bluuebunny/crossref_metadata_2025 huggingface dataset:
Localization and functional effects of adenosine A1receptors on cardiac vagal afferents in adult rats
Authors: Middlekauff Holly R. , Rivkees Scott A. , Raybould Helen E. , Bitticaca Melo , Goldhaber Joshua I. , Weiss James N.
Published: December 2017

There is evidence to suggest that during ischemia adenosine acts on cardiac vagal afferent neurons to activate systemic reflexes and to modulate cardiac nociception. The purpose of this study was to determine whether adenosine receptors are present and have direct cellular electrophysiological actions on cardiac vagal afferent neurons. In radioreceptor assays of nodose ganglion tissue from rats, binding was detectable for A1(39.6 ± 1.2 fmol/mg protein) but not A2aadenosine receptors. These findings were confirmed using the complementary approach of receptor-labeling autoradiography. Using in situ hybridization, we saw specific labeling over ∼50% of neurons in the nodose ganglia, but not over nonneuronal cells. In colabeling studies, cardiac vagal afferent neurons were identified by retroneuronal labeling with fluororuby. Of cardiac vagal afferents approximately one-half were strongly positive for A1adenosine receptors (immunocytochemistry). In patch-clamping experiments, adenosine inhibited peak inward calcium current in 7 of 11 cells by 48 ± 13%. In conclusion, adenosine A1receptors reside on a subset of vagal afferent neurons, including cardiac vagal afferents, and have electrophysiological effects that modulate neuroexcitability in cultured nodose ganglion neurons.
Angiotensin receptor antagonist improves cardiac reflex control of renal sodium handling in heart failure
Authors: Dibona Gerald F. , Jones Susan Y. , Sawin Linda L.
Published: December 2017

In rats with congestive heart failure, type 1 angiotensin II receptor antagonist treatment (losartan) decreases basal renal sympathetic nerve activity and improves arterial baroreflex regulation of renal sympathetic nerve activity. This investigation examined the effect of losartan on cardiac baroreflex regulation of renal sympathetic nerve activity and renal sodium handling in rats with congestive heart failure. Losartan treatment decreased arterial pressure from 120 ± 3 to 93 ± 5 mmHg and increased the afferent (from 0.95 ± 0.21 to 2.22 ± 0.42% Δafferent vagal nerve activity/mmHg mean right atrial pressure, P < 0.05) and overall gain (from −1.14 ± 0.19 to −4.20 ± 0.39% Δrenal sympathetic nerve activity/mmHg mean right atrial pressure, P < 0.05) of the cardiac baroreflex. During isotonic saline volume loading, urinary sodium excretion increased from 2.4 ± 0.8 to 10.5 ± 1.3 μeq/min in vehicle-treated rats (excretion of 52 ± 3% of the load) and from 3.0 ± 1.0 to 15.1 ± 1.8 μeq/min in losartan-treated rats (excretion of 65 ± 4% of the load, P < 0.05). When rats were changed from a low- to a high-sodium diet, cumulative sodium balance over 5 days was 7.8 ± 0.6 meq in vehicle-treated rats and 4.2 ± 0.4 meq in losartan-treated rats ( P < 0.05). In congestive heart failure, losartan treatment improved cardiac baroreflex regulation of renal sympathetic nerve activity, which was associated with improved ability to excrete acute and chronic sodium loads.
Effect of PGE1, PGI2, and PGF2αanalogs on collagen gel compaction in vitro and interstitial pressure in vivo
Authors: Berg Ansgar , Ekwall Anna-Karin Hultgård , Rubin Kristofer , Stjernschantz Johan , Reed Rolf K.
Published: December 2017

Acute inflammation in skin is accompanied by increased negativity of interstitial fluid pressure (PIF), which will increase capillary fluid filtration and thereby potentiate edema formation. A series of studies indicates that the connective tissue cells in rat dermis are involved in the control of PIFand mediate this response. The present study describes a novel effect of prostaglandin (PG) E1isopropyl ester, carbaprostacyclin (PGI2analog), and latanoprost (PGF2αanalog) on edema formation and PIFin parallel with their action on the fibroblast-populated collagen gel contraction assay. The prostaglandins were injected subdermally in pentobarbital-anesthetized rats. PIFwas measured with a servo-controlled counterpressure system after circulatory arrest had been induced with saturated potassium chloride. Circulatory arrest was induced to limit edema formation that would raise interstitial fluid volume and thereby attenuate a possible increased negativity of PIF. PGE1(0.91 mM) and carbaprostacyclin (1.28 mM) lowered PIFfrom a control value of −0.8 ± 0.4 mmHg to −3.0 ± 0.4 ( P < 0.01) and −3.7 ± 0.9 ( P < 0.01) mmHg, respectively, within 45 min in a dose-dependent manner. Edema formation was measured in separate experiments. PGE1and carbaprostacyclin significantly increased interstitial fluid volume (extravascular51Cr-EDTA space) at concentrations as low as 0.1 and 1.1 μM, respectively. Latanoprost had no effect on PIFor edema formation. However, latanoprost reversed, in a dose-dependent manner, an increased negativity of PIFaccompanying the anaphylactic reaction to dextran. In the gel contraction assay with human diploid fibroblasts (AG 1518), a corresponding specificity was observed where PGE1and carbaprostacyclin effectively inhibited gel contraction although latanoprost had no effect. Thus the present data demonstrate a novel effect of prostaglandins and provide further evidence for active modulation of PIFvia loose connective tissue cells.
Mathematical considerations for modeling cerebral blood flow autoregulation to systemic arterial pressure
Authors: Gao Erzhen , Young William L. , Pile-Spellman John , Ornstein Eugene , Ma Qiyuan
Published: December 2017

The shape of the autoregulation curve for cerebral blood flow (CBF) vs. pressure is depicted in a variety of ways to fit experimentally derived data. However, there is no general empirical description to reproduce CBF changes resulting from systemic arterial pressure variations that is consistent with the reported data. We analyzed previously reported experimental data used to construct autoregulation curves. To improve on existing portrayals of the fitting of the observed data, a compartmental model was developed for synthesis of the autoregulation curve. The resistive arterial and arteriolar network was simplified as an autoregulation device (ARD), which consists of four compartments in series controlling CBF. Each compartment consists of a group of identical vessels in parallel. The response of each vessel category to changes in perfusion pressure was simulated using reported experimental data. The CBF-pressure curve was calculated from the resistance of the ARD. The predicted autoregulation curve was consistent with reported experimental data. The lower and upper limits of autoregulation (LLA and ULA) were predicted as 69 and 153 mmHg, respectively. The average value of the slope of the CBF-pressure curve below LLA and beyond ULA was predicted as 1.3 and 3.3% change in CBF per mmHg, respectively. Our four-compartment ARD model, which simulated small arteries and arterioles, predicted an autoregulation function similar to experimental data with respect to the LLA, ULA, and average slopes of the autoregulation curve below LLA and above ULA.
Species variability in angiotensin receptor expression by cultured cardiac fibroblasts and the infarcted heart
Authors: Gallagher Ann Marie , Bahnson Tristram D. , Yu Hisahiro , Kim Noel N. , Printz Morton P.
Published: December 2017

Cardiac fibroblasts, an abundant cell of the left ventricle (LV), proliferate and synthesize collagen in the heart after acute injury and during pressure overload hypertrophy. From many studies, angiotensin II (ANG II) receptors have been implicated in promoting collagen formation by the rat cardiac fibroblast. The present study examined species variability in ANG II receptor expression. Cultured rat fibroblasts expressed 43,000 ± 15,000 ANG II (AT1-specific) receptors per cell (dissociation constant = 0.92 ± 0.34 nM), whereas rabbit and neonate human cardiac fibroblast cultures expressed few receptors. Angiotensin increased intracellular Ca2+concentration in rats but not in rabbit or human cardiac fibroblasts and stimulated arachidonic acid release in rat but not rabbit fibroblasts. In situ, 6 days after coronary artery ligation, angiotensin receptor expression was increased 34.8 ± 13.4-fold in the infarcted area relative to the noninfarcted tissue in the rat LV, whereas rabbit hearts demonstrated only a 3.2 ± 1.6-fold increase in ANG II binding within the infarcted tissue. These species differences in receptor expression raise questions as to the role of angiotensin as a mediator of collagen formation across species and as a direct target of angiotensin-converting enzyme inhibitors to regulate cardiac fibroblast function.
Flow-induced arterial remodeling in rat mesenteric vasculature
Authors: Tulis David A. , Unthank Joseph L. , Prewitt Russell L.
Published: December 2017

This study was designed to characterize in vivo arterial remodeling of male Wistar rat small mesenteric arteries exposed to varying levels of elevated blood flow in the presence of normal arterial pressure. Through a series of arterial ligations, respective ileal artery and second-order branch blood flows acutely increased ∼36 and ∼170% over basal levels. Their respective diameters increased 12 and 38% and their wall area increased 58 and 120% in a time-dependent fashion between 1 and 7 days postligation compared with same-animal control vessels. Medial extracellular connective tissue increased concomitantly with medial wall hypertrophy. Immunostaining for proliferating cell nuclear antigen and nuclear profile analyses suggests that both smooth muscle and endothelial cell hyperplasia contribute to flow-induced vascular remodeling. The initial stimulus in this model is flow-mediated shear stress, with possible augmentation by hoop stress, which is increased ∼7% by the resultant vasodilation. Stable wall thickness-to-lumen diameter ratios at 1, 3, and 7 days, however, suggest chronic hoop stress is tightly regulated and remains constant. The model described herein allows analyses of two arteries with different degrees of flow elevation within the same animal and demonstrates that the magnitude of vessel remodeling in vivo is directly dependent on the duration of flow elevation after abrupt arterial occlusion.
Left ventricular diastolic function of remodeled myocardium in dogs with pacing-induced heart failure
Authors: Solomon Steven B. , Nikolic Srdjan D. , Glantz Stanton A. , Yellin Edward L.
Published: December 2017

In patients with heart failure, decreased contractility resulting in high end-diastolic pressures and a restrictive pattern of left ventricular filling produces a decrease in early diastolic filling, suggesting a stiff ventricle. This study investigated the elastic properties of the myocardium and left ventricular chamber and the ability of the heart to utilize elastic recoil to facilitate filling during pacing-induced heart failure in the anesthetized dog. Elastic properties of the myocardium were determined by analyzing the myocardial stress-strain relation. Left ventricular chamber properties were determined by analyzing the pressure-volume relation using a logarithmic approach. Elastic recoil was characterized using a computer-controlled mitral valve occluder to prevent transmitral flow during diastole. We conclude that, during heart failure, the high end-diastolic pressures suggestive of a stiff ventricle are due not to stiffer myocardium but to a ventricle whose chamber compliance characteristics are changed due to geometric remodeling of the myocardium. The restrictive filling pattern is a result of the ventricle being forced to operate on the stiff portion of the diastolic pressure-volume relation to maintain cardiac output. Slowed relaxation and decreased contractility result in an inability of the heart to contract to an end-systolic volume below its diastolic equilibrium volume. Thus the left ventricle cannot utilize elastic recoil to facilitate filling during heart failure.
Cerebral arteriolar dilations by KATP channel activators needl-lysine orl-arginine
Authors: Kontos Hermes A. , Wei Enoch P.
Published: December 2017

We investigated the effects of various amino acids on responses to ATP-sensitive potassium (KATP) channel openers in anesthetized cats equipped with cranial windows. The application of pinacidil by superfusion caused transient vasodilation, whereas there was sustained vasodilation from the application of stationary solution of pinacidil. In the presence ofl-arginine orl-lysine, pinacidil by superfusion led to sustained vasodilation, suggesting that the rapid flow of fluid displaced these amino acids from binding on the channel and that such binding was essential for opening the channel. N G-nitro-l-arginine blocked responses to pinacidil, and this blockade was reversed byl-lysine orl-arginine but not byd-arginine,d-lysine, methyl-l-arginine, glycine,l-histidine, dimethylarginine, dimethyl-l-arginine, or hydroxylysine. The blockade of responses to pinacidil induced by glyburide was also reversed completely byl-arginine orl-lysine but not byd-arginine, suggesting that these amino acids act on the sulfonylurea receptor. Hydroxylysine but not methyl-l-lysine, dimethylarginine, or dimethyl-l-arginine blocked responses to pinacidil. The findings show that KATP channels in cerebral arterioles need l-lysine orl-arginine to open in response to agonists.
Tyrosine phosphorylation and association of p130Casand c-Crk II by ANG II in vascular smooth muscle cells
Authors: Takahashi Tomosaburo , Kawahara Yasuhiro , Taniguchi Takahiro , Yokoyama Mitsuhiro
Published: December 2017

In cultured vascular smooth muscle cells (VSMC), angiotensin II (ANG II) stimulated tyrosine phosphorylation of multiple proteins including a 130-kDa protein. This 130-kDa protein was identified as a Crk-associated substrate, p130Cas. ANG II-stimulated tyrosine phosphorylation of p130Caswas rapid, concentration dependent, and inhibited by the AT1-receptor antagonist CV-11974. Neither downregulation of protein kinase C by long exposure of cells to phorbol 12,13-dibutyrate nor blockade of Ca2+mobilization by 1,2-bis(2-aminophenoxy)ethane- N, N, N′, N′-tetraacetic acid acetoxymethyl ester had an effect on ANG II-stimulated tyrosine phosphorylation of p130Cas. Stimulation with ANG II enhanced the specific association of p130Caswith c-Crk II. The time course of the association of p130Casand c-Crk II was similar to that of tyrosine phosphorylation of p130Cas. c-Crk II was also tyrosine phosphorylated in response to ANG II. These results indicate that ANG II induces tyrosine phosphorylation of p130Casand c-Crk II and their specific association, suggesting a potential role of the p130Cas-c-Crk II complex in ANG II signal transduction in VSMC.
Alterations in dynamic heart rate control in the β1-adrenergic receptor knockout mouse
Authors: Rohrer Daniel K. , Schauble Eric H. , Desai Kavin H. , Kobilka Brian K. , Bernstein Daniel
Published: December 2017

β1-Adrenergic receptors (β1-ARs) are key targets of sympathetic nervous system activity and play a major role in the beat-to-beat regulation of cardiac chronotropy and inotropy. We employed a β1-AR gene knockout model to test the hypothesis that β1-AR function is critical for maintenance of resting heart rate and baroreflex responsiveness and, on the basis of its important role in regulating chronotropy and inotropy, is also required for maximal exercise capacity. Using an awake unrestrained mouse model, we demonstrate that resting heart rate and blood pressure are normal in β1-AR knockouts and that the qualitative responses to baroreflex stimulation are intact. Chronotropic reserve in β1-AR knockouts is markedly limited, with peak heart rates ∼200 beats/min less than wild types. During graded treadmill exercise, heart rate is significantly depressed in β1-AR knockouts at all work loads, but despite this limitation, there are no reductions in maximal exercise capacity or metabolic indexes. Thus, in mice, the β1-AR is not essential for either maintenance of resting heart rate or for maximally stressed cardiovascular performance.
Novel catheterization technique for the in vivo measurement of pulmonary vascular responses in rats
Authors: Hyman Albert L. , Hao Qingzhong , Tower Allen , Kadowitz Philip J. , Champion Hunter C. , Gumusel Bulent , Lippton Howard
Published: December 2017

A novel cardiac catheterization technique was devised to investigate the pulmonary arterial pressure-blood flow relationship in intact spontaneously breathing rats (ISBR) under physiological conditions with constant left atrial pressure and controlled blood flow within the normal range. Observations using this new technique in vivo were contrasted with data derived with isolated perfused rat lungs in vitro. Unlike results in in vitro isolated perfused rat lungs, the pressure-flow curves in vivo were curvilinear, with pulmonary artery pressure increasing more rapidly at low pulmonary blood flows of 4–8 ml/min and less rapidly at higher flow rates. Pressure-flow curves were reproducible and were not altered by 1–1.5 h of arrested perfusion, cyclooxygenase blockade, or perfusion with aortic or mixed venous blood. In contrast to results in in vitro isolated perfused rat lungs, NG-nitro-l-arginine methyl ester (l-NAME) increased pulmonary arterial pressure at all but the lowest flow rates with a slight effect on the curvilinear pressure-flow relationship. l-NAME reversed pulmonary vasodilator responses to acetylcholine and bradykinin and enhanced the pulmonary vasodilator response to nitroglycerin. The present data suggest that actively induced pulmonary hypertension is under greater control by endothelium-derived relaxing factor (EDRF). Unlike previous results in in vitro perfused rat lungs, results in ISBR demonstrate that the pulmonary vasodilator response to adrenomedullin-(13—52) is not mediated by calcitonin gene-related peptide receptors, which are not coupled to the release of EDRF. These results indicate that this novel technique may provide a useful model for the study of the pulmonary circulation in the intact chest rat.
Do β2-adrenergic receptors modulate Ca2+in adult rat ventricular myocytes?
Authors: Laflamme Michael A. , Becker Peter L.
Published: December 2017

We examined the role of β2-adrenergic receptors (ARs) in modulating calcium homeostasis in rat ventricular myocytes. Zinterol (10 μM), an agonist with a 25-fold greater affinity for β2-ARs over β1-ARs, modestly enhanced L-type calcium current ( ICa) magnitude by ∼30% and modestly accelerated the rate of Ca2+concentration ([Ca2+]) decline (∼35%) but had little effect on the magnitude of the [Ca2+] transient (a nonsignificant 6% increase). However, 1 μM of the highly selective β1-AR antagonist CGP-20712A completely blocked the ICaincrease induced by 10 μM zinterol. Pretreatment of cells with pertussis toxin (PTX) did not alter ICaenhancement by 10 μM zinterol, although it did abolish the ability of acetylcholine to block the forskolin-induced enhancement of ICa. Zinterol (10 μM) approximately doubled adenosine 3′,5′-cyclic monophosphate (cAMP) accumulation, although one-half of this increase was blocked by CGP-20712A. In contrast, 1 μM of the nonselective β-agonist isoproterenol increased cAMP production 15-fold. Thus we found no evidence that activation of β2-ARs modulates calcium homeostasis in rat ventricular myocytes, even after treatment with PTX.
Involvement of SA channels in orienting response of cultured endothelial cells to cyclic stretch
Authors: Naruse Keiji , Yamada Takako , Sokabe Masahiro
Published: December 2017

The present work was designed to elucidate the involvement of Ca2+-permeable stretch-activated (SA) channels in the orienting response of endothelial cells to uniaxial cyclic stretch. Endothelial cells from human umbilical vein were cultured on an elastic silicone membrane and subjected to uniaxial cyclic stretch (120% in length, 1 Hz). The cells started to change their morphology 15 min after the onset of stretch, and >90% of the cells oriented perpendicularly to the stretch axis after 2 h. Associated with the orienting response, cell elongation proceeded with a slower rate. Both of the orientating and elongating responses were largely inhibited by the removal of external Ca2+or by Gd3+, a potent blocker for the SA channel, but not by nifedipine. Intracellular Ca2+concentration ([Ca2+]i) transiently increased in response to uniaxial stretch, and the basal [Ca2+]igradually increased during cyclic stretch. This Ca2+response was inhibited by the removal of extracellular Ca2+or by the addition of Gd3+. These results suggest that stretch-dependent Ca2+influx through SA channels is essential in the stretch-dependent cell orientation and elongation.
Estrogen replacement, vascular distensibility, and blood pressures in postmenopausal women
Authors: De Meersman Ronald E. , Zion Adrienne S. , Giardina Elsa G. V. , Weir Joseph P. , Lieberman James S. , Downey John A.
Published: December 2017

The pathogenesis of blood pressure (BP) rise in aging women remains unexplained, and one of the many incriminating factors may include abnormalities in arteriolar resistance vessels. The aim of this study was to determine the effects of unopposed estrogen on arteriolar distensibility, baroreceptor sensitivity (BRS), BP changes, and rate-pressure product (RPP). We tested the hypotheses that estrogen replacement therapy (ERT) enhances arteriolar distensibility and ameliorates BRS, which leads to decreases in BP and RPP. Postmenopausal women participated in a single-blind crossover study; the participants of this study, after baseline measurements, were randomly assigned to receive estrogen (ERT) or a drug-free treatment with a 6-wk washout period between treatments. The single-blind design was instituted because subjects become unblinded due to physiological changes (i.e., fluid shifts, weight gain, and secretory changes) associated with estrogen intake. However, investigators and technicians involved in data collection and analyses remained blind. After each treatment, subjects performed identical autonomic tests, during which electrocardiograms, beat-by-beat BPs, and respiration were recorded. The area under the dicrotic notch of the BP wave was used as an index of arteriolar distensibility. The magnitude of the reflex bradycardia after a precipitous rise in BP was used to determine BRS. Power spectral analysis of heart rate variability was used to assess autonomic activity. BPs were recorded from resistance vessels in the finger using a beat-by-beat photoplethysmographic device. RPP, a noninvasive marker of myocardial oxygen consumption, was calculated. Repeated-measures analyses of variance revealed a significantly enhanced arteriolar distensibility and BRS after ERT ( P < 0.05). A trend of a lower sympathovagal balance at rest was observed after ERT; however, this trend did not reach statistical significance ( P = 0.061) compared with the other treatments. The above autonomic changes produced significantly lower systolic and diastolic BP changes and RPPs ( P < 0.05) at rest and during isometric exercise. We conclude that short-term unopposed ERT favorably enhances arteriolar distensibility, BRS, and hemodynamic parameters in postmenopausal women. These findings have clinical implications in the goals for treating cardiovascular risk factors in aging women.
Mechanisms of the cardiovascular deconditioning induced by tail suspension in the rat
Authors: Martel Eric , Ponchon Pascal , Champéroux Pascal , Elghozi Jean-Luc , De La Faverie Jean-François Renaud , Dabiré Hubert , Pannier Bruno , Richard Serge , Safar Michel , Cuche Jean-Louis
Published: December 2017

The aim of the present work was to obtain insights into the pathophysiology of cardiovascular deconditioning (CVD) induced by tail suspension (TS) in the rat: during TS, when central venous pressure (CVP) has been normalized (E. Martel, P. Champéroux, P. Lacolley, S. Richard, M. Safar, and J. L. Cuche. J. Appl. Physiol. 80: 1390–1396, 1996), and during simulated orthostatism (SO), when transient episodes of hypotension and bradycardia are disclosed, bradycardia with SO represents a response that seems peculiar to the rat compared with humans. According to basic physiology, a reduced activity of the sympathetic system induced by increased CVP was suspected but was not supported by data obtained through spectral analysis of blood pressure (BP) and heart rate (HR) variability or measurements of plasma catecholamine concentration during TS. Nonetheless, indirect evidence was obtained. During SO, plasma catecholamine concentration was lower in TS rats than in controls, suggesting a reduced synthesis of catecholamines, itself secondary to reduced activity of the sympathetic system. Furthermore, after 48 h of TS, the number of binding sites and affinity of α-receptors in rat aorta were increased, compatible with a reduced level of neurotransmitter in the synaptic cleft. A second series of experiments was carried out to study hypotension and bradycardia in TS rats during SO. Hypersensitivity of serotonergic mechanisms was suspected. Two 5-HT3 receptor antagonists (ondansetron and MDL-72222) blocked hypotension and restored tachycardia, basic features of orthostatic adaptation of the circulatory system. Response to the 5-HT3 receptor agonist was measured through dose-response curves of BP and HR after injection of 2-methylserotonin. After low doses, hypotension (10 μg/kg) and bradycardia (3 and 10 μg/kg) were significantly greater in 48-h TS rats than in controls. Thus CVD in the rat induced by TS appears to implicate at least two mechanisms: reduced activity of the sympathetic system and hypersensitivity of serotonergic mechanisms.
Tyrosine confounds oxidative electrochemical detection of nitric oxide
Authors: Stingele R. , Wilson D. A. , Traystman R. J. , Hanley D. F.
Published: December 2017

We report evidence that a porphyrinic microsensor for detection of nitric oxide (NO) also detects biologically relevant concentrations of tyrosine (Tyr) in dog brain. Tyr is oxidized by this sensor at the same potential as NO, and the sensitivity for NO and Tyr are of the same order of magnitude. The interference from Tyr is of importance because 1) Tyr is abundant and 2) there is a concentration gradient of Tyr across the blood-brain barrier that can lead to unpredictable results if disturbed by ischemia or hypoxia. The knowledge of this interference is important for the interpretation of results obtained with this sensor and for the design of future studies.
In vivo and in vitro mechanical properties of the sheep thoracic aorta in the perinatal period and adulthood
Authors: Wells Sarah M. , Langille B. Lowell , Adamson S. Lee
Published: December 2017

The mammalian aorta undergoes rapid remodeling during the perinatal period and more gradual remodeling during subsequent development, but the implications of this remodeling for arterial mechanics are poorly understood. In this study in vivo and in vitro techniques were used to determine the static and viscoelastic properties of the thoracic aortas of 119-day-gestation fetal sheep (full term = 145 days), 21-day-old lambs, and adult sheep at control distending pressures and after 70% increases or 30% decreases in pressure. In the weeks surrounding birth, aortic wall tissue became substantially stiffer (static elastic modulus in vitro increased by 28%, and pressure wave velocity in vivo increased by 61%) but less viscous (pressure wave attenuation in vivo decreased by 46%, and viscoelastic phase angle in vitro decreased by 15%), whereas the wall thickness-to-radius ratio was unchanged. By contrast, modest changes in tissue viscoelasticity from neonatal to adult life were accompanied by a halving of the wall thickness-to-radius ratio from 0.19 ± 0.01 to 0.10 ± 0.01. The relative thinning of the vessel wall, combined with a doubling of blood pressure after birth, resulted in a 265% increase in aortic wall tensile stress over the period of study. We concluded that rapid remodeling in the perinatal period primarily alters the viscoelastic properties of aortic wall tissues, whereas more gradual postnatal remodeling largely affects vessel geometry.
End-systolic stress-velocity and pressure-dimension relationships by transthoracic echocardiography in mice
Authors: Williams Richard V. , Lorenz John N. , Witt Sandra A. , Hellard David T. , Khoury Philip R. , Kimball Thomas R.
Published: December 2017

The purposes of this study were to assess load-independent, end-systolic relationships in mice and compare these relationships to ejection phase indexes in assessing contractility. In 13 mice, ejection phase indexes (shortening fraction and velocity of fiber shortening) and end-systolic relationships [pressure-dimension relationship (ESPDR) and stress-velocity relationship (ESSVR)] were determined using M-mode echocardiography and simultaneous left ventricular pressure. Load was altered with phenylephrine and nitroprusside. Contractility was increased with dobutamine and decreased by induction of hypothyroidism. Ejection phase indexes increased with dobutamine infusion but were not significantly decreased with hypothyroidism. However, end-systolic relationships changed significantly with both dobutamine ( y-intercepts: ESPDR from 22 to 48 mmHg, ESSVR from 3.7 to 6.6 circ/s, P < 0.05) and hypothyroidism ( y-intercepts: ESPDR from 22 to 11 mmHg, ESSVR from 3.7 to 3.2 circ/s, P< 0.05). We conclude that end-systolic indexes can be accurately measured in the intact mouse by echocardiography with simultaneous left ventricular pressure recording and appear to be more sensitive to inotropic state than ejection phase indexes.
Test of a two-pathway model for small-solute exchange across the capillary wall
Authors: Fu B. M. , Adamson R. H. , Curry F. E.
Published: December 2017

We previously proposed a two-pathway model for solute and water transport across vascular endothelium (Fu, B. M., R. Tsay, F. E. Curry, and S. Weinbaum. J. Biomech. Eng. 116: 502–513, 1994) that hypothesized the existence of a continuous slit 2 nm wide along tight junction strands within the interendothelial cleft in parallel with 20 × 150-nm breaks in tight junctions. We tested this model by measuring capillary permeability coefficients ( P) to a small solute (sodium fluorescein, radius 0.45 nm), assumed to permeate primarily the 2-nm small pore, and an intermediate-sized solute (FITC-α-lactalbumin, radius 2.01 nm) excluded from the small pore. Mean values of the paired diffusive permeability coefficients, Psodium fluoresceinand PFITC-α-lactalbumin, were 34.4 and 2.9 × 10−6cm/s, respectively, after corrections for solvent drag and free dye ( n = 26). These permeabilities were accounted for by transport through the large-break pathway without the additional capacity of the hypothetical 2-nm pathway. As a further test we examined the relative reductions of Psodium fluoresceinand PFITC-α-lactalbuminproduced by elevated intracellular cAMP. Within 20 min after the introduction of rolipram and forskolin, Psodium fluoresceinand PFITC-α-lactalbumindecreased to 0.67 and 0.64 times their respective baseline values. These similar responses to permeability decrease were evidence that the two solutes were carried by a common pathway. Combined results in both control and reduced permeability states did not support the hypothesis that a separate pathway across tight junctions is available for solutes with a radius as large as 0.75 nm. If such a pathway is present, then its size must be smaller than that of sodium fluorescein.
Autonomic control of vasovagal syncope
Authors: Jardine David L. , Ikram Hamid , Frampton Christopher M. , Frethey Rachell , Bennett Sinclair I. , Crozier Ian G.
Published: December 2017

In the pathophysiological study of vasovagal syncope, the nature of the interaction between baroreceptor sensitivity (BS), sympathetic withdrawal, and parasympathetic activity has yet to be ascertained. Altered BS may predispose toward abnormal sympathetic and parasympathetic responses to orthostasis, causing hypotension that may progress to syncope if there is sympathetic withdrawal. To examine this hypothesis, we monitored blood pressure (BP), heart rate (HR), BS, forearm blood flow, and muscle nerve sympathetic activity (MNSA) continuously in 18 vasovagal patients during 60° head-up tilt, syncope, and recovery. Results were compared with those of 17 patients who were able to tolerate tilt for 45 min. During early tilt, BP was maintained in both groups by an increase in HR and MNSA from baseline ( P < 0.01), but BS decreased more in the syncopal group ( P < 0.05). At the start of presyncope (mean 2.7 ± 0.2 min before syncope and 15.2 ± 12 min after tilt), when BP fell, HR and sympathetic activity remained increased from baseline ( P< 0.01). Thereafter, BP and HR correlated directly with sympathetic activity and regressed in linear fashion until syncope ( P < 0.001), whereas BS increased to baseline. At syncope, BP, HR, and sympathetic activity fell below baseline ( P < 0.01, P < 0.05, and P < 0.01, respectively), but BS did not increase. During recovery, sympathetic activity increased to baseline and BS increased ( P < 0.05), whereas HR and BP remained low ( P < 0.01 and P < 0.05, respectively). The mechanism for the initiation of hypotension during presyncope remains unknown, but BS may contribute. Vasodilatation and bradycardia during presyncope appear to be more closely related to withdrawal of sympathetic activity than to increased parasympathetic cardiac activity.
Chronic alcohol-induced changes in cardiac contractility are not due to changes in the cytosolic Ca2+transient
Authors: Figueredo Vincent M. , Chang Kevin C. , Baker Anthony J. , Camacho S. Albert
Published: December 2017

Long-standing heavy alcohol consumption acts as a chronic stress on the heart. It is thought that alcohol-induced changes of contractility are due to altered Ca2+handling, but no measurements of cytosolic Ca2+([Ca2+]c) after chronic alcohol exposure have been made. Therefore experiments were performed to determine whether alcohol-induced changes in contractility are due to altered Ca2+handling by measuring [Ca2+]c(indo 1) in hearts from rats drinking 36% ethanol for 7 mo and age-matched controls. Peak left ventricular pressure was depressed (−16%), whereas rates of contraction (12%) and relaxation (14–20%) were faster in alcohol-exposed hearts. Systolic [Ca2+]c(808 ± 45 vs. 813 ± 45 nM), diastolic [Ca2+]c(195 ± 11 vs. 193 ± 10 nM), and rates of [Ca2+]crise and decline were the same in alcohol-exposed and control hearts. Protein levels of Ca2+-handling proteins, sarcoplasmic reticulum Ca2+-ATPase and phospholamban, were the same in myocytes isolated from alcohol-exposed and control hearts (SDS-polyacrylamide gel). These data suggest that chronic alcohol-induced contractile changes are not due to altered Ca2+handling but may be due to changes at the level of the myofilament. As a first step in elucidating the mechanism(s) of alcohol-induced changes at the myofilament, we assessed myosin heavy chain (MHC) isoform content (SDS-polyacrylamide gel). α-MHC was decreased relative to β-MHC ( a/ a+ b = 0.55 ± 0.03 vs. 0.66 ± 0.02; P < 0.02) in alcohol-exposed hearts, which cannot account for the observed alcohol-induced contractile changes. In conclusion, changes of myocardial contractility due to chronic alcohol exposure do not result from altered Ca2+handling but from changes at the level of the myofilament that do not involve MHC isoform shifts.
Effects of dobutamine on left ventricular restoring forces
Authors: Bell Stephen P. , Fabian Judit , LeWinter Martin M.
Published: December 2017

Restoring forces, which are generated when the left ventricle contracts below its equilibrium volume (Veq), are responsible for diastolic suction. Their magnitude is inversely related to end-systolic volume (ESV). In previous studies in which the mitral valve was replaced with a prosthesis, increased contractility was shown to augment restoring forces independently of ESV. In the present study, we quantified restoring forces in the presence of an intact mitral valve in open-chest dogs ( n = 6) as the fully relaxed pressure (FRP) after completion of left ventricular pressure (LVP) fall during nonfilling diastoles produced by a servomotor system that clamped left atrial pressure below LVP. A negative FRP indicated a restoring force was present. We related FRP to ESV during control, intravenous, and left anterior descending coronary artery (intracoronary) administration of dobutamine. With intravenous dobutamine, we observed an approximately parallel downward and rightward shift of the FRP-ESV relation, indicating increased restoring forces at any ESV less than Veq. The downward shift averaged −2.6 ± 1.6 (SD) mmHg at the control Veq. A similar shift occurred with intracoronary dobutamine. In additional experiments ( n = 2), we found that over a common range of ESV dobutamine slightly increased wall thickness (<10%) during nonfilling diastoles, consistent with an increase in coronary blood volume. We conclude that dobutamine increases restoring forces independently of changes in ESV in conjunction with an increase in Veq. This effect may partly be related to increased coronary blood volume.
Renal denervation alters cardiovascular and endocrine responses to hemorrhage in conscious newborn lambs
Authors: Smith Francine G. , Abu-Amarah Isam
Published: December 2017

To investigate the role of renal sympathetic nerves in modulating cardiovascular and endocrine responses to hemorrhage early in life, we carried out three experiments in conscious, chronically instrumented lambs with intact renal nerves (intact; n = 8) and with bilateral renal denervation (denervated; n = 5). Measurements were made 1 h before and 1 h after 0, 10, and 20% hemorrhage. Blood pressure decreased transiently after 20% hemorrhage in intact lambs and returned to control levels. In denervated lambs, however, blood pressure remained decreased after 60 min. After 20% hemorrhage, heart rate increased from 170 ± 16 to 207 ± 18 beats/min in intact lambs but not in denervated lambs, in which basal heart rates were already elevated to 202 ± 21 beats/min. Despite an elevated plasma renin activity (PRA) measured in denervated (12.0 ± 6.4 ng ANG I ⋅ ml−1 ⋅ h−1) compared with intact lambs (4.0 ± 1.1 ng ANG I ⋅ ml−1 ⋅ h−1), the increase in PRA in response to 20% hemorrhage was similar in both groups. Plasma levels of arginine vasopressin increased from 11 ± 8 to 197 ± 246 pg/ml after 20% hemorrhage in intact lambs but remained unaltered in denervated lambs from baseline levels of 15 ± 10 pg/ml. These observations provide evidence that in the newborn, renal sympathetic nerves modulate cardiovascular and endocrine responses to hemorrhage.
Chronic isolation of carotid sinus baroreceptor region in conscious normotensive and hypertensive rats
Authors: McKeown Kelly P. , Shoukas Artin A.
Published: December 2017

We have developed a chronic technique to isolate the carotid sinus baroreceptor region in the conscious rat model. Our technique, when used in conjunction with other methods, allows for the study of the control of arterial pressure, heart rate, and cardiac output by the carotid sinus baroreceptor reflex in conscious, unrestrained rats. The performance of our technique was evaluated in two strains: normotensive Sprague-Dawley (SD) rats and spontaneously hypertensive rats (SHR). Each rat was instrumented with an aortic flow probe and a catheter placed in the right femoral artery to monitor cardiac output and arterial pressure, respectively. The cervical sympathetic trunk and aortic depressor nerve were ligated and cut bilaterally, leaving vagus nerves intact. The right and left carotid sinuses were isolated using our new technique. We tested the open-loop function of the carotid sinus baroreceptor reflex system in the conscious rat after recovery from the isolation surgery. We found that changes in nonpulsatile carotid sinus pressure caused significant changes in arterial pressure, heart rate, and total peripheral resistance in both rat strains. However, the cardiac output responses differed dramatically between strains. Significant changes were seen in the cardiac output response of SHR, whereas no significant changes were observed in normotensive SD rats. We have found this technique to be a highly reliable tool for the study of the carotid sinus baroreceptor reflex system in the conscious rat.
Alcohol consumption reduces ischemia-reperfusion injury by species-specific signaling in guinea pigs and rats
Authors: Miyamae Masami , Camacho S. Albert , Zhou Hui-Zhong , Diamond Ivan , Figueredo Vincent M.
Published: December 2017

We recently discovered that regular alcohol consumption reduces ischemia-reperfusion injury to the same degree as ischemic preconditioning in guinea pig hearts. Ischemic preconditioning, like this cardioprotective effect of alcohol, is mediated by adenosine signaling in guinea pigs. In rats, ischemic preconditioning may be mediated predominantly by α1-adrenergic signaling. To be certain that this protective effect of alcohol is a general biological response, we searched for alcohol’s cardioprotection in rat and identified a potential signaling mechanism. Hearts isolated from alcohol-fed guinea pigs and rats were subjected to ischemia-reperfusion. Hearts from alcohol-fed animals showed greater recovery of left ventricular developed pressure than controls (guinea pigs, 46 vs. 29%; rats, 50 vs. 31%) and decreased myocyte necrosis assessed by creatine kinase release (guinea pigs, 204 ± 42 vs. 440 ± 70 U ⋅ ml−1⋅ g dry wt−1; rats 158 ± 13 vs. 328 ± 31 U ⋅ ml−1⋅ g dry wt−1). Adenosine receptor blockade [8-( p-sulfophenyl)theophylline] abolished alcohol’s protection in guinea pig but not rat hearts. By contrast, α1-adrenergic blockade (prazosin) abolished alcohol’s protection in rat but not guinea pig hearts. We conclude that regular alcohol consumption reduces ischemia-reperfusion injury and is mediated by species-specific signaling mechanisms. A major goal of cardiovascular research is to find a pharmacologically induced chronic state of preconditioning. Understanding the mechanisms of alcohol’s cardioprotection against ischemia-reperfusion injury may aid in reaching this goal.
Microtubules are involved in early hypertrophic responses of myocardium during pressure overload
Authors: Takahashi Masaru , Tsutsui Hiroyuki , Tagawa Hirofumi , Igarashi-Saito Keiko , Imanaka-Yoshida Kyoko , Takeshita Akira
Published: December 2017

Mechanical overloading to cardiac muscle causes fetal contractile protein gene expression and acceleration of protein synthesis. Myocyte microtubules might be involved in these pressure overload-induced hypertrophic responses. We assessed c- fos and fetal contractile protein genes such as β-myosin heavy chain (MHC) and α-skeletal actin using Northern blot analysis and quantified total cardiac protein, DNA, and RNA content in the left ventricular myocardium obtained from four groups of rats: sham-operated rats; sham-operated rats treated with colchicine, which depolymerized microtubules; rats in which acute pressure overload was imposed by abdominal aortic constriction for 3 days (AoC); and AoC rats treated with colchicine (AoC + colchicine). Systolic arterial pressure was elevated to a similar degree in AoC and AoC + colchicine rats. c- fos and β-MHC mRNA levels were significantly upregulated in AoC rats, which was attenuated by microtubule inhibition. Both RNA content and RNA-to-DNA ratio, the index of the protein synthesis capacity, were increased in AoC rats, which effect was also abolished by colchicine. Furthermore, induction of nonfunctioning microtubules by taxol or deuterium oxide exerted the same inhibitory effects. Thus the hypertrophic responses of the myocardium during pressure overload might depend on the integrity of myocyte microtubules.
Effects of growth hormone and IGF-I on cardiac hypertrophy and gene expression in mice
Authors: Tanaka Nobuaki , Ryoke Tsutomu , Hongo Minoru , Mao Lan , Rockman Howard A. , Clark Ross G. , Ross John
Published: December 2017

Cardiac hypertrophic and contractile responses were studied in mice administered growth hormone (GH) and insulin-like growth factor (IGF-I) (8 mg ⋅ kg−1⋅ day−1), alone or in combination (IGF-I/GH), for 2 wk. Also, changes in expression of selected left ventricular (LV) genes in response to IGF-I/GH were compared with those in other forms of cardiac hypertrophy. GH or IGF-I alone at three to four times the usual dose in rats failed to produce increases in heart and LV weights and hemodynamic effects; however, IGF-I/GH was synergistic, increasing body weight and LV weights by 39 and 35%, respectively. A measure of myocardial contractility (maximal first derivative of LV pressure, catheter-tip micromanometry) was increased by 34% in the IGF/GH group, related in part to a force-frequency effect, since the heart rate increased by 21%. Other mice were treated surgically to produce pressure overload (transverse aortic constriction) or volume overload (arteriovenous fistula) for 2 wk; LV weights were then matched to those in the IGF-I/GH group, and mRNA levels of selected markers were assessed. In contrast to the increased mRNA levels of atrial natriuretic factor, α-skeletal actin, and collagen III generally observed in overloaded hearts, changes in IGF-I/GH-treated mice were not significant. Thus high-dose IGF-I/GH produce cardiac hypertrophy and a positive inotropic effect without causing significant changes in expression of fetal and other selected myocardial genes, suggesting that this hypertrophy may be of a more physiological type than that due to mechanical overload.
Vascular effects of LPS in mice deficient in expression of the gene for inducible nitric oxide synthase
Authors: Gunnett Carol A. , Chu Yi , Heistad Donald D. , Loihl Angela , Faraci Frank M.
Published: December 2017

The inducible isoform of nitric oxide synthase (iNOS) is expressed after systemic administration of lipopolysaccharide (LPS). The importance of expression of iNOS in blood vessels is poorly defined. Because nitric oxide from iNOS may alter vasomotor function, we examined effects of LPS on vasomotor function in carotid arteries from iNOS-deficient mice. We studied contraction of the carotid artery from wild-type and iNOS-deficient mice in vitro 12 h after injection of LPS (20 mg/kg ip). Contractile responses to PGF2α(3–30 μM) and thromboxane A2analog (U-46619; 3–100 nM) were evaluated using vascular rings from mice treated with vehicle or LPS. Maximum force of contraction generated by rings in response to PGF2αwas 0.39 ± 0.02 and 0.25 ± 0.01 (SE) g ( n = 14) in vehicle and LPS-treated wild-type mice, respectively ( P < 0.001 vs. vehicle). Thus LPS reduced constrictor responses in wild-type mice. Thiocitrulline and aminoguanidine (inhibitors of iNOS) improved contractile responses from LPS-treated wild-type vessels. Indomethacin also improved constrictor responses in arteries from wild-type mice injected with LPS. In contrast, contraction of the carotid arteries in response to PGF2αand U-46619 was not impaired in LPS-treated iNOS-deficient mice, and contraction was not altered by inhibitors of iNOS. Expression of iNOS mRNA was confirmed using RT-PCR in carotid arteries from wild-type mice after injection of LPS but not vehicle. PCR products for iNOS were not observed in iNOS-deficient mice. These findings provide the first direct evidence that iNOS mediates impairment of vascular contraction after treatment with LPS.