infarct model. Reduction in regional 201Tl uptake correlated well with the magnitude of tissue creatine phosphokinase depletion and microsphere estimates of transmural blood flow. In low flow endocardial regions 201Tl occasionally under-estimated the magnitude of flow reduction. Even slight reductions of 201Tl uptake (less than 0.86 of normal) were associated with histopathological and histochemical evidence of necrosis.

Four-valve polymicrobial endocarditis caused by Pseudomonas aeruginosa and Serratia marcescens.

This report describes what is believed to be the first case of mixed Pseudomonas and Serratia endocarditis, of probable nosocomial etiology, with involvement of all four heart valves in a 56 year old nonaddicted patient. Although both organisms were recovered in culture, infection and tissue invasion were documented by light and electron microscopy. The clinical course in this patient differed from more typical patterns of Pseudomonas or Serratia endocarditis that have been observed as complications of narcotic addiction or compromised cardiac status. Our patient had the rare occurrence of endocarditis with two organisms and four-valve involvement. Clinically, however, this presented as a right-sided endocarditis and behaved as though only a single organism were present.

Laryngeal chemosensitivity: a possible mechanism for sudden infant death.

In 32 anaesthetized piglets 1 to 42 days of age the distal trachea was cannulated and pressure changes were recorded. The proximal trachea was cannulated for introduction of test fluids into the laryngeal area. Arterial pressure, heart rate, and central venous pressure were continuously recorded. Arterial blood samples were obtained at intervals and analyzed for PO2, PCO2, pH, and hematocrit. Normal saline produced no, or brief, transitory alterations of the respiratory pattern and arterial pressure. In contrast, instillation of distilled water produced apnea in 29 of 30 piglets. In 20 the apnea was sustained. Eleven died within approximately 50 minutes of asphyxia. An additional nine were expected to die with continuing apnea (PO2, 10 to 15 mm Hg; PCO2 greater than 100 mm Hg; pH smaller than 6.8) but the sequence was interrupted by replacement of water with saline. Twenty-three of 29 piglets showed an apneic response to cow's milk similar to that seen with distilled water. Seven died of asphyxia and an additional three showed sustained respiratory inhibition until milk was replaced with saline. The responses were completely abolished by superior laryngeal nerve (SLN) sectioning. Electrical stimulation of the SLN produced sustained apnea in seven of eight piglets tested. Studies in two 3-day-old lambs showed similar discrimination but only transitory apnea with water or cow's milk. Both died during SLN stimulation. Two ewes showed insignificant responses. These findings suggest a lethal reflex mechanism with implications for the SIDS problem.

Hemodynamic and morphologic evaluation of the spleen after splenic vein ligation in the dog.

The splenic vein was ligated in ten dogs in order to evaluate the time course of changes in splenic size and to relate them to splenic arterial flow, splenic pressure and development of venous collaterals. Following ligation of the splenic vein, splenic size and venous pressure immediately rose in all dogs. Arterial flow to the spleen simultaneously fell in roughly inverse proportion to the elevation of venous pressure. During the following weeks, the splenic parenchymal pressure decreased to basline levels in all but one dog, as collateral veins developed through the gastric venous network to the portal vein. Splenic size gradually decreased toward normal in eight of the ten dogs. At the time of sacrifice, 8-16 weeks after splenic vein ligation, pathologic examination demonstrated fibrosis from healed infarction. Recent hemorrhage, indicating persistence of the congestive process, we also present, although difficult to explain in view of normal splenic parenchymal pressure.

Amelioration of hyperlipidemia by low fat diets in chronically streptozotocin-diabetic rats.

The effects of reduced dietary fat intake on plasma lipid levels were examined in diabetic rats. One week after induction of diabetes (D) with streptozotocin (65 mg/kg, iv), the animals were fed food pellets consisting of 1.5% (D1.5), 2.5% (D2.5) or 5% (D5) fat for two weeks. Irrespective of the diets, both food and water consumed by untreated diabetic rats were 2- to 5-fold greater respectively compared to normal. Plasma glucose concentrations were also similarly increased. Plasma and skeletal muscle lipid levels were significantly greater than controls in D2.5 and D5, but not in the D1.5 group. Plasma and muscle lipid concentrations correlated directly with fat consumption. In D5 rats receiving insulin treatment, plasma glucose and lipid concentrations were comparable to control values. These findings indicate that the degree of hyperlipidemia in chronically diabetic rats is directly related to dietary fat intake. They also demonstrate that dietary interventions can modulate some of the metabolic abnormalities in diabetes.

Cardiac dimensions in severely anemic neonatal pigs.

The effects of chronic severe anemia on weights and chamber volumes of hearts were studied in 9 spontaneously anemic neonatal pigs (mean hematocrit = 10.1%) and 10 healthy piglets (mean hematocrit = 28.3%) of approximately the same age and similar body weights. All cardiac chamber weights, as well as total heart weight/body weight ratios, were significantly higher in the anemic pigs than in the healthy pigs (P less than 0.001). The left ventricular free wall/right ventricular free wall weight ratio was identical in the 2 groups. Calculated left ventricular volume/body weight ratio also was significantly greater in the anemic pigs (P less than 0.05). It is concluded that cardiac dilatation and hypertrophy occur consistently in chronically anemic neonatal pigs. These changes are independent of age or body weight of the animal.

Potentiation by calcium channel blockade of hypoxic myocardial depression in the neonate.

The objectives of this study were to examine the independent and combined effects of beta blockade (practolol) and calcium channel blockade (verapamil) on cardiac responses to hypoxia in the neonate. Lambs were anaesthetized with pentobarbital (20 mg/kg) and were prepared for measurements of left ventricular (LV) performance under controlled hemodynamic conditions. Force generation was assessed from curves relating LV systolic pressure (SP) to end-diastolic pressure (LVEDP) over a broad range of afterloading. Velocity was determined from simultaneous measurements of LV dP/dtmax. Values obtained at LVEDP 10 cm H2O were used to compare interventions. Practolol (P) caused no significant reduction in SP10, but dP/dt10 fell from 51 to 37 (X 10(2] mm Hg/sec (p less than 0.05). Verapamil (V), 2 micrograms/min/kg, reduced measures of contractility (p less than 0.01). Doubling the dose of V further reduced SP10 to 79% of control. Hypoxemia (PaO2, 32 torr) increased SP10 from 172 to 192 mm Hg, and dP/dt10 from 51 to 85 (X 10(2] mm Hg/s (p less than 0.001). After P, the same degree of hypoxia elicited no changes in LV function. During infusion of V (4 micrograms/min/kg), hypoxia reduced SP10 from 138 to 122 mm Hg (p less than 0.01) and dP/dt10 from 29 to 24 (X 10(2] mm Hg/sec (p less than 0.05). It is concluded that in the absence of adrenergic support, hypoxia significantly depresses both force and velocity parameters of contractility in hearts with calcium channel blockade.

Restoration of coronary dilator action of adenosine in experimental diabetes.

We have recently shown that the coronary dilator action of adenosine is reduced in animals with experimental diabetes mellitus. Effects of insulin replacement are reported in the present study. Lambs, age 6-17 days, were studied 1-2 days after induction of diabetes with alloxan (150 mg/kg; n = 6). These were compared with nondiabetic controls, age 4-15 days (n = 5). A third group was studied after 8-15 days of diabetes (n = 3). In the acute diabetics blood glucose was 362 +/- 48 mg/dl. Heart rate, dP/dtmax, and myocardial O2 consumption did not differ from controls, but pH tended to be lower (7.29 +/- 0.03). Adenosine was given by left ventricular infusion. Coronary flow changes were significantly lower at all infusion rates (3-15 micrograms X min-1 X kg-1) in the untreated diabetics. Dose-response curves before and after insulin (10 U/kg) were identical in controls. However, in the diabetics, insulin enhanced the dilator response to adenosine, and changes in coronary flow at each infusion rate did not differ from controls. Aminophylline (6 mg/kg) abolished or sharply reduced the dilator responses to adenosine in both controls and diabetics (P less than 0.01). Animals diabetic 1-2 wk were unresponsive to adenosine. But after insulin, the nucleoside elicited vigorous coronary dilatation. It is concluded that insulinopenic diabetes is accompanied by sharply reduced adenosine sensitivity of coronary resistance vessels. Sensitivity is restored by giving insulin. This hormone may modulate adenosine receptor properties of vascular smooth muscle.

Wall tension and myocardial dysfunction after ischemia and reperfusion.

Cell viability is maintained during prolonged ischemia (ISCH) in isolated heart systems because mechanical function is nil (acute hibernation). By contrast, a noncontracting ischemic segment in an in vivo heart exhibits irreversible damage after < or = 30 min. To explore this difference, isolated rabbit hearts were buffer perfused and exposed to elevations of ventricular balloon pressure (BP) during ISCH to mimic systolic stresses of a dyskinetic (DYSK) segment. Relationships of magnitude and duration of stress to recovery of systolic function and metabolism were assessed. After 30 min of reperfusion (R30) in hearts subjected to 90 min of ISCH [10% coronary flow (CF)] and BP = 0, peak systolic pressure (PSP) returned to 69% of control. With BP set at 120 mmHg, recovery was to only 24%. With BP = 80, PSP at R30 was 46%. Extent of recovery was inversely affected by the duration of elevated pressure. Tissue ATP was reduced from 18.5 to 3.7 and glycogen from 164 to 28 mumol/g in the BP = 120 group. CF and myocardial O2 consumption were reduced to 50% at R30; there was a threefold increase in wall stiffness. These data suggest that mechanical stress of DYSK contributes significantly to metabolic and functional deterioration of ischemic myocardium.

Cardiac performance in hemorrhagic shock.

Blood loss of sufficient magnitude to over-ride compensatory mechanisms and result in a lowering of arterial pressure will ultimately lead to irreversible circulatory collapse. Identification of the organ or tissues which may trigger a terminal cascade remains controversial. The weight of evidence supports the view that cardiac performance deteriorates with prolonged oligemic hypotension, although this may not be the initiating or sole reason for irreversible failure of the circulation. Controversy regarding the heart as an important target organ is no doubt in part due to the multiplicity of preparations and protocols, and variety of methods used to characterize cardiac function. We have used ventricular function curves to calibrate LV performance in terms of pump function, while arterial pressure remains at a pre-determined level. With this approach, a progressive decline in stroke volume for a given LV end diastolic pressure is consistently observed in hemorrhagic shock (AP, 30 mmHg). If arterial pressure is briefly re-elevated at 30 minute intervals, permanent deterioration is prevented. However, if the hypotension is sustained for 2 hours, LV performance remains depressed following pressure re-elevation. Among the mechanisms responsible for deterioration of performance, coronary perfusion pressure (CPP) exerts a pivotal role. Thus, no LV depression occurs after 2 hours of shock provided CPP is maintained at normotensive levels. But if myocardial O2 availability falls below 10 ml/min/100 gm of heart, both O2 uptake and extraction decline and this is uniformly accompanied by cardiac failure. This likely reflects mitochondrial damage and impaired aerobic metabolism. These changes are potentiated by the appearance of metabolic acidosis and failure of sympathetic neurohumoral activity. Both factors directly reduce myocardial contractility, but assume much greater importance during shock. While E. coli endotoxin has been shown to reduce cardiac performance, the relative importance of bacterial products which may enter the circulation during hemorrhagic shock in uncertain. Reduced O2 availability, metabolic acidosis and adrenergic failure appear the major determinants of diminished cardiac performance and thereby may contribute to irreversible collapse of circulatory function.

Myocardial oxygen availability and cardiac failure in hemorrhagic shock.

The relationships between left ventricular function and myocardial O2 availability and metabolism were studied in cats with hemorrhagic shock (AP=30 mm. Hg) with the use of a right heart bypass preparation. Aortic flow and heart rate were held constant. Oxygen-carrying capacity was reduced by diluting donor blood with an equal volume of 5 per cent glucose in saline. Oxygen availability was estimated as the product of arterial O2 content and coronary blood flow. All shock animals showed a progressive metabolic acidemia with time, and a fall in coronary flow concomitantly. Four control animals (AP=75 mm. Hg) as well as two shock animals with high arterial oxygen content and hematocrit showed no significant changes in myocardial O2 metabolism or performance over a period of 90 minutes. Nine shock animals with reduced hematocrit demonstrated a progressive reduction in ventricular function, myocardial O2 metabolism, and O2 availability. As O2 availability fell below 10 ml. per minute per 100 Gm. of heart weight, cardiac failure uniformly appeared and was accompanied by a reduction in O2 extraction and consumption. The correlation between left ventricular dP/dt max and O2 availability was highly significant (r = 0.75, p less than 0.01) in shock animals but not in controls. Thus a close relationship between myocardial O2 metabolism and function during the course of hemorrhagic shock has been demonstrated. Reduced myocardial O2 availability is directly linked with the appearance of cardiac failure.

Effects of insulin on cardiac muscle contraction and responsiveness to norepinephrine.

The effects of insulin (In) on contractile activity of isolated cardiac muscle were studied in right ventricular moderator band (MB) of piglets and papillary muscle (PM) of cats and kittens. The muscles were bathed in modified Krebs solution containing 5.6 mM glucose at 30 degrees C and gassed with 95% O2 and 5% CO2. They were paced at 24 contractions per minute isometrically at Lmax. Addition of In (1 U/ml) to the bath induced a biphasic inotropic response to piglet MB. The initial negative effect was due to the preservative (0.2% phenol) in the regular commercial In solution. Following the transitory depression, both active isometric tension (AT) and maximal rate of tension development increased to a maximum (about 120% of control) within 15 min and then declined slightly toward control. Similar positive responses were observed in both cat and kitten PM, but without the initial negative effect. Maximal responses were not diminished by the absence of glucose in the bath. Increases in AT and dT/dt of both MB and PM in response to NE were significantly attenuated in the presence of In compared with untreated muscle. These findings demonstrate that In elicits a positive inotropic effect on mammalian cardiac muscle and that it impairs the inotropic action of NE.

A simplified technique for postmortem evaluation of coronary arteries.

The growth of complex diagnostic and therapeutic technologies in the clinical management of cardiovascular diseases has mandated a more comprehensive and detailed analysis of cases which reach the pathology laboratory. This report describes in detail the relatively simple techniques and protocol which we have employed for postmortem evaluation of the coronary vascular bed and myocardium. The key elements include the use of a pigmented gelatin mass containing radiopaque material (Barosperse), proper injection technique with simultaneous filling of the main coronary vessels at identical pressures, postmortem arteriography, cardiac dissection, and histologic confirmation of coronary and myocardial lesions. Three cases with sharply differing cardiac diseases are presented to illustrate the kind of information which may be obtained with this approach. Our experience in terms of frequency and distribution of occlusive coronary vascular disease and the relationship to age and sex has been summarized. Significant disease (> 75% lumenal obstruction) was identified angiographically and confirmed by dissection in 46 of 57 cases of clinically suspected disease. None of six hearts from patients without clinical evidence for cardiovascular disease demonstrated actual or angiographically false-positive occlusive coronary disease. It is suggested that a more detailed analysis of the coronary vascular bed can be accomplished in the pathology laboratory with this relatively simple approach and that important information bearing on clinical management can be reliably obtained.

Inotropic responses to digoxin during hypoxia and autonomic blockade.

Inotropic responses to digoxin (0.08 mg/kg) were studied in dogs and compared with responses during hypoxemia and autonomic blockade. Changes in left ventricular contractility (VC) were assessed by constructing function curves relating left ventricular (dP/dt)max and stroke volume to end-diastolic pressure. Augmentation of VC was observed 20 min after digoxin infusion and continued to increase until termination of the experiment after 60 min. In animals subjected to autonomic blockade with practolol, TEAC, and atropine, the increases in VC after digoxin were substantially greater. Equally large increases occurred in blocked dogs during sustained hypoxia (Pao2 = 28 mmHg). However, in animals without blockade there was a progressive fall in VC during hypoxia despite digoxin infusion, although less than in those not given digoxin. Serum digoxin levels were measured by radioimmunoassay and did not differ significantly in blocked compared to unblocked dogs or in hypoxic compared to nonhypoxic animals. These findings indicate that digoxin protects the heart from the decrease in myocardial contractility which occurs during extended hypoxia. This protective effect is more pronounced in animals deprived of autonomic function, possibly reflecting the elimination of reflex sympathetic withdrawal ordinarily induced by digitalis.