Cardiovascular effects of the combination of levosimendan and valsartan in hypertensive Dahl/Rapp rats

Hypertension is the main risk factor for left ventricular hypertrophy and development of diastolic heart failure. There is no yet treatment, which can effectively reduce mortality in patients suffering from heart failure with preserved systolic function. We tested whether the calcium sensitizer levosimendan and the AT1-receptor antagonist valsartan could protect from salt-induced hypertension, cardiovascular mortality and heart failure in Dahl/Rapp salt-sensitive rats fed for 7 weeks with a high salt diet (8% NaCl). Levosimendan (1 mg/kg/day via drinking water) and valsartan (30 mg/kg in the food) monotherapies and their combination prevented mortality in Dahl/Rapp rats. The drug combination evoked an additive effect on blood pressure, cardiac hypertrophy, cardiomyocyte cross-sectional area, target organ damage and myocardial ANP mRNA expression. There was a close correlation between systolic blood pressure and cardiac hypertrophy, cardiac and renal damage. As compared to Dahl/Rapp controls kept on low-salt diet (NaCl 0.3%). The high salt rats exhibited impaired diastolic relaxation as assessed by isovolumic relaxation time. Levosimendan alone and in combination with valsartan, improved diastolic relaxation without significantly improving systolic function. Our findings are evidence for an additive effect between levosimendan and valsartan on blood pressure and a blood pressure-dependent protection against the development of salt-induced target organ damage. The present study also demonstrates that levosimendan, alone or in combination with valsartan, can correct diastolic dysfunction induced by salt-dependent hypertension.     

Leukotoxin, 9, 10-epoxy-12-octadecenoate, causes cardiac failure in dogs

An epoxy derivative of linoleate, 9, 10-epoxy-12-octadecenoate, was demonstrated to be biosynthesized by leukocytes, thus nominated as leukotoxin. Its chemical structure was determined by gas-chromatography/mass spectrometry and nuclear magnetic resonance measurements. When it was injected intravenously, 15 mg/kg, canine heart showed signs of a typical cardiac failure; viz. Aortic flow started to drop immediately after the injection, and fell to 22% of the original at 40 min after the injection. At that point, systolic aortic pressure dropped to 35%, diastolic aortic pressure to 23%, and electronically differentiated maximal rate of left ventricular pressure rise (LV dp/dt) to 29%. All of experimental dogs died 40 to 50 min after the injection. On the contrary, administration of linoleic acid (15 mg/kg) did not affect these hemodynamical parameters. Therefore, leukotoxin seems to be an important factor to the genesis of heart failure.     

p21CIP1/WAF1-dependent inhibition of cardiac hypertrophy in response to Angiotensin II involves Akt/Myc and pRb signaling

The cyclin-dependent kinase inhibitor p21^CIP1/WAF1 (p21) is highly expressed in the adult heart. However, in response to stress, its expression is downregulated. Therefore, we investigated the role of p21 in the regulation of cardiac hypertrophic growth. At 2 months of age, p21 knockout mice (p21KO) lack an overt cardiac phenotype. In contrast, by 10 months of age, p21KO developed age-dependent cardiac hypertrophy and heart failure. After 3 weeks of trans-aortic banding (TAB), the heart/body weight ratio in 11 week old p21KO mice increased by 57%, as compared to 42% in wild type mice indicating that p21KO have a higher susceptibility to pressure overload-induced cardiac hypertrophy. We then chronically infused 8 week old wild type mice with Angiotensin II (2.0 mg/kg/min) or saline subcutaneously by osmotic pumps for 14 days. Recombinant TAT conjugated p21 protein variants (10 mg/kg body weight) or saline were intraperitoneally injected once daily for 14 days into Angiotensin II and saline-infused animals. Angiotensin II treated mice developed pathological cardiac hypertrophy with an average increase of 38% in heart/body weight ratios, as compared to saline-treated controls. Reconstitution of p21 function by TAT.p21 protein transduction prevented Angiotensin II-dependent development of cardiac hypertrophy and failure. Taken together, our genetic and biochemical data show an important function of p21 in the regulation of growth-related processes in the heart.     

Involvement of Rho kinase pathway in the mechanism of renal vasoconstriction and cardiac hypertrophy in rats with experimental heart failure

Rho-dependent kinases serve as downstream effectors of several vasoconstrictor systems, the activities of which are upregulated in congestive heart failure (CHF). We evaluated renal and cardiac effects of Y-27632, a highly selective Rho kinase inhibitor, in an experimental model of volume-overload CHF. Effects of acute administration of Y-27632 (0.3 mg/kg) on renal hemodynamic and clearance parameters and effects of chronic treatment (10.0 mg.kg(-1).day(-1) for 7 days via osmotic minipumps) on cardiac hypertrophy and cumulative Na+ excretion were studied in male Wistar rats with aortocaval fistula and control rats. The Y-27632-induced decrease in renal vascular resistance (from 40.4 +/- 4.6 to 26.0 +/- 3.1 resistance units, P < 0.01) in CHF rats was associated with a significant increase in total renal blood flow (+34%) and cortical and medullary blood flow (approx +37 and +27%, respectively). These values were significantly higher than those in control rats and occurred despite a decrease in mean arterial pressure (-15 mmHg). Despite the marked renal vasodilatory effect, Y-27632 did not alter glomerular filtration rate and renal Na+ excretion. Chronic administration of Y-27632 did not alter daily or cumulative renal Na+ excretion in CHF rats but was associated with a significant decrease in heart-to-body weight ratio, an index of cardiac hypertrophy: 0.32 +/- 0.007, 0.46 +/- 0.017, and 0.37 +/- 0.006% in control, CHF, and CHF + Y-27632 rats, respectively. The findings suggest that Rho kinase-dependent pathways are involved in the mechanisms of renal vasoconstriction and cardiac hypertrophy in rats with volume-overload heart failure. Selective blockade of these signaling pathways may be considered an additional tool to improve renal perfusion and attenuate cardiac hypertrophy in heart failure.     

The effect of FK664, a new cardiovascular drug, on systemic capacitance vessels in anesthetized dogs.

To characterize the cardiovascular effect of FK664, a compound developed for the treatment of heart failure, the mean circulatory pressure (MCP), cardiac output and other parameters were measured in open-chest anesthetized dogs. Milrinone, a cardiotonic agent, and nifedipine, a calcium channel blocker were used as reference substances. Nifedipine (10 micrograms/kg), FK664 (0.1 mg/kg) or milrinone (0.1 mg/kg) given intravenously reduced the total peripheral resistance in a similar extent (35-40%). Whereas nifedipine had no effect on MCP, FK664 produced a significant decrease in MCP. Milrinone caused a minimal decrease in MCP, but not significantly. These results indicate that FK664 dilates the systemic capacitance vessels. This action to reduce the pre-load would be beneficial in the treatment of heart failure.     

The chemical chaperone 4-phenylbutyric acid attenuates pressure-overload cardiac hypertrophy by alleviating endoplasmic reticulum stress

Evidence has shown that endoplasmic reticulum stress (ERS) is associated with the pathogenesis of cardiac hypertrophy. The aim of this study was to investigate whether direct alleviation of ER stress by 4-phenylbutyric acid (PBA), a known chemical chaperone drug, could attenuate pressure-overload cardiac hypertrophy in mice. The effects of orally administered PBA (100mg/kg body weight daily for a week) were examined using mice undergoing transverse aortic constriction (TAC-mice), an animal model to produce pressure overload. TAC application for 1 week led to a 1.8-fold increase in the ratio of the heart weight over body weight (HW/BW) and up-regulation of the hypertrophy markers ANF and BNF accompanied by up-regulation of ERS markers (GRP78, p-PERK, and p-elF2α). The oral administration of PBA to the TAC-mice reduced hypertrophy (19%) and severely downregulated the fibrosis-related genes (transforming growth factor-β1, phospho-smad2, and pro-collagen isoforms). We conclude that ERS is induced as a consequence of remodeling during pathological hypertrophy and that PBA may help to relieve ERS and play a protective role against cardiac hypertrophy and possibly heart failure. We suggest PBA as a novel therapeutic agent for cardiac hypertrophy and fibrosis.     

Involvement of mitogen-activated protein kinases in adriamycin-induced cardiomyopathy

The current study investigated the phosphorylation of mitogen-activated protein kinases (MAPKs) as well as pro- and anti-apoptotic proteins in adriamycin (ADR)-induced cardiomyopathy (AIC) and heart failure in rats. Modulatory effects of antioxidant probucol on the activation of MAPKs were also examined. Male rats were administered with ADR (15 mg/kg body wt ip, over 2 wk) with and without probucol (120 mg/kg body wt for 4 wk ip). Hearts from these animals were studied at 1- to 24-h as well as at 3-wk posttreatment durations. In the 3-wk group, ADR depressed cardiac function, increased left ventricular end-diastolic pressure (LVEDP), and caused dyspnea and mortality. These changes were prevented by probucol. Phosphorylation of extracellular signal-regulated kinase (ERK)1/2, in the early stage of AIC, showed a biphasic response, with a maximum increase to 513% seen at 4 h, followed by a decrease to 66.8% at 3 wk after the last injection of ADR. Phosphorylation of p38 and c-Jun NH(2)-terminal kinases (JNKs) showed a steady increase through 2, 4, and 24 h and 3 wk (116% to 148%). In gene microarray analysis at 3 wk (heart failure stage), mRNA expression for both ERK1/2 and p38 kinases was decreased, whereas JNK mRNA was undetectable. Probucol completely prevented these MAPK changes. Activation of caspase-3 as well as the increase in the ratio of Bax to Bcl-xl were seen at early time points (1-24 h) as well as in the heart failure stage (3 wk). It is suggested that a transient increase in ERK1/2 at a shorter interval indicate an early adaptive response, and failure of this response corresponded with heart failure. In contrast, a gradual and persistent increase in p38 and JNK MAPKs as well as in caspase-3 and the Bax-to-Bcl-xl ratio may contribute in the initiation of apoptosis and progression of heart failure. Because probucol modulated changes in cellular signaling pathways and cardiac function, it is likely that oxidative stress plays a key role in AIC and heart failure.     

The cardiac contractile function and hemodynamic control in rats after chronic adriamycin treatment

Cardiac contractile function and hemodynamic parameters of control and adriamycin-treated (2 mg/kg once a week for 10 weeks) rats were studied both in the anesthetized (hexenal, 20 mg/kg) and conscious state. Radiolabelled microspheres (diameter, 15 microns) were used to measure systemic and regional hemodynamics. No significant differences between the control and adriamycin-treated groups in cardiac contractile function, total peripheral resistance, and regional blood flow (except muscles) was found in anesthetized animals. In the conscious state, a significantly higher (+70%) total peripheral resistance combined with lower blood flow in the skin and spleen was observed in adriamycin-treated rats. The response of the heart rate to changes in the arterial pressure induced by nitroglycerin and phenylephrine injection was greatly diminished after adriamycin treatment. Isoprenaline (0.64 micrograms.kg-1.min-1) increased left ventricular contractile indices approximately twofold and heart rate by 30% in the control group, while in adriamycin-treated rats only minor changes in these parameters were observed. However, cardiac output rose by 36% and total peripheral resistance fell by 36% in these animals. Results show that prolonged adriamycin treatment leads to decreased inotropic response to beta-adrenoceptor stimulation and reduced baroreflex control. These changes occur in the stage preceding congestive heart failure.     

Reduction of cardiac endothelin-1 by angiotensin II type 1 receptor antagonist in viral myocarditis of mice

Renin angiotensin system contributes to activation of circulating endothelin in congestive heart failure. To investigate the effects of angiotensin II receptor antagonist and angiotensin converting enzyme inhibitors (ACEI) on the levels of endothelin-1 (ET-1), we administered orally angiotensin II type 1 receptor (AT1) antagonist, L-158,809 (ATA) (6, 1.2 and 0.12 mg/kg/day), enalapril (1 mg/kg/day) and captopril (7.5 mg/kg/day) for 14 days to mice with viral myocarditis, beginning 7 days after encephalomyocarditis virus (500 pfu/mouse) inoculation. Plasma ET-1, cardiac ET-1, heart weight (HW) and HW/ body weight (BW) ratio were examined and compared with infected untreated mice. Moreover, the HW (mg) and HW/BW (x 10(-3)) ratio were significantly (P<0.05) reduced in mice treated with ATA and ACEIs in comparison with infected control. ACEIs and higher dosed of ATA reduced myofiber hypertrophy. Both of plasma and cardiac ET-1 proteins were significantly elevated in infected control compared with uninfected normal mice. Plasma ET-1 was significantly (P<0.01) reduced in mice with three different concentrations of ATA but were not decreased in mice with captopril or enalapril compared with infected control. The expression of endothelin-1 mRNA was significantly reduced in mice with ATA in comparison with infected untreated mice by competitive RT-PCR. ATA reduced ET-1 protein and mRNA in the myocardium of mice with myocarditis, improving congestive heart failure and myofiber hypertrophy. We suggest the effect of ATA on the reduction of endothelin has a different pathway from angiotensin converting inhibitor and that ATA seems to be a useful agents for congestive heart failure due to viral myocarditis.     

Rapid ventricular pacing of dogs to heart failure: biochemical and physiological studies

Chronic, rapid ventricular pacing produces congestive heart failure in dogs. The objectives of this study were to determine whether or not (i) in vitro myocardial biochemical alterations reported for heart failure by volume or pressure overload also occurred with heart failure due to rate overload, and (ii) these biochemical alterations were related to relevant in vivo cardiac physiologic alterations. We compared 27 dogs that were paced to advanced heart failure with 21 sham-operated dogs. Dogs with heart failure had 55% lower left ventricular ejection fraction (22.5 +/- 7.6 vs. 50.5 +/- 5.1%) and cardiac index (81 +/- 22 vs. 178 +/- 48 mL.min-1.kg-1), 287% higher pulmonary capillary wedge pressure (27.5 +/- 6.8 vs. 7.1 +/- 3.4 mmHg; 1 mmHg = 133.3 Pa), and 64% greater left ventricular diastolic area (18.4 +/- 3.7 vs. 11.2 +/- 1.3 cm2) (all p less than 0.05). Dogs with heart failure also had (i) 69% lower norepinephrine (232 +/- 139 vs. 747 +/- 220 ng/g protein), (ii) 25-50% lower activities of myofibrillar Ca ATPase (0.188 +/- 0.026 vs. 0.253 +/- 0.051 U/mg myofibrils), sarcoplasmic reticulum Ca-transport ATPase (0.155 +/- 0.074 vs. 0.288 +/- 0.043 U/mg membrane), and the glycolytic enzyme phosphofructokinase (33.4 +/- 10.0 and 47.7 +/- 15.8 U/g), (iii) 32% higher activity of the beta-oxidation enzyme hydroxyacyl-CoA dehydrogenase (11.43 +/- 1.48 vs. 8.67 +/- 1.70 U/g), and (iv) 60% higher activity of Krebs cycle oxoglutarate dehydrogenase (2.89 +/- 0.77 vs. 1.81 +/- 0.95 U/g) (all p less than 0.05). No differences between groups were observed for isozyme patterns and ATPase activity of myosin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Significance of cardiac cannabinoid receptors in regulation of cardiac rhythm,myocardial contractility,and electrophysiologic processes in heart

Intravenous administration of cannabinoid (CB) receptor agonists (HU-210, 0.1 mg/kg; ACPA, 0.125 mg/kg; methanandamide, 2.5 mg/kg; and anandamide, 2.5 mg/kg) induced bradycardia in chloralose-anesthetized rats irrespective of the solubilization method. Methanandamide, HU-210, and ACPA had no effect on the electrophysiological activity of the heart, while anandamide increased the duration of the QRS complex. The negative chronotropic effect of HU-210 was due to CB1 receptor activation since it was not observed after CB1 receptor blockade by SR141716A (1 mg/kg intravenously) but was present after pretreatment with CB2 receptor antagonist SR144528 (1 mg/kg intravenously). CB receptor antagonists SR141716A and SR144528 had no effect on cardiac rhythm or ECG indices. Hence, in the intact heart, endogenous CB receptor agonists are not involved in the regulation of cardiac rhythm and electrophysiological processes. The chronotropic effect of CBs was independent of the autonomic nervous system because it remained significant after autonomic ganglion blockade by hexamethonium (1 mg/kg intravenously). CB receptor activation by HU-210 (0.1 and 1 μM) in vitro decreased the rate and force of isolated heart contractions, the rates of contraction and relaxation, and end diastolic pressure. The negative chronotropic effect of HU-210 was less pronounced in vitro than in vivo. The maximum inotropic effect of HU-210 was reached at the concentration of 0.1 μM.     

Effects of cocaine alone and in combination with haloperidol and SCH 23390 on cardiovascular function in squirrel monkeys

The potential involvement of D1 and D2 dopamine receptors in the effects of cocaine on cardiovascular function in squirrel monkeys was evaluated. A low dose of cocaine (0.1 mg/kg i.v.) produced increases in both blood pressure and heart rate. At the higher doses of cocaine (1.0-3.0 mg/kg) the heart rate response was biphasic, consisting of an early decrease followed by an increase in heart rate 10-20 min following injection. The dopamine D2 antagonist haloperidol (0.1 mg/kg i.m.) attenuated the heart rate increasing effect of cocaine, but doses as high as 0.03 mg/kg did not alter the blood pressure increase. The D1 antagonist SCH 23390 (0.01-0.03 mg/kg i.m.) did not attenuate either the blood pressure or heart rate increasing effects of cocaine. The D2 agonist quinpirole (1.0 mg/kg i.v.) produced increases in heart rate similar to cocaine, with little effect on blood pressure. Although effective against the heart rate increasing effect of cocaine, haloperidol (0.01 mg/kg) did not antagonize the heart rate increasing effects of quinpirole. The D1 agonist SKF 38393 (3.0 mg/kg i.v.) decreased heart rate and increased blood pressure. The blood pressure increasing effect of SKF 38393 was antagonized by 0.01 mg/kg SCH 23390. Haloperidol's ability to partially antagonize the tachycardiac response to cocaine suggests the involvement of D2 receptors in that response. However, the failure of haloperidol to antagonize quinpirole's tachycardiac effect suggests that non-dopaminergic mechanisms may also be involved in haloperidol's antagonism of cocaine's tachycardiac effect. The pressor effects of cocaine do not appear to be controlled by selective dopamine receptors.     

Paeoniflorin attenuates pressure overload-induced cardiac remodeling via inhibition of TGFβ/Smads and NF-κB pathways

Cardiac remodeling is a key determinant in the clinical course and outcome of heart failure and characterized by cardiac hypertrophy, fibrosis, cardiomyocyte apoptosis and inflammation. The anti-inflammatory, anti-apoptotic and anti-fibrotic effects of paeoniflorin have been identified in various types of tissue and cells. However, the role of paeoniflorin in cardiac remodeling remains unclear. We performed aortic banding (AB) in mice to induce a cardiac remodeling model in response to pressure overload. Paeoniflorin (20 mg/kg) was administered by daily intraperitoneal (i.p.) injection. Paeoniflorin treatment promoted the survival rate and improved cardiac function of mice at 8 weeks post surgery. AB-induced cardiac hypertrophy, as assessed by heart weight, gross heart, HE and WGA staining, cross-sectional area of cardiomyocyte and mRNA expresssion of hypertrophic makers, was attenuated by paeoniflorin. Paeoniflorin also inhibited collagen deposition, expression of TGFβ, CTGF, collagen Iα and collagen IIIα, and phosphorylation of Smad2 and Smad3 in the heart exposed to pressure overload. Cardiomyocyte apoptosis and induction of Bax and cleaved caspase3 in response to AB were suppressed by paeoniflorin. Furthermore, paeoniflorin decreased the quantity of CD68+ cells, protein levels of TNF-α and IL-1β, and phosphorylation of IκBα and NFκB-p65 in the heart after AB. In conclusion, paeoniflorin attenuated cardiac hypertrophy, fibrosis, apoptosis and inflammation, and improved left ventricular function in pressure overloaded mice. The cardioprotective effect of paeoniflorin is associated with the inhibition of TGFβ/Smads and NF-κB pathways.     

不同剂量法舒地尔对压力负荷心力衰竭大鼠心肌细胞凋亡和凋亡相关基因表达的影响

目的从细胞凋亡角度探讨不同剂量法舒地尔(fasudil)对升主动脉缩窄压力超负荷心力衰竭大鼠的影响及作用机制。方法采用升主动脉缩窄术建立大鼠心力衰竭模型。观察不同剂量fasudil治疗心力衰竭时对心肌细胞凋亡指数(AI)、bcl-2、c-myc蛋白表达水平的影响。结果fasudil干预心功能不全可以使心肌细胞凋亡指数降低,使bcl-2蛋白表达水平上调,c-myc蛋白表达水平降低,且剂量大时效果更明显。结论fasudil能有效减少心力衰竭大鼠心肌细胞凋亡指数,使bcl-2蛋白表达水平上调,c-myc蛋白表达水平降低,防治心力衰竭,这是其治疗心力衰竭的重要机制之一,且剂量大时更明显。     

Pirfenidone alleviates cardiac fibrosis induced by pressure overload via inhibiting TGF‐β1/Smad3 signalling pathway

Cardiac fibrosis critically injured the cardiac structure and function of the hypertensive patients. However, the anti‐fibrotic strategy is still far from satisfaction. This study aims to determine the effect and mechanism of Pirfenidone (PFD), an anti‐lung fibrosis medicine, in the treatment of cardiac fibrosis and heart failure induced by pressure overload. Male C57BL/6 mice were subjected to thoracic aorta constriction (TAC) or sham surgery with the vehicle, PFD (300 mg/kg/day) or Captopril (CAP, 20 mg/kg/day). After 8 weeks of surgery, mice were tested by echocardiography, and then sacrificed followed by morphological and molecular biological analysis. Compared to the sham mice, TAC mice showed a remarkable cardiac hypertrophy, interstitial and perivascular fibrosis and resultant heart failure, which were reversed by PFD and CAP significantly. The enhanced cardiac expression of TGF‐β1 and phosphorylation of Smad3 in TAC mice were both restrained by PFD. Cardiac fibroblasts isolated from adult C57BL/6 mice were treated by Angiotensin II, which led to significant increases in cellular proliferation and levels of α‐SMA, vimentin, TGF‐β1 and phosphorylated TGF‐β receptor and Smad3. These changes were markedly inhibited by pre‐treatment of PFD. Collectively, PFD attenuates myocardial fibrosis and dysfunction induced by pressure overload via inhibiting the activation of TGF‐β1/Smad3 signalling pathway.     

Effect of chronic left ventricular failure on beta-endorphin.

Stimulation of endogenous opiate secretion worsens circulatory dysfunction in several forms of shock, in part by inhibiting sympathetic activity. To investigate whether endogenous opiates have a similar effect in chronic heart failure (HF), we measured beta-endorphin concentrations and hemodynamic responses to naloxone infusion (2 mg/kg bolus + 2 mg.kg-1 x h-1) in six control (C) dogs and eight dogs with low-output HF produced by 3 wk of rapid ventricular pacing. The dogs with HF exhibited reduced arterial blood pressure (C, 123 +/- 4 vs. HF, 85 +/- 7 mmHg; P < 0.01) and cardiac outputs (C, 179 +/- 14 vs. HF, 76 +/- 2 ml.min-1 x kg-1; P < 0.01) and elevated plasma norepinephrine concentrations (C, 99 +/- 12 vs. HF, 996 +/- 178 pg/ml; P < 0.01) but normal beta-endorphin concentrations (C, 30 +/- 11 vs. HF, 34 +/- 12 pg/ml; P = NS). Naloxone produced similar transitory increases in blood pressure (C, 14 +/- 5 vs. HF, 26 +/- 25%) and cardiac output (C, 37 +/- 13 vs. HF, 22 +/- 15%) in both groups (both P = NS). No significant changes in norepinephrine concentration or systemic vascular resistance were observed in either group. These findings suggest that beta-endorphin secretion does not exacerbate circulatory dysfunction in chronic heart failure.     

Electrocardiographic evidence for cocaine cardiotoxicity in cat

Recent case studies suggest that cocaine overdose may produce life-threatening cardiac arrhythmias. We therefore investigated its effects on the electrocardiogram (leads II and V1) and arterial blood pressure in cats anesthetized with pentobarbital. Cocaine was administered by intravenous infusion over a 2-min interval at 1 mg/kg in 10 cats. In 5 out of 10 cats an additional infusion of 3 mg/kg cocaine was also administered after hemodynamic and electrocardiographic parameters had returned to control values (i.e., within 10 min). During and following infusion of 1 mg/kg cocaine, no significant change in heart rate or systolic or diastolic blood pressure were found, however the QRS duration increased by 38% (from 46 +/- 5 to 64 +/- 12 ms) (p less than 0.01). Evidence for bundle branch block and (or) premature ventricular beats was observed in 9 out of 10 cats after 1 mg/kg cocaine. Infusion of a further 3 mg/kg cocaine in five cats significantly lowered diastolic blood pressure (from 98 +/- 18 to 64 +/- 28 mmHg; 1 mmHg = 133.3 Pa) (p less than 0.01), and further prolonged QRS to 79 +/- 14 ms, a 75% increase from the mean control value (p less than 0.01). In addition, 1st and 2nd degree atrioventricular block, ventricular extrasystoles, and ectopic rhythms (AV junctional or idioventricular) were observed in four out of five cats given 3 mg/kg cocaine. Mean plasma concentrations of cocaine were 1.37 +/- 0.39 micrograms/mL (4.28 +/- 1.22 microM) (n = 5) at the end of a 1 mg/kg infusion and 2.93 +/- 0.43 micrograms/mL (9.16 +/- 1.34 microM) after a 3 mg/kg infusion (n = 3).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiomegaly produced by chronic beta-adrenergic stimulation in the rat: comparison with alpha-adrenergic effects.

Chronic administration of d, l isoproterenol, 0.2 – 5 mg/kg/day, for 14–21 days in the male rat produced marked increases in dry ventricle weight (21.1 – 43.6%; p < 0.001). In comparison, an α-adrenergic agonist, phenylephrine (7.5 mg/kg/day) decreased ventricle weight (?15.3%; p < 0.025). Also, isoproterenol injection at 5 mg/kg/day decreased cardiac actomyosin ATPase activity by 23.3% (p < 0.0025) while phenylephrine, administered as above, did not influence ATPase activity. The effect of isoproterenol on heart weight was completely blocked by the β₁-adrenergic antagonist practolol (5 mg/kg/day). Albuterol, a relatively specific β₂-adrenergic agonist was less potent than isoproterenol in producing cardiac hypertrophy. l-Epinephrine injection, 0.8 mg/kg/day for 14 days, had no effect on heart weight. However, l-epinephrine produced cardiac hypertrophy (22.4% p < 0.001) when the animals were preinjected with the α-adrenergic antagonist, phenoxybenzamine (5 mg/kg/day). The data indicate that cardiac hypertrophy can be produced by stimulation of the β₁-adrenergic receptors of the heart; apparently, stimulation of α-adrenergic receptors opposes β-adrenergic hypertrophic effects.     

Naloxone pretreatment prevents the bloody diarrhea of canine endotoxic shock

We examined the importance of timing with endorphin involvement in shock by giving the opiate receptor antagonist naloxone as a pretreatment in canine endotoxic shock. Dogs anesthetized with pentobarbital (30 mg/kg iv) were given Escherichia coli endotoxin at LD80 doses iv. Naloxone (2 mg/kg plus 2 mg/kg/hr iv, N = 10) started 15 min before endotoxin attenuated the fall in mean arterial pressure, cardiac index, and the first derivative of left ventricular pressure due to endotoxin in comparison with control animals given 0.9% NaCl (N = 10). Naloxone attenuated the endotoxin-induced decrease in superior mesenteric arterial blood flow and the increases in portal venous pressure and pulmonary arterial pressures. Moreover, naloxone pretreatment prevented the characteristic bloody diarrhea and reduced mortality. Our findings implicate endorphins acting on opiate receptors as important mediators of endotoxin-induced cardiovascular failure and bloody diarrhea in canine endotoxemia. These are early manifestations and dictate expeditious use of naloxone in endotoxic shock.