bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac-cardiovascular reflexes induced by hydrogen peroxide in cats
Authors: Huang H. S. , Stahl G. L. , Longhurst J. C.
Published: December 2017

We have shown previously that reactive oxygen species stimulate abdominal sympathetic afferents to cause reflex cardiovascular activation. Because myocardial ischemia and reperfusion also generate reactive oxygen species, we investigated the possibility that cardiovascular reflexes could be induced by topical application of H2O2 to the anterior or posterior ventricular surface in cats anesthetized with alpha-chloralose. Mean arterial pressure (MAP), heart rate (HR), left ventricular (LV) pressure, aortic flow (AF), and first derivative of LV pressure at 40 mmHg developed pressure (LV dP/dt40) were monitored. H2O2 (44 and 130 mumol) significantly increased MAP but not HR or LV dP/dt40 in intact cats (n = 8). Application of H2O2 (44 mumol) significantly increased MAP (129 +/- 9 to 152 +/- 10 mmHg), HR (240 +/- 11 to 245 +/- 10 beats/min), AF (191 +/- 13 to 212 +/- 17 ml/min), total peripheral resistance (0.68 +/- 0.13 to 0.73 +/- 0.04 peripheral resistance units), and LV dP/dt40 (2,666 +/- 145 to 3,012 +/- 205 mmHg/s) after bilateral cervical vagotomy (n = 6). These H2O2-induced excitatory responses were abolished after bilateral T1-T4 ganglionectomy. In six additional cats, H2O2 (44 mumol) significantly decreased MAP (114 +/- 5 to 102 +/- 5 mmHg), HR (207 +/- 7 to 190 +/- 7 beats/min), and LV dP/dt40 (2,776 +/- 168 to 2,600 +/- 153 mmHg/s) after sympathectomy. These depressor responses were eliminated after vagotomy. The magnitude of the cardiovascular reflexes was increased or decreased in a dose-dependent fashion in vagotomized or sympathectomized cats, respectively, over a range of 440 nmol to 44 mumol H2O2. Application of H2O2 to the anterior or posterior ventricular surface resulted in similar pressor or depressor reflexes. Dimethylthiourea and deferoxamine abolished pressor or depressor responses evoked by H2O2 in both vagotomized (n = 8) and sympathectomized (n = 8) cats. We conclude that reactive oxygen species, particularly the hydroxyl radical, can participate in activating cardiac afferents responsible for reflex cardiovascular responses during myocardial ischemia and reperfusion. An inhibitory reflex is transmitted through vagal afferents, whereas an excitatory reflex is conducted by sympathetic cardiac afferents.
Roles of colloidal molecules in Starling's hypothesis and in returning interstitial fluid to the vasa recta
Authors: Hammel H. T.
Published: December 2017

To begin to understand the role of colloidal molecules, a simple question requires an answer: How do the solutes alter water in an aqueous solution? Hulett's answer deserves attention, namely, the water in the solution at temperature and external pressure applied to solution (T,pe1) is altered in the same way that pure water is altered by reducing the pressure applied to it by the osmotic pressure of the water at a free surface of the solution. It is nonsense to relate the lower chemical potential of water in a solution to a lower fugacity or to a lower activity of the water in the solution, since these terms have no physical meaning. It is also incorrect to attribute the lower chemical potential of the water to a lower concentration of water in the solution. Both claims are derived from the teachings of G. N. Lewis and are erroneous. Textbook accounts of the flux of fluid to and from capillaries in the kidney and other tissues are inadequate, if not in error, as they are based on these bogus claims. An understanding of the process by which colloidal proteins in plasma affect the flux of nearly protein-free fluid across the capillary endothelium must start with insights derived from the teachings of G. Hulett and H. Dixon. The main points are 1) colloidal molecules can exert a pressure against a membrane that reflects them and, thereby, displace a distensible membrane; 2) they can alter the internal tension of the fluid through which they diffuse when there is a concentration gradient of the molecules; and 3) only by these means can they influence the flux of plasma fluid across the capillary endothelium. However, the process is complex, since both the hydrostatic pressure and protein concentrations of fluids inside and outside the capillary vary with both position and time as plasma flows through the capillary.
Direct and reversible inhibition of endothelial nitric oxide synthase by nitric oxide
Authors: Ravichandran L. V. , Johns R. A. , Rengasamy A.
Published: December 2017

The objective of this study was to investigate the regulation of endothelial nitric oxide (NO) synthase by NO. Partially purified endothelial NO synthase was exposed to authentic NO (10-200 microM) and to the nitrovasodilators sodium nitroprusside (SNP; 10-1,000 microM) and S-nitroso-N-acetylpenicillamine (SNAP; 100-1,000 microM), and enzyme activity was assayed by measuring the conversion of L-[3H]arginine to L-[3H]citrulline in the presence of added cofactors. NO, SNP, and SNAP inhibited NO synthase activity in a dose-dependent manner, NO being the most potent inhibitor. The Michaelis constant for L-arginine was not altered (4.87 microM) by NO (50 microM), whereas the maximal velocity of the enzyme decreased from 784 to 633 pmol.mg-1.min-1. Oxyhemoglobin (10 microM) partially prevented the inhibition of NO synthase by NO (50 microM). The data also suggest that NO inhibits endothelial NO synthase activity by directly interacting with the NO synthase and not by an indirect mechanism such as limitation of cofactor or oxygen availability. Dialysis of NO synthase treated with NO (50 microM) partially restored the enzyme activity. This study demonstrates a direct and reversible inhibition of NO synthase by NO, suggesting a feedback mechanism in vivo.
5-Hydroxytryptamine-induced NO-dependent relaxation in isolated strips of monkey popliteal lymph nodes
Authors: Mizuno R. , Ohhashi T.
Published: December 2017

5-Hydroxytryptamine (5-HT, 0.01-100 microM) and 5-carboxamidotryptamine (5-CT, 0.001-10 microM) produced dose-related relaxations in strips cut from monkey popliteal lymph nodes precontracted with a perfusion of Krebs bicarbonate solution containing 80 mM KCl. These 5-HT agonists caused no significant effect on the basal tone of the lymph node strips. The 5-HT-induced relaxation is competitively antagonized by pretreatment with a selective 5-HT1-like receptor antagonist, methiothepin (0.01-0.1 microM). Schild plot analysis showed that the pA2 value and slope of methiothepin against 5-HT were 8.80 +/- 0.11 and 0.99 +/- 0.07 (n = 6), respectively. Pretreatment with methysergide (0.01-0.1 microM) significantly attenuated the 5-HT-induced relaxation of the strips. On the other hand, treatment with ketanserin (0.01-0.1 microM) and ICS-205-930 (0.01-0.1 microM) caused no significant effect on the 5-HT-or the 5-CT-induced relaxation. The 5-HT-induced relaxation was significantly reduced by 10 microM NG-monomethyl-L-arginine, which was reversed by 1 mM L-arginine. The relaxation in the lymph node strips was also significantly reduced by treatment with 10 microM methylene blue but not with 30 microM aspirin. These results suggest that 5-HT1-like receptors exist in the monkey popliteal lymph nodes. Stimulation of these receptors produces an endogenous nitric oxide (NO)-dependent relaxation in lymph node smooth muscle through an activation of cytosolic guanylate cyclase in the cells.
Differential influence of arachidonic vs. eicosapentaenoic acid on experimental pulmonary hypertension
Authors: Grimminger F. , Wahn H. , Kramer H. J. , Stevens J. , Mayer K. , Walmrath D. , Seeger W.
Published: December 2017

The impact of the 2- and 3-series prostanoid precursors arachidonic acid (AA) and eicosapentaenoic acid (EPA) on experimental pulmonary hypertension was investigated. The model of buffer-perfused rabbit lungs was stimulated by infusion of Escherichia coli hemolysin (HlyA), which is known to provoke sustained thromboxane (Tx)-mediated pulmonary hypertension. Release of di- and trienoic Tx into the recirculating perfusate was quantified by a post-high-performance liquid chromatography enzyme-linked immunosorbent assay technique. HlyA at 0.08 hemolytic unit/ml caused a sustained rise in pulmonary arterial pressure (PAP; maximum increase 14 +/- 2 mmHg) accompanied by progressive TxB2 liberation (maximum perfusate concn 33 +/- 4 pg/ml, baseline < 2 pg/ml). Between 5 and 30 nM, AA provoked a transient monophasic rise in PAP (maximum pressor response 1.5-15 mmHg) and concomitant TxB2 release (peak concn 2-30 pg/ml). Simultaneous administration of HlyA and AA exhibited additive effects with regard to mediator release and pressor responses. EPA at 200-2,000 nM caused a transient rise in PAP similar to that provoked by 5-30 nM AA (maximum pressor response 3-18 mmHg). This was accompanied by liberation of TxB2 (peak concn 16 +/- 5 and 28 +/- 4 pg/ml after 1,000 and 2,000 nM EPA) and TxB3 (peak concn 9 +/- 4 and 30 +/- 3 pg/ml). Combined application of HlyA and EPA resulted in approximate addition of the TxB2 release reaction to each single compound, and TxB3 liberation more than doubled (maximum concn 59 +/- 12 pg/ml). The pressor responses to HlyA-EPA (200-2,000 nM) did not, however, surpass those to HlyA-AA (5-30 nM).(ABSTRACT TRUNCATED AT 250 WORDS)
Contraction to endothelin-1 in pulmonary arteries from endotoxin-treated rats is modulated by endothelium
Authors: Curzen N. P. , Griffiths M. J. , Evans T. W.
Published: December 2017

Sepsis is characterized by hyporesponsiveness of vascular smooth muscle to pressor agents. Levels of the potent vasoconstrictor, endothelin-1 (ET-1), are elevated in animal models of sepsis and in patients. This study assesses the contractile response of pulmonary artery from endotoxin-pretreated rats to ET-1 to determine whether this contraction is modified by the endothelium. Both intact and denuded rings from endotoxin-pretreated rats exhibited hyporesponsiveness to ET-1, but the endothelium was found to be essential for maximal ET-1-induced contraction. Upon pretreatment of vessels with the cyclooxygenase inhibitor, indomethacin (10(-5) M), the novel ETB-receptor antagonist, BQ-788 (10(-8) and 10(-6) M), and the thromboxane A2-receptor antagonist, ICI-192605 (10(-5) M), each of these agents caused a reduction in the ET-1-induced contraction of endotoxin-pretreated rat pulmonary artery only in the presence of the endothelium but had no effect in endothelium-denuded vessels or in sham-treated groups. These findings demonstrate that ET-1-induced contraction in pulmonary arteries from septic rats is partially dependent upon an endothelially derived cyclooxygenase product, the release of which appears to involve ETB-receptor stimulation.
Regional short-term myocardial hibernation in swine does not involve endogenous adenosine or KATP channels
Authors: Schulz R. , Rose J. , Post H. , Heusch G.
Published: December 2017

Short-term hibernating myocardium is characterized by reduced contractile function during persistent ischemia, the recovery of metabolism over time, a recruitable inotropic reserve, and the lack of necrosis. The mechanisms underlying myocardial hibernation are unclear. The present study addressed the role of endogenous adenosine and that of activation of ATP-dependent potassium (KATP) channels. In 22 enflurane-anesthetized swine, coronary inflow was reduced to decrease regional myocardial work (W, measured by sonomicrometry) by 60-70% at 5 min of ischemia; this flow reduction has previously been shown to be compatible with the development of myocardial hibernation. Systemic hemodynamics, W, subendocardial blood flow (measured by microspheres), and the myocardial creatine phosphate content (measured by biopsies, mumol/g wet wt) were measured under control conditions and during 90 min of ischemia, with an intracoronary dobutamine infusion during the last 5 min of ischemia. The impact of endogenous adenosine was eliminated by infusion of intracoronary adenosine deaminase (ADA), and the impact of activation of KATP channels by glibenclamide. Creatine phosphate content recovered in the placebo-treated swine (n = 8, 3.8 +/- 1.9 to 5.8 +/- 2.0 mumol/g wet wt) as well as in swine receiving ADA (n = 7, 4.1 +/- 1.2 to 6.0 +/- 1.7 mumol/g wet wt) or glibenclamide (n = 7, 2.8 +/- 1.3 to 6.7 +/- 1.6 mumol/g wet wt) when ischemia was prolonged from 5 to 85 min. At the end of 90 min of ischemia, W increased during intracoronary dobutamine in all three groups to a comparable extent, and myocardial necrosis was absent in all three groups of swine.(ABSTRACT TRUNCATED AT 250 WORDS)
Regression of cardiac hypertrophy after closing an aortocaval fistula in rats
Authors: Gerdes A. M. , Clark L. C. , Capasso J. M.
Published: December 2017

To determine whether the series addition of sarcomeres observed during eccentric hypertrophic growth is reversible upon removal of the initiating stimulus, an aortocaval fistula was created and myocyte geometry evaluated at 2 and 12 wk after shunt occlusion. A 76% cardiac enlargement was produced in rats with an aortocaval fistula. This enlargement was reduced to 22 and 18% at 2 and 12 wk of fistula reversal, respectively. Hemodynamic performance was altered as a result of fistula induction as evidenced by a 28% increase in peak rate of pressure rise. This pressure increase remained elevated by 30% 2 wk after fistula reversal but was not different from sham-operated control animals at 12 wk of reversal. Significant increases in overall myocyte length were detected as a result of the creation of the fistula [left ventricle (LV), 20%; right ventricle (RV), 29%; septum, 23% greater than shams]. Although these increases diminished only slightly 2 wk after closure of the fistula (LV, 12%; RV, 17%; septum, 12% greater than shams), linear measurements of myocyte length in two of three regions had reverted to values that were not significantly different from those of age-matched, sham-operated controls at 12 wk after fistula closure (LV, 8%; RV, 10%; septum, 7%). Myocyte cross-sectional area and cell volume followed a similar pattern. Thus myocytes possess the necessary machinery to remove recently added series sarcomeres, returning altered pump function and dilated ventricular chamber geometry toward control values. In addition, it appears that cardiac hypertrophic growth with this experimental model of volume overload is largely, but not completely, reversible.
Cardiac quick-release contraction mechanoenergetics analysis using a cardiac muscle cross-bridge model
Authors: Taylor T. W. , Goto Y. , Hata K. , Takasago T. , Saeki A. , Nishioka T. , Suga H.
Published: December 2017

Huxley's sliding filament cross-bridge muscle model coupled with parallel and series elastic components was simulated to examine the conflicting reports on the amount of energy saved by quick release at the peak contraction time. Cross-bridge energy utilization was determined by considering the ATP hydrolysis for the cross-bridge cycling. The quick-release cases were simulated by letting the muscle fiber suddenly shorten to the resting fiber length at peak systole, and then the contraction was allowed to continue at the resting length. Simulation results demonstrated that, using realistic parameter values, typically approximately 15% of the muscle fiber energy is used after peak systole (and approximately 30% of the cross-bridge energy), but this is also a function of the muscle fiber properties characterized by cross-bridge association and dissociation rate constants. Increasing the kinetic rate constants, the series elasticity, the initial fiber length, or the time of peak intracellular calcium will increase the amount of energy left, which may explain some of the discrepancies in the literature. Cardiac muscle hypertrophy will increase the fraction of muscle fiber energy left after peak systole to approximately 30%. The strongest indicator of the percent energy left at peak systole was the time the fiber reached peak systole, and as the fiber reached peak systole faster, the amount of energy saved by quick release increased.
Visualization of oxygen level inside a single cardiac myocyte
Authors: Takahashi E. , Doi K.
Published: December 2017

The present paper describes theoretical and experimental bases for quantitation of the oxygen level inside a single isolated ventricular rat myocyte. We applied three-wavelength microspectrophotometry to a single cardiomyocyte, where the sensitivity of the spectrophotometry was augmented by a digital image processing technique known as video-enhanced microscopy. Oxygen-dependent changes in light absorption of the intracellular pigments were detected and represented with the use of a newly defined variable, Z, where one pixel of the reconstructed cell image corresponded to 0.2 microns. Theoretically, Z is a single-valued function of the fractional oxygen saturation of the intracellular pigment. We demonstrated in quiescent cardiomyocytes that Z changed according to extracellular PO2, where the relationship was sigmoidal with the extracellular PO2 for a half-maximal Z of 3.2 Torr. In the aerobic cell, conversion of cytochromes to the reduced forms by NaCN did not affect Z value. Therefore, we conclude that Z mainly represents the fractional oxygen saturation of myoglobin, thus reporting cytosolic PO2. We also demonstrated that for extracellular PO2 of 1.3 Torr, abolition of mitochondrial oxygen consumption by NaCN significantly elevated the intracellular oxygen level, suggesting existence of oxygen pressure gradients in a quiescent single cardiomyocyte that were proportional to oxygen flux.
Myocardial electrophysiological effects of vasoactive intestinal peptide in dogs
Authors: Kralios Alexandros C. , Anderson Fred L. , Kralios Fany A.
Published: December 2017

Pages H1559–H1565: Alexandros C. Kralios, Fred L. Anderson, and Fany A. Kralios. “Myocardial electrophysiological effects of vasoactive intestinal peptide in dogs.” On p. H1562, the columns of Fig. 4 were identified in reverse in the legend. The correct sentence should read as follows. Columns represent means ± SD of data from 32 sites in each experiment with epicardial (filled bars) ( n = 16) and endocardial (hatched bars) ( n = 12) mapping.
Cholesterol feeding enhances vasoconstrictor effects of products from rabbit polymorphonuclear leukocytes
Authors: Hart J. L. , Sobey C. G. , Woodman O. L.
Published: December 2017

We have studied the vasoactive properties of products released from rabbit polymorphonuclear leukocytes (PMNs) before and after short-term (4 and 8 wk) dietary supplementation with 1% cholesterol. Plasma cholesterol levels were similar after 4 and 8 wk of cholesterol diet, whereas gross atherosclerotic lesions were present at 4 wk but significantly more extensive after 8 wk. PMN products from all rabbits caused endothelium-dependent contraction of isolated, control (nonatherosclerotic) rabbit aorta submaximally contracted with phenylephrine. However, both 4 and 8 wk of cholesterol feeding resulted in equivalent contractions by PMN products, which were significantly greater than contractions by control PMNs. Endothelium-dependent contraction (by PMN products) and relaxation (by acetylcholine) were attenuated by 8 wk of cholesterol feeding. PMN products attenuated acetylcholine-induced relaxation of aorta from cholesterol-fed rabbits and of control aorta treated with phenoxybenzamine to reduce muscarinic receptor reserve. We conclude that elevation of plasma cholesterol results in increased release of a PMN product(s) that causes endothelium-dependent constriction.
Central cardiovascular effects induced by intracisternal PACAP in dogs
Authors: Seki Y. , Suzuki Y. , Baskaya M. K. , Saito K. , Takayasu M. , Shibuya M. , Sugita K.
Published: December 2017

The cardiovascular responses to intracisternally administered pituitary adenylate cyclase-activating polypeptide (PACAP) were investigated and compared with those of vasoactive intestinal peptide (VIP) in anesthetized dogs. Intracisternal administration of 10 nmol of PACAP-27 increased mean arterial blood pressure (MABP) significantly with a simultaneous increase of plasma arginine vasopressin and epinephrine concentrations. Intracisternal administration of VIP increased plasma arginine vasopressin concentration significantly but caused no appreciable change in MABP. Systemic infusion of the nonpeptide vasopressin V1 receptor antagonist OPC-21268 did not inhibit the PACAP-27-induced increase in MABP, whereas phentolamine, an alpha-adrenoceptor blocker, reversed the increase. Intracisternal pretreatment with the vasopressin V1 receptor antagonist [Pmp1, Tyr(Me)2]Arg8-vasopressin also inhibited the increase. These findings suggest that PACAP has a central pressor action by increasing sympathetic outflow, which is probably mediated by the vasopressinergic neural network. PACAP seems to play important roles in hormonal and neural control of systemic circulation.
4-Hydroxynonenal, a novel indicator of lipid peroxidation for reperfusion injury of the myocardium
Authors: Blasig I. E. , Grune T. , Schonheit K. , Rohde E. , Jakstadt M. , Haseloff R. F. , Siems W. G.
Published: December 2017

4-Hydroxynonenal (HNE) has been proposed as an important marker of radical-induced lipid peroxidation (LPO) during postischemic reperfusion injury of the myocardium. Therefore, the liberation of HNE into the effluent of isolated perfused rat hearts was investigated. For the first time, the formation of the aldehyde is demonstrated in myocardium. During control perfusion, 1.28 +/- 0.33 pmol HNE.min-1.mg protein-1 were formed by the hearts of 18-mo-old Wistar-Kyoto (WKY) rats and 2.74 +/- 1.12 pmol.min-1.mg protein-1 by those of 18-mo-old spontaneously hypertensive (SHR) rats, respectively. In the WKY group, HNE release increased to 3.35 +/- 1.13 pmol.min-1.mg protein-1 2 min after the onset of reperfusion following 30 min of total and global ischemia compared with the preischemic control period (P < 0.05). In the SHR group, HNE liberation was higher during reperfusion (8.66 +/- 1.33 pmol.min-1.mg protein-1, maximum at 2 min reperfusion) compared with both the respective preischemic control and the respective reperfusion interval of the WKY group (P < 0.05 each). The SHR rats showed signs of congestive cardiac failure of a decompensated hypertrophy in comparison to the normotensive WKY rats. Moreover, the SHR rat hearts exhibited a lower release of adenine nucleotide degradation products (adenine, inosine, hypoxanthine plus uric acid: 48.1 +/- 10.2 nmol.30 min-1.mg protein-1; P < 0.05) and a diminished functional recovery (left ventricular developed pressure, 32 +/- 16 mmHg; P < 0.05) during 30 min of reperfusion compared with the WKY group (77.9 +/- 14.4 nmol.30 min-1.mg protein-1; 90 +/- 21 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)
Modulation of resistance artery force generation by extracellular Ca2+
Authors: Bian K. , Bukoski R. D.
Published: December 2017

We tested the hypothesis that increasing extracellular Ca2+ (Cao) over a physiological concentration range depresses vascular smooth muscle force generation by altering the intracellular Ca2+ (Cai)-force relationship. Mesenteric resistance arteries were isolated from Wistar rats; Cai and isometric force were measured using a fura-based method and wire myography. Vessels were depleted of releasable Cai by repeated contraction with norepinephrine; Cao was then cumulatively added back from 0.025-2.5 mM in the presence of an agonist. With norepinephrine, serotonin, prostaglandin F2 alpha, and K+, Cao from 0.025 to 0.8 mM induced a graded increase in Cai and active stress. With the receptor agonists but not K+ raising Cao from 0.8 to 1.6 mM and from 1.6 to 2.5 mM decreased active stress to 82 +/- 6 and 54 +/- 6% of maximum, respectively, P < 0.05. Although there was a transient decrease in Cai in response to both 1.6 and 2.5 mM Cao, steady-state Cai only decreased significantly in response to 2.5 mM Cao (85 +/- 3% of maximum). Inhibition of the sarcoplasmic reticulum Ca(2+)-adenosinetriphosphatase with 1 microM thapsigargin had no effect on the decrease in force induced by high Ca2+. The decrease in active stress induced by 1.6 and 2.5 mM Cao was inhibited by Ca2+ channel antagonists and by blockade of Ca(2+)-activated K+ channels with charybdotoxin (with 1.6 mM Cao, control tension = 67 +/- 10% of maximum vs. charybdotoxin = 99.2 +/- 1%, P < 0.05; n = 9).(ABSTRACT TRUNCATED AT 250 WORDS)
Pentoxifylline inhibits FMLP-induced macromolecular leakage
Authors: Nakagawa K. , Miller F. N. , Knott A. W. , Edwards M. J.
Published: December 2017

The acute inflammatory responses to the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) and the effects of pentoxifylline (PTXF) on the responses in vivo were studied. We used intravital microscopy with rat cremaster muscle preparation to determine inflammatory responses of microcirculation. Macromolecular leakage from postcapillary venules was evaluated by quantifying the extravasation of fluorescein isothiocyanate conjugated to bovine serum albumin. FMLP induced a rapid increase in macromolecular leakage, an increase in leukocyte-endothelium adhesion, and a decrease in blood flow in the microcirculation. PTXF inhibited FMLP-induced responses in a dose-dependent manner but failed to block the histamine-dependent leakage induced by compound 48/80. In addition, diphenhydramine, a histamine-receptor blocker, did not affect the macromolecular leakage induced by FMLP. The cell-permeable adenosine 3',5'-cyclic monophosphate (cAMP) analogue N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate mimicked PTXF's effects on the microcirculation and also inhibited FMLP-induced macromolecular leakage. PTXF is known to inhibit phosphodiesterase and increase intracellular cAMP, which modulates functions of endothelial cells, smooth muscle cells, and neutrophils in vitro. Our findings suggest that FMLP induces acute inflammatory responses through activation of neutrophils, independent of endogenous histamine release, and that PTXF inhibits these responses through elevated intracellular cAMP.
Inhibition of vascular nitric oxide-cGMP pathway by plasma from ischemic hindlimb of rats
Authors: Jin J. S. , Webb R. C. , D'Alecy L. G.
Published: December 2017

The hypothesis was tested that plasma from ischemic hindlimbs facilitates hypertension. Ischemia-induced hypertension was generated in rats by infrarenal aortic cross clamping for 5 h after which plasma was obtained from femoral vein blood. In vitro contractile activity of naive aortic rings incubated for 2 h in plasma collected from ischemic rats demonstrated reduced relaxation to acetylcholine and nitroglycerin. Methylene blue (10(-5) M) induced greater contraction in rings incubated in control vs. ischemic plasma, suggesting that endogenous guanylate cyclase activity is decreased by ischemic plasma. However, 8-bromo-guanosine 3',5'-cyclic monophosphate (cGMP) relaxed equally strips incubated in ischemic or control plasma. Acetylcholine-induced nitrite release was significantly lower in ischemic vs. control plasma-incubated strips (8.6 +/- 2.7 vs. 28.2 +/- 2.3 ng/10 mg tissue wt, respectively). The impaired relaxation to acetylcholine in ischemic plasma-incubated rings was significantly increased by L-arginine but not by prior treatment of ischemic plasma with heating or superoxide dismutase and catalase. These findings suggest the impaired relaxation is mediated through inhibition of the nitric oxide-cGMP pathway. Prolonged blunting of vasodilation by ischemic plasma may therefore contribute to maintenance of a sustained vasoconstriction and ischemic hypertension.
Antihypertensive actions of angiotensin-(1-7) in spontaneously hypertensive rats
Authors: Benter I. F. , Ferrario C. M. , Morris M. , Diz D. I.
Published: December 2017

Observations that angiotensin-(1-7) [ANG-(1-7)] may oppose the vasoconstrictor actions of angiotensin II (ANG II) prompted an investigation of the effects of the heptapeptide on the maintenance of elevated blood pressure in spontaneously hypertensive rats (SHR). ANG-(1-7) (24 micrograms.kg-1.h-1) was infused into the jugular vein of 13-wk-old SHR (n = 64), Wistar-Kyoto (WKY, n = 50), and Sprague-Dawley (SD, n = 18) rats for 2 wk, with the use of osmotic minipumps. Blood pressure, fluid and electrolyte balance, plasma vasopressin, and urinary excretion of prostaglandin E2 and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured at days 2, 7, and 12 of the infusion. In SHR, ANG-(1-7) caused a sustained and significant reduction in plasma vasopressin concentration that was associated with an increase in urinary prostaglandin E2 and 6-keto-PGF1 alpha excretion at day 2 after the commencement of the infusion. These changes were accompanied by diuresis and natriuresis during the first 3 days of infusion in SHR but not in WKY or SD rats. Direct measurements of arterial pressure confirmed the lowering effect of ANG-(1-7) on systolic pressure of SHR on day 2 of treatment with a restoration of the pressure by days 7 and 12. These findings, along with our previous demonstration that ANG-(1-7) is an active depressor peptide in the intact animal, suggest that ANG-(1-7) may play a significant role as a vasodepressor system opposing the hemodynamic actions of ANG II in this genetic form of experimental hypertension.
Morphometry and muscle gene expression in hypertrophied hearts from polyomavirus large T antigen transgenic mice
Authors: Holder E. , Mitmaker B. , Alpert L. , Chalifour L.
Published: December 2017

Transgenic mice expressing polyomavirus large T antigen (PVLT) in cardiomyocytes develop a cardiac hypertrophy in adulthood. Morphometric analysis identified cardiomyocytes enlarged up to ninefold in cross-sectional area in the adult transgenic hearts compared with normal age-matched nontransgenic hearts. Most enlarged cardiomyocytes were found in the subendocardium, whereas normal-sized cardiomyocytes were localized to the midmyocardium. Transgenic hearts did not express detectable skeletal muscle actin mRNA or protein, or skeletal troponin I isoform mRNA. Some, but not all, transgenic hearts expressed an increase in the beta-myosin heavy chain mRNA. All five transgenic mice tested had increased expression of atrial natriuretic factor (ANF) mRNA. Whereas normal hearts expressed three myosin light chain proteins of 19, 16, and 15 kDa, we found that the 19-kDa myosin light chain was not observed in the transgenic hearts. We conclude that adult, PVLT-expressing, transgenic mice developed enlarged cardiomyocytes with an increase in beta-myosin heavy chain and ANF mRNA expression, but a widespread skeletal isoform usage was not present in these transgenic mice. The adult transgenic hearts thus display histological and molecular changes similar to those found in hypertrophy induced by a pressure overload in vivo.
Dipyridamole, a cGMP phosphodiesterase inhibitor, causes pulmonary vasodilation in the ovine fetus
Authors: Ziegler J. W. , Ivy D. D. , Fox J. J. , Kinsella J. P. , Clarke W. R. , Abman S. H.
Published: December 2017

Endogenous nitric oxide (NO) modulates fetal pulmonary vascular tone by stimulating guanosine 3',5'-cyclic monophosphate (cGMP) production in vascular smooth muscle. Because cGMP is hydrolyzed and inactivated by phosphodiesterase enzymes, we evaluated the hemodynamic effects of two cGMP-specific phosphodiesterase (PDE5) inhibitors, dipyridamole and zaprinast, in the near-term chronically prepared ovine fetus. Brief (10 min) intrapulmonary infusions of dipyridamole caused dose-dependent increases in left pulmonary artery flow and decreases in left pulmonary arterial resistance that persisted for > 40 min after termination of the infusion. Prolonged (2 h) infusions of dipyridamole caused sustained pulmonary vasodilation throughout the infusion period. To compare the hemodynamic effects of dipyridamole with the PDE5 antagonist zaprinast, we studied the responses to equimolar doses of both agents in four fetuses. Zaprinast caused dose-dependent pulmonary vasodilation that was equivalent to that noted with equimolar doses of dipyridamole. To determine whether adenosine is involved with dipyridamole-induced pulmonary vasodilation, we compared the hemodynamic response to dipyridamole before and after administration of the potent adenosine receptor (P1) antagonist 8-phenyltheophylline (8-PT). Pretreatment with 8-PT markedly attenuated adenosine-induced pulmonary vasodilation but had no effect on the hemodynamic response to dipyridamole. We conclude that cGMP-specific phosphodiesterase activity is important in regulating fetal pulmonary vascular tone. In addition, dipyridamole administration causes dose-dependent pulmonary vasodilation that is equivalent to zaprinast and not primarily due to its effects on adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
Splenic contraction-induced increases in arterial O2 reduce requirement for CBF in conscious dogs
Authors: Sato N. , Shen Y. T. , Kiuchi K. , Shannon R. P. , Vatner S. F.
Published: December 2017

We investigated the extent to which sympathomimetic amines induced splenic contraction and associated increases in arterial O2 content (CaO2) and how these mechanisms affected control of the coronary circulation by sympathomimetic amines in conscious dogs. Blood hemoglobin (Hb) and CaO2 increased by 16 +/- 2 and 18 +/- 2%, respectively, during norepinephrine (NE, 0.8 micrograms.kg-1.min-1 iv) in the intact, conscious state after splenic contraction. Phenylephrine (PE) induced similar effects. After either alpha 1-adrenergic-receptor blockade or splenectomy, these effects were abolished. Isoproterenol (Iso) also decreased splenic thickness, which was abolished after ganglionic, alpha-, or beta 1/beta 2-adrenergic-receptor blockade. Direct infusions of NE and PE into the splenic artery decreased splenic thickness and increased Hb and CaO2, whereas Iso had no effect. After splenectomy, NE did not increase CaO2, but coronary blood flow (CBF) increased more (73 +/- 6%) vs. before splenectomy (49 +/- 7%) without any differences before and after splenectomy in the responses of pressures, contractility, and myocardial O2 consumption (MVO2). In contrast, renal, mesenteric, and iliac artery blood flows were not significantly different in response to sympathomimetic amines before and after splenectomy. These data indicate that sympathomimetic amines induced splenic contraction either directly or reflexly via alpha-adrenergic-receptor stimulation. The consequent increase in Hb and CaO2 allows for equivalent increases in MVO2, but at a smaller increase in CBF.
Myocardial and endothelial protection by TMS in ischemia-reperfusion injury
Authors: Murohara T. , Buerke M. , Margiotta J. , Ruan F. , Igarashi Y. , Hakomori S. , Lefer A. M.
Published: December 2017

N,N,N-trimethylsphingosine (TMS), a stable synthetic sphingosine derivative, was investigated in a feline model of myocardial ischemia (90 min) and reperfusion (270 min) injury. TMS (60 micrograms/kg), administered intravenously 10 min before reperfusion, significantly attenuated myocardial necrosis (15 +/- 3 vs. 31 +/- 4% necrosis of area at risk, P < 0.01) and cardiac myeloperoxidase activities, a marker of neutrophil accumulation, compared with vehicle-treated cats. Endothelium-dependent relaxation to acetylcholine in ischemic-reperfused coronary artery rings treated with TMS was also significantly preserved compared with vehicle (73 +/- 4 vs. 34 +/- 4% vasorelaxation, P < 0.01). Polymorphonuclear neutrophil (PMN) adherence to coronary endothelium 270 min after reperfusion was markedly attenuated in the TMS group compared with vehicle-treated cats (37 +/- 5 vs. 76 +/- 5 PMN/mm2, P < 0.01). TMS also attenuated upregulation of P-selectin on coronary venular endothelium by immunohistochemistry. This was consistent with in vitro findings that TMS attenuates PMN adherence to thrombin-stimulated coronary endothelium and P-selectin upregulation on thrombin-stimulated cat platelets. A sphingolipid derivative, TMS at physiological concentrations exerts cardioprotective actions and preserves coronary endothelial function following myocardial ischemia and reperfusion in vivo. The effects appear to be mediated by the inhibition of PMN-endothelial interaction and subsequent accumulation into the ischemic myocardium. Thus TMS may be a useful agent in attenuating myocardial reperfusion injury.
Altered regulation of nerve growth factor secretion by cultured VSMCs from hypertensive rats
Authors: Spitsbergen J. M. , Stewart J. S. , Tuttle J. B.
Published: December 2017

Vascular tissues from spontaneously hypertensive rats (SHR) exhibit increased nerve growth factor (NGF) levels and increased density of sympathetic innervation compared with those from normotensive Wistar-Kyoto (WKY) rats. The present study asked whether basal NGF secretion or secretion elicited by agents analogous to sympathetic neurotransmitters differ in cultured vascular smooth muscle cells (VSMCs) from SHR and WKY rats. VSMCs were maintained in serum-free medium (SFM) for 72 h and then treated and sampled at 4, 6, 8, and 24 h. Conditioned medium was assayed for NGF using a two-site enzyme-linked immunoassay. NGF secretion by SHR (19.2 +/- 4.6 pg.well-1.48 h-1) and WKY VSMCs (16.7 +/- 5.4 pg.we..-1.48 h-1) was similar in cultures grown in serum-containing medium, whereas SHR VSMCs maintained in SFM secrete more NGF than WKY VSMCs (9.1 +/- 1.9 vs. 2.9 +/- 0.4 pg.well-1.24 h-1, respectively). Treatment of cultures with phenylephrine (0.1-10 microM), neuropeptide Y (1-1,000 nM), or alpha beta-methyleneadenosine 5'-triphosphate (10 and 100 microM) had no effect on NGF secretion by WKY VSMCs, while increasing NGF secretion by SHR VSMCs. Treatment with isoproterenol (0.1-10 microM) decreased NGF secretion by WKY VSMCs but not SHR VSMCs. These data indicate that the regulation of NGF secretion by sympathetic neurotransmitter receptors is different for cultured VSMCs from SHR and WKY rats. If similar differences exist in vivo, they could account for the alterations in NGF levels and sympathetic innervation that are observed.
Advantages of continuous measurement of cardiac output 24 h a day
Authors: Montani J. P. , Mizelle H. L. , Van Vliet B. N. , Adair T. H.
Published: December 2017

To test the hypothesis that continuous measurement of cardiac output 24 h a day would provide a better day-by-day reproducibility of the daily average cardiac output than acute measurements, we developed a computer-assisted method to monitor cardiac output continuously using an electromagnetic flow transducer. Because the diastolic aortic flow, which is used as a zero-flow reference, can drift significantly with electromagnetic flow probes, automatic tracking of the diastolic flow baseline was considered essential for long-term measurements. To accomplish this, the analog pulsatile flow signal was digitally converted and processed by an IBM PC to correct for signal drift on a beat-per-beat basis. Using this computerized system in 19 chronically instrumented dogs, we compared the values of cardiac output during 5 consecutive control days, measured either for 20 h each day (allowed 4 h for special care) or for 30 min in the morning when the trained dogs were required to lie quietly in their cages. The results show that the coefficient of variation of the five daily averages in cardiac output for each individual dog was three times smaller when cardiac output was measured 20 h each day (2.9 +/- 0.3 vs. 9.7 +/- 1.0%). Whole-day coefficients of variation were also smaller for mean arterial pressure, heart rate, stroke volume, and total peripheral resistance. Because of this greater day-by-day reproducibility, continuous monitoring of cardiac output is likely to be more sensitive to small changes in cardiac output induced by experimental protocols.
Mechanisms of vascular preservation by a novel NO donor following rat carotid artery intimal injury
Authors: Guo J. P. , Panday M. M. , Consigny P. M. , Lefer A. M.
Published: December 2017

We studied the effects of a novel organic nitric oxide (NO) donor, 4-hydroxymethyl-furazan-3-carboxylic acid-2-oxide (CAS-1609), in a rat carotid artery intimal injury model. The NO donor, CAS-1609, or its non-NO-donating control compound, 4-hydroxymethyl-furazan-3-carboxylic acid (C-93-4845), was infused intravenously at 30 micrograms/day. Seven days after injury, carotid artery rings contracted only 56 +/- 6 mg to NG-nitro-L-arginine methyl ester in C-93-4845-treated rats, compared with 120 +/- 17 mg in CAS-1609-treated rats (P < 0.02), indicating a preservation of endogenous NO release. Improved responses to the endothelium-dependent dilator, acetylcholine, also occurred in injured arteries treated with CAS-1609. Morphometric analysis of injured carotid arteries given the inactive compound showed marked intimal thickening with an intimal-to-medial ratio (I/M) of 0.76 +/- 0.02, compared with a significantly lower I/M of 0.32 +/- 0.04 (P < 0.01) in injured carotid arteries given CAS-1609. Additionally, CAS-1609 was found to have a concentration-dependent stimulatory effect on cultured rat aortic endothelial cell proliferation (P < 0.01) but and inhibitory effect on platelet-derived growth factor-BB (10 ng/ml)-stimulated rat aortic smooth muscle cell proliferation (P < 0.01). This is the first study to demonstrate that NO plays a dual role in vascular cell proliferation, stimulating endothelial cells but inhibiting smooth muscle cell proliferation. This dual effect of NO on cell proliferation is associated with an in vivo reduction in neointimal thickening and an acceleration of endothelial recovery determined by both anatomic and functional methods.
Ischemia- and reperfusion-sensitive cardiac sympathetic afferents: influence of H2O2 and hydroxyl radicals
Authors: Huang H. S. , Pan H. L. , Stahl G. L. , Longhurst J. C.
Published: December 2017

Activation of cardiac sympathetic afferents leads to excitatory cardiovascular reflexes and pain during myocardial ischemia. We hypothesized that cardiac sympathetic afferents are activated by reactive oxygen species produced during ischemia and reperfusion. Single-unit nerve activity of 55 afferents was recorded from the left paravertebral sympathetic chain (T1-T4) in cats anesthetized with alpha-chloralose. Receptive fields of all afferents were located on the right or left ventricle. Mechanical and chemical sensitivities of each afferent ending were evaluated by von Frey hairs, cardiac distension, and local application of bradykinin (BK, 142 pmol) or H2O2 (7.5-15 mumol) to the receptive field. Thirty-one afferents (56%) were responsive to bradykinin (BK), H2O2, and ischemia (2 or 10 min). Deferoxamine (Def, 10-100 mg/kg), dimethylthiourea (DMTU, 10-100 mg/kg), or iron-loaded Def (10 mg/kg) were employed to evaluate the role of H2O2 and hydroxyl radicals (.OH) in activating these afferents (10A delta and 21C fibers) during ischemia and reperfusion. Treatment with the nonspecific scavenger DMTU (n = 10) significantly diminished the increase in discharge activity evoked by ischemia and reperfusion. Treatment with Def also significantly attenuated the responses during ischemia and reperfusion. Thus reactive oxygen species, particularly .OH, activate a group of cardiac sympathetic A delta- and C-fiber afferents during myocardial ischemia and reperfusion and may play an important role in mediating cardiovascular sympathetic reflex responses and/or pain transmission.
Diastolic time: an important determinant of regional arterial blood flow
Authors: Saupe K. W. , Smith C. A. , Henderson K. S. , Dempsey J. A.
Published: December 2017

In unanesthetized dogs we measured heart rate, blood pressure, and external iliac, celiac, and renal artery flows on a beat-by-beat basis. All three flows fluctuated in synchrony with breathing. Although the fluctuations in renal flow could to a large degree be explained by fluctuations in blood pressure, this was not the case in the external iliac artery where flow increased when pressure decreased and decreased when pressure increased. These paradoxical fluctuations in flow appear to be caused by respiratory fluctuations in heart rate, since we observed a strong (r = 0.89) correlation between external iliac flow and the length of the preceding diastole. Single long diastolic periods, induced by atropine, were always followed by a beat of increased flow even though arterial pressure was constant. We conclude that diastolic time has a profound impact on blood flow during the next beat. Our data support a model of the arterial system in which backpressure to flow through a bed is dependent on the amount of time for diastolic runoff into the capillaries.
Captopril-induced hypotension is inhibited by the bradykinin blocker HOE-140 in Na(+)-depleted marmosets
Authors: Panzenbeck M. J. , Loughnan C. L. , Madwed J. B. , Winquist R. J. , Fogal S. E.
Published: December 2017

Inhibition of angiotensin-converting enzyme (ACE) inhibits formation of angiotensin II and, by inhibition of kinin metabolism, may also increase vascular bradykinin. The present experiments were done in sodium-depleted, conscious, unrestrained marmosets (n = 5-11) to examine the contribution of bradykinin to ACE inhibitor-induced hypotension. Aortic blood pressure and heart rate (HR) were monitored via telemetry. After sodium depletion (low-sodium diet and furosemide), captopril (1 mg/kg po) caused a significant (P < 0.05) decrease in mean arterial blood pressure (MABP) (-34 +/- 3 mmHg, maximally, from 79 +/- 2 mmHg) but no change in HR compared with vehicle treatment. The bradykinin receptor antagonist HOE-140 (1 mg/kg sc) significantly inhibited the hypotensive response to captopril and caused marked tachycardia (+133 +/- 14 beats/min from 214 +/- 8 beats/min). HOE-140 (1 mg/kg sc) followed by vehicle administration had no effect on MABP but increased HR similarly. The hypotensive response to captopril was inhibited by HOE-140 regardless of the order of administration or the route of captopril administration (by mouth vs. subcutaneously). The hypotensive response to a renin inhibitor, A-72517 (3 mg/kg sc), was not inhibited by prior HOE-140 administration despite a similar HOE-140-induced tachycardia. These data suggest that the hypotensive effect of captopril in sodium-depleted, conscious marmosets is dependent on functional bradykinin B2 receptors. Also, blockade of B2 receptors uncovers marked tachycardia in this model, suggesting a tonic effect of bradykinin on control of HR in marmosets.
Resting oxygenation of rat and rabbit intestine: arteriolar and capillary contributions
Authors: Bohlen H. G. , Lash J. M.
Published: December 2017

Counter-current exchange of oxygen may occur between inflow and outflow microvessels of the small intestine and greatly influence the dominant sites of tissue oxygenation. To determine the location and magnitude of potential exchange, percent saturation of hemoglobin with oxygen (%SHb) was measured in microvessels throughout the intestine of rats and rabbits. Oxygen losses from systemic arterial blood through large and intermediate arterioles (second order, 2A) was 5-7%SHb in both species, and there was no evidence of an increase in percent saturation along intermediate and large venules. A larger loss of oxygen from arterioles and an increase in venous saturation would be evident if significant arteriolar to venular counter-current exchange of oxygen occurred in the submucosa. From 2A to the villus tip, arteriolar saturation decreased approximately 10%SHb in rabbits and approximately 15%SHb in rats; the villus tip percent saturation was 72.9 +/- 3.9%SHb in rabbits and 69.9 +/- 2.9%SHb in rats. An additional decrease of 5%SHb in rabbits and 15%SHb in rats occurred across the villus capillaries and smallest venules. Although the total reduction in percent saturation across the villi was different between the two species, 70-90% of the total arteriovenous oxygen losses occurred in the capillaries and small arterioles of the villi. We found no evidence of counter-current exchange of oxygen in villi or any other vascular region. Rather, as appears to occur in most organs, small arterioles in conjunction with capillaries dominate resting oxygen exchange to tissue.