bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective inhibition of cGMP-inhibitable cAMP phosphodiesterase decreases pulmonary vasoreactivity
Authors: Haynes J. , Kithas P. A. , Taylor A. E. , Strada S. J.
Published: December 2017

Guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) are mediators of smooth muscle relaxation. In this study, selective inhibitors of phosphodiesterase (PDE) isozymes were used to assess the role of cyclic nucleotide hydrolysis in angiotensin II (ANG II) and hypoxic pulmonary vasoconstriction. In isolated rat lungs, the hypoxic pressor response (HPR) was induced with a 95% N2-5% CO2 gas mixture. When administered during the plateau of the HPR, trequinsin (nonselective PDE inhibitor) and indolidan (cGMP-inhibitable cAMP PDE inhibitor) significantly (P = 0.01) decreased the pulmonary arterial pressure (Ppa) by 60 +/- 7 and 53 +/- 3%, respectively, compared with zaprinast (cGMP PDE inhibitor), rolipram (cGMP-insensitive cAMP PDE inhibitor), and the 0.1% dimethyl sulfoxide (DMSO) vehicle control, which decreased the Ppa by 6 +/- 3, 4 +/- 3, and 0%, respectively. In the trequinsin and indolidan groups, the subsequent ANG II pressor responses and HPRs were significantly (P = 0.01) decreased when compared with the zaprinast, rolipram, and DMSO groups. During normoxia, none of the PDE inhibitor (0.3-30 microM) had an effect on the baseline Ppa. These results suggest that cAMP hydrolysis by the cGMP-inhibitable cAMP PDE play a significant role in pulmonary vascular tone regulation.
Depressed intracellular calcium transients and contraction in myocytes from hypertrophied and failing guinea pig hearts
Authors: Siri F. M. , Krueger J. , Nordin C. , Ming Z. , Aronson R. S.
Published: December 2017

We investigated the basis for impaired left ventricular function of hearts in which hypertrophy was produced by gradual pressure overload. We measured myoplasmic free calcium concentration ([Ca2+]i) with fura-2 and sarcomere shortening in single myocytes isolated from control hearts and hypertrophied failing hearts. Diastolic [Ca2+]i was normal, but [Ca2+]i at the peak of contraction was depressed in myocytes from failing hypertrophied hearts. Increasing drive rate from 0.20 Hz to 5.00 Hz increased both diastolic and peak [Ca2+]i. Norepinephrine (3 x 10(-6) M) increased diastolic [Ca2+]i in all cells and tended to normalize peak [Ca2+]i in myocytes from hypertrophied failing hearts during 5.00 Hz drive. Depressed peak [Ca2+]i in the hypertrophied cells was paralleled by significant decreases in both the velocity and percent of sarcomere shortening, which were measured in cells not loaded with fura-2. Sarcomere length was correlated with estimates of [Ca2+]i in intact cells and with controlled levels of [Ca2+] in chemically "skinned" myocytes. A plot of sarcomere length against [Ca2+] gave a single continuous relationship that spanned resting and peak values at all drive rates in both the control and hypertrophied myocytes. Thus heart failure in this model is reflected in impaired myocyte contraction, which is closely related to reduced levels of [Ca2+]i during systole rather than to depressed myofilament sensitivity to Ca2+.
Two new inbred rat strains derived from SHR: WKHA, hyperactive, and WKHT, hypertensive, rats
Authors: Hendley E. D. , Ohlsson W. G.
Published: December 2017

Two new strains of inbred rats have been developed. One, WKHA, exhibits hyperactivity, and the other, WKHT, exhibits hypertension. Both of these traits are expressed in the SHR. By crossing spontaneously hypertensive rats (SHRs) with Wistar-Kyoto (WKY) controls, followed by recombinant selected inbreeding, we succeeded in genetically separating the hyperactivity from the hypertension in two new strains. Longitudinal studies indicate a persistence of hypertension without hyperactivity in WKHTs, and hyperactivity without hypertension in WKHAs, over at least 1 year. Ventricular enlargement, another characteristic of SHRs, was observed in adult WKHTs after the onset of hypertension; however, ventricles were already enlarged in normotensive WKHAs at 6 wk. The emergent behavioral profile of WKHAs indicates that they retain the hyperactivity trait and hyperreactivity to stress, and not some of the other behaviors of SHRs, such as poor habituation. Studies in WKHTs suggest that they are an improvement over SHRs as a model of genetic hypertension as they lack some prominent behavioral abnormalities. Nevertheless, the four genetically related strains (WKHA, WKHT, SHR, and WKY), used together, are considered most appropriate for seeking correlations of biological differences with either hypertension or hyperactivity.
Characterization of positive inotropic effect of endothelin on mammalian ventricular myocardium
Authors: Takanashi M. , Endoh M.
Published: December 2017

Endothelin-1 elicited a positive inotropic effect (PIE) on isolated rabbit, guinea pig, and rat but not on dog ventricular myocardium. Specific high-affinity binding of 125I-labeled endothelin-1 was detected in the ventricular membrane fraction of these species. Maximal binding capacity was the highest in the rabbit, lowest in the dog, and in between in the guinea pig and rat; this rank order corresponds roughly to the effectiveness of endothelin-1 in producing a PIE. There was no difference in the potency or efficacy for the PIE of the endothelin isoforms endothelin-1, -2, and -3 in the rabbit papillary muscle. A tumor-promoting phorbol ester, phorbol 12,13-dibutyrate, inhibited selectively the PIE and the accumulation of [3H]inositol monophosphate induced by endothelin-1 as well as those of myocardial alpha 1-adrenoceptor stimulation in a concentration that did not (10(-8) M) or only slightly (10(-7) M) reduced the PIE of BAY K 8644. Phorbol 12,13-dibutyrate did not affect the specific binding of 125I-labeled endothelin-1 in the ventricular membrane fraction of the rabbit. The present findings indicate that the characteristics of the endothelin-induced PIE in mammalian ventricular myocardium are similar to those of myocardial alpha 1-adrenoceptor activation that may involve phosphoinositide hydrolysis. The receptor density and the PIE of endothelin on mammalian cardiac muscle show a wide range of variation among species.
Effect of local pH on interstitial fluid pressure
Authors: Gilanyi M. , Kovach A. G.
Published: December 2017

It has been suggested that electrostatic interactions between the electric charges on the interstitial gel matrix play a significant role in determining tissue elasticity and interstitial fluid pressure (IFP). The relationship between the net charge and IFP, however, has not been adequately established. Our purpose was to explore the net electric charge-IFP relationship, and in vivo experiments were performed to test its validity. IFP was measured in the subcutaneous tissue of anesthetized rats with the chronically implanted capsule method, and the acid-base status in blood and interstitial fluid was monitored. The net charge, which can be varied by pH, was altered by electrolysis procedure. H+ and OH- generated inside the capsule caused transient and dose-dependent IFP responses. The curve, describing the relationship between capsular pressure changes and amount of generated H+ and OH-, has a maximum at zero net charge, and the excess electric charge, either positive or negative, results in a significant decrease in capsular pressure in accordance with the hypothesis. The time course, as well as the dose dependency, of IFP suggests that the subcutaneous tissue gel in control condition has slightly positive net charge.
Time-course effects of sinoaortic denervation on contractile state of the rat myocardium
Authors: Vassallo D. V. , Vasquez E. C. , Mill J. G. , Cabral A. M.
Published: December 2017

Sinoaortic baroreceptor denervation (SAD) in the rat immediately produces hypertension and tachycardia, as the result of an increased sympathetic tone to the heart and resistance vessels. Adaptive processes are then installed, changing according to the duration of the SAD. In this work we studied the time course of adaptive changes occurring in the rat heart within a 30-day period. Heart rate and mean blood pressure were measured before mechanical studies in the isometrically contracting left ventricle papillary muscles. Results showed that heart rate and mean blood pressure increased immediately after the SAD. Heart rate normalized 15 days later, although hypertension persisted. Thirty days later both rate and pressure normalized. Mechanical studies showed that isometric force development (F) and its first-time derivative (dF/dt) behaved similar to controls until the 1st wk but displayed a contractile depression in the 2nd wk after SAD. However, after 30 days this depression subsided and both F and dF/dt were back to normal values. The beta-adrenoceptor responsiveness also changed during this 30-day period. Three days after denervation there was an increased sensitivity to isoproterenol action in the muscles. This sensitivity was progressively reduced as the time after denervation increased. The absence of a similar behavior with the rest-potentiated contractions suggests that these time-course adaptive changes are specific for beta-adrenoceptor stimulation.
Adenosine inhibits postischemic leukocyte-endothelium interaction in postcapillary venules of the hamster
Authors: Nolte D. , Lehr H. A. , Messmer K.
Published: December 2017

The reduction of postischemic reperfusion injury by exogenous adenosine has been ascribed to reduced oxygen radical generation and adhesion of leukocytes to the vascular endothelium. To provide in vivo evidence for this concept we investigated the effects of adenosine (110 micrograms.kg-1.min-1 iv) on postischemic leukocyte-endothelium interaction in the dorsal skinfold chamber model in awake hamsters by intravital fluorescence microscopy. Leukocytes were stained in vivo with acridine orange and classified according to their interaction with the endothelium as nonadherent, rolling, or sticking leukocytes. In control animals, reperfusion after a 4-h pressure-induced ischemia to the striated muscle in the dorsal skinfold chamber elicited a marked increase in leukocyte rolling and sticking. This phenomenon was significantly attenuated in adenosine-treated animals 30 min after reperfusion. Postischemic changes in vessel diameters and red cell velocities were not affected by adenosine. The data suggest that systemic adenosine administration reduces reperfusion injury by the inhibition of postischemic leukocyte adherence to the microvascular endothelium.
NPY modulates neurotransmission of CGRP-containing vasodilator nerves in rat mesenteric arteries
Authors: Kawasaki H. , Nuki C. , Saito A. , Takasaki K.
Published: December 2017

The effect of neuropeptide Y (NPY) in neurotransmission of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves was investigated in rats. In perfused mesenteric vascular beds with active tone, perivascular nerve stimulation (PNS; 1-8 Hz) caused a frequency-dependent vasodilator response, which was abolished by 300 nM tetrodotoxin (TTX), 500 nM capsaicin, 1 microM human CGRP-(8-37), or cold storage denervation (4 degrees C for 72 h). NPY (5, 10, and 50 nM) concentration dependently inhibited the vasodilator response to PNS, whereas NPY had little effect on vasodilation induced by exogenous CGRP (10 and 100 pmol) or 1 nmol acetylcholine (ACh). NPY (10 nM) inhibited the neurogenic release of CGRP-like immunoreactivity induced by PNS (4 and 8 Hz), which was abolished by 300 nM TTX and the removal of Ca2+ from the medium. Combined perfusion with 5 nM NPY and 10 nM norepinephrine additively inhibited the vasodilator response to PNS but not to exogenous CGRP and ACh. Immunohistochemistry showed the distinct distribution of CGRP- and NPY-like immunoreactivity-containing fibers in rat mesenteric arteries. These results suggest that NPY modulates presynaptically the release of CGRP from CGRP-containing vasodilator nerves in rat mesenteric arteries.
Influence of metabolic substrate on rat heart function and metabolism at different coronary flows
Authors: Burkhoff D. , Weiss R. G. , Schulman S. P. , Kalil-Filho R. , Wannenburg T. , Gerstenblith G.
Published: December 2017

The influence of metabolic substrate on contractile strength, myocardial oxygen consumption (MVO2), high- and low-energy phosphate levels, and intracellular pH were determined in isovolumically contracting isolated rat hearts perfused with solutions containing either glucose or hexanoate at both high and low coronary perfusion pressures (CPP). Contractile strength was not significantly influenced by substrate at a CPP of 80 mmHg. As coronary flow was decreased, developed pressure measured at a fixed left ventricular volume (LVV) was lower during hexanoate than glucose perfusion. The relationship between MVO2 and mechanical work determined at a CPP of 80 mmHg over a range of LVVs was shifted upward in a parallel manner when substrate was switched from glucose to hexanoate. The MVO2-work relationship measured at a fixed LVV but over a range of coronary flows (7-20 ml/min) was also parallel shifted upward on switching from glucose to hexanoate. Basal MVO2 was greater during hexanoate than glucose perfusion by an amount that accounted for two-thirds the total increase in MVO2 observed between the substrates under unloaded beating conditions. The remainder of the difference was attributed to increased energy requirements for excitation-contraction coupling. Inorganic phosphate concentrations increased more and phosphocreatine concentrations decreased more during low-flow conditions (3 ml/min) when hearts were perfused with hexanoate compared with glucose. Thus hexanoate decreases myocardial efficiency compared with glucose in large part by increasing non-work-related oxygen demands. This inefficiency impacts adversely on contractile strength and high-energy phosphate concentrations at low coronary flows.
Effects of coronary occlusion duration on reactive hyperemia in conscious dogs and ponies
Authors: Sarazan R. D. , Krause G. F. , Franklin D. , Garner H. E. , Griggs D. M.
Published: December 2017

Coronary reactive hyperemia duration (RHD) and coronary blood flow debt repayment (BFDR) were compared in conscious dogs and ponies instrumented with coronary artery Doppler flow probes and pneumatic occluders. Additional ponies were instrumented with pacing electrodes. With the use of a Latin square design, eight animals of each species were subjected to a randomized series of nine coronary occlusions ranging from 5 s to 2 min in duration. In both species, postocclusion blood flow velocity rose rapidly and plateaued at similar peak levels relative to control, but in ponies this plateau lasted significantly longer. The interspecies difference in plateau duration increased as a function of coronary occlusion duration (COD). RHD ranged from 19.5 +/- 5.9 to 139.7 +/- 5.9 s in dogs and from 26.6 +/- 9.0 to 395.0 +/- 9.0 s in ponies. The slope of the RHD vs. COD curve was steeper in ponies. BFDR was similar in dogs and ponies at the shortest COD (418.1 +/- 26 vs. 451.4 +/- 58%) but declined in dogs as a function of COD to 232.3 +/- 26%. In ponies, BFDR increased as a function of COD to a maximum of 945.4 +/- 58% with a 60-s occlusion and then declined to 614.3 +/- 58%. RHD was not significantly altered in ponies when heart rate was changed to match that in dogs. Although the underlying basis for these interspecies differences in RHD and BFDR was not determined, the differences were considered to be too large to be explained by animal model differences in coronary conductance, collateral blood flow, or myocardial oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)
Leukotrienes, thromboxane A2, and prostaglandins during systemic anaphylaxis in sheep
Authors: Morel D. R. , Skoskiewicz M. , Robinson D. R. , Bloch K. J. , Hoaglin D. C. , Zapol W. M.
Published: December 2017

We investigated the roles of eicosanoid mediators in acute systemic anaphylaxis in anesthetized sheep. Sheep were sensitized with dinitrophenylated Ascaris suum extract and were challenged with an intravenous injection of dinitrophenylated bovine serum albumin. During anaphylaxis, cyclooxygenase inhibitors eliminated the elevation of arterial plasma levels of thromboxane B2 and 6-ketoprostaglandin F 1 alpha but markedly elevated the levels of leukotriene E4 in lung lymph without significantly eliminating elevation of plasma levels of histamine. Most of the measured physiological abnormalities accompanying anaphylaxis were aggravated by cyclooxygenase blockade. Enhancement of this anaphylactic mediator response was associated with an accentuated and prolonged increase of airway pressure (P less than 0.05, compared with sensitized, antigen-challenged but otherwise untreated sheep), a more intense hypoxemia (P less than 0.0001), and leukopenia (P less than 0.001), changes that were largely eliminated by pretreating with the sulfidopeptide leukotriene (SPLT) antagonist FPL 55712, suggesting that the SPLTs were important mediators of these responses. In contrast, the prolonged, but less severe, systemic vascular collapse and the reduced pulmonary hypertension induced by cyclooxygenase inhibitors were not influenced by the SPLT antagonist. These results demonstrate that in sheep cyclooxygenase metabolites are mainly involved in the acute, but transient, systemic and pulmonary vascular response of systemic anaphylaxis, whereas SPLTs are primarily implicated in the airway and secondary cardiovascular response. SPLT may act either directly or by potentiating the release of and reactivity to histamine and other mediators. Our data therefore suggest that a combination of cyclooxygenase and lipoxygenase inhibition will be necessary to more effectively protect against the consequences of an anaphylactic reaction.
Myoglobin function and energy metabolism of isolated cardiac myocytes: effect of sodium nitrite
Authors: Doeller Jeannette E. , Wittenberg Beatrice A.
Published: December 2017

Pages H53–H62, 1991: Jeannette E. Doeller and Beatrice A. Wittenberg. “Myoglobin function and energy metabolism of isolated cardiac myocytes: effect of sodium nitrite.” We regret that the following references were inadvertently dropped during printing.

26. Wittenberg, B. A., J. E. Doeller, R. K. Gupta, and R. L. White. Measurement of sarcolemmal permeability and intracellular pH, free magnesium, and high energy phosphates of isolated heart cells. In: Biology of Isolated Adult Cardiac Myocytes, edited by W. A. Clark, R. S. Decker, and T. K. Borg. New York: Elsevier, 1988, p. 188–130.

27. Wittenberg, B. A., and T. F. Robinson. Oxygen requirements, morphology, cell coat and membrane permeability of calcium tolerant myocytes from hearts of adult rats. Cell Tissue Res. 216: 231–251, 1981.

28. Wittenberg, B. A., and J. B. Wittenberg. Oxygen pressure gradients in isolated cardiac myocytes. J. Biol. Chem. 260: 6548–6554, 1985.

29. Wittenberg, B. A., and J. B. Wittenberg. Myoglobin-mediated oxygen delivery to mitochondria of isolated cardiac myocytes. Proc. Natl. Acad. Sci. USA 84: 7503–7607, 1987.

30. Wittenberg, B. A., and J. B. Wittenberg. Transport of oxygen in muscle. Annu. Rev. Physiol. 51: 857–878, 1989.

31. Wittenberg, B. A., J. B. Wittenberg, and P. R. B. Caldwell. Role of myoglobin in the oxygen supply to red skeletal muscle. J. Biol. Chem. 250: 9038–9043, 1975.

32. Wittenberg, J. B., and B. A. Wittenberg. Preparation of myoglobins. In: Methods of Enzymology, edited by S. P. Colowick and N. O. Kaplan. New York: Academic, 1981, vol. 76, p. 29–42.

33. Wittenberg, J. B., and B. A. Wittenberg. Mechanisms of cytoplasmic hemoglobin and myoglobin function. Annu. Reu. Biophys. Biophys. Chem. 19: 217–241, 1990.
Phenotypic changes of human aortic smooth muscle cells during development and in the adult vessel
Authors: Glukhova Marina A. , Frid Maria G. , Koteliansky Victor E.
Published: December 2017

To characterize phenotypic expression of human aortic smooth muscle cells (SMCs), we have studied the content of cytodifferentiation-related cytoskeletal proteins, and of fibronectin (FN) variants in the samples of media from the fetal, child, and adult aorta and in the subendothelial intima of the normal and atherosclerotic aorta. Mature SMCs from the adult aortic media contained high amounts of -SM-actin, SM-myosin heavy chains, meta-vinculin, and 150 kDa caldesmon. Cytokeratin 8 and extra domain-containing variants of FN (A-FN and B-FN) were not found in these cells. The SMCs from the aortic media of 10-wk-old fetus contained low amounts of the SM markers, expressed cytokeratin 8, A-FN, and B-FN. In 25-wk-old fetus, as well as in 2- and 6-mo-old child, aortic medial SMCs expressed an intermediate phenotype, and only in 18-mo-old child were the cells found to be similar to those from adult media. SMCs from the normal adult subendothelial intima contained reduced amounts of meta-vinculin and of 150 kDa caldesmon, and they expressed A-FN. In addition, the SMCs from atherosclerotic fibrous plaque contained a decreased proportion of -SM-actin and of SM-myosin heavy chains, whereas cytokeratin 8 was found. Therefore we conclude that the SMCs from intimal thickenings appear to express a less mature phenotype than that of the medial cells from adult aorta. Rather, these SMCs contain reduced amounts of the SM markers and express proteins typical of the fetal SMC phenotype, A-FN and cytokeratin 8.

cytodifferentiation; cytoskeletal proteins; fibronectin variant forms
Free radical metabolites in myocardium during ischemia and reperfusion
Authors: Ruuge Enno K. , Ledenev Alexander N. , Lakomkin Vladimir L. , Konstantinov Alexander A. , Ksenzenko Marina Yu.
Published: December 2017

Low-temperature electron paramagnetic resonance (EPR) spectroscopy and spin traps were used to measure paramagnetic species generation in rat hearts and isolated mitochondria. The hearts were freeze-clamped at 77 K during control perfusion by the Langendorff procedure, after 20–30 min of normothermic ischemia or 10–30 s of reperfusion with oxygenated perfusate. All EPR spectra measured at 4.5–50 K exhibited signals of both mitochondrial free radical centers and FeS proteins. The analysis of spectral parameters measured at 243 K showed that free radicals in heart tissue were semiquinones of coenzyme Q10 and flavins. The appearance of a typical “doublet” signal at g = 1.99 in low-temperature spectra indicated that a part of ubisemiquinones formed a complex with a high potential FeS protein of succinate dehydrogenase. Ischemia decreased the free radical species in myocardium 50%; the initiation of reflow of perfusate resulted in quick increase of the EPR signal. Mitochondria isolated from hearts during control perfusion and after 20–30 min of ischemia were able to produce superoxide radicals in both the NADH-coenzyme Q10 reductase and the bc1 segments of the respiratory chain. The rate of oxyradical generation was significantly higher in mitochondria isolated from ischemic heart.

electron paramagnetic resonance; oxygen paradox; oxyradicals; rat heart; semiquinones
Capillary growth and geometry during long-term hypertension and myocardial hypertrophy in dogs
Authors: Tomanek R. J. , Wessel T. J. , Harrison D. G.
Published: December 2017

Angiogenic response of the myocardial capillary bed to long-term (7 mo) renovascular hypertension (one-kidney, one-clip) was assessed in eight mongrel dogs and compared with seven control dogs. Image analyses of histological sections from four transmural specimen sites of left ventricular (LV) free wall were performed. While mean cross-sectional cardiocyte area increased in all transmural layers (epi-endo) in dogs with LV hypertrophy (LVH), the greatest increases occurred in the inner layers. Although capillary length density was significantly lower in two of the four transmural regions of LVH dogs, these decrements were much less than the lateral expansion of cardiocytes as indicated by cross-sectional areas. Calculations of total capillary length indicate that approximately one-fifth of the capillary bed in LVH dogs was formed during the 7-mo period of hypertension in hypertrophied hearts. Capillary volume and surface densities in LVH dogs decreased to a greater extent due to a larger population of capillaries with lumen diameters less than 4 microns. Capillary volume density in LVH dogs was remarkably similar across the wall despite large transmural differences in cardiocyte hypertrophy. LVH did not alter the log SD of capillary domains, a measure of the heterogeneity of spacing, or capillary orientation (degree or anisotropy). These data support several important conclusions regarding long-term hypertension-induced LVH in dogs. First, although capillary growth does not fully compensate for the increase in LV mass, a myriad of new capillaries are formed as indicated by a substantial increase in total capillary length. This growth minimizes the increase in intercapillary distance characteristic of LVH.(ABSTRACT TRUNCATED AT 250 WORDS)
Hyperpolarization contributes to endothelium-dependent relaxations to acetylcholine in femoral veins of rats
Authors: Nagao T. , Vanhoutte P. M.
Published: December 2017

The contribution of membrane hyperpolarization to endothelium-dependent relaxations induced by acetylcholine was investigated in the femoral vein of the rat using a microelectrode technique and isometric tension recordings. Acetylcholine caused endothelium-dependent relaxations and hyperpolarization in tissues contracted with norepinephrine. The relaxation was sustained during a prolonged exposure to acetylcholine (less than or equal to 10 min). In contrast, the hyperpolarization declined with time. In the presence of nitro-L-arginine, a blocker of nitric oxide synthesis, the relaxation became smaller and transient, whereas the hyperpolarization was not affected. There was a temporal relationship between the relaxation and the hyperpolarization in the presence of nitro-L-arginine, when the two parameters were recorded simultaneously. In tissues contracted with 60 mM K+, in which hyperpolarization could not be observed, acetylcholine caused relaxations and these relaxations were abolished by nitro-L-arginine. The results suggest a contribution of both nitric oxide and membrane hyperpolarization to the endothelium-dependent relaxation induced by acetylcholine in the femoral vein of the rat.
Mechanisms of renal effects of different agents stimulating production of cGMP
Authors: Grandes S. , Gallego M. J. , Riesco A. , Lopez Farre A. , Millas I. , Casado S. , Hernando L. , Caramelo C.
Published: December 2017

The effect of agents stimulating the production of guanosine 3',5'-cyclic monophosphate (cGMP) by different mechanisms was compared in conscious unrestrained Wistar rats by administration of infusions of acetylcholine (ACh), sodium nitroprusside (SNP), and atrial natriuretic peptide (ANP). ACh (10 micrograms.kg-1.min-1, n = 8), SNP (200 micrograms.kg-1.min-1, n = 8), and ANP (0.5 micrograms.kg-1.min-1, n = 7) induced natriuresis (urinary Na gradient: 399, 499, and 504 microeq/h, respectively; P less than 0.001 with respect to baseline) and diuresis (urine volume gradient: 0.87, 0.82, and 0.92 ml/h, respectively; P less than 0.001). Urinary cGMP increased (P less than 0.001) with the three agents (delta pmol cGMP/min: ACh 22.3, SNP 42.5, and ANP 48.4); in addition, a parallel increase in renal cGMP content was observed with the three agents (ACh 1.6, SNP 2.8, and ANP 3.5 times with respect to controls; P less than 0.05). Mean arterial pressure did not change with the aforementioned dose of ANP but decreased by 10 and 40% with ACh and SNP, respectively. Glomerular filtration rate increased by a similar magnitude with the three compounds. The competitive inhibitor of L-arginine, N omega-nitro-L-arginine (L-NNA), significantly decreased the diuretic, natriuretic, and hypotensive effects of ACh without affecting the actions of SNP and ANP.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiac contractile injury after intestinal ischemia-reperfusion
Authors: Horton J. W. , White D. J.
Published: December 2017

Experimental and clinical data suggest that even a brief period of intestinal ischemia followed by reperfusion initiates a sequence of events that include release of inflammatory mediators and multiorgan failure. In this study, 41 rats were subjected to occlusion of the superior mesenteric artery (SMA) for 20 min and collateral arcade ligation. Twelve rats were sham operated and served as controls (group 1). Groups of rats with SMA occlusion were killed at several time intervals after reperfusion (group 2, 2-3 h; group 3, 4-5 h; group 4, 12-16 h). In group 5, rats were pretreated with enterally administered allopurinol (10 mg.kg-1.day-1) for 4 days before the intestinal ischemia episode and were studied 2-3 h after reperfusion. In vivo studies confirmed that 20 min of intestinal ischemia produced a transient bradycardia (P less than 0.05) and no change in systemic blood pressure, acid-base balance, or hematocrit. In vitro studies showed marked cardiac contractile depression as early as 2 h after ischemia-reperfusion as indicated by a fall in left ventricular pressure (LVP; from 77 +/- 3 to 63 +/- 4 mmHg, P = 0.01) and +dP/dtmax (from 1,827 +/- 59 to 1,557 +/- 99 mmHg/s, P less than 0.02) and -dP/dtmax (from 1,267 +/- 57 to 953 +/- 67 mmHg/s, P = 0.02), a rightward shift in LV function curves, and a decreased responsiveness to perfusate Ca2+. Allopurinol pretreatment prevented ischemia-reperfusion-mediated deficits in cardiac contraction and relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
Morphological and functional alterations of mesenteric small resistance arteries in early renal hypertension in rats
Authors: Deng L. Y. , Schiffrin E. L.
Published: December 2017

We investigated the structure and reactivity of small resistance arteries of two-kidney, one-clip (2K,1C) and one-kidney, one-clip (1K,1C) Goldblatt hypertensive rats within 4-6 wk of development of hypertension. Blood vessels from the mesenteric vascular bed with lumen diameter less than 300 microns were mounted on a wire myograph. The media of the vessel wall was significantly increased and lumen diameter was decreased in 2K,1C and 1K,1C rats. External diameter of blood vessels was reduced in both 2K,1C and 1K,1C rats, whereas cross-sectional area of the wall was increased significantly in 1K,1C rats. Wall tension in response to KCl was significantly lower in 2K,1C and 1K,1C hypertensive rats, whereas tension in response to norepinephrine (NE) was reduced in 1K,1C hypertensive rats but was similar in 2K,1C rats and controls. Active tension in response to arginine vasopressin (AVP) was similar in all groups. As a consequence of the reduced lumen circumference of small arteries, effective pressure in response to NE was similar in hypertensive and control rats, whereas effective pressure in response to AVP was exaggerated in the hypertensive rats. The sensitivity to NE and AVP was similar in all groups. These results show the rapid development of functional and structural changes in small resistance arteries in renal hypertensive rats within 4-6 wk of hypertension, with significant reduction in external and lumen diameters, increased media width, and increased media-to-lumen ratio, which enhance vascular reactivity to vasoconstrictors, in particular NE and AVP.
Inhibition of elastolysis by SC-37698 reduces development and progression of monocrotaline pulmonary hypertension
Authors: Ye C. L. , Rabinovitch M.
Published: December 2017

Our previous studies showed that increased pulmonary artery elastolytic activity is associated with monocrotaline-induced pulmonary hypertension in rats, and the latter is reduced by the elastase inhibitor SC-39026. This agent, given orally, decreases monocrotaline-induced muscularization of normally nonmuscular peripheral arteries but not medial hypertrophy of muscular arteries. To establish whether constant infusion of an elastase inhibitor would reduce both vascular lesions induced by monocrotaline injection, SC-37698 (an analogue of SC-39026) was given intravenously by osmopump. To separately assess whether SC-37698 would inhibit development of the vascular changes as well as their progression, SC-37698 or vehicle was infused for the first 2 wk (2-wk study) or was delayed until 1 wk after monocrotaline injection (3-wk study). Hemodynamic data were recorded from indwelling catheters, and the lungs were evaluated morphologically. Saline-injected control rats given SC-37698 or vehicle were similar at both time points. Monocrotaline-injected rats given SC-37698 compared with those given vehicle alone had lower pulmonary artery pressures, 17.9 +/- 0.5 vs. 23.7 +/- 0.8 mmHg (P less than 0.01) in the 2-wk study and 24.0 +/- 1.8 vs. 33.5 +/- 3.1 mmHg (P less than 0.05) in the 3-wk study. This was associated with significant decreases in muscularization of peripheral arteries and reductions in medial hypertrophy of muscular arteries. In the hilar pulmonary arteries assessed at 3 wk only, SC-37698 significantly decreased monocrotaline-induced endothelial injury, subendothelial edema, migration of smooth muscle cells into subendothelium, medial hypertrophy, collagen accumulation, and abnormal distribution of elastin as interlamellar islands. Pulmonary artery elastolytic activity was reduced in SC-37698-treated compared with untreated monocrotaline-injected rats (P less than 0.05). Thus infusion of SC-37698 reduces monocrotaline-induced pulmonary hypertension when administered before or even after development of early vascular changes.
A technique for production of complete atrioventricular block in dogs
Authors: Day T. K. , Muir W. W.
Published: December 2017

A simple and reliable technique for producing complete atrioventricular (AV) block in dogs by the injection of a 38% formaldehyde solution into the area of the AV node is described. This technique, a modification of previous methods utilizing formaldehyde injection for the production of complete AV block, uses the coronary sinus as the major landmark. Complete heart block was produced in 20 of 20 dogs. The technique is simple and associated with few problems, does not require special equipment, is associated with little or no hemorrhage from the injection site, and does not enter a cardiac chamber. The only side effect noted was the development of ventricular arrhythmias in 2 of 20 dogs. A detailed description of the technique is included with comparisons to previous techniques utilizing injection of a 40% formaldehyde solution.
A new approach to in situ left ventricular volume clamping in dogs
Authors: Ohtani M. , Nikolic S. D. , Glantz S. A.
Published: December 2017

Major contributing factors modulating left ventricular (LV) diastolic behavior are active relaxation of myocardium and volume change during filling, the interaction of which complicates analysis of diastolic pressure-volume relationship, especially in early diastole. To separate the effect of active relaxation and filling, a method was introduced [E. L. Yellin, M. Hori, C. Yoran, E. H. Sonnenblick, S. Gabbay, R. W. M. Frater, Am. J. Physiol. 250 (Heart Circ. Physiol. 19): H620-H629, 1986] to interrupt mitral inflow and keep LV volume constant throughout diastole. Their preparation requires replacing the mitral valve with an artificial valve using cardiopulmonary bypass, which might cause significant change in cardiac performance or produce detrimental systemic effects. We developed a new volume-clamping method that preserves the native mitral valve and apparatus intact and avoids cardiopulmonary bypass. A modified Bjork-Shiley prosthetic valve (20 mm orifice diam) in a special mounting ring was placed above the native mitral valve through the left atrium and secured from outside the heart. This prosthetic valve was controlled by a cable connected to solenoids outside the dog, triggered by the electrocardiogram or other physiological signal. We compared our method (n = 7) with that of Yellin et al. (n = 2) in nine random source dogs. In our method, no end-diastolic pressure gradient or regurgitant pressure wave was observed, and the prosthetic valve did not disturb movement of the native mitral valve. When the prosthetic valve was forced to a closed position at end systole, LV volume, measured with a conductance catheter, was maintained at or near end-systolic volume throughout diastole.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of pentoxifylline in rabbit pulmonary circulation: influence of age and vasomotor tone
Authors: Kaapa P. , Raj J. U. , Ibe B. O. , Anderson J.
Published: December 2017

We determined the influence of vasomotor tone and age on pentoxifylline (PTX) effects in rabbit lungs. Lungs of adult, juvenile, and neonatal rabbits were isolated and perfused with blood at constant flow in zone 3. In adult lungs only, pressures were measured in 20- to 50-microns-diameter subpleural arterioles and venules (by micropuncture) to partition the circulation into arteries, microvessels, and veins during baseline, after PTX infusion (20 mg/kg), and terminally, after treatment with papaverine. In some adult and juvenile lungs, vasomotor tone was elevated with KCl, and some adult lungs were pretreated with indomethacin to inhibit cyclooxygenase. We found that PTX's vasodilator effect was influenced by age; it was approximately 52, approximately 65, and approximately 82% as effective as papaverine in untreated neonatal, juvenile, and adult lungs, respectively, and approximately 49 and approximately 93% as effective as papaverine in KCl-constricted adult and juvenile lungs, respectively. The site(s) of PTX action depended on basal vasomotor tone; in lungs with moderate tone, PTX dilated arteries only, and in lungs with high tone, PTX dilated both arteries and veins. Cyclooxygenase inhibition did not attenuate PTX effects. We conclude that, in rabbit lungs, PTX dilates arteries and veins and that the magnitude of PTX effect is dependent on age and basal vasomotor tone.
Cerebral blood flow response to hypercapnia in immature fetal sheep
Authors: Helou S. M. , Hudak M. L. , Jones M. D.
Published: December 2017

We have reported recently that the cerebral blood flow (CBF) response to isocapnic hypoxic hypoxia is blunted in fetal sheep in utero at 93 days of gestation (term = 145-150 days), a time of rapid brain differentiation in this species. Cerebral O2 transport fell rather than being maintained, as it is in more mature fetuses. The reason for the blunted response was not clear. We hypothesized that the CBF response to hypercapnia also might be blunted. We studied 10 immature fetal sheep in utero at a mean gestational age of 92 days 24 h after catheters were placed into the superior sagittal sinus, axillary artery, and inferior vena cava. We raised the fetal arterial carbon dioxide tension (PaCO2) by changing the mother's inspired PCO2. CBF was measured before and during hypercapnia by the microsphere method. The overall increase in CBF in response to hypercapnia in immature fetuses was lower than in near-term fetuses. However, the difference was eliminated after correcting for differences in cerebral O2 consumption. This study failed to show any defect in the ability of cerebral vessels in immature fetal sheep to respond to carbon dioxide.
Mechanisms of calcium relaxation of vascular smooth muscle
Authors: Wu C. C. , Bohr D. F.
Published: December 2017

We examined mechanisms of relaxation in intact and endothelium-denuded thoracic aortic rings of rat in response to various concentrations of calcium (from 1.6 to 10.1 mM) after contraction induced by 30 mM KCl. The relaxation to calcium was concentration dependent in intact and denuded rings. This effect was greater in intact preparations than in denuded preparations or in intact preparations treated with methylene blue (10(-5) M). This indicates that the relaxation by calcium is partly mediated by releasing endothelium-derived relaxing factors (EDRFs). In the presence of A23187, the relaxation to calcium was attenuated in intact rings but not in denuded rings, whereas calcium relaxation was not significantly altered by sodium nitroprusside. These observations suggest that the calcium-induced relaxation is reduced if EDRF has already been released by A23187. We conclude that, paradoxically, the same increase in extracellular Ca2+ concentration that causes an increase in endothelial intracellular calcium concentration ([Ca2+]i) to produce EDRF also results in membrane stabilization of the vascular smooth muscle cell to decrease [Ca2+]i and cause relaxation. These two mechanisms are additive in producing calcium relaxation in the intact artery.
Involvement of Ca2+ influx-induced Ca2+ release in contractions of intact vascular smooth muscles
Authors: Ito K. , Ikemoto T. , Takakura S.
Published: December 2017

Application of Ca2+ (0.1-2.5 mM) to guinea pig aortas incubated in Ca(2+)-free isotonic KCl solution induced a contraction (Ca contraction), a part of which depended on preloading the intracellular stores with Ca2+ and which was sensitive to 3 x 10(-5) M ryanodine. Because 45Ca2+ influx from the external fluid upon the addition of Ca2+ was not modified either by the state of filling of the Ca2+ store or by the presence of ryanodine, the ryanodine-sensitive component of the contraction could be attributed to the Ca2+ influx-induced Ca2+ release from the Ca2+ store. Supporting the possibility of involvement of Ca(2+)-induced Ca2+ release, the Ca contraction due to 0.1 mM Ca2+ was enhanced either by decreasing Mg2+ in the medium or by low temperature. The ratio of the ryanodine-sensitive fraction in the Ca contraction was inversely related to the concentration of Ca2+ added and also to the extent of 45Ca2+ influx. When the Ca2+ influx was decreased by verapamil or cadmium, the ratio of ryanodine-sensitive fraction increased. On the contrary, an increase of Ca2+ influx by CGP-28392 decreased the ratio. These results suggest that Ca2+ influx at a physiological level triggers Ca2+ release from the Ca2+ store, resulting in the amplification of contractile force.
Contractile dysfunction during metabolic acidosis: role of impaired energy metabolism
Authors: Zhou H. Z. , Malhotra D. , Shapiro J. I.
Published: December 2017

To investigate the mechanisms by which acidosis depresses cardiac function, a Langendorff isolated perfused rat heart preparation was studied using 31P magnetic resonance spectroscopy. Isolated hearts were subjected to normal perfusion conditions or experimental manipulations simulating severe metabolic acidosis, substrate depletion, impairment of oxidative metabolism, or low perfusate calcium concentrations. All maneuvers resulted in marked reductions in oxygen consumption and the force of myocardial contraction (dP/dt). Metabolic acidosis had bioenergetic changes suggestive of impaired energy production, specifically, increases in Pi and decreases in phosphocreatine concentrations, which did not occur in hearts subjected to low perfusate calcium concentrations. In acidotic perfusions as well as substrate depletion and impairment of oxidative metabolism, the change in dP/dt correlated best with the change in the intracellular concentration of monovalent Pi (P(im)) (r = 0.70, P less than 0.01), whereas in hearts subjected to a low perfusate calcium concentration, there was no relationship between dP/dt and the change in Pim concentrations. More detailed analysis of the time course of the metabolic and physiological changes with metabolic acidosis revealed a discordance between changes in Pim and the decreases in dP/dt during the first 20 min of the induction of acidosis and the first 10 min of recovery from acidosis. These data suggest that metabolic acidosis has a major direct effect on energy metabolism in this model. Moreover, impairment of oxidative metabolism in concert with decreases in intracellular pH may be important in the contractile failure associated with prolonged metabolic acidosis.
Ultrasound as a novel method for selective damage of endocardial endothelium
Authors: Andries L. J. , Meulemans A. L. , Brutsaert D. L.
Published: December 2017

Damage of endocardial endothelium by mechanochemical methods in isolated cardiac muscle induces typical changes in the contractile performance of the myocardium. Functional and morphological features of isolated cat papillary muscles treated with ultrasound, a new technique for in vitro damage of endocardial endothelium, were compared with damage by Triton X-100. Treatment with either short bursts of continuous wave ultrasound (25 W; 1.05 MHz) or with 1-s immersion in 0.5% Triton X-100 resulted in an irreversible abbreviation of twitch contraction with concomitant decrease in total peak twitch tension but without significant changes in maximal unloaded velocity of shortening. Decrease of total peak isometric tension was significantly more pronounced after Triton X-100 administration. Scanning electron microscopy showed an extracted endothelium following immersion in Triton X-100 and a nearly complete desquamated surface after ultrasound. Fluorochromes in muscles treated with Triton X-100 or ultrasound did not enter myocytes, which maintained a normal ultrastructure. After Triton X-100, more endocardial fibroblasts were labeled and showed ultrastructural damage than after ultrasound. Ultrasound constitutes a powerful technique for selective in vitro damage of endocardial endothelium. The technique is also suitable for experimental in vivo intracardiac application.
Chronic hypoxic pulmonary hypertension in rats and increased elastolytic activity
Authors: Maruyama K. , Ye C. L. , Woo M. , Venkatacharya H. , Lines L. D. , Silver M. M. , Rabinovitch M.
Published: December 2017

Previously in rats injected with the toxin monocrotaline and administered SC-39026, a serine elastase inhibitor, pulmonary hypertension was decreased in association with reduced muscularization of peripheral pulmonary arteries. To determine whether inhibition of elastolytic activity might prevent this vascular change in other conditions producing pulmonary hypertension, we administered SC-39026 to rats during a 10-day exposure to chronic hypobaric hypoxia. We also measured elastolytic activity in the central pulmonary arteries of rats using [3H]elastin substrate and determined whether there was an increase in activity either as early as 2 days or at completion of the hypoxic exposure, which could be inhibited by SC-39026. to further determine whether the mechanism of muscularization of peripheral arteries is modulated by degradation of elastin or other elastase-susceptible extracellular matrix proteins, we assessed desmosine excretion and ultrastructural alterations in elastin as well as in type IV collagen, fibronectin, and laminin. SC-39026 reduced the number of muscularized arteries and the level of pulmonary arterial pressure during exposure to chronic hypoxia. Elastolytic activity was fourfold higher in central pulmonary arteries 2 days after hypoxia when compared with values in control vessels, and the activity was inhibited by SC-39026. In small peripheral pulmonary arteries there were no significant changes with hypoxia reflected in desmosines or in the immunocytochemistry of elastase-susceptible glycoproteins, with the exception of decreased laminin. This feature was not inhibited by SC-39026. To further assess whether the protective effect of SC-39026 was related to its inhibition of elastase, an extended study was carried out using a different elastase inhibitor, alpha 1-proteinase inhibitor. An even greater reduction in hypoxia-induced pulmonary hypertension and vascular changes was observed with this elastase inhibitor and the latter included medial hypertrophy.