Beneficial effects of alpha 2-adrenoceptor activity on ischemic myocardium during coronary hypoperfusion in dogs

We have previously reported that alpha 2-adrenoceptor stimulation enhances adenosine-induced coronary vasodilation. In the present study, we tested the hypothesis that alpha 2-adrenoceptor activity exerts beneficial effects on myocardial ischemia through augmentation of vasodilatory effects of released adenosine. In open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the carotid artery. Propranolol was infused into the bypass tube to exclude the metabolic effects of norepinephrine. When clonidine (0.24 micrograms/kg/min i.c.) was infused for 10 minutes after reduction of coronary blood flow by partial occlusion of the bypass tube, coronary blood flow was increased by 43% from 27 +/- 1 ml/100 g/min despite no changes in coronary perfusion pressure (38 +/- 5 mm Hg) and a slight decrease in adenosine release. Both fractional shortening and lactate extraction ratio of the perfused area were significantly improved (fractional shortening, 1.8 +/- 1.0 to 10.9 +/- 1.5%, p less than 0.001; lactate extraction ratio, -57.8 +/- 6.5 to -31.9 +/- 2.4%, p less than 0.005). Identical results were observed in the denervated hearts, indicating that the beneficial effect of clonidine is not attributed to the prevention of norepinephrine release from the sympathetic nerve terminals. The beneficial effects of clonidine were prevented by yohimbine, an alpha 2-adrenoceptor blocking agent. An adenosine receptor antagonist, 8-phenyltheophylline, also prevented the beneficial effects of clonidine, indicating that these beneficial effects are mediated by effects of adenosine. Furthermore, the extent of augmentation of coronary flow in the ischemic heart was coincided with that of augmentation of exogenous adenosine-induced hyperemic flow (40%) by clonidine. Production of cyclic AMP in the coronary artery during myocardial ischemia was augmented by clonidine. In 12 other dogs, myocardial ischemia was produced by intracoronary embolization of microspheres (15 microns in diameter). Clonidine enhanced (39%) the hyperemic coronary flow and improved both fractional shortening and lactate extraction ratio. Thus, we conclude that alpha 2-adrenoceptor stimulation can ameliorate myocardial ischemia mainly due to enhancement of vasodilatory effects of adenosine released from the ischemic myocardium.     

Effect of alpha 1-adrenoceptor blockade on the left ventricular force-length relationship in dogs.

We used the left ventricular (LV) end-systolic force-diameter (Fes-Des) relation to evaluate the effect of an alpha1-adrenoceptor antagonist (bunazosin hydrochloride) on the contractility of the beta-blocked left ventricle. Nine adult mongrel dogs were instrumented with ultrasonic crystals to measure LV diameter and a micromanometer to measure LV pressure. Beta-adrenergic and vagal blockade was induced with intravenous propranolol (2 mg/kg) and atropine (0.2 mg/kg), respectively, and preload was decreased by inferior vena caval occlusion. The slope (Ec) and extrapolated diameter intercept (Do) of the LV Fes-Des relation were derived from end-systolic data obtained in the control state (after beta-blockade) and after bunazosin infusion (1 mg/kg). Ec was used as a new index of LV contractility. After bunazosin infusion, the heart rate and Ec were decreased by 7 and 22%, respectively, in comparison with the control state, whereas Do did not change. These results indicate that alpha1-adrenoceptor blockade significantly reduces myocardial contractility in the beta-blocked canine heart, perhaps by decreasing the intracellular calcium concentration and/or myosin ATPase activity.     

Effects of selective alpha 1-adrenoceptor blockade in dogs with hypoxic pulmonary vasoconstriction

The acute effects of the selective alpha 1-blocker, E-643 (Bunazosine), on experimental pulmonary hypertension (PH) caused by hypoxic pulmonary vasoconstriction (HPV) in mongrel dogs were examined. Ninety second ventilation with 5% O2 and 95% N2 was used for hypoxic stimulation. The effects of E-643 were evaluated at doses of 1, 5, 10, 20 and 50 micrograms/kg in this order until the systemic arterial mean pressure (SAm) had decreased by 20 mmHg when compared with the control value during room air ventilation. PaO2 and PaCO2 decreased by 64.6 +/- 11.0 Torr and 2.4 +/- 2.5 Torr, respectively, and the pH increased by 0.031 +/- 0.012 during hypoxic ventilation. These blood gas changes affected during hypoxic stimulation were almost the same before E-643 administration. Progression of arterial blood hypoxemia due to E-643 administration during room air ventilation was not observed. SAm decreased by 8.0 +/- 11.9 mmHg after E-643 administration, while left atrial mean pressure (LAm) and cardiac output (CO) did not change significantly. Prior to E-643 administration, mean pulmonary arterial pressure (PAm) and pulmonary vascular resistance (PVR) increased by 6.4 +/- 3.3 mmHg and 6.2 +/- 3.8 HRU, respectively, during the 90 sec hypoxic ventilation period. After E-643 administration, the increases in PAm and PVR were 3.9 +/- 1.7 mmHg and 3.3 +/- 2.3 HRU, respectively. The suppression of increases in PAm and PVR was significant. The conclusion is that E-643, a selective alpha 1-blocker, is effective at restraining HPV in the dog model.     

Effect of alpha 1-adrenoceptor blockade on ventricular ectopic beats inacute myocardial infarction

Experimental studies have shown that alpha1-adrenoceptor blockade can reduce ventricular arrhythmia associated with myocardial ischaemia. To examine the efficacy of prazosin in clinical acute infarction 38 patients were randomized, on presentation, to prazosin or placebo. Oral therapy was commenced at 0.5 mg, incremented and continued for seven days, Holter recordings being obtained for the first 48 hours and on day 7. The final dose of prazosin was 2.5 +/- 1.7 (SD) mg and placebo, 3.1 +/- 2.0 mg. During dose titration in the first 24 hours, and on day 7, there was no difference in ventricular ectopic beats. In the second 24 hours, ventricular ectopic beats averaged two per hour in the prazosin group (n = 9) and 60 per hour in placebo (n = 15) (P = 0.05, Mann-Whitney rank testing). The results indicate that alpha1-adrenoceptor blockade may reduce ventricular arrhythmia in clinical acute myocardial infarction. While early and adequate therapy is currently limited by vasodilation, this small study suggests that more extensive clinical trials will be warranted as relatively cardio-selective alpha1-adrenoceptor blocking drugs are developed.     

Effect of adenosine deaminase inhibition with pentostatin on myocardial stunning in dogs

Pentostatin (2-deoxycoformycin) is a potent inhibitor of adenosine deaminase and has been demonstrated to augment endogenous adenosine levels during regional and global myocardial ischemia. Based on the rationale that increasing endogenous adenosine during ischemia may be cardioprotective, the objective of this study was to determine if adenosine deaminase inhibition with pentostatin could improve postischemic contractile dysfunction (stunning) in open-chest anesthetized dogs. All animals underwent 15 min of coronary occlusion followed by 3 h of reperfusion preceded by an intravenous bolus of either 0.2 mg/kg of pentostatin (n=8) or saline (n=7). Sonomicrometers were plced in the ischemic area and were used to measure systolic wall thickening before, during, and after occlusion of the left anterior descending artery. Myocardial blood flow was measured with tracer labeled microspheres at baseline, 10 min of occlusion and at 1 h of reperfusion. Both groups were equally dyskinetic during occlusion (–21±5% of baseline thickening in the controls and –28±8% in the pentostatin group). The pentostatin group, however, demonstrated better contractile function at all time points during reperfusion, which was significantly different from the control group at 3 h of reperfusion. The improvement in regional function in the pentostatin group was not due to significant disparities in hemodynamic variables, size of the region at risk, or in collateral blood flow. These results indicate that pentostatin can ameliorate the severity of myocardial stunning, an effect we propose is due to increasing endogenous levels of adenosine during the ischemic interval. Although significant improvement was detected with pentostatin, the improvement was modest compared to controls, suggesting that the utility of inhibiting adenosine deaminase to modify regional mechanical stunning is limited.Presented in part at the 1993 American Heart Association Scientific Sessions in Atlanta, GA     

Beneficial effects of ibuprofen in acute myocardial ischemia.

Ibuprofen, a nonsteriodal anti-inflammatory agent, was studied in the early stages of myocardial ischemia in order to determine whether it helps preserve myocardial integrity. Ibuprofen was administered intravenously at a dose of 12.5 mg/kg at the time of coronary artery occlusion and again 2.5 h later. Ibuprofen significantly prevented the loss of myocardial creatine phosphokinase (CPK) release in ischemic cardiac tissue. In addition, this drug significantly returned S-T segment elevation toward normal values, and significantly prevented the myocardial loss of compounds having free amino nitrogen groups, an index of proteolysis. Although ibuprofen moderated the increased plasma CPK activity, plasma CPK values 5 h after coronary occlusion were above control values. Thus, ibuprofen significantly prevented alterations in three of the four indices used to assess myocardial ischemic damage. The protective mechanism of ibuprofen may be via stabilization of cellular membranes (i.e., lysosomal membranes) and to a lesser extent on reduction in myocardial oxygen demand.     

Abnormal myocardial contraction in alpha(1A)- and alpha(1B)-adrenoceptor double-knockout mice

We used double-knockout mice (ABKO) lacking both predominant myocardial alpha(1)-adrenergic receptor (AR) subtypes (alpha(1A) and alpha(1B)) to determine if alpha(1)-ARs are required for normal myocardial contraction. Langendorff-perfused ABKO hearts had higher developed pressure than wild type (WT) hearts (123 +/- 3 mmHg n = 22 vs. 103 +/- 3 mmHg, n = 38, P < 0.001). Acutely inhibiting alpha(1)-ARs in WT hearts with prazosin did not increase pressure, suggesting that the increased pressure of ABKO hearts was mediated by long-term trophic effects on contraction rather than direct regulatory effects of alpha(1)-AR removal. Similar to perfused hearts, ABKO ventricular trabeculae had higher submaximal force at 2 mM extracellular [Ca(2+)] than WT (11.4 +/- 1.7 vs. 6.9 +/- 0.6 mN/mm(2), n = 8, P < 0.05); however, the peaks of fura-2 Ca(2+) transients were not different (0.79 +/- 0.11 vs. 0.75 +/- 0.16 microM, n = 10-12, P > 0.05), suggesting ABKO myocardium had increased myofilament Ca(2+)-sensitivity. This conclusion was supported by measuring the Ca(2+)-force relationship using tetanization. Increased myofilament Ca(2+)-sensitivity was not explained by intracellular pH, which did not differ between ABKO and WT (7.41 +/- 0.01 vs. 7.39 +/- 0.02, n = 4-6, P > 0.05; from BCECF fluorescence). However, ABKO displayed impaired troponin I phosphorylation, which may have played a role. In contrast to increased submaximal force, ABKO trabeculae had lower maximal force than WT at high extracellular [Ca(2+)] (29.6 +/- 1.9 vs. 37.6 +/- 1.4 mN/mm(2), n = 7, P < 0.01). However, peak cytosolic [Ca(2+)] was not different (1.13 +/- 0.15 vs. 1.19 +/- 0.04 microM, n = 6-7, P > 0.05), suggesting ABKO myocardium had impaired myofilament function. Finally, ABKO myocardium had decreased responsiveness to beta-AR stimulation. We conclude: alpha(1)-ARs are required for normal myocardial contraction; alpha(1)-ARs mediate long-term trophic effects on contraction; loss of alpha(1)-AR function causes some of the functional abnormalities that are also found in heart failure.     

缺氧预处理对于老年大鼠心肌顿抑的影响

目的　探讨缺氧预处理对于老年大鼠心肌顿抑的影响及其保护机制。方法　老年和成年SD大鼠分别随机分为单纯心肌顿抑组、缺氧预处理 +心肌顿抑组、SB2 0 35 80 +缺氧预处理 +心肌顿抑组和假手术组 4组 ,采用在体心脏心肌顿抑模型 ,观察缺氧预处理对于心肌舒缩功能、乳酸脱氢酶、肌酸激酶漏出和亚硝酸盐含量的影响 ,以及p38丝裂素活化蛋白激酶 (p38MAPK)选择性抑制剂SB2 0 35 80对于缺氧预处理作用的影响。结果　缺氧预处理明显减轻老年大鼠心肌收缩功能抑制的程度 ,与单纯心肌顿抑组比较 ,收缩期左心室内压力变化最大速率 (+dp dtmax)和零负荷时左室心肌最大收缩速率 (Vmax)分别高 35 %和 4 9% (P <0 .0 5 )。缺氧预处理减轻再灌注结束时心肌顿抑大鼠血清亚硝酸盐的下降程度 ,与老年心肌顿抑组大鼠比较 ,其含量高 5 4 % (P <0 .0 1) ,SB2 0 35 80 2消除缺氧预处理上调血清亚硝酸盐含量和老年大鼠心肌收缩功能的保护作用。结论　缺氧预处理可以减轻老年大鼠心肌顿抑所致收缩功能抑制 ,其保护机制涉及p38MAPK介导的一氧化氮的上调。     

Energy metabolism in myocardial stunning.

We investigated the effect of reversible ischemia, leading to persistent contractile dysfunction (stunning), on myocardial energy metabolism. The balance of energy metabolism is expressed by the phosphorylation state of cytosolic nucleotides. This variable cannot be measured directly because of nucleotide compartmentation, but in the isolated heart it can be estimated by the release of purine catabolites. We have previously shown that increased energy consumption or impaired energy production cause purine release to increase, while primary reduction in energy consumption has the opposite effect. Isolated working rat hearts were reperfused after 10 min of global ischemia, measuring hemodynamic variables, tissue high energy phosphate compounds and purine release. In post-ischemic recovery, aortic flow and minute work decreased to 82 +/- 3% and 77 +/- 4% of control, adenine nucleotide pool was reduced by 4.6 mumol/g dry wt, phosphocreatine to creatine ratio increased significantly and purine release decreased to 42 +/- 6% (P < 0.01). The rate of purine salvage, as evaluated by the incorporation of exogenous 3H-adenosine and 14C-hypoxanthine into tissue nucleotides, was much lower than net purine release, and was unchanged after ischemia and reperfusion. The adenine nucleotide pool could be depleted to the same extent as in the stunned myocardium by prolonged (60 min) aerobic perfusion. In this group the hemodynamic variables were unchanged and purine release averaged 87 +/- 9% of control (P = NS). In other experiments prolonged perfusion was combined with preload reduction in order to decrease energy demand. This protocol reproduced the effects of ischemia-reperfusion: aortic flow and minute work averaged 79 +/- 4% and 73 +/- 9% of control, adenine nucleotide depletion was 4.4 mumol/g dry wt and purine release decreased to 38 +/- 5% (P < 0.01). Our findings support the view that stunning is not due to adenine nucleotide depletion or to impairment in energy production, which would cause purine release to increase, but rather to primary reduction in energy utilization.     

Staged reperfusion attenuates myocardial stunning in dogs. Role of transient acidosis during early reperfusion.

BACKGROUND. Acidosis during early reperfusion is reported to be beneficial for myocardial stunning. We tested in 31 dogs the hypothesis that staged reperfusion is beneficial to myocardial stunning. METHODS AND RESULTS. Contractile dysfunction was observed 3 hours after the onset of reperfusion after 15 minutes of occlusion of the coronary artery. In the staged reperfusion, pH of the coronary venous blood was lower for 20 minutes and fractional shortening was significantly improved compared with the control reperfusion group. When we increased pH of the reperfused myocardium by an intracoronary infusion of sodium bicarbonate, beneficial effects of the staged reperfusion were abolished. Furthermore, an intracoronary infusion of hydrogen chloride, which mimicked the changes in pH in coronary venous blood of the staged reperfusion, attenuated myocardial stunning. CONCLUSIONS. These results indicate that acidosis during staged reperfusion primarily attenuates myocardial stunning. This procedure is clinically applicable for attenuation of reperfusion injury.     

Ischemic event characteristics determine the extent of myocardial stunning in conscious dogs

Both the severity and duration of postischemic myocardial dysfunction (stunned myocardium) are unpredictable and may vary considerably between subjects that underwent apparently similar ischemic insults. To explain this heterogeneous response of the heart to ischemia and reperfusion, we investigated the determinants of stunning in conscious dogs.Twenty-five dogs were chronically instrumented for measurement of global and regional myocardial performance (wall thickening) and myocardial perfusion (coloured microspheres). A hydraulic occluder was positioned around the LAD coronary artery. Conscious dogs were subjected to acute coronary artery occlusions of predetermined duration (2, 5 and 10 min), followed by complete reperfusion.Multiple regression analysis identified the following variables as determinants of postischemic contractile recovery: 1) the duration of ischemia (p<0.01), 2) the amount of collateral perfusion (p=0.01) and 3) left ventricular end-diastolic pressure during ischemia (p<0.01). Neither the severity of regional dyskinesia during ischemia nor indices of global systolic hemodynamic performance correlated with the rate of recovery.Our data confirm that myocardial stunning relates primarily to the intensity of preceding ischemia. Variations in the preexisting level of collateral perfusion may result in markedly different recovery profiles. Except for LV end-diastolic pressure during ischemia, indices of global and regional cardiac performance fail to predict the severity of postischemic contractile failure.Supported in part by the Nationaal Fonds voor Wetenschappelijk Onderzoek: grant #3.0071.90     

Alpha 1-adrenoceptor activity regulates release of adenosine from the ischemic myocardium in dogs

The goal of this study was to test the hypothesis that alpha 1-adrenoceptor activity plays a key role in the release of adenosine from the ischemic myocardium. In 51 open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the carotid artery, and adenosine release into the local coronary vein was measured by the radioimmunoassay technique following the reduction of perfusion pressure for 20 minutes under alpha 1-, alpha 2-, and beta-adrenoceptor attenuations. Adenosine and lactate concentrations in the coronary arterial and venous blood sampled from the perfused area were determined, as well as fractional shortening. In the untreated condition, adenosine release was significantly (p less than 0.01) increased from 1.7 +/- 0.8 (SEM) to 8.8 +/- 1.3 nmol/100 g/min, 20 minutes after the onset of hypoperfusion (coronary blood flow: 28 +/- 2 ml/100 g/min) following the initial overshoot release. Neither beta- nor alpha 2-adrenoceptor attenuation affected the increase in adenosine release during hypoperfusion except for the slight attenuation of the overshoot release by beta-attenuation. In contrast, intracoronary infusions of prazosin and phentolamine during coronary hypoperfusion markedly attenuated (p less than 0.01) release of adenosine (1.8 +/- 0.7 nmol/100 g/min at 20 minutes). The extents of decreases in fractional shortening and lactate production were comparable between the untreated and alpha 1-adrenoceptor attenuation.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Arg389Gly beta1-adrenoceptor polymorphism and catecholamine effects on plasma-renin activity.

OBJECTIVES: The purpose of this research was to find out whether, in humans, dobutamine-induced hemodynamic effects and increase in plasma-renin activity (PRA) might be beta1-adrenoceptor (beta1AR) genotype-dependent. BACKGROUND: In vitro Arg389Gly-beta1AR polymorphism exhibits decreased receptor signaling. METHODS: We studied 10 male homozygous Arg389-beta1AR subjects and 8 male homozygous Gly389beta1AR subjects; to avoid influences of codon 49 polymorphism, all were homozygous Ser49-beta1AR. Subjects were infused with dobutamine (1 to 6 microg/kg/min) with or without bisoprolol (10 mg orally) pretreatment, and PRA, heart rate, contractility, and blood pressure were assessed. RESULTS: With regard to PRA, dobutamine increased PRA more potently in Arg389-beta1AR versus Gly389-beta1AR subjects. Bisoprolol markedly suppressed the dobutamine-induced PRA increase in Arg389- but only marginally in Gly389-beta1AR subjects. With regard to hemodynamics, dobutamine caused larger heart rate and contractility increases and diastolic blood pressure decreases in Arg389- versus Gly389-beta1AR subjects. Bisoprolol reduced dobutamine-induced heart rate and contractility increases and diastolic blood pressure decreases more potently in Arg389- versus Gly389-beta1AR subjects. CONCLUSIONS: Codon 389 beta1AR polymorphism is a determinant not only of hemodynamic effects but also of PRA. Thus, beta1AR polymorphisms may be useful for predicting therapeutic responses to betaAR-blocker treatment.     

Mechanism of decongestant activity of alpha 2-adrenoceptor agonists

The vascular bed in nasal mucosa of different species, including human, is highly vascularized and an extensive sinusoidal network of large capacitance vessels is present deep within the submucosa. When this network of venous sinusoids is engorged with blood, the swollen mucosa reduces the size of the airway lumen and congestion ensues. Nasal vasculature tone is strongly influenced by the sympathetic nervous system and the only drugs approved specifically to relieve vascular nasal obstruction are alpha-adrenoceptor sympathomimetic agents. Due to their vasoconstrictor action, the sympathomimetic decongestants oppose vasodilation, reducing nasal airway resistance and thus facilitating nose breathing. However, standard decongestants that are non-selective alpha-adrenoceptor agonists are associated with the potential for side-effect liabilities including hypertension, stroke, insomnia and nervousness. We propose than a selective alpha 2-adrenoceptor agonist, by acting preferentially on nasal venous capacitance vessels, will elicit decongestion with a reduced side-effect liability. In the present study, we evaluated the effects of the selective alpha 2-adrenoceptor agonist BHT-920 in a real-time tissue contractility assay using isolated pig nasal explants and in an in vivo cat model of congestion. The vasoconstrictor and decongestant effects of BHT-920 were compared to the non-selective alpha-adrenoceptor agonist epinephrine and the standard decongestant oxymetazoline. Our results showed that the alpha 2-adrenoceptor agonist BHT-920 preferentially contracts venous sinusoids confirming previous observations [Corboz MR, Varty LM, Rivelli MA, Mutter JC, Mingo G, McLeod R, et al. Effects of an alpha 2-adrenoceptor agonist in nasal mucosa. Arch Physiol Biochem 2003;11: 335-6, Corboz MR, Rivelli MA, Varty LM, Mutter J, Cartwright M, Rizzo CA, et al. Pharmacological characterization of postjunctional alpha-adrenoceptor in human nasal mucosa. Am J Rhinol 2005;19: 495-502] and displays decongestion without affecting blood pressure. Therefore, an alpha 2-adrenoceptor agonist, by causing constriction in the capacitance vessels of nasal mucosa, can produce nasal decongestion without the effects on blood pressure observed with the standard selective alpha 1-adrenoceptor and non-selective alpha-adrenoceptor sympathomimetic decongestants.     

Adenosine attenuates in vivo myocardial stunning with minimal effects on cardiac energetics

Adenosine has been shown to modulate myocardial intermediary metabolism. The purpose of this study was to determine whether adenosine-mediated attenuation of in vivo myocardial stunning is associated with improved myocardial phosphorylation potential. Adult, open chest pigs were subjected to 10 minutes of regional myocardial ischemia and 90 minutes reperfusion. Regional ventricular function was assessed by measuring systolic wall thickening. Myocardial phosphorylation potential was estimated from the tissue (CrP/CrxP_i) ratio determined in rapid-frozen tissue biopsy samples from normal and stunned myocardium. Control pigs were compared to animals treated prior to ischemia with intracoronary adenosine (50 μg/kg/min). Postischemic regional systolic wall thickening in adenosine treated pigs was significantly improved (40±3% of preischemic values) compared to control untreated pigs (26±3%). Myocardial stunning was associated with decreased ATP levels, but neither the total creatine pool (CrP+Cr) nor the (CrP/CrxP_i) ratio was reduced. Adenosine pretreatment was associated with decreased P_i and Cr contents resulting in improved postischemic (CrP/CrxP_i) ratio in the stunned bed compared to controls, but this effect occurred only after postischemic function had attained maximal improvement. These results suggest that adenosine attenuation of in vivo myocardial stunning is independent of elevated myocardial phosphorylation potential. Received: 6 January 1998, Returned for 1. revision: 2 February 1998, 1. Revision received: 24 February 1998, Accepted: 12 March 1998     

Effects of nifedipine on triggered activity in 1-day-old myocardial infarction in dogs

Triggered activity arising from a delayed afterdepolarization occurs in canine subendocardial Purkinje fibers 1 day after myocardial infarction (MI). Standard microelectrode techniques were used to study small preparations (20 to 48 mm2) in vitro. Nifedipine, 1 mg/liter, reversibly suppressed triggered activity by reducing maximum diastolic potential, action potential amplitude and the rate of depolarization of the delayed afterdepolarization. Complete quiescence or exit block resulted. The effects of nifedipine were antagonized by elevating extracellular calcium ion concentration. These results suggest that spontaneous ectopic rhythms 1 day after MI that are the result of triggered activity are dependent on transmembrane calcium ion movement, which nifedipine can directly antagonize.     

Beneficial effects of methionine on myocardial hemodynamic and cellular functions in hemorrhagic shock.

Hypochlorous acid (HOCl), produced by activated polymorphonuclear (PMN) leukocytes, has been reported to depress cardiac function and contractility. Various mechanisms exist for activation of PMN leukocytes during hemorrhagic shock and reperfusion. In order to determine the role of HOCl in hemorrhagic shock and reinfusion, the authors studied the effects of shock and reinfusion on the cardiac function, contractility, blood lactate, blood gases, and creatine kinase (CK) and MB fraction of CK (MBCK) with and without methionine (quencher of HOCl) in anesthetized dogs. Dogs were divided into two groups: Group I, hemorrhagic shock (two hours) and reinfusion (two hours): Group II, hemorrhagic shock and reinfusion with methionine treatment. Cardiac index, mean arterial pressure, and index of cardiac contractility were similar in the two groups during shock. Postinfusion recovery of cardiac function and contractility was better in group II. Increases in blood lactate were similar in the two groups during shock. The rate of return of blood lactate to preshock values after reinfusion was greater in group II. The increases in serum CK and MBCK of the two groups during shock were similar but not significant. Following reinfusion the levels of these enzymes increased significantly, but the increases in group II were less. These results suggest that HOCl produced by activated PMN leukocytes may play a role in cardiac damage during hemorrhagic shock and reinfusion. Methionine may have beneficial effects in the hemodynamic and metabolic recovery and may reduce cellular damage during hemorrhage shock and reinfusion.     

Beneficial metabolic effects of methylprednisolone sodium succinate in acute myocardial ischemia.

The metabolic and hemodynamic effects of methylprednisolone sodium succinate (40 mg/kg body weight) after acute myocardial ischemia were determined in 24 heparinized mongrel dogs. Myocardial ischemia was produced by ligation of the left anterior descending coronary artery. Catheters in the coronary sinus and the vein draining the left anterior descending coronary arterial area were used to collect blood samples from nonischemic and ischemic myocardium. Lactate, pyruvate, glucose, free fatty acids and oxygen were measured in arterial and venous blood from ischemic and nonischemic areas before and 3, 30 and 60 minutes after myocardial ischemia in animals with (Group II) and without (Group I) steroid treatment. In both Groups I and II glucose, lactate, free fatty acids, oxygen and coronary blood flow in nonischemic areas were not significantly changed, whereas glucose uptake in ischemic areas was significantly increased with myocardial ischemia and remained elevated. In Group I lactate uptake in ischemic areas became negative after coronary arterial ligation and remained so; in Group II, it increased after 30 (70%) and 60 (111%) minutes. Free fatty acid uptake in ischemic areas was reduced after myocardial ischemia in Group I, but in Group II it increased after 30 (224%) and 60 minutes (173%), and there was a concomitant increase in oxygen uptake. Pyruvate uptake in nonischemic areas decreased after 60 minutes in Group I, whereas it was reduced after 30 (68%) and 60 minutes (513%) in Group II. The changes were similar in ischemic myocardium. There were no significant changes in hemodynamic indexes. Coronary blood flow in ischemic areas decreased in Group I after myocardial ischemia and further after 30 and 60 minutes, but in Group II it increased after 30 (82%) and 60 minutes (53%). The data indicate that administration of methylprednisolone results in improved collateral blood flow into the infarcted area and a significantly improved metabolic response of ischemic myocardium. The glucocorticoid may also have a direct benefical effect on carbohydrate metabolism and cause the increased pyruvate neccesary to maintain the generation of energy-producing substrates. The results also suggest that methylprednisolone increases cell survival time and results in greater salvage of ischemic myocardium.