bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of blockade of endogenous angiotensin II on baroreflex function in conscious diabetic rats
Authors: Maliszewska-Scislo Maria , Scislo Tadeusz J. , Rossi Noreen F.
Published: March 2015

Little is known about baroreflex control of renal nerve sympathetic activity (RSNA) or the effect of angiotensin II (ANG II) on the baroreflex in diabetes. We examined baroreflex control of RSNA and heart rate (HR) in conscious, chronically instrumented rats 2 wk after citrate vehicle (normal) or 55 mg/kg iv streptozotocin (diabetic) before and after losartan (5 mg/kg iv) or enalapril (2.5 mg/kg iv). Resting HR and RSNA were lower in diabetic versus normal rats. The range of baroreflex control of HR and the gain of baroreflex-mediated bradycardia were impaired in diabetic rats. Maximum gain was unchanged. The baroreflex control of RSNA was reset to lower pressures in the diabetic rats but remained otherwise unchanged. Losartan decreased mean arterial pressure (MAP) and increased HR and RSNA in both groups but had no influence on the baroreflex. Enalapril decreased MAP only in normal rats, yet the increase in HR and RSNA was similar in both groups. Thus in diabetic rats enalapril produced a pressure-independent increase in HR and RSNA. Enalapril exerted no effect on the baroreflex control of HR or RSNA in either group. These data indicate that in conscious rats resting RSNA is lower but baroreflex control of RSNA is preserved after 2 wk of diabetes. At this time, the baroreflex control of HR is already impaired and blockade of endogenous ANG II does not improve this dysfunction.
Lipid peroxidation-derived aldehydes and oxidative stress in the failing heart: role of aldose reductase
Authors: Srivastava Sanjay , Chandrasekar Bysani , Bhatnagar Aruni , Prabhu Sumanth D.
Published: March 2015

Lipid peroxidation-derived aldehydes (LP-DA) can propagate oxidative injury and are detoxified by the aldose reductase (AR) enzyme pathway in myocardium. Whether there are alterations in the AR axis in heart failure (HF) is unknown. Sixteen instrumented dogs were studied before and after either 24 h or 4 wk of rapid left ventricular (LV) pacing (early and late HF, respectively). Six unpaced dogs served as controls. In early HF, there was subtle depression of LV performance (maximum rate of LV pressure rise, P < 0.05 vs. baseline) but no chamber enlargement, whereas in late HF there was significant ( P < 0.05) contractile depression and LV dilatation. Oxidative stress was increased at both time points, indexed by tissue malondialdehyde, total glutathione, and free C6–C9 LP-DA ( P < 0.025 vs. control). AR protein levels and activity decreased progressively during HF ( P < 0.025 early/late HF vs. control); however, AR mRNA expression decreased only in late HF ( P < 0.005 vs. early HF and control). DNA binding of tonicity-responsive enhancer binding protein (TonEBP, a transcriptional regulator of AR) paralleled AR mRNA, declining >50% in late HF ( P < 0.025 vs. control). We conclude that AR levels and attendant myocardial capacity to detoxify LP-DA decline during the development of HF. In early HF, decreased AR occurs due to a translational or posttranslational mechanism, whereas in late HF reduced TonEBP transcriptional activation and AR downregulation contribute significantly. Reduced AR-mediated LP-DA metabolism contributes importantly to LP-DA accumulation in the failing heart and thus may augment chronic oxidative injury.
Heart rate dynamics in monoamine oxidase-A- and -B-deficient mice
Authors: Holschneider D. P. , Scremin O. U. , Chialvo D. R. , Chen K. , Shih J. C.
Published: March 2015

Heart rate (HR) dynamics were investigated in mice deficient in monoamine oxidase A and B, whose phenotype includes elevated tissue levels of norepinephrine, serotonin, dopamine, and phenylethylamine. In their home cages, spectral analysis of R-R intervals revealed more pronounced fluctuations at all frequencies in the mutants compared with wild-type controls, with a particular enhancement at 1–4 Hz. No significant genotypic differences in HR variability (HRV) or entropies calculated from Poincaré plots of the R-R intervals were noted. During exposure to the stress of a novel environment, HR increased and HRV decreased in both genotypes. However, mutants, unlike controls, demonstrated a rapid return to baseline HR during the 10-min exposure. Such modulation may result from an enhanced vagal tone, as suggested by the observation that mutants responded to cholinergic blockade with a decrease in HRV and a prolonged tachycardia greater than controls. Monoamine oxidase-deficient mice may represent a useful experimental model for studying compensatory mechanisms responsible for changes in HR dynamics in chronic states of high sympathetic tone.
Attenuation of heart failure due to coronary stenosis by ACE inhibitor and angiotensin receptor blocker
Authors: Sato Hidetoshi , Yaoita Hiroyuki , Maehara Kazuhira , Maruyama Yukio
Published: March 2015

It is not known how the angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) attenuate heart failure (HF) in viable ischemic hearts. To assess HF in a rat coronary stenosis (CS) model, we administered vehicle and quinapril or candesartan (or both) orally for 12 wk. Compared with the sham group, the vehicle group showed impaired myocardial perfusion, impaired coronary endothelial nitric oxide (NO) function in vitro, exhausted myocardial mitochondrial respiration, larger left ventricular (LV) dimensions and lower ejection fraction, lower LV rate of pressure development over time (dP/d t), lower slopes of LV end-systolic pressure-dimension relations (ESPDRs), and increased myocardial fibrosis. Treatment with quinapril or candesartan ameliorated these parameters without modifying the epicardial CS severity. Moreover, their combination maintained similar myocardial perfusion, despite a trend toward lower blood pressure, and showed distinctive neurohumoral modulation, normalized mitochondrial respiration, and increased ESPDR slopes. Thus improved myocardial blood flow and coronary flow reserve by quinapril or candesartan are the key to alleviate CS-induced HF, and their combination may have a therapeutic significance partly through ameliorated mitochondrial respiration and improved LV systolic function.
Comparison of three rat models of cerebral vasospasm
Authors: Gules Ilker , Satoh Motoyoshi , Clower Ben R. , Nanda Anil , Zhang John H.
Published: March 2015

A substantial number of rat models have been used to research subarachnoid hemorrhage-induced cerebral vasospasm; however, controversy exists regarding which method of selection is appropriate for this species. This study was designed to provide extensive information about the three most popular subarachnoid hemorrhage rat models: the endovascular puncture model, the single-hemorrhage model, and the double-hemorrhage model. In this study, the basilar artery and posterior communicating artery were chosen for histopathological examination and morphometric analysis. Both the endovascular puncture model and single-hemorrhage model developed significant degrees of vasospasm, which were less severe when compared with the double-hemorrhage model. The endovascular puncture model and double-hemorrhage model both developed more vasospasms in the posterior communicating artery than in the basilar artery. The endovascular puncture model has a markedly high mortality rate and high variability in bleeding volume. Overall, the present study showed that the double-hemorrhage model in rats is a more suitable tool with which to investigate mechanism and therapeutic approaches because it accurately correlates with the time courses for vasospasm in humans.
Biomechanical response of femoral vein to chronic elevation of blood pressure in rabbits
Authors: Hayashi K. , Mori K. , Miyazaki H.
Published: March 2015

Venous diseases like iliofemoral deep vein thrombosis and valvular dysfunction induce venous hypertension. To know the effects of the hypertension on venous mechanics, blood pressure in the left femoral vein in the rabbit was chronically elevated by the constriction of the left external iliac vein. Wall dimensions and biomechanical properties of the femoral vein were studied in vitro at 1, 2, or 4 wk after surgery. Blood pressure measured immediately before the animal was killed was significantly higher in the left femoral vein than in the sham-operated, contralateral vein. Wall thickness was increased by blood pressure elevation even at 1 wk, which restored circumferential wall stress to a control level. The stress was kept at normal up to 4 wk. Vascular tone and vascular contractility were increased by the elevation of blood pressure; however, wall elasticity and compliance were kept at a normal level. These results are very similar to those observed in hypertensive arteries, indicating that not only arteries but veins optimally operate against blood pressure elevation.
Pregnancy alters hemodynamic responses to hemorrhage in conscious rabbits
Authors: Clow Kathy A. , Giraud George D. , Ogden Bryan E. , Brooks Virginia L.
Published: March 2015

Pregnant animals are less able to maintain mean arterial pressure (MAP) during hemorrhage compared with nonpregnant animals, but the hemodynamic basis of this difference is unknown. The hypothesis that pregnancy attenuates responses of cardiac output, as well as total peripheral resistance (TPR) and femoral conductance, to hemorrhage was tested in conscious rabbits in both the pregnant and nonpregnant state ( n = 10). During continuous slow blood loss (2% of the initial blood volume per minute), MAP was maintained initially in both groups. However, MAP then abruptly decreased to <45 mmHg in all animals after a smaller percentage of the initial blood volume was removed in pregnant compared with nonpregnant rabbits (43.6 ± 1.7%, nonpregnant; 29.6 ± 2.2%, pregnant; P < 0.005). The more rapid transition to hypotension exhibited by pregnant rabbits was associated with greater initial falls in cardiac output (−56 ± 10 ml/min, nonpregnant; −216 ± 33 ml/min, pregnant; P < 0.005) and stroke volume (0.8 ± 0.1 ml/beat, nonpregnant; −1.3 ± 0.1 ml/beat, pregnant; P < 0.05). In addition, the increase in TPR as a function of the decrease in cardiac output was markedly attenuated ( P < 0.0001) during pregnancy. Whereas femoral conductance decreased in nonpregnant rabbits, it did not change significantly in pregnant animals. In conclusion, the lesser ability of conscious pregnant rabbits to maintain MAP during hemorrhage is due largely to a greater decrease in cardiac output but also to inadequate reflex increases in TPR, possibly in part in the femoral vascular bed.
NO produced by endothelial NO synthase is a mediator of delayed preconditioning-induced endothelial protection
Authors: Laude Karine , Favre Julie , Thuillez Christian , Richard Vincent
Published: March 2015

Preconditioning with brief periods of ischemia-reperfusion (I/R) induces a delayed protection of coronary endothelial cells against reperfusion injury. We assessed the possible role of nitric oxide (NO) produced during prolonged I/R as a mediator of this endothelial protection. Anesthetized rats were subjected to 20-min cardiac ischemia/60-min reperfusion, 24 h after sham surgery or cardiac preconditioning (1 × 2-min ischemia/5-min reperfusion and 2 × 5-min ischemia/5-min reperfusion). The nonselective NO synthase (NOS) inhibitor l-NAME, the selective inhibitors of neuronal (7-nitroindazole) or inducible (1400W) NOS, or the peroxynitrite scavenger seleno-l-methionine were administered 10 min before prolonged ischemia. Preconditioning prevented the reperfusion-induced impairment of coronary endothelium-dependent relaxations to acetylcholine (maximal relaxation: sham 77 ± 3; I/R 44 ± 6; PC 74 ± 5%). This protective effect was abolished by l-NAME (41 ± 7%), whereas 7-NI, 1400W or seleno-l-methionine had no effect. The abolition of preconditioning by l-NAME, but not by selective nNOS or iNOS inhibition, suggests that NO produced by eNOS is a mediator of delayed endothelial preconditioning.
Decrease in cardiac output and muscle sympathetic activity during vasovagal syncope
Authors: Jardine D. L. , Melton I. C. , Crozier I. G. , English S. , Bennett S. I. , Frampton C. M. , Ikram H.
Published: March 2015

The importance of cardiac output (CO) to blood pressure level during vasovagal syncope is unknown. We measured thermodilution CO, mean blood pressure (MBP), and leg muscle mean sympathetic nerve activity (MSNA) each minute during 60° head-up tilt in 26 patients with recurrent syncope. Eight patients tolerated tilt (TT) for 45 min (mean age 60 ± 5 yr) and 15 patients developed syncope during tilt (TS) (mean age 58 ± 4 yr, mean tilt time 15.4 ± 2 min). In TT patients, CO decreased during the first minute of tilt (from 3.2 ± 0.2 to 2.5 ± 0.3 l · min−1 · m−2, P = 0.001) and thereafter remained stable between 2.5 ± 0.3 ( P = 0.001) and 2.4 ± 0.2 l · min−1 · m−2( P = 0.004) at 5 and 45 min, respectively. In TS patients, CO decreased during the first minute (from 3.3 ± 0.2 to 2.7 ± 0.1 l · min−1 · m−2, P = 0.02) and was stable until 7 min before syncope, falling to 2.0 ± 0.2 at syncope ( P = 0.001). Regression slopes for CO versus time during tilt were −0.01 min−1 in TT versus −0.1 l · min−1 · m−2 · min−1in TS ( P = 0.001). However, MBP was more closely correlated to total peripheral resistance ( R = 0.56, P = 0.001) and MSNA ( R = 0.58, P = 0.001) than CO ( R = 0.32, P = 0.001). In vasovagal reactions, a progressive decline in CO may contribute to hypotension some minutes before syncope occurs.
Reduced cardiovagal baroreflex gain in visceral obesity: implications for the metabolic syndrome
Authors: Beske Stacy D. , Alvarez Guy E. , Ballard Tasha P. , Davy Kevin P.
Published: March 2015

The influence of excess total and abdominal adiposity on cardiovagal baroreflex gain remains unclear. We tested the hypotheses that cardiovagal baroreflex gain would be reduced in men with 1) higher [higher fat (HF), mass >20 kg, n = 11] compared with lower [lower fat (LF), mass <20 kg, n = 10] levels of total body and abdominal fat and 2) higher abdominal visceral fat (HAVF; n = 10) compared with total body weight- and subcutaneous fat-matched peers with lower abdominal visceral fat (LAVF; n = 7) levels. To accomplish this, we measured cardiovagal baroreflex gain (modified Oxford technique), body composition (dual energy X-ray absorptiometry), and abdominal visceral and subcutaneous fat (computed tomography) in sedentary men (age, 18–40 yr; body mass index, <34.9 kg/m2) across a wide range of adiposity. Cardiovagal baroreflex gain was significantly lower in HF compared with LF (14.3 ± 2.8 vs. 21.4 ± 2.8 ms/mmHg, respectively). In addition, cardiovagal baroreflex gain was lower in HAVF compared with LAVF (13.0 ± 2.0 vs. 21.4 ± 3.6 ms/mmHg, P< 0.05). Therefore, the results of the present study indicate that cardiovagal baroreflex gain is reduced in men with elevated total body and abdominal fat mass. The reduced cardiovagal baroreflex gain in these individuals appears to be linked to their higher level of abdominal visceral fat. Importantly, reduced cardiovagal baroreflex gain may contribute to the increased risk of cardiovascular disease observed in men with the metabolic syndrome.
Cocaine enhances myocarditis induced by encephalomyocarditis virus in murine model
Authors: Wang Ju-Feng , Zhang Jielin , Min Jiang-Yong , Sullivan Matthew F. , Crumpacker Clyde S. , Abelmann Walter H. , Morgan James P.
Published: March 2015

This study was designed to investigate whether cocaine can exacerbate viral myocarditis and increase its incidence. Recent clinical evidence suggests that cocaine abuse increases the incidence of myocarditis. However, it has not been directly demonstrated that cocaine exposure enhances murine myocarditis. BALB/c mice were divided into eight groups: saline control, encephalomyocarditis virus (EMCV), 10 mg/kg cocaine (Coc-10), 30 mg/kg cocaine (Coc-30), 50 mg/kg cocaine (Coc-50), EMCV+Coc-10, EMCV+Coc-30, EMCV+Coc-50. After inoculation with EMCV, the mice were treated daily with either cocaine or saline for 90 days. Mice were euthanized at different days after EMCV inoculation. Mortality was recorded and myocarditis severity was evaluated. The mortality of the myocarditis mice treated with cocaine increased significantly, from 22% (EMCV) to 25.7% (Coc-10+EMCV), 41.4% (Coc-30+EMCV), and 51.4% (Coc-50+EMCV) ( P < 0.05), respectively. The incidence and severity of inflammatory cell infiltration and myocardial lesions was higher in infected mice exposed to cocaine. Cocaine administered only before infection did not exacerbate myocarditis. Norepinephrine (NE) assay showed that cocaine exposure significantly increased myocardial NE concentration but this increase was partially inhibited in infected animals. Adrenalectomy abolished the effect of cocaine on mortality. Furthermore, propranolol, a β-blocker, significantly decreased the enhancing effects of cocaine on myocarditis mice. In conclusion, cocaine increases the severity and mortality of viral myocarditis in mice. Increased catecholamines may be a major factor responsible for this effect.
Role of microtubules versus myosin heavy chain isoforms in contractile dysfunction of hypertrophied murine cardiocytes
Authors: Ishibashi Yuji , Takahashi Masaru , Isomatsu Yukihisa , Qiao Fei , Iijima Yoshihiro , Shiraishi Hirokazu , Simsic Janet M. , Baicu Catalin F. , Robbins Jeffrey , Zile Michael R. , Cooper George
Published: March 2015

In large mammals there is a correlation between microtubule network densification and contractile dysfunction in severe pressure-overload hypertrophy. In small mammals there is a similar correlation for the shift to β-myosin heavy chain (MHC), a MHC isoform having a slower ATPase Vmax. In this study, murine left ventricular (LV) pressure overload invoked both mechanisms: microtubule network densification and β-MHC expression. Cardiac β-MHC was also augmented without altering tubulin levels by two load-independent means, chemical thyroidectomy and transgenesis. In hypertrophy, contractile function of the LV and its cardiocytes decreased proportionally; microtubule depolymerization restored normal cellular contraction. In hypothyroid mice having a complete shift from α-MHC to β-MHC, contractile function of the LV and its cardiocytes also decreased, but microtubule depolymerization had no effect on cellular contraction. In transgenic mice having a cardiac β-MHC increase similar to that in hypertrophy, contractile function of the LV and its cardiocytes was normal, and microtubule depolymerization had no effect. Thus, although both mechanisms may cause contractile dysfunction, for the extent of MHC isoform switching seen even in severe murine LV pressure-overload hypertrophy, microtubule network densification appears to have the more important role.
Systemic α1A-adrenoceptor antagonist inhibits neointimal growth after balloon injury of rat carotid artery
Authors: Teeters John C. , Erami Cauveh , Zhang Hua , Faber James E.
Published: March 2015

Previous in vitro and in vivo studies have shown that norepinephrine, acting through α1A-adrenoceptors, stimulates hypertrophy, proliferation, and migration of vascular smooth muscle cells and adventitial fibroblasts and may contribute to neointimal growth, lumen loss, and inward remodeling caused by iatrogenic wall injury and vascular disease. Our present aim was to determine whether intravenous administration of the α1A-adrenoceptor antagonist KMD-3213, at dosages without systemic hemodynamic effects, inhibits wall growth after injury. Inhibition of α1A-adrenoceptors with 12.8 and 32 μg/kg KMD-3213 had no effect on arterial pressure or renal and hindquarter resistances in anesthetized rats. A second group then received carotid balloon injury and continuous intravenous KMD-3213 at 4 and 10 μg · kg−1 · h−1for 2 wk. Mean, systolic, and diastolic arterial pressures and heart rate of conscious unrestrained rats were unaffected. KMD-3213 reduced neointima growth by ∼30 and 46% at the two doses ( P< 0.01). These data support the novel hypothesis that a direct α1A-adrenoceptor-dependent trophic action of catecholamines is augmented by injury and may contribute significantly to hypertrophic vascular disease.
Effective protection by NHE-1 inhibition in ischemic and reperfused heart under preconditioning blockade
Authors: Haist James V. , Hirst Claire N. , Karmazyn Morris
Published: March 2015

We compared the protective effects of ischemic preconditioning (IPC) and the Na+/H+ exchanger-1 (NHE-1) inhibitor cariporide in isolated rat hearts subjected to global ischemia (45 or 90 min) and 30-min reperfusion and determined the protective effects of cariporide under IPC blockade with the mitochondrial ATP-sensitive K+ channel blocker 5-hydroxydecanoate (5-HD). With 45-min ischemia, both IPC and cariporide equally increased maximum recovery of left ventricular developed pressure twofold ( P < 0.05), although recovery was significantly greater with cariporide for the first 15 min of reperfusion. 5-HD almost completely blocked the protective effects of IPC on recovery but had no influence on the salutary effects of cariporide. With 90-min ischemic control, recovery was only 3% of preischemia and was unaffected by IPC, although cariporide increased recovery to ∼30% ( P < 0.05). This was associated with a 37% preservation of viable cardiac cells, whereas no structurally intact cells were found in either IPC or control hearts. Our study shows that NHE-1 inhibition is a more effective cardioprotective strategy than IPC in this model, possibly because of enhanced myocyte salvage, and because protection by NHE-1 inhibition is completely unaffected by IPC blockade with 5-HD.
High plasma norepinephrine attenuates the dynamic heart rate response to vagal stimulation
Authors: Miyamoto Tadayoshi , Kawada Toru , Takaki Hiroshi , Inagaki Masashi , Yanagiya Yusuke , Jin Yintie , Sugimachi Masaru , Sunagawa Kenji
Published: March 2015

To better understand the pathophysiological significance of high plasma norepinephrine (NE) concentration in regulating heart rate (HR), we examined the interactions between high plasma NE and dynamic vagal control of HR. In anesthetized rabbits with sinoaortic denervation and vagotomy, using a binary white noise sequence (0–10 Hz) for 10 min, we stimulated the right vagus and estimated the transfer function from vagal stimulation to HR response. The transfer function approximated a first-order low-pass filter with pure delay. Infusion of NE (100 μg · kg−1 · h−1 iv) attenuated the dynamic gain from 6.2 ± 0.8 to 3.9 ± 1.2 beats · min−1 · Hz−1( n = 7, P < 0.05) without affecting the corner frequency or pure delay. Simultaneous intravenous administration of phentolamine (1 mg · kg−1 · h−1) and NE (100 μg · kg−1 · h−1) abolished the inhibitory effect of NE on the dynamic gain (6.3 ± 0.8 vs. 6.4 ± 1.3 beats · min−1 · Hz−1, not significant, n = 7). The inhibitory effect of NE at infusion rates of 10, 50, and 100 μg · kg−1 · h−1 on dynamic vagal control of HR was dose-dependent ( n = 5). In conclusion, high plasma NE attenuated the dynamic HR response to vagal stimulation, probably via activation of α-adrenergic receptors on the preganglionic and/or postganglionic cardiac vagal nerve terminals.
Effects of ω-3 polyunsaturated fatty acids on cardiac sarcolemmal Na+/H+exchange
Authors: Goel Danny P. , Maddaford Thane G. , Pierce Grant N.
Published: March 2015

Myocardial ischemia-reperfusion activates the Na+/H+exchanger, which induces arrhythmias, cell damage, and eventually cell death. Inhibition of the exchanger reduces cell damage and lowers the incidence of arrhythmias after ischemia-reperfusion. The ω-3 polyunsaturated fatty acids (PUFAs) are also known to be cardioprotective and antiarrhythmic during ischemia-reperfusion challenge. Some of the action of PUFAs may occur via inhibition of the Na+/H+exchanger. The purpose of our study was to determine the capacity for selected PUFAs to alter cardiac sarcolemmal (SL) Na+/H+exchange. Cardiac membranes highly enriched in SL vesicles were exposed to 10–100 μM eicosapentanoic acid (EPA) or docosahexanoic acid (DHA). H+-dependent22Na+uptake was inhibited by 30–50% after treatment with ≥50 μM EPA or ≥25 μM DHA. This was a specific effect of these PUFAs, because 50 μM linoleic acid or linolenic acid had no significant effect on Na+/H+exchange. The SL vesicles did not exhibit an increase in passive Na+efflux after PUFA treatment. In conclusion, EPA and DHA can potently inhibit cardiac SL Na+/H+exchange at physiologically relevant concentrations. This may explain, in part, their known cardioprotective effects and antiarrhythmic actions during ischemia-reperfusion.
Cardiac kinin level in experimental diabetes mellitus: role of kininases
Authors: Koch Matthias , Wendorf Michael , Dendorfer Andreas , Wolfrum Sebastian , Schulze Karsten , Spillmann Frank , Schultheiss Heinz-Peter , Tschöpe Carsten
Published: March 2015

Diabetes mellitus impairs the cardiac kallikrein-kinin system by reducing cardiac kallikrein (KLK) and kininogen levels, a mechanism that may contribute to the deleterious outcome of cardiac ischemia in this disease. We studied left ventricular (LV) function and bradykinin (BK) coronary outflow in buffer-perfused, isolated working hearts ( n = 7) of controls and streptozotocin (STZ)-induced diabetic rats before and after global ischemia. With the use of selective kininase inhibitors, the activities of angiotensin I-converting enzyme, aminopeptidase P, and neutral endopeptidase were determined by analyzing the degradation kinetics of exogenously administered BK during sequential coronary passages. Basal LV function and coronary flow were impaired in STZ-induced diabetic rats. Neither basal nor postischemic coronary BK outflow differed between control and diabetic hearts. Reperfusion after 15 min of ischemia induced a peak in coronary BK outflow that was of the same extent and duration in both groups. In diabetic hearts, total cardiac kininase activity was reduced by 41.4% with an unchanged relative kininase contribution compared with controls. In conclusion, despite reduced cardiac KLK synthesis, STZ-induced diabetic hearts are able to maintain kinin liberation under basal and ischemic conditions because of a primary impairment or a secondary downregulation of kinin-degrading enzymes.
Energetics of the Frank-Starling effect in rabbit myocardium: economy and efficiency depend on muscle length
Authors: Holmes Jeffrey W. , Hünlich Mark , Hasenfuss Gerd
Published: March 2015

We tested the hypothesis that economy and efficiency are independent of length in intact cardiac muscle over its normal working range. We measured force, force-time integral, force-length area, and myocardial oxygen consumption in eight isometrically contracting rabbit right ventricular papillary muscles. 2,3-Butanedione monoxime was used to partition nonbasal oxygen consumption into tension-independent and tension-dependent components. Developed force, force-time integral, and force-length area increased by factors of 2.4, 2.7, and 4.8, respectively, as muscle length was increased from 90% to 100% maximal length, whereas tension-dependent oxygen consumption increased only 1.6-fold. Economy (the ratio of force-time integral to tension-dependent oxygen consumption) increased significantly with muscle length, as did contractile efficiency, the ratio of force-length area to tension-dependent oxygen consumption. The average force-length area-nonbasal oxygen consumption intercept was more than the twice tension-independent oxygen consumption. We conclude that economy and efficiency increase with length in rabbit myocardium. This conclusion is consistent with published data in isolated rabbit and dog hearts but at odds with studies in skinned myocardium.
Cardiac effects of adenosine in A2A receptor knockout hearts: uncovering A2B receptors
Authors: Morrison R. Ray , Talukder M. A. Hassan , Ledent Catherine , Mustafa S. Jamal
Published: March 2015

To clarify the relative roles of A2 adenosine receptor subtypes in the regulation of coronary flow and myocardial contractility, coronary vascular and functional responses to adenosine and its analogs were examined in isolated wild-type (WT) and A2A receptor knockout (A2AKO) mouse hearts. Nonselective agonists adenosine and 5′- N-ethyl-carboxamido-adenosine (NECA) increased coronary flow in A2AKO hearts, albeit with a rightward shift of concentration-response curves and decreased maximal vasodilation compared with WT hearts. 2- p-(2-Carboxy-ethyl)phenethylamino-5′- N-ethyl-carboxamidoadenosine (CGS-21680, a selective A2A receptor agonist) increased coronary flow in WT hearts but did not affect A2AKO hearts. Adenosine and NECA each elicited equal maximal increases in developed pressure in WT and A2AKO hearts, whereas CGS-21680 did not affect developed pressure in A2AKO hearts. Alloxazine, a selective A2B receptor antagonist, attenuated NECA-induced coronary vasodilation (from 202 ± 14% to 128 ± 9% of baseline, P < 0.05) and NECA-induced increases in developed pressure (from 133 ± 8% to 112 ± 7% of baseline, P < 0.05) in A2AKO hearts. Together, these findings support the conclusion that A2Badenosine receptor activation increases coronary flow and developed pressure in isolated murine hearts.
GABAA receptor activation at medullary sympathetic neurons contributes to postexercise hypotension
Authors: Kajekar Radhika , Chen Chao-Yin , Mutoh Tatsushi , Bonham Ann C.
Published: March 2015

A single bout of exercise results in a postexercise hypotension (PEH) that is accompanied by a reduced baroreflex function. Based on the role of rostral ventrolateral medulla (RVLM) neurons in controlling sympathetic nerve activity (SNA) and blood pressure, the role of γ-aminobutyric acid (GABA) in controlling RVLM neuronal activity, and the reduced baroreflex-SNA relationship during PEH, we determined whether: 1) RVLM neuronal activity is decreased during PEH, 2) GABAA-receptor mechanisms mediate the decrease, and 3) baroreflex control of RVLM activity is reduced. Spontaneously hypertensive rats (SHR) were subjected to 40 min of treadmill or sham exercise (Sham PEH). PEH lasted 10 h in conscious and anesthetized SHR, indicating that the anesthetics did not affect the expression of PEH. Extracellular RVLM neuronal activity having a cardiac and sympathetic rhythm, lumbar SNA, and blood pressure were recorded at rest and during baroreflex function curves. Resting RVLM neuronal activity was lower and was increased to a greater extent by GABAA-receptor antagonism in PEH versus Sham PEH ( P < 0.05). Baroreflex control of RVLM neuronal activity operated with a reduced gain ( P < 0.05). Thus increased GABA signaling at RVLM neurons may contribute to PEH.
Cardiac enkephalins interrupt vagal bradycardia via δ2-opioid receptors in sinoatrial node
Authors: Farias Martin , Jackson Keith E. , Yoshishige Darice , Caffrey James L.
Published: March 2015

Local cardiac opioids appear to be important in determining the quality of vagal control of heart rate. Introduction of the endogenous opioid methionine-enkephalin-arginine-phenylalanine (MEAP) into the interstitium of the canine sinoatrial node by microdialysis attenuates vagally mediated bradycardia through a δ-opioid receptor mechanism. The following studies were conducted to test the hypothesis that a δ2-opiate receptor subtype mediates the interruption of vagal transmission. Twenty mongrel dogs were anesthetized and instrumented with microdialysis probes inserted into the sinoatrial node. Vagal frequency responses were performed at 1, 2, and 3 Hz during vehicle infusion and during treatment with the native agonist MEAP, the δ1-opioids 2-methyl-4aa-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydroquinolino[2,3,3- g]isoquinoline (TAN-67) and [d-pen2,5]-enkephalin (DPDPE), and the δ2opioid deltorphin II. The vagolytic effects of intranodal MEAP and deltorphin were then challenged with the δ1- and δ2-opioid receptor antagonists 7-benzylidenenaltrexone (BNTX) and naltriben, respectively. Although the positive control deltorphin II was clearly vagolytic in each experimental group, TAN-67 and DPDPE were vagolytically ineffective in the same animals. In contrast, TAN-67 improved vagal bradycardia by 30–35%. Naltriben completely reversed the vagolytic effects of MEAP and deltorphin. BNTX was ineffective in this regard but did reverse the vagal improvement observed with TAN-67. These data support the hypothesis that the vagolytic effect of the endogenous opioid MEAP was mediated by δ2-opioid receptors located in the sinoatrial node. These data also support the existence of vagotonic δ1-opioid receptors also in the sinoatrial node.
A computationally efficient electrophysiological model of human ventricular cells
Authors: Bernus O. , Wilders R. , Zemlin C. W. , Verschelde H. , Panfilov A. V.
Published: March 2015

Recent experimental and theoretical results have stressed the importance of modeling studies of reentrant arrhythmias in cardiac tissue and at the whole heart level. We introduce a six-variable model obtained by a reformulation of the Priebe-Beuckelmann model of a single human ventricular cell. The reformulated model is 4.9 times faster for numerical computations and it is more stable than the original model. It retains the action potential shape at various frequencies, restitution of action potential duration, and restitution of conduction velocity. We were able to reproduce the main properties of epicardial, endocardial, and M cells by modifying selected ionic currents. We performed a simulation study of spiral wave behavior in a two-dimensional sheet of human ventricular tissue and showed that spiral waves have a frequency of 3.3 Hz and a linear core of ∼50-mm diameter that rotates with an average frequency of 0.62 rad/s. Simulation results agreed with experimental data. In conclusion, the proposed model is suitable for efficient and accurate studies of reentrant phenomena in human ventricular tissue.
Relationship between tissue damage and heme oxygenase expression in chorionic villi of term human placenta
Authors: Lash G. E. , McLaughlin B. E. , MacDonald-Goodfellow S. K. , Smith G. N. , Brien J. F. , Marks G. S. , Nakatsu K. , Graham C. H.
Published: March 2015

Heme oxygenase (HO) catalyzes the oxidation of heme to carbon monoxide (CO), biliverdin, and iron and is thought to play a role in protecting tissues from oxidative damage. There are three isoforms of HO: HO-1 (inducible), HO-2 (constitutive), and HO-3 (unknown function). Preeclampsia is characterized by an inadequately perfused placenta and areas of tissue damage. We hypothesized that damaged areas of placentas from women with PE and uncomplicated pregnancies are associated with an alteration in HO expression. Compared with microsomes isolated from morphologically normal and peri-infarct chorionic villi of pathological placentas, microsomes from infarcted chorionic villi from the same placentas had decreased HO activity measured under optimized assay conditions. There was no correlation between microsomal HO levels and activity and tissue damage in uncomplicated pregnancies. Whereas there was no significant difference in HO-1 protein levels across all regions of uncomplicated and mildly preeclamptic pregnancies, HO-2 protein levels were decreased ( P < 0.05) in peri-infarct regions and infarcted chorionic villi of mildly preeclamptic pregnancies. Immunohistochemical analysis revealed an apparent decrease in both HO-1 and HO-2 protein expression in damaged tissues. HO-1 and HO-2 were immunolocalized in the syncytiotrophoblast layer of the chorionic villi, the underlying cytotrophoblast, and in the vascular endothelium. This study suggests that the ability of the chorionic villi to oxidize heme to CO, biliverdin, and iron may be compromised in areas of tissue damage in the placenta of women with preeclampsia.
Cardiac overexpression of A1-adenosine receptor protects intact mice against myocardial infarction
Authors: Yang Zequan , Cerniway Rachael J. , Byford Anne M. , Berr Stuart S. , French Brent A. , Matherne G. Paul
Published: March 2015

Previous studies have shown that high-level (300-fold normal) cardiac overexpression of A1-adenosine receptors (A1-ARs) in transgenic (TG) mice protects isolated hearts against ischemia-reperfusion injury. However, this high level of overexpression is associated with bradycardia and increased incidence of arrhythmia during ischemia in intact mice, which interfered with studies to determine whether this line of TG mice might also be protected against myocardial infarction (MI) in vivo. For these studies, we therefore selected a line of TG mice that overexpresses the A1-AR at more moderate levels (30-fold normal), which affords cardioprotection in the isolated heart while minimizing bradycardia and arrhythmia during ischemia in intact mice. Wild-type (WT; n = 10) and moderate-level A1-AR TG ( n = 10) mice underwent 45 min of left anterior descending coronary artery occlusion, followed by 24-h reperfusion. Infarct size and region at risk were determined by triphenyltetrazolium chloride and phthalo blue staining, respectively. Infarct size (% region at risk) in WT mice was 52 ± 3%, whereas overexpression of A1-ARs in the TG mice markedly reduced infarct size to 31 ± 3% ( P < 0.05). Furthermore, contractile function (left ventricular ejection fraction) as determined by cardiac magnetic resonance imaging 24 h after MI was better preserved in TG vs. WT mice. Cardiac overexpression of A1-ARs reduces infarct size by 40% and preserves cardiac function in intact mice after MI.
A new method for assessing arteriolar diameter and hemodynamic resistance using image analysis of vessel lumen
Authors: Tyml Karel , Anderson Donald , Lidington Darcy , Ladak Hanif M.
Published: March 2015

To characterize the nonuniform diameter response in a blood vessel after a given stimulus (e.g., arteriolar conducted response), frequent serial diameter measurements along the vessel length are required. We used an advanced image analysis algorithm (the “discrete dynamic contour”) to develop a quick, reliable method for serial luminal diameter measurements along the arteriole visualized by intravital video microscopy. With the use of digitized images of the arteriole and computer graphics, the method required an operator to mark the image of the two inner edges of the arteriole at several places along the arteriolar length. The algorithm then “filled in” these marks to generate two continuous contours that “hugged” these edges. A computer routine used these contours to determine luminal diameters every 20 μm. Based on these diameters and on Poiseuille's law, the routine also estimated the hemodynamic resistance of the blood vessel. To demonstrate the usefulness of the method, we examined the character of spatial decay of KCl-induced conducted constriction along ∼500-μm-long arteriolar segments and the KCl-induced increase in hemodynamic resistance computed for these segments. The decay was only modestly fitted by a simple exponential, and the computed increase in resistance (i.e., 5- to 70-fold) was only modestly predicted by resistance increase based on our mathematical model involving measurements at two arteriolar sites (Tyml K, Wang X, Lidington D, and Oullette Y. Am J Physiol Heart Circ Physiol 281: H1397–H1406, 2001). We conclude that our method provides quick, reliable serial diameter measurements. Because the change in hemodynamic resistance could serve as a sensitive index of conducted response, use of this index in studies of conducted response may lead to new mechanistic insights on the response.
Relation of effective arterial elastance to arterial system properties
Authors: Segers Patrick , Stergiopulos Nikos , Westerhof Nico
Published: March 2015

Effective arterial elastance ( E a), defined as the ratio of left ventricular (LV) end-systolic pressure and stroke volume, lumps the steady and pulsatile components of the arterial load in a concise way. Combined with E max, the slope of the LV end-systolic pressure-volume relation, E a/ E max has been used to assess heart-arterial coupling. A mathematical heart-arterial interaction model was used to study the effects of changes in peripheral resistance ( R; 0.6–1.8 mmHg · ml−1 · s) and total arterial compliance (C; 0.5–2.0 ml/mmHg) covering the human pathophysiological range. E a, E a/ E max, LV stroke work, and hydraulic power were calculated for all conditions. Multiple-linear regression analysis revealed a linear relation between E a, R/ T (where T is cycle length), and 1/C: E a= −0.13 + 1.02 R/ T + 0.31/C, indicating that R/ T contributes about three times more to E a than arterial stiffness (1/C). It is demonstrated that different pathophysiological combinations of R and C may lead to the same E a and E a/ E max but can result in differences of 10% in stroke work and 50% in maximal power.
Microinjection of a cannabinoid receptor antagonist into the NTS increases baroreflex duration in dogs
Authors: Rademacher David J. , Patel Sachin , Hopp Francis A. , Dean Caron , Hillard Cecilia J. , Seagard Jeanne L.
Published: March 2015

Baroreceptor afferent fibers synapse in the nucleus tractus solitarius (NTS) of the medulla. Neuronal cannabinoid (CB)1 receptors are expressed in the NTS and central administration of CB1 receptor agonists affect blood pressure (BP) and heart rate. In addition, there is evidence that endocannabinoids are produced in the brain stem. This study examined whether changes in CB1 receptor activity in the NTS modulated the baroreceptor reflex, contributing to changes seen in BP and heart rate. Baroreflexes were evoked in anesthetized dogs by pressure ramp stimulations of the isolated carotid sinus before and after microinjection of CB1 receptor agonist WIN-55212-2 (1.25–1.50 pmol) or antagonist SR-141716 (2.5–3.0 pmol) into cardiovascular regions of the NTS. Microinjection of the SR-141716 did not affect baseline BP or baroreflex sensitivity. However, SR-141716 significantly prolonged the time needed to return to the baseline level of BP after the pressure ramp. Microinjection of WIN-55212-2 had no effect on the baroreflex. These data suggest that endocannabinoids can modulate the excitability of NTS neurons involved in the baroreceptor reflex, leading to modulation of baroreflex regulation.
Gender-dependent modulation of α1-adrenergic responses in rat mesenteric arteries
Authors: McKee Alyson P. , Van Riper Dee A. , Davison Cathy A. , Singer Harold A.
Published: March 2015

The purpose of this study was to test the hypothesis that pathways modulating vasoconstriction in rat mesenteric resistance arteries are gender dependent. Net contractile responses to phenylephrine were significantly increased by endothelium disruption in arteries from males but not females. This gender-dependent effect was stimulus specific, because disruption of endothelium increased reactivity to serotonin comparably in arteries from both genders. Ovariectomy unmasked an increase in net α1-adrenergic contractile responsiveness after endothelium disruption, suggesting α1-adrenergic-stimulated production of endothelial vasodilators is suppressed in control females by gonadal sex steroids. Production of modulatory endothelium-derived vasodilators in males is balanced by production of vasoconstricting arachidonic acid metabolites. This was revealed by decreased α1-adrenergic contractile responses in arteries from males after pretreatment with indomethacin or the cyclooxygenase-1 selective inhibitor SC-560. The indomethacin-induced effect persisted after endothelium disruption, indicating smooth muscle as the source of cyclooxygenase-1-derived vasoconstrictors and was attenuated after orchiectomy. This study indicates gender differences in the expression of two pathways modulating α1-adrenergic sensitivity in mesenteric arteries: an endothelium-dependent vasodilator pathway and a balancing smooth muscle cyclooxygenase-1-dependent vasoconstrictor pathway. One consequence of these differences is that endothelial damage produces a selective increase in α1-adrenergic agonist reactivity in arteries from males.
Reduced coronary and inotropic reserves with coronary microembolization
Authors: Skyschally Andreas , Schulz Rainer , Erbel Raimund , Heusch Gerd
Published: March 2015

Microembolized myocardium is characterized by perfusion-contraction mismatch with reduced contractile function and unchanged or even elevated blood flow. The present study investigated the consequences of microembolization on coronary and inotropic reserves. In eight anesthetized dogs, left circumflex coronary blood flow (CBF), regional blood flow (RBF), and posterior systolic wall thickening were measured. Repetitive injection of 42-μm microspheres into the left circumflex coronary artery decreased systolic wall thickening by 50% (17.2 ± 2.4% vs. 8.0 ± 1.4%; means ± SD). Coronary reserve was determined by either intracoronary infusion of adenosine ( n = 4) or the reactive hyperemia response following 15 s of coronary occlusion ( n = 4); inotropic reserve was recruited by intracoronary infusion of dobutamine. The amount of injected microspheres was 158,000 ± 48,000. CBF (45.5 ± 16.5 vs. 47.8 ± 14.4 ml/min) and RBF (1.15 ± 0.18 vs. 1.33 ± 0.39 ml · min−1 · g−1) remained unchanged. Coronary reserve in response to intracoronary infusion of adenosine (410 ± 94% vs. 290 ± 77%; P < 0.05) and reactive hyperemia repayment (360 ± 174% vs. 155 ± 66%; P < 0.05) were blunted after microembolization. Inotropic reserve, i.e., the increment in systolic wall thickening with dobutamine, was decreased from 12.4 ± 3.9% to 8.0 ± 3.3% ( P < 0.05). We conclude that coronary microembolization reduces coronary and inotropic reserves.
Angiotensin II contributes to arterial compliance in congestive heart failure
Authors: Lage Silvia G. , Kopel Liliane , Medeiros Caio C. J. , Carvalho Ricardo T. , Creager Mark A.
Published: March 2015

Arterial compliance is determined by structural factors, such as collagen and elastin, and functional factors, such as vasoactive neurohormones. To determine whether angiotensin II contributes to decreased arterial compliance in patients with heart failure, this study tested the hypothesis that administration of an angiotensin-converting enzyme inhibitor improves arterial compliance. Arterial compliance and stiffness were determined by measuring carotid artery diameter, using high-resolution duplex ultrasonography, and blood pressure in 23 patients with heart failure secondary to idiopathic dilated cardiomyopathy. Measurements were made before and after intravenous administration of enalaprilat (1 mg) or vehicle. Arterial compliance was inversely related to both baseline plasma angiotensin II ( r = −0.52; P = 0.015) and angiotensin-converting enzyme concentrations ( r = −0.45; P = 0.041). During isobaric conditions, enalaprilat increased carotid artery compliance from 3.0 ± 0.4 to 5.0 ± 0.4 × 10−10N−1· m4( P = 0.001) and decreased the carotid artery stiffness index from 17.5 ± 1.8 to 10.1 ± 0.6 units ( P = 0.001), whereas the vehicle had no effect. Thus angiotensin II is associated with reduced carotid arterial compliance in patients with congestive heart failure, and angiotensin-converting enzyme inhibition improves arterial elastic properties. This favorable effect on the pulsatile component of afterload may contribute to the improvement in left ventricular performance that occurs in patients with heart failure treated with angiotensin-converting enzyme inhibitors.