Depressed Cardiac Contractility Research Articles

Studies of hypoxemic/reoxygenation injury: Without aortic clamping:: V. Role of the l-arginine–nitric oxide pathway: The nitric oxide paradox

This study tests the hypothesis that nitric oxide, which is endothelial-derived relaxing factor, produces reoxygenation injury via the L-arginine–nitric oxide pathway in hypoxemic immature hearts when they are placed on cardiopulmonary bypass. Twenty 3-week-old piglets undergoing 2 hours of hypoxemia (oxygen tension about 25 mm Hg) on a ventilator were reoxygenated by initiating cardiopulmonary bypass (oxygen tension about 400 mm Hg). Five animals were not treated, whereas the pump circuit was primed with the nitric oxide–synthase inhibitor N G -nitro- L-arginine methyl ester( L-NAME, 4 mg/kg) in five piglets. L-Arginine, the substrate for nitric oxide, was administered in a fivefold excess (20 mg/kg), together with L-NAME in five piglets ( L-NAME and L-arginine), and given alone in five other piglets ( L-arginine). Five normoxemic, instrumented piglets served as a control group, and five others underwent 30 minutes of cardiopulmonary bypass without preceding hypoxemia. Left ventricular contractility was determined as end-systolic elastance by pressure-dimension loops. Myocardial conjugated dienes were measured as a marker of lipid peroxidation, and the antioxidant reserve capacity (malondialdehyde production in tissue incubated with t-butylhydroperoxide) was measured. Nitric oxide level was determined in coronary sinus plasma as its spontaneous oxidation product, nitrite. Cardiopulmonary bypass per se did not alter left ventricular contractility, cause lipid peroxidation, or lower antioxidant capacity. Reoxygenation without treatment depressed cardiac contractility (end-systolic elastance 38% ± 12% of control*), raised nitric oxide (127% above hypoxemic values), increased conjugated dienes (1.3 ± 0.2 vs 0.7 ± 0.1, control*), and reduced antioxidant reserve capacity (910 ± 59 vs 471 ± 30, control*). Inhibition of nitric oxide production by L-NAME improved end-systolic elastance to 84% ±12%,** limited conjugated diene elution (0.8 ± 0.1 vs 1.3 ± 0.2, no treatment**), and improved antioxidant reserve capacity (679 ± 69 vs 910 ± 59, no treatment**). Conversely, L-arginine counteracted these beneficial effects of L-NAME, because left ventricular function recovered only 24% ± 6%,* conjugated dienes were 1.2 ± 0.1,* and antioxidant reserve capacity was 826 ± 70.* L-Arginine alone caused the same deleterious biochemical changes as L-NAME/ L-arginine and resulted in 60% mortality. The close relationship between postbypass left ventricular dysfunction (percent end-systolic elastance) and myocardial conjugated diene production ( r = 0.752) provides in vivo evidence that lipid peroxidation contributes to myocardial dysfunction after reoxygenation. These results suggest the L-arginine–nitric oxide pathway, which is normally of physiologic benefit by producing endothelial-derived relaxing factor, is involved in the pathogenesis of myocardial reoxygenation injury (* p < 0.05 vs control; ** p < 0.05 vs no treatment, analysis of variance). (J T HORAC C ARDIOVASC S URG 1995;110:1200-11)

Anesthetic alteration of ryanodine binding by cardiac calcium release channels

Differential cardiac contractile depression by volatile anesthetics is well documented, and evidence points to differing actions on the myocardial sarcoplasmic reticulum (SR). Since the Ca 2+-release channel (CaRC) of the SR binds ryanodine with high-affinity when opened by micromolar Ca 2+ concentrations, ryanodine binding to cardiac SR membrane vesicles was employed as an assay of anesthetic modulation of CaRC activity. Canine ventricle was homogenized, centrifuged preparatively and then differentially on a sucrose gradient. A fraction enriched with CaRCs was defined by: the presence of a ∼450 kDa protein consistent with CaRC; ∼3-fold enhancement of vesicular 45Ca 2+ uptake by ruthenium red; Ca 2+-activated [ 3H]ryanodine binding. Specific binding of 10 nM ryanodine was activated by > 0.5 μ M Ca 2+ and was maximal at ∼6 pmol/mg protein in ≥ 20 μM Ca 2+. Halothane (1.5%), but not isoflurane, shifted the Ca 2+-dependence of ryanodine binding to lower [Ca 2+]. With submaximal activation by 5 μM Ca 2+, 1.5% and 0.75% halothane enhanced binding of 10–80 μM ryanodine, while 2.5% isoflurane and 3.5% enflurane did not. A plot of bound/free vs. bound ryanodine suggests that halothane causes a dose-dependent increase in ryanodine binding to a high-affinity site, while isoflurane has no such action. In intact myocardium, this effect will decrease Ca 2+ retention in the SR so that less Ca 2+ will be available to activate contractions, consistent with halothane's depressant action.

Free Radical Scavengers Prevent Intestinal Ischemia-Reperfusion-Mediated Cardiac Dysfunction

Our previous studies show that intestinal ischemia impairs cardiac function. This present study examined the contribution of oxygen-derived free radicals to cardiac dysfunction after intestinal ischemia-reperfusion in a rat model of superior mesenteric artery (SMA) occlusion (atraumatic clip for 20 min) and ligation of collateral arcades from the right colic and jejunal arteries. Controls were sham operated (Group 1, n = 10); in Group 2, 20 rats with SMA occlusion were sacrificed 2-5 hr after reperfusion without treatment. Superoxide dismutase (SOD) and catalase, scavengers of oxygen-derived free radicals which have been shown to effectively reduce ischemic injury in several models of traumatic injury, were given as 6000 units/350 g body wt either 1 min after SMA occlusion (Group 3, n = 11) or 2 min after reperfusion (Group 4, n = 10). To examine the contribution of neutrophils as a source of free radicals, additional groups of animals were treated with pentoxifylline (PTX, a methylxanthine derivative which has been shown to decrease neutrophil adherence and aggregation as well as to decrease superoxide production) either 1 min after SMA occlusion (Group 5, n = 10) or 2 min after reperfusion (Group 6, n = 10). Cardiac contractile depression occurred in the untreated ischemic group as indicated by a fall in left ventricular pressure (from 77 ± 3 to 63 ± 4 mm Hg, P < 0.01) and + dP/dt max (from 1827 ± 60 to 1558 ± 98 mm Hg/sec, P < 0.03) and - dP/dt max (from 1267 ± 57 to 953 ± 68 mm Hg/sec, P < 0.02). Contractile depression after untreated ischemia-reperfusion was confirmed by a rightward shift in left ventricular function curves and decreased responsiveness to perfusate calcium. Both free radical scavengers (SOD and catalase) and neutrophil stabilization (PTX) prevented ischemia-reperfusion-mediated cardiac dysfunction, and left ventricular function curves for these treated groups were identical to those generated by control hearts. We conclude that oxygen-derived free radicals from activated neutrophils contribute, in part, to intestinal ischemia-reperfusion-mediated cardiac dysfunction.

Lipid peroxidation contributes to cardiac deficits after ischemia and reperfusion of the small bowel.

Our previous studies showed that intestinal ischemia-reperfusion (IR) impairs cardiac contractile function. The present study examined the contribution of oxygen free radicals and lipid peroxidation of cardiac cell membrane to cardiac dysfunction after intestinal IR in a rat model of superior mesenteric artery (SMA) occlusion (atraumatic clip for 20 min) and collateral arcade ligation. Controls were sham operated (group 1, n = 25). In group 2, 30 rats with SMA occlusion were killed 3-4 h after reperfusion without treatment. Aminosteroid (U-74389F), a pharmacological agent known to inhibit lipid peroxidation of membranes, was given 1 min before occlusion of the SMA (group 3, n = 19). All rats were killed 3-4 h after reperfusion of the ischemic intestine, and the hearts were harvested for in vitro assessment of cardiac function (Langendorff preparation). Cardiac contractile depression occurred in the untreated group as indicated by a fall in left ventricular pressure (from 76 +/- 3 to 64 +/- 3 mmHg, P = 0.01), maximum +dP/dt (from 1,830 +/- 60 to 1,577 +/- 64 mmHg/s, P = 0.05), and maximum -dP/dt (from 1,260 +/- 50 to 950 +/- 60 mmHg/s, P = 0.005). Lipid peroxidation of cardiac membranes occurred after untreated IR as indicated by the rise in cardiac malondialdehyde levels (MDA) (from 0.203 +/- 0.046 to 0.501 +/- 0.044 nM/mg protein, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia.

We investigated whether increased nitric oxide (NO) synthase activity within cardiac myocytes contributes to the depressed cardiac contractility observed in endotoxic shock. Isolated ventricular myocytes were studied to examine the effects of substrates and inhibitors of NO synthase on myocyte contractility. When stimulated electrically, the resting length of myocytes from control animals shortened by 5.3 +/- 0.3% (means +/- SE, n = 32). Baseline contraction of myocytes from endotoxin-treated animals was reduced to 3.0 +/- 0.3% (n = 17, P < 0.001). The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) had no effect on myocytes from control animals, but it increased the contraction of myocytes from endotoxin-treated animals by 40% (fractional shortening increased to 4.3 +/- 0.4%, P < 0.01). Similar results were obtained with NG-methyl-L-arginine. The effect of L-NAME could be reversed by excess L-arginine, but not D-arginine. The effect of endotoxin was abolished by dexamethasone pretreatment. Methylene blue also reversed the effects of endotoxin but had toxic effects on myocytes. Agents that either prevent synthesis or the effects of NO reverse the depression of myocyte contraction seen following endotoxin treatment.

N GMethyl-L-arginine decreases contractility, cGMP and cAMP in isoproterenol-stimulated rat hearts in vitro

N G-Methyl-L-arginine (NMA), an inhibitor of nitric oxide synthesis by vascular endothelium, depresses cardiac function and causes systemic vasoconstriction in vivo. The mechanism of cardiac depression is unclear. Since cGMP inhibits one isoform of myocardiai phosphodiesterase (PDE), we hypothesized that a decrease in cGMP might increase PDE activity and lower myocardial cAMP levels, resulting in decreased contractility. Experiments were conducted in isolated, paccd, Langendorff-perfused (constant flow) rat hearts under control or isoproterenol-stimulated conditions. In non-stimulated hearts, a 15 min infusion of 30 μM NMA had no effect on cAMP content or on left ventricular dP/dt; however, myocardial cGMP content was decreased. Infusion of 0.01 μM isoproterenol caused dP/dt to increase and caused coronary resistance to fall; myocardial cAMP levels increased while cGMP remained unchanged by isoproterenol. In this stimulated condition, infusion of 30 μM NMA decreased dP/dt and myocardial cGMP and cAMP concentrations. NMA caused coronary resistance to increase to similar maximal values in isoproterenol-stimulated and non-stimulated hearts. Although coronary flow was kept constant during NMA administration, NMA depressed cardiac contractility in isoproterenol-stimulated hearts, but not in non-stimulated hearts, and the depressed contractility in isoproterenol-treated hearts was associated with a decrease in myocardial content of cGMP and cAMP. Therefore, these results arc consister with the hypothesis that NMA may decrease myocardial contractility by decreasing cGMP which leads to increased PDE activity and decreased cAMP.

Acute Hypotension Caused by Rapid Hypertonic Saline Infusion in Anesthetized Dogs

Small volumes (4-6 mL/kg) of 7.5% hypertonic saline solution (HTS) are reported to be effective for resuscitation from circulatory shock. When infused rapidly into either hypovolemic or normovolemic subjects, HTS can cause an immediate and severe hypotension before cardiovascular improvement. In the present study, we examined the hypothesis that the early hypotension produced by HTS was mediated by an acute and transient depression of cardiac contractility. left ventricular pressure and wall motions were measured simultaneously in 10 anesthetized dogs for the assessment of cardiac contractility. Infusion of HTS at 3 mL/kg in 1 min significantly decreased mean arterial blood pressure by 49%, from 95 +/- 4 to 51 +/- 5 mm Hg (P less than 0.05, mean +/- SEM) at 45 s after the onset of infusion. This initial decrease in arterial blood pressure was abrupt and transient (106 +/- 9 s). Concomitantly, cardiac output and coronary blood flow increased significantly from 2.8 +/- 1.0 to 3.9 +/- 1.1 L/min and from 23.7 +/- 5.3 to 49.8 +/- 4.7 mL/min, respectively. Although heart rate remained constant, systolic shortenings of left ventricular diameter and wall thickness increased from 5.6% +/- 0.5% to 7.8% +/- 0.5% and from 13.9% +/- 0.6% to 15.1% +/- 1.2%, respectively, indicating an improvement in cardiac contractility. This was confirmed by subsequent analysis of the left ventricular end-systolic pressure-diameter relationship. Systemic and pulmonary vascular resistance decreased by 60% and 27%, respectively. Despite an initial period of hypotension after rapid infusion of HTS, mean arterial blood pressure, cardiac output, and contractility were all significantly increased at 5 min after HTS infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac contractile injury after intestinal ischemia-reperfusion

Experimental and clinical data suggest that even a brief period of intestinal ischemia followed by reperfusion initiates a sequence of events that include release of inflammatory mediators and multiorgan failure. In this study, 41 rats were subjected to occlusion of the superior mesenteric artery (SMA) for 20 min and collateral arcade ligation. Twelve rats were sham operated and served as controls (group 1). Groups of rats with SMA occlusion were killed at several time intervals after reperfusion (group 2, 2-3 h; group 3, 4-5 h; group 4, 12-16 h). In group 5, rats were pretreated with enterally administered allopurinol (10 mg.kg-1.day-1) for 4 days before the intestinal ischemia episode and were studied 2-3 h after reperfusion. In vivo studies confirmed that 20 min of intestinal ischemia produced a transient bradycardia (P less than 0.05) and no change in systemic blood pressure, acid-base balance, or hematocrit. In vitro studies showed marked cardiac contractile depression as early as 2 h after ischemia-reperfusion as indicated by a fall in left ventricular pressure (LVP; from 77 +/- 3 to 63 +/- 4 mmHg, P = 0.01) and +dP/dtmax (from 1,827 +/- 59 to 1,557 +/- 99 mmHg/s, P less than 0.02) and -dP/dtmax (from 1,267 +/- 57 to 953 +/- 67 mmHg/s, P = 0.02), a rightward shift in LV function curves, and a decreased responsiveness to perfusate Ca2+. Allopurinol pretreatment prevented ischemia-reperfusion-mediated deficits in cardiac contraction and relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic response of endotoxemic calves to treatment with small-volume hypertonic saline solution

Summary The hemodynamic effects of hypertonic saline solution (hss) resuscitation on endotoxic shock were examined in pentoharhital-anesthetized calves (8 to 20 days old). Escherichia coli (055:B5) endotoxin was infused iv at dosage of 0.1 μg/kg of body weight for 30 minutes. Endotoxin induced large decreases in cardiac index, stroke volume, maximal rate of change of left ventricular pressure (+ dP/dtmax), femoral and mesenteric arterial blood flow, glomerular filtration rate, urine production, and mean aortic pressure. Severe pulmonary arterial hypertension and increased pulmonary vascular resistance were evident at the end of endotoxin infusion. Treatment with hss (2,400 mosm of NaCl/L, 4 ml/kg) or an equivalent sodium load of isotonic saline solution (iss: 300 mosm of NaCl/L, 32 ml/kg) was administered 90 minutes after the end of endotoxin administration. Both solutions were infused iv over a 4- to 6-minute period. Administration of hss induced immediate and significant (P &lt; 0.05) increase in stroke volume and central venous pressure, as well as significant decrease in pulmonary vascular resistance. These effects were sustained for 60 minutes, after which all variables returned toward preinfusion values. The hemodynamic response to hss administration was suggestive of rapid plasma volume expansion and redistribution of cardiac output toward splanchnic circulation. Plasma volume expansion by hss was minimal 60 minutes after resuscitation. Administration of iss induced significant increase in cardiac index, stroke volume, femoral arterial blood flow, and urine production. These effects were sustained for 120 minutes, at which time, calves were euthanatized. Compared with hss, iss induced sustained increase in mean pulmonary arterial pressure and only a small increase in mesenteric arterial blood flow. The rapid administration of large-volume iss appears superior to small-volume hss for initial resuscitation of acutely endotoxemic, anesthetized calves. At this time, we do not advocate rapid infusion of iss to septicemic calves because exacerbation of pulmonary hypertension may potentially depress respiratory function, and rapid increase in preload may hemodynamically compromise calves with depressed cardiac contractility.

Effects of bradykinin in the rat isolated perfused heart: role of kinin receptors and endothelium-derived relaxing factor.

1. The effects of bradykinin (BK) in the microcirculation of the isolated perfused heart of the rat were examined. The kinin receptors mediating the effects of BK were characterized and the role of endothelium-derived relaxation factor (EDRF) and prostacyclin investigated. 2. The dose-related vasodilator responses elicited by bolus doses of BK (0.001-10.0 nmol) were competitively blocked by the selective kinin B2 receptor antagonist [D-Arg0,Hyp3, Thi5.8,D-Phe7]-bradykinin (pA2 = 6.8). Des-Arg9-bradykinin, a selective kinin B1 receptor agonist had no vasodilator activity at doses of up to 10 nmol. 3. L-NG-nitro arginine (100 microM; L-NOArg), an inhibitor of endothelium-dependent vasodilatation, reduced the duration but not the magnitude of the BK vasodilator response. This action of L-NOArg was not reversed by L-arginine (100 microM). 4. Superoxide dismutase (10 units ml-1), haemoglobin (10 microM) and methylene blue (MB; 1 microM), all known to modify EDRF-mediated responses, failed to alter the vasodilator action of BK. 5. Gossypol (1-15 microM), a presumed inhibitor of EDRF biosynthesis, caused a marked drop in perfusion pressure followed by vasoconstriction. These changes in coronary tone were accompanied by an irreversible depression of cardiac contractility and heart rate. Over the same concentration range gossypol abolished the vasodilator action of BK (1.0 nmol), however it also blocked the endothelium-independent vasodilator response to sodium nitroprusside (30 nmol) and the vasoconstrictor effect of endothelin-1 (10 pmol) which suggests non-specific toxic actions of gossypol. 6. Bolus injections of BK (0.001-1.Onmol) failed to elevate basal levels of prostacyclin (PGI2) as shown by assaying for its stable metabolite 6-keto-PGF<,,. In addition, BK-induced vasodilatation was not blocked by flurbiprofen (2 microM) or BW755C (7.5 microM) which are inhibitors of the arachidonic acid pathway. When added with L-NOArg (100 microM), flurbiprofe(10 microM) did not potentiate the inhibitory action of L-NOArg on the BK response. 7. These results show that the vasodilator action of BK in the rat heart is dependent on the activation of the kinin B2 receptors but independent of PGI2 release. Although a conclusive role for EDRF could not be established, this study has questioned the suitability of several agents commonly used as inhibitors of EDRF-mediated responses.

Effects of thiopental on resistance vessels in cat skeletal muscle

Barbiturates are used clinically as anaesthetics and to reduce raised intracranial pressure. One side effect is hypotension, usually ascribed to a depression of cardiac contractility, while their effects on the resistance vessels are more controversial: both vasodilation and vasoconstriction have been described. This study analyzes the effects of thiopental on basal vascular tone in the cat skeletal muscle. We found that total resistance increased by almost 20% at low (50 mumol/l) and decreased down to about 50% of control at high (350 mumol/l) plasma concentrations of thiopental. The vasoconstriction dominated in the large arterioles (i.d. greater than 25 microns) and the vasodilation in the small arterioles (i.d. less than 25 microns). A dose-dependent inhibition of myogenic vascular reactivity (here defined as the maximum resistance increase to a transient rise in transmural pressure) coincided with the vasodilation. Autoregulation of blood flow was depressed by thiopental. During vasoconstriction there was a net transcapillary fluid absorption and during vasodilation a net fluid filtration. The fluid movements could be ascribed to variations in capillary hydrostatic pressure. If applicable to the cerebral circulation these results suggest that thiopental at high plasma concentrations might induce, instead of reduce, interstitial brain oedema.

Cardiac dysfunction in isolated perfused hearts from spontaneously diabetic BB rats

The purpose of this investigation was to examine cardiac function and biochemistry in spontaneously diabetic BB rats, a strain in which diabetes occurs spontaneously and closely resembles insulin-dependent diabetes in humans. The study involved two groups: nondiabetic littermates of BB rats and BB diabetic rats treated daily with a very low insulin dose such that the rats were severely hyperglycemic and hyperlipidemic. The hearts from these two groups were isolated and heart function (using isolated perfused working hearts) and biochemistry were examined 6 weeks after the onset of diabetes. BB diabetic rats exhibited a lower calcium-stimulated myosin ATPase activity and depressed left ventricular developed pressure, cardiac contractility, and ventricular relaxation rates compared with BB nondiabetic littermates. These results suggest that the chronically diabetic state in the BB rat produces cardiac changes similar to those demonstrable after chemical diabetes induced by alloxan or STZ, or that seen during human diabetes mellitus.

Depression of Cardiac Contractility by Anesthetics

Depression of Cardiac Contractility by Anesthetics

Effect of L-carnitine treatment on lipid metabolism and cardiac performance in chronically diabetic rats.

The beneficial effects of L-carnitine administration were studied in vivo in isolated perfused working hearts from control and diabetic rats. Control and streptozocin-induced diabetic (STZ-D) rats were treated daily for 6 wk with high-dose L-carnitine (3 g.kg-1.day-1 i.p.). STZ-D results in loss of body weight and hypoinsulinemia. These effects were not altered by L-carnitine treatment. Myocardial free-carnitine levels were decreased in the untreated diabetic rats. L-Carnitine treatment of the diabetic rats increased myocardial free-carnitine levels, which were comparable with those of control rats. Six weeks after STZ administration, hearts from untreated diabetic animals exhibited depressed left ventricular developed pressure, cardiac contractility, and ventricular relaxation rates compared with control animals. However, this depression was not seen in the L-carnitine-treated diabetic animals. L-Carnitine treatment of diabetic rats significantly reduced plasma glucose and lipid levels but had no effect on control rats. Furthermore, thyroid hormone levels were higher in the L-carnitine-treated diabetic rats than in the untreated diabetic group. The data suggest that high-dose L-carnitine treatment may reduce the severity of diabetes and result in improved cardiac performance.

Chronic ethanol exposure in the embryonic chick heart: effect on myocardial function and structure.

To investigate the effect of chronic ethanol exposure on the embryonic chick heart, chick embryos were exposed daily to one of seven graded doses of ethanol or to saline only (shams) from 0 to 96 hr of incubation. One hour before and after exposure at 72 hr, and 1 hr before and after exposure at 96 hr, embryos were analyzed for changes in heart function, embryo tissue ethanol content, occurrence of anomalies, and embryo weights. At both 71 and 73 hr of incubation (during cardiogenesis), when compared to shams, heart rate (HR) in embryos receiving ethanol doses greater than 0.0375 ml increased significantly (P less than .05) with commensurate increases in injected ethanol. Additionally, at 73 hr, depressed cardiac contractility, measured as shortening fraction, was noted at doses greater than or equal to .0375 when compared to shams. While slight increases in shortening fraction (SF) across dose were noted at 95 and 97 hr, only random doses were statistically significant from shams, with no specific trend in either HR or SF at this postcardiogenesis stage. Within each time group, gas chromatography analysis of embryo tissue ethanol content demonstrated a linear relationship between dose injected and tissue ethanol content retrieved. With increasing dose and stage, viability decreased. Weights of ethanol-injected embryos were not significantly different from shams within each time group. Our studies of the response of the embryonic chick heart to ethanol indicate both dose and stage susceptibility, with greater susceptibility to ethanol injury during active cardiogenesis.

Immune cytokine inhibition of beta-adrenergic agonist stimulated cyclic AMP generation in cardiac myocytes

We hypothesize that reversible depression of cardiac function in cardiac allograft rejection and lymphocytic myocarditis reflects down modulation of the beta-adrenergic receptor system by a soluble product of activated immune cells. Thus, exposure of cultured cardiac myocytes to mixed lymphocyte culture or activated splenocyte supernatants produces 70% inhibition of isoproterenol-stimulated cAMP concentrations (K i = 5% supernatant) in the absence of gross cellular injury or control media effects. This cAMP suppressive factor is not dialyzable and is ammonium sulfate precipitable. Beta-adrenergic receptor density, binding constant and affinity states are unaffected. These results demonstrate the existence of a cytokine inhibitor of cAMP accumulation that may mediate, in part, depression of cardiac contractility observed when immune cells invade the myocardium.

Control of myocardial tissue components and cardiocyte organelles in pressure-overload hypertrophy of the cat right ventricle.

Previous studies have demonstrated that there is a disproportionate increase in connective tissue in right ventricular myocardium subjected to pressure-overload hypertrophy associated with depressed cardiac contractility. While the myocardium is primarily responsive to load, the aim of the present study was to determine whether catecholamines also modulate the response of myocardial tissue components and cardiocyte organelles in pressure-overload-induced cardiac hypertrophy. Four experimental groups of cats were examined: a sham-operated control group, a group which had their pulmonary arteries banded in order to induce a pressure overload, a group which had been subjected to the same pressure overload, but in addition had beta-adrenoceptor blockade produced prior to and during the pressure overloading, and a group which had been subjected to the same pressure overload, but in addition had alpha-adrenoceptor blockade produced prior to and maintained during the pressure overloading. As in our previous study, there was a significant and equivalent degree of right ventricular hypertrophy in all experimental groups with pressure overload when assessed either as the ratio of right ventricular weight to body weight or as cardiocyte cross-sectional area. At the light microscopic level, the disproportionate increase in the volume density of myocardial connective tissue seen in banded animals was completely prevented by either alpha- or beta-adrenoceptor blockade. At the electron microscopic level, there was a reduction in the mitochondrial and myofibrillar volume fractions following beta-adrenoceptor blockade. The results of this study provide evidence for a modulatory role of catecholamines in the control of myocardial connective-tissue proliferation in pressure-overload-induced cardiac hypertrophy. There is also evidence to support the role of the adrenergic nervous system in regulating cardiocyte subcellular organelles, independent of the regulation of cardiocyte size.

Left ventricular function during lethal and sublethal endotoxemia in swine.

Our previous studies suggested that after a median lethal dose (LD50) of endotoxin, cardiac contractility was depressed in nonsurviving dogs. The canine cardiovascular system is unlike humans in that dogs have a hepatic vein sphincter that is susceptible to adrenergic stimulation capable of raising hepatic and splanchnic venous pressures. We retested the hypothesis that lethality after endotoxin administration is associated with cardiac contractile depression in pigs, because the hepatic circulation in this species is similar to that of humans. We compared cardiac mechanical function of pigs administered a high dose (250 micrograms/kg) or a low dose (100 micrograms/kg) endotoxin by use of the slope of the end-systolic pressure-diameter relationship (ESPDR) as well as other measurements of cardiac performance. In all the pigs administered a high dose, ESPDR demonstrated a marked, time-dependent depression, whereas we observed no significant ESPDR changes after low endotoxin doses. The other cardiodynamic variables were uninterpretable, due to the significant changes in heart rate, end-diastolic diameter (preload), and aortic diastolic pressure (afterload). Plasma myocardial depressant factor activity accumulated in all endotoxin-administered animals, tending to be greater in the high-dose group. In this group, both subendocardial blood flow and global function were depressed, whereas pigs administered the low dose of endotoxin demonstrated slight, but nonsignificant, increases in flow and function. These observations indicate that myocardial contractile depression is associated with a lethal outcome to high doses of endotoxin. One possible mechanism for this loss of contractile function may be a relative hypoperfusion of the subendocardium.

Disparate unloading efficacy of the calcium channel blockers, verapamil and nifedipine, on the failing hypertensive left ventricle

Calcium channel blockers reduce arterial smooth muscle tone and lower blood pressure. They may be regarded as left ventricular (LV) unloading agents. LV unloading efficacy of nifedipine (15 patients) and verapamil (14 patients) was tested in hypertensive decompensated patients, during a 1-month treatment period. Nifedipine persistently reduced systemic vascular resistance (SVR), mean arterial pressure, mean pulmonary wedge pressure (PWP), and LV diastolic diameter, and improved cardiac index and velocity of circumferential fiber shortening (Vcf). All of the patients had relief from dyspnea and reduction in heart size. The only side effect was ankle edema in six. Verapamil reduced SVR and mean arterial pressure and was not effective on PWP, LV diastolic diameter, and Vcf. The drug was discontinued in two patients who developed severe dyspnea at rest after 3 to 4 days of continuous oral treatment. Clinical symptoms and signs did not improve in the remaining patients despite persistent pressure reduction. A less potent vasodilating action of verapamil and a prominent depression in cardiac contractility may account for the differential results with the two compounds, in spite of a shared vasodilating antihypertensive effect. These findings indicate that functional changes in the failing hypertensive heart may differ from one calcium blocker to another as a result of interaction and relative preponderance of influence on afterload and contractility.

Acute effects of iron on contractile function in isolated rabbit myocardium.

Changes in contractile function following exposure to iron (Fe) salts were evaluated in isolated isometrically contracting rabbit left atrial strips and right ventricular papillary muscles. Fe acutely depressed myocardial contractility as evidenced by dose-related declines in developed force and maximal rate of force development. There were no significant changes in duration of contraction or resting force. The tissue Fe content was increased nearly 3-fold after a 60 min exposure to Fe and subsequently was not decreased by repeated washing or by treatment with deferoxamine. Isoproterenol, but not deferoxamine, reversed the Fe-mediated impairment of myocardial contractility. These findings suggest that in cases of severe acute iron poisoning, depression of cardiac contractility might occur which may be improved by treatment with isoproterenol.