Effects of endothelial and inducible nitric oxide synthases inhibition on circulatory function in rats after myocardial infarction.

OBJECTIVES: To examine the relative roles of eNOS and iNOS (endothelial and inducible nitric oxide synthases) on basal and beta-adrenergic receptor (beta-AR)-stimulated arterial hemodynamic responses after myocardial infarction (MI). METHODS: Left ventricular (LV) pressures and steady-state and pulsatile arterial hemodynamics were measured at baseline, and after acute NOS inhibition with either NG-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg) or iNOS inhibition with aminoguanidine (AG, 75 mg/kg) in sham-operated and MI Sprague-Dawley rats. RESULTS: In sham rats, L-NAME decreased (P < 0.05) peak positive LV dP/dt and aortic blood velocity by 19% and 53%, respectively, and increased (P < 0.05) mean arterial pressure (MAP); systemic vascular resistance, and LV end-diastolic pressure (EDP) by 20, 189 and 89%, respectively. The frequency-dependent components of hemodynamics including aortic input impedance modulus, characteristic impedance, and phase shift were increased (P < 0.05) with L-NAME, while pulsatile power was decreased (P < 0.05). AG increased (P < 0.05) aortic input impedance modulus and characteristic impedance but had no effect on any other hemodynamic variable. In MI rats, L-NAME decreased (P < 0.05) LV dP/dt and aortic blood velocity by 22 and 55%, respectively, and increased (P < 0.05) SVR by 108%. There was no effect of L-NAME on MAP or LV EDP in MI rats. After MI, AG increased (P < 0.05) heart rate and LV dP/dt but had no effect on other LV or pulsatile hemodynamic variables. Compared to sham rats, heart rate, LV dP/dt, and blood velocity-isoproterenol dose responses were shifted downward (P < 0.05), while SVR-isoproterenol dose response was shifted upward (P < 0.05) in MI rats. In sham rats, L-NAME potentiated (P < 0.05, at > 10(-2) micrograms/kg) the isoproterenol-induced increase in LV dP/dt and aortic blood velocity, and potentiated (P < 0.05) the isoproterenol-induced decline in SVR. As expected, AG had no effects on isoproterenol-stimulated hemodynamics in sham rats. After MI, there was no effect of L-NAME or AG on isoproterenol-stimulated hemodynamics. CONCLUSIONS: (1) Circulatory and cardiac responses to inhibition of NO by L-NAME suggest that eNOS, but not iNOS, is the principal regulator of integrated arterial hemodynamic function in rats. (2) Both basal and beta-AR-stimulated NO regulation of hemodynamic are attenuated after MI. (3) The attenuation of arterial hemodynamic effects after isoproterenol is mediated, in part, by alterations in the beta-AR-activation of eNOS system after MI.     

Nucleotide precursors modify the effects of isoproterenol. Studies on heart function and cardiac adenine nucleotide content in intact rats

In closed-chest rats, isoproterenol (ISO, 25 mg/kg), 5 hours after subcutaneous administration, increased heart rate by 53%, left ventricular (LV) dP/dtmax by 80%, and cardiac output by 37%. LV systolic pressure (LVSP, -10%), mean arterial pressure (MAP, -12%), and total peripheral resistance (TPR, -36%) were diminished. In separate experiments, continuous intravenous infusion of adenine (50 mg/kg/hr) for 5 hours reduced heart rate (-11%), LVSP (-16%), MAP (-20%), TPR (-33%), and LV dP/dtmax (-20%). Cardiac output was increased (+20%). Inosine has been shown to have similar effects, except for a decline in cardiac output. Adenine (50 mg/kg/hr) attenuated the ISO-induced increase in heart rate and LV dP/dtmax and aggravated the decline in LVSP, MAP, and TPR. The increase in cardiac output was not changed. Inosine (200 mg/kg/hr) modified the ISO effects to a similar extent. Ribose (200 mg/kg/hr) added to the adenine infusion did not have functional effects. However, it aggravated the modifying influence of inosine on LVSP, LV dP/dtmax, and MAP. ISO reduced the cardiac ATP content (mumol/g) from a control value of 5.02 +/- 0.06 (n = 12) to 3.51 +/- 0.13 (n = 10). Adenine (3.56 +/- 0.21, n = 7) and ribose (3.64 +/- 0.11, n = 9) alone did not affect it, but inosine attenuated it (4.33 +/- 0.08, n = 8). Adenine and inosine in combination with ribose abolished the ISO-induced ATP decline (5.18 +/- 0.23, n = 7, and 4.76 +/- 0.10, n = 8, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term endothelin receptor blockade improves cardiovascular function in diabetes

To evaluate the potential contribution of endothelin-1 (ET-1) toward the cardiovascular complications of diabetes, the present study examined the effects of chronic ET receptor blockade with bosentan on heart function and vascular reactivity in streptozotocin (STZ)-induced diabetic rats. Wistar rats were divided into four groups: control, control bosentan-treated, diabetic, and diabetic bosentan-treated. After chronic bosentan treatment, cardiac function and vascular reactivity were assessed. Exvivo working heart function was determined in terms of rate of contraction (+dP/dt), rate of relaxation (−dP/dt), and left ventricular developed pressure (LVDP). Contractile responses to ET-1 were determined in isolated superior mesenteric arteries. In addition, ET-1-like immunoreactivity was determined in ventricular and vascular tissues by immunohistochemistry. Cardiac function was depressed in the untreated-diabetic group. Bosentan treatment improved working heart function; hearts from the diabetic bosentan-treated group exhibited improved LVDP and −dP/dt. The contractile responses of mesenteric arteries to ET-1 were exaggerated in the untreated-diabetic group. Long-term bosentan treatment normalized these responses. Immunohistochemical analyses revealed increased ET-1-like immunoreactivity in ventricular and vascular tissues from untreated diabetic rats. These data show the beneficial effects of ET_A/B receptor blockade on cardiovascular function in STZ-diabetic rats. An altered ET-1 system may contribute toward the pathogenesis of cardiovascular dysfunction in diabetes.     

Left ventricular function after chronic insulin treatment in diabetic and normal rats

Previous reports have documented a cardiomyopathy in rats resulting from streptozotocin-induced diabetes. In order to determine the reversibility of streptozotocin-induced cardiomyopathy to insulin therapy, hearts from rats made diabetic by streptozotocin for 6 weeks and then treated with insulin for 3 weeks were compared with untreated diabetic rats and control rats not injected with streptozotocin. When perfused in an isolated working heart apparatus with 5.5 mM glucose as substrate, hearts from untreated diabetic rats when compared to hearts from either streptozotocin-injected rats treated with insulin or control rats showed significant depressions in peak left ventricular pressure, maximal positive and negative dP/dt, oxygen extraction, lactate production and effluent lactate; pyruvate ratio. Ca2+-actomyosin ATPase was also depressed in untreated diabetics. As left atrial pressure was raised in untreated diabetic rats, a decline in cardiac output was observed, whereas in insulin-treated or control groups there was no such negative response. Indices of cardiac performance were significantly greater in insulin-treated rats when compared to control rats suggesting overcorrection with insulin therapy. To explore whether insulin treatment may have a beneficial effect on the myocardium control rats were made hyperinsulinemic for 6 to 7 weeks. Shorter isovolumic relaxation times and elevated values for Ca2+-actomyosin ATPase were observed in hearts from hyperinsulinemic animals when compared to hearts from control animals. These results demonstrate complete reversibility of streptozotocin-induced cardiomyopathy and confirm that this condition is due to insulin deficiency and not to a primary cardiotoxic effect of streptozotocin.     

Role of nitric oxide in posthypoxic contractile dysfunction of diabetic cardiomyopathy

We investigated the role of nitric oxide synthase (NOS) in the contractile dysfunction of diabetic cardiomyopathy, comparing streptozotocin-treated (60 mg/kg) diabetic Wistar rats with matched non-diabetic controls. Isolated isovolumic heart function was studied during normoxia and in response to brief hypoxia-reoxygenation. Diabetic hearts had significantly lower left-ventricular pressure and slower isovolumic relaxation than controls (relaxation time constant, T 40.2+/-2.3 vs. 27.7+/-0.9 ms; P<0.05) and a blunted response to hypoxia. These abnormalities were unaffected by NOS inhibition. Upon reoxygenation after brief hypoxia, diabetic hearts exhibited substantial worsening of LV relaxation compared to normal hearts (T 69.1+/-3.3 vs. 56.6+/-7.9 ms; P<0.05). This post-hypoxic diastolic dysfunction was significantly attenuated either by the non-selective NOS inhibitor L-NAME, the iNOS inhibitor L-NIL, or the reactive-oxygen-species (ROS) scavenger thiourea. Only diabetic hearts expressed iNOS protein, whereas eNOS expression was similar in both groups. In conclusion, diabetic hearts exhibit markedly abnormal post-hypoxic relaxation, which is attributable to both ROS and NO derived from iNOS.     

Cardiac dysfunction in the Goto-Kakizaki rat

METHODS: Both isolated perfused hearts and isolated ventricular myocytes from GK and matched control Wistar rat hearts were studied. Percent myocyte twitch shortening (%TS) and corresponding intracellular calcium transients (indo-1 fluorescence ratio, R) were measured over a range of stimulation frequencies (0.5-2.5 Hz; 32 degrees C, n = 16-24 cells). In isolated Langendorff-perfused hearts, we measured systolic LV pressure (LVP(max)), left ventricular end diastolic pressure (LVEDP), maximal rate of LV pressure rise (LV dP/dt(max)) and fall (LV dP/dt(min)) and isovolumic LV relaxation (exponential time constant, T) both at baseline and during brief (10 minutes) hypoxia. RESULTS: The %TS and corresponding indo-1 R were similar between GK and control myocytes at all stimulation frequencies (e.g. at 2.5 Hz: % TS = 8.6 +/- 0.77 and 8.2 +/- 0.19; R = 0.19 +/- 0.009 and 0.18 +/- 0.018, GK and control respectively, P = NS). Similarly, there were no significant differences in baseline LVP(max) (129 +/- 6.2 and 135 +/- 9.6 mmHg; GK and control respectively, P = NS), LV dP/dt(max) (3169.5 +/- 165.80 and 3390.6 +/- 232.60 mmHg/s; GK and control respectively, P = NS), LV dP/dt(min) or T (24 +/- 0.7 and 25 +/- 0.6 ms, GK and control respectively, P = NS). During 10 min hypoxia, LV dP/dt(max) decreased significantly more, and LVEDP and T increased significantly more, in GK compared to control hearts (LV dP/dt(max): 668.90 +/- 32.8 versus 1027.10 +/- 84.0 mmHg/s; LVEDP: 21.4 +/- 4.3 versus 11.6 +/- 0.6 mmHg; T: 102 +/- 13.8 versus 56 +/- 3.0 ms; GK versus control respectively; all P < 0.05). These abnormalities in GK hearts were reversed with acute addition of insulin (0.01 i. u./ml) to the perfusion buffer. CONCLUSION: The GK model of Type II diabetes displays a mild cardiomyopathy evident as exaggerated diastolic dysfunction during hypoxia. The mechanism is likely to involve substrate deficiency. Experimental study of cardiac function in the diabetic heart has focussed mostly on models of Type I diabetes. We studied cardiac function in the Goto-Kakizaki (GK) rat, an inbred model of spontaneous non-obese, Type II diabetes.     

Central nervous system is involved in the cardiovascular responses to naloxone in canine endotoxic but not hemorrhagic shock

We used naloxone to investigate the role of central nervous system opiate receptors in the cardiovascular depression of canine hemorrhagic and endotoxic shock. Shock was induced by bleeding dogs into a reservoir to achieve and maintain a mean arterial pressure (MAP) of 45 mmHg for 30 min; at 30 min the reservoir was clamped and the animals were treated with intracerebroventricular (ICV) perfusion of naloxone 0.1 mg/kg (n = 5) or artificial CSF (n = 5) for 30 min. Endotoxemic shock was induced by the iv injection of E. coli endotoxin 1 mg/kg; 15 min later the animals were given naloxone 0.1 mg/kg (n = 5) or artificial CSF (n = 5) ICV for 30 min. ICV naloxone significantly increased MAP, cardiac output (CO), and left ventricular performance (LV dP/dt max) compared to artificial CSF in canine endotoxic shock but not hemorrhagic shock. Naloxone 0.1 mg/kg (n = 5) given into the cisterna magna failed to significantly improve MAP, CO, or LV dP/dt max in dogs subjected to reservoir hemorrhagic shock for 60 min compared to artificial CSF (n = 5). These results are compatible with opiate-receptor-mediated central cardiovascular depression in endotoxic shock and peripheral cardiovascular depression in hemorrhagic shock. Accordingly, the sites of action of naloxone are mainly central in endotoxic shock and peripheral in hemorrhagic shock.     

Hemodynamic effects of naloxone on hemorrhagic shock in the beagle

Naloxone reverses the hypotension in various types of hemorrhagic shock models. What has yet to be firmly established is the mechanism by which naloxone reverses the hypotension. In a canine hemorrhagic shock model, impedance cardiography and invasive methods were used to measure various cardiovascular parameters. All dogs (beagles, 10-15 kg) were bled to and maintained at a mean arterial blood pressure (MAP) of 60 mmHg for 90 min and were then given either naloxone (2 mg/kg; n = 6) or an equivalent volume of saline (n = 6) intravenously (IV). After another 90 min observation period, the shed blood was reinfused. No significant differences in the preshock and shock cardiodynamics were noted between the naloxone and the control animals. During the treatment period, MAP was significantly increased in the naloxone group. There was no increase in cardiac output (CO), stroke volume (SV), end diastolic volume (EDV), dP/dt max, dP/dt/P, or HI (the impedance contractility index) over control animals. The most significant parameter improvement was total peripheral resistance (TPR). The data suggest that naloxone in this hemorrhagic shock model improves hemodynamics primarily by increasing vascular resistance.     

Augmented age-associated innate immune responses contribute to negative inotropic and lusitropic effects of lipopolysaccharide and interferon gamma

Innate immunity not only mediates early host defenses to infection, but also contributes to septic hemodynamic compromise through nitric oxide synthase (NOS2) induction and inhibition of cardiovascular adrenergic responses. Because of increased age-related susceptibility to sepsis, we hypothesized that hearts from old (28-29 months) adult rats would exhibit greater beta-adrenergic hyporesponsiveness than young (6-8 months) following lipopolysaccharide (LPS, 6 mg/kg) with and without interferon gamma (INF-gamma, 5000 units). LPS/INF-gamma depressed baseline +dP/dt and isoproterenol-stimulated inotropy in both old and young hearts. beta-adrenergic inotropic (+dP/dt) and lusitropic responses were more depressed in old v young LPS/INF-gamma hearts. Additionally isoproterenol-stimulated cAMP elaboration was less in old (1950+/-160 fmol/min/g) v young (2440+/-170 fmol/min/g, P=0.05) LPS/INF-gamma hearts. LPS alone also depressed basal +dP/dt and prolonged myocardial relaxation in old and young hearts, but suppressed isoproterenol +dP/dt responses only in old hearts. Depressed beta-adrenergic inotropic responses were augmented with the selective NOS2 inhibitor N-iminoethyl-L-lysine. To establish biochemical mechanisms for this, we tested whether induction of NOS2 and innate immune system receptors (CD14 and Toll-like receptor 4, TLR4) were enhanced in old v young hearts. Induction of myocardial NOS2 and CD14 (not present in control) by LPS/INF-gamma was approximately 2-3-fold greater in old compared to young animals. TLR4 was constitutively expressed in old and young hearts and was unaffected by LPS/INF-gamma. These findings indicate that advanced age is associated with augmented cardiac beta-adrenergic depression and enhanced CD14-NOS2 signaling in response to cytokines. Upregulation of cardiovascular innate immunity may have clinical implications for increased mortality in older individuals with systemic inflammatory response syndromes.     

Comparison between angiotensin receptor antagonism and converting enzyme inhibition in heart failure

This study was designed to assess the influence of the activation status of the renin angiotensin system (RAS) on the hemodynamic effects of EXP 3174 (an angiotensin AT1 receptor antagonist) and enalaprilat (an angiotensin converting enzyme inhibitor) in tachycardia-induced heart failure. Thirteen dogs were chronically instrumented to measure left ventricular (LV) pressure, its first time derivative (LV dP/dt), atrial and aortic pressures, and cardiac output. EXP 3174 (0.1 mg/kg, iv) or enalaprilat (1 mg/kg, iv) were administered in conscious dogs with heart failure induced by right ventricular pacing (250 beats/min, 3 weeks). EXP 3174 and enalaprilat produced significant vasodilation but the effects of EXP 3174 on mean aortic pressure (MAP), cardiac output, and total peripheral resistance (TPR) were only 50% of those produced by enalaprilat. When dogs were grouped according to their baseline plasma renin activity (PRA) values, in dogs with normal PRA (0.5 ± 0.1 ng/ml/h) EXP 3174 did not produce significant change in MAP and TPR, while enalaprilat decreased significantly MAP and TPR. In contrast, in dogs with high PRA (6.7 ± 3.2 ng/ml/h), EXP 3174 produced significant reductions in MAP and TPR, which were similar to those produced by enalaprilat. Thus, in conscious dogs with heart failure, enalaprilat is effective whether the RAS is activated or not. In contrast, EXP 3174 is effective only when the RAS is activated. These results may help in the choice of inhibitors of the RAS in heart failure. Received: 22 September 1998, Returned for revision: 14 October 1998, Revision received: 23 November 1998, Accepted: 8 December 1998     

不同HO-1表达水平对糖尿病模型大鼠血管舒张功能及NOS的影响

目的 探讨改变血红素加氧酶-1(HO-1)表达水平对糖尿病(DM)大鼠血管舒张功能的影响及与一氧化氮合酶(NOS)/一氧化氮(NO)的关系.方法 以链脲佐菌素(STZ)诱导DM大鼠模型.SD大鼠分成4组:对照组、DM组、正铁血红素(HO-1诱导剂)组、锌原卟啉(HO-1抑制剂)组.应用离体血管张力检测技术观察胸主动脉舒张功能变化;RT-PCR法及比色法分别检测血管组织和血清中诱生型NOS(iNOS)及内皮型NOS(eNOS)的表达和NO含量.结果 与DM组相比,正铁血红素组血管环对乙酰胆碱舒张百分率有所提高,而锌原卟啉组血管舒张反应继续下降.应用正铁血红素可在提高DM大鼠血管和血清eNOS表达的同时降低iNOS/NO表达;而锌原卟啉组血清中iNOS活性及其在血管组织表达均增高.结论 提高HO-1的表达水平有益于改善DM大鼠血管舒张反应失调,这种保护作用与抑制iNOS/NO的生成、上调eNOS表达水平有关.     

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.     

Basal inotropic state in rats with renal hypertension: influence of coronary flow and perfusion pressure

Cardiac performance in renal hypertensive animals has been variously reported as normal, increased, or decreased. Because of the many factors that can alter cardiac function in vivo ventricular contractility was investigated in isolated, paced, isovolumic heart preparations (modified Langendorff). Twenty one hypertensive rats (2 kidney, 1 clip Goldblatt) and 21 matched sham operated controls, were studied. Mean(SD) blood pressure and left ventricular weight were significantly higher in the study rats (228(5) vs 125(2) mmHg and 4.16(0.12) vs 2.35(0.04) mg X kg-1 respectively). In the first experiment performed at 50 mmHg perfusion pressure left ventricular +dP/dt and myocardial flow rate were lower in 12 study rats (mean(SD) 1782(79) vs 2270(105) mmHg X s-1, 5.8(0.4) vs 14.0(1.0) ml X g-1 LV weight X min-1, respectively) than in the controls. In a second experiment performed at 80 mmHg perfusion pressure (nine study hearts and seven controls) the increased myocardial flow rate resulted in a higher left ventricular +dP/dt in both groups, but the study hearts still had a lower mean(SD) myocardial flow rate than the controls (12.5(0.9) vs 19.8(2.2) ml X g-1 LV weight X min-1; the difference in left ventricular +dP/dt became non-significant (2646(186) vs 2951(136) mmHg X s-1). Similarly, at equal myocardial flow rates (study hearts at 80 mmHg perfusion pressure and controls at 50 mmHg perfusion pressure) ventricular performance was similar in the two groups (mean(SD) left ventricular +dP/dt 2270(105) in controls vs 2646(186) mmHg X s-1 in study hearts).(ABSTRACT TRUNCATED AT 250 WORDS)     

Significance of matrix metalloproteinases in norepinephrine-induced remodelling of rat hearts

OBJECTIVE: Norepinephrine (NE) induced hypertrophy and remodelling of the extracellular matrix (ECM) in the left ventricle (LV) of the rat heart with resulting fibrosis. However, there was no increased collagen deposition in the right ventricle (RV). To test the hypothesis that lack of RV fibrosis is the result of elevated cleavage of collagens we inhibited the activity of matrix metalloproteinases (MMP) by doxycycline (Doxy) and then measured function and collagen metabolism in the RV as compared to the LV. METHODS: Female Sprague-Dawley rats were treated with 30 mg/kg per day doxycycline alone or in combination with i.v. infusion of NE (0.1 mg/kg per h). The activity of MMP-2 was increased both in the LV and RV after 3 days of NE infusion and reduced after concomitant doxycycline treatment which also caused inhibition when given alone. RESULTS: After 14 days of NE infusion in combination with doxycycline there was an additional increase in the NE-induced elevation of collagen accumulation in the LV (interstitial collagen fraction: NE-Doxy 1.797%, P<0.05 versus control and NE; NE 1.113%, P<0.05 versus control) and significant fibrosis in the RV (2.105%, P<0.05 versus control). This correlated with the prevention of the NE-induced elevation of RV systolic pressure (NE: 71.3 mmHg, P<0.05; NE-Doxy: 36.4 mmHg) and RV dP/dt(max) (NE: 5500 mmHg/s, P<0.05; NE-Doxy: 2550 mmHg/s). Also in the NE-stimulated LV, the doxycycline-induced collagen accumulation was associated with reduced LV dP/dt(max) (NE-Doxy: 13169 mmHg/s; NE: 18849 mmHg/s, P<0.05). CONCLUSION: MMP inhibition leads to myocardial stiffness with negative functional consequences for the RV and LV in NE-treated rat hearts.     

High mobility group box 1 induces a negative inotropic effect on the left ventricle in an isolated rat heart model of septic shock: a pilot study.

BACKGROUND: Sepsis can be exacerbated by an inappropriate immune response and the severe impact of this disease on the cardiovascular system is well documented. High mobility group box 1 (HMGB1) protein is an important mediator in the pathogenesis of sepsis and its role in cardiovascular system dysfunction was investigated in an lipopolysaccharide (LPS)-induced rat model of sepsis. METHODS AND RESULTS: Twelve hours after intravenous bolus injections of LPS (5 mg/kg), rats were killed and heart samples were harvested. Immunoblot analysis was performed to assess expression levels of HMGB1 in cardiac myocytes. Left ventricular developed pressure (LVDP) served as a measure of systolic function. LPS administration was associated with an increase in the expression of HMGB1 in cardiac myocytes and a decrease in cardiac function. Hearts from the LPS-treated rats were also perfused with recombinant HMGB1 and cardiac function measured. The dose-dependent effects observed with elevated HMGB1 included decreased LVDP, decreased left ventricular (LV) + dP/dt(max), decreased absolute value of LV- dP/dt(min), and increased LV end-diastolic pressure. CONCLUSIONS: HMGB1 stimulation produces a negative inotropic effect during septic shock, suggesting an important role for this molecule in cardiovascular system dysfunction during sepsis.     

Orally administered benidipine and manidipine prevent ischemia-reperfusion injury in the rat heart.

BACKGROUND: The present study was designed to investigate whether orally administered benidipine and manidipine protect the myocardium from ischemia - reperfusion injury. METHODS AND RESULTS: Each drug (1, 3 or 10 mg/kg) was administered orally once daily for 1 week. The isolated rat heart model (Langendorff perfusion) was used, and each heart was subjected to global ischemia at 37 degrees C for 40 min followed by reperfusion. Post-ischemic recovery of left ventricular (LV) function (measured as developed pressure (LVDP), dP/dt max and end-diastolic pressure) was compared with a control group. Creatine kinase (CK) leakage was also measured. Post-ischemic recovery of LVDP and LV dP/dt max were significantly increased by 3 mg/kg benidipine (LVDP: 87.5+/-10.1 vs 64.6+/-11.9%; LV dP/dt max: 97.8+/-10.4 vs 70.2+/-15.7%; p<0.05). CK leakage was significantly lower than in the control group (39.4+/-7.5 vs 61.1 +/-9.8 IU per 15 min per kg; p<0.05). Manidipine produced significant recoveries in LVDP and dP/dt max at a dose of 1 mg/kg (LVDP: 93.7+/-16.5% vs 53.4+/-9.5%; dP/dt max: 104.2+/-21.9% vs 55.5+/-15.5%; p<0.05). CK leakage was also significantly reduced at the same dose (50.0+/-18.3 vs 80.1+/-14.0 IU per 15 min per kg; p<0.05). CONCLUSIONS: Orally administered benidipine and manidipine exerted significant cardioprotective effects against ischemia - reperfusion injury.     

Vanadate improves cardiac function and myocardial energy metabolism in diabetic rat hearts

Vanadium mimicking the metabolic effects of insulin is known to decrease serum glucose levels and to influence glucose metabolism in diabetes mellitus. However, it is unclear whether vanadium ameliorates the metabolic disorder in diabetic hearts causing myocardial dysfunction. The purpose of this study was to assess the effects of vanadium on cardiac performance and energy metabolism in diabetic rat hearts. Four groups of Wistar rats were studied: untreated control rats (group C, n = 8). vanadate-treated rats (group V, n = 10), untreated diabetic rats (group DM, n = 9) induced by streptozotocin. and vanadate-treated diabetic rats (group DMV, n = 8). Vanadate-treated rats drank a 1.5 mM sodium orthovanadate (Na3VO4) solution during a 4 week diabetic condition. Hearts were perfused with Krebs-Henseleit buffer after the diabetic duration. After the maximum left ventricular dP/dt and cardiac efficiency were calculated, the myocardial contents of ATP and creatine phosphate (P-Cr) and myocardial energy metabolism were assessed by cytosolic phosphorylation potential. Peak positive and negative dP/dt, and cardiac efficiency decreased significantly in group DM compared with group C, while there were no significant differences between groups C and DMV. The myocardial contents of ATP (micromol/g wet heart) and P-Cr (micromol/g wet heart), and cytosolic phosphorylation potential (M(-1)) increased from 2.72 +/- 0.46. 1.45 +/- 0.58. and 3,530 +/- 1,220 in group DM to 3.88 +/- 0.76, 3.81 +/- 1.36, and 11,200 +/- 2,400 in group DMV, respectively. It is concluded that vanadium restored the production of high energy phosphates in the myocardium and improved myocardial dysfunction by regulating metabolic processes in diabetic rat hearts.     

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.     

Heart function and molecular biological parameters are comparable in young adult and aged rats after chronic myocardial infarction

OBJECTIVE: To test the hypothesis that IL-1beta and IL-6 play a pivotal role after myocardial infarction (MI) particularly in aged rats. METHODS: Chronic MI was induced in young adult (3.5 months) and aged (18 months) female Sprague-Dawley rats by ligation of the left coronary artery. Sham-operated animals of corresponding age served as controls. Heart function was measured by catheterization 4 weeks after MI. The expression of IL-1beta, IL-6, TGF-beta-isoforms, ANF, and components of the extracellular matrix (pro-collagen I and III, colligin, MMP-2 and TIMP2) was measured by ribonuclease protection assay. RESULTS: Aged control rats differed from young adult rats in that LV-developed pressure (LVDP) was higher (161 vs. 147 mmHg, p<0.05) in response to the elevated total peripheral resistance (0.71 vs. 0.47 mmHg ml min/kg, p<0.05). Contractility was reduced in aged controls as indicated by decreased LV dP/dt (8.106 vs. 10.606 mmHg/s, p<0.05). LV function was severely depressed in both MI groups (reduction in LVDP by about 35% and LV dP/dt by about 30%, increase in LVEDP to 24 mmHg) while RVP and RV dP/dt markedly increased by about 100%. This was not different between both MI groups. ANF expression as a marker of hypertrophy was induced in both MI groups, but less pronounced in the LV of aged rats. Also, the mRNA expression pattern was qualitatively comparable, but showed gradual differences. CONCLUSION: These results indicate that aged rats compensate well for hemodynamic overload induced by MI. Also, the mechanisms of myocardial post-MI remodeling are comparable in young adult and aged rats.     

Cardiac function and ischaemic tolerance during acute loss of metabolic control in the diabetic BB Wor rat

Abstract The effect of loss of metabolic control, by with-holding insulin treatment, on reperfusion recovery of cardiac function following ischaemia was studied in the spontaneously diabetic “BB” Wor rat. The study involved a group of insulin-treated diabetic BB rats (insulin-treated) and diabetic BB rats in which insulin treatment was withheld 24 h prior to study (insulin-withdrawn). Hearts were isolated and perfused at a constant left atrial filling pressure of 15 cm H₂O and aortic afterload resistances of 100 and 140 cm H₂O. Hearts were then subjected to 20 min of ischaemia followed by 30 min of reperfusion. Withdrawing insulin treatment from the BB Wor rat resulted in a dramatic increase in the levels of plasma glucose and free fatty acids. Hearts from these rats perfused under aerobic conditions demonstrated reductions in heart rate, positive and negative dP/dt, cardiac output and left ventricular minute work, whereas diastolic pressure was elevated. Following ischaemia, recovery of cardiac function in the insulin-treated BB Wor rat returned to preischaemic levels, whereas hearts from insulin-withdrawn rats displayed impaired recovery. Throughout reperfusion, heart rate, positive dP/dt, cardiac output and left ventricular minute work remained significantly lower in hearts from insulin-withdrawn rats compared to treated rats. Our results indicate that acute loss of metabolic control increases the sensitivity of the heart to ischaemia, even in the acutely diabetic BB Wor rat.