Showing papers in "American Journal of Physiology-heart and Circulatory Physiology in 1997"

Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity.

Abstract: Although sympathetic activation is believed to promote atrial fibrillation (AF), the effects of sympathetic stimulation on AF have not been systematically studied. In seven morphine-chloralose-anesthetized dogs, autonomic decentralization increased atrial effective refractory period (ERP) and reentrant wavelength (WL) and decreased the duration of AF induced by burst atrial pacing. Graded bilateral stellate ansa stimulation decreased ERP and WL to values similar to those before decentralization but did not return AF duration to predecentralization values. Sympathetic and bilateral vagal stimulation were adjusted in six additional dogs to produce similar effects on ERP and WL. Despite comparable effects on mean WL, the duration of AF was increased by vagal stimulation from 14 +/- 5 (control) to 372 +/- 96 s (P < 0.001) but was not altered significantly (26 +/- 10 s) by sympathetic stimulation. Vagal stimulation increased the variability in atrial refractoriness, as indicated by the standard deviation of ERP at seven atrial sites and of activation frequency during AF at 112 recording sites, whereas sympathetic stimulation had no significant effect on these indexes of ERP heterogeneity. We conclude that sympathetic stimulation is much less effective than vagal stimulation in promoting AF and that heterogeneity in atrial ERP may be important in determining the ability to sustain AF.

Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat.

Abstract: The transition from compensated hypertrophy to failure in spontaneously hypertensive rats (SHR) of advanced age is associated with a marked increase in collagen, a reduction in myocyte mass, and a reduction in maximum Ca(2+)-activated myofibrillar force. We hypothesized that the reduction in myocyte mass and associated functional loss may be due to increased cell death by apoptosis. To test this hypothesis, we studied hearts from failing (SHR-F) and nonfailing SHR (SHR-NF) and age-matched Wistar-Kyoto rats (WKY). In addition, hearts from SHR-F that had been treated with an angiotensin-converting enzyme inhibitor (captopril) for an average of 27 days were also studied. Apoptotic cells were quantified in cross sections of myocardium by the terminal deoxynucleotidyltransferase- mediated 2'-deoxyuridine 5'-triphosphate nick end labeling technique. To identify the type of the cells undergoing apoptosis, sections were also stained for alpha-sarcomeric actin. Apoptotic cells were significantly increased in the SHR-F (38.92 +/- 12.79 vs. 8.05 +/- 3.98 cells/100,000 nuclei in SHR-NF; P < 0.05 and vs. 2.21 +/- 1.4 cells/100,000 nuclei in WKY; P < 0.01). Captopril treatment of SHR-F reduced the number of apoptotic cells to the level in SHR-NF (9.17 +/- 1.53 cells/100,000 nuclei; P < 0.01 vs. SHR-F). Most apoptotic cells were of cardiac myocyte origin. There was no significant difference in Bcl-2 protein expressed by hearts among the three groups. WAF-1 mRNA levels were increased in both SHR groups vs. WKY; in SHR-F, the density of WAF-1 mRNA was higher than in SHR-NF. Thus increased numbers of apoptotic cells are present in failing SHR hearts, suggesting that apoptosis might be a mechanism involved in the reduction of myocyte mass that accompanies the transition from stable compensation to heart failure in this model. Administration of the angiotensin-converting enzyme inhibitor captopril, which ameliorates heart failure in this model, is associated with a reduction in the exaggerated apoptosis that accompanies heart failure.

Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts

Abstract: Cardiomyocyte DNA synthesis was examined in normal and injured adult mouse hearts In preliminary studied DNA synthesis was monitored by [3H]thymidine incorporation, followed by autoradiographic analysis of dispersed cell preparations No synthetic cells were identified when 20,000 ventricular cardiomyocytes from normal adult hearts were examined A high throughput assay was developed to establish the actual labeling index for the adult mouse heart The assay utilized [3H]thymidine incorporation in transgenic mice which expressed a nuclear-localized beta-galactosidase (beta-Gal) reporter gene exclusively in cardiac myocytes Cardiomyocyte DNA synthesis was evidenced by colocalization of beta-Gal activity and silver grains in autoradiograms of histological sections Examination of 180,000 ventricular cardiomyocyte nuclei from normal adult transgenic mice identified a single synthetic nucleus, suggesting a maximum labeling index of 00005% Cardiomyocyte DNA synthesis was next examined in hearts injured by focal cauterization of the left ventricular free wall Only three synthetic nuclei were identified when 36,000 cardiomyocyte nuclei in the perinecrotic zone of the injured heart were examined No additional synthetic nuclei were identified when 180,000 nuclei in regions distal to the necrotic zone were examined These data confirm that cardiomyocyte DNA synthesis in the adult mouse heart is extremely rare and provide baseline data for analyses in genetically modified animals

Laminar structure of the heart: a mathematical model

Abstract: A mathematical description of cardiac anatomy is presented for use with finite element models of the electrical activation and mechanical function of the heart. The geometry of the heart is given in terms of prolate spheroidal coordinates defined at the nodes of a finite element mesh and interpolated within elements by a combination of linear Lagrange and cubic Hermite basis functions. Cardiac microstructure is assumed to have three axes of symmetry: one aligned with the muscle fiber orientation (the fiber axis); a second set orthogonal to the fiber direction and lying in the newly identified myocardial sheet plane (the sheet axis); and a third set orthogonal to the first two, in the sheet-normal direction. The geometry, fiber-axis direction, and sheet-axis direction of a dog heart are fitted with parameters defined at the nodes of the finite element mesh. The fiber and sheet orientation parameters are defined with respect to the ventricular geometry such that 1) they can be applied to any heart of known dimensions, and 2) they can be used for the same heart at various states of deformation, as is needed, for example, in continuum models of ventricular contraction.

Four weeks of cycle training increases basal production of nitric oxide from the forearm.

Abstract: The purpose of this study was to determine whether nontrained vascular beds might contribute to the beneficial effects of exercise, including reduced blood pressure by enhanced nitric oxide production. Thirteen healthy, sedentary male volunteers performed 4 wk of normal sedentary activity and 4 wk of cycle training in a randomized order. At the end of each intervention, venous occlusion plethysmography was used to study the forearm blood flow responses to intra-arterial infusions of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA), acetylcholine, and sodium nitroprusside. Training increased the maximal work-load and maximal oxygen consumption, whereas intrabrachial blood pressure was reduced. L-NMMA caused a greater vasoconstriction after training (P = 0.004). Net nitrate and nitrite consumption by the forearm was less after training both before and after administration of L-NMMA (P = 0.04), consistent with increased nitrate and nitrite production from nitric oxide metabolism. There was no difference in the response to acetylcholine or sodium nitroprusside between the two states. Preliminary studies showed an increase in forearm blood flow and blood viscosity after cycling, suggesting that elevated shear stress in this vascular bed may contribute to endothelial adaptation and the cardiovascular protective effects of exercise training.

Angiogenesis but not collateral growth is associated with ischemia after femoral artery occlusion

Abstract: It remains unclear whether capillary sprouting (angiogenesis) and in situ growth of muscular collateral arteries share the same or different molecular mechanisms. To study the role of ischemia in these two forms of vascular proliferation, we measured tissue flows and maximum collateral conductances in hindlimbs of 22 rabbits previously subjected to either acute, 7-day, 21-day, or no femoral artery occlusion. After 1 wk of femoral artery occlusion, corkscrew collaterals were observed radiographically in the thigh. These collaterals showed histochemical evidence for active proliferation of endothelial and smooth muscle cells. Maximum collateral conductance increased sixfold in the 1st wk. Perfusion deficits, however, were only observed in the distal adductor muscles (region of collateral reentry). In the lower leg, which suffered from a profound perfusion deficit, conductance increased in the absence of any visible collateral arteries but with evidence for capillary proliferation. This study therefore demonstrates that upon femoral artery occlusion angiogenesis occurs in regions of profound ischemia, whereas no direct correlation can be drawn between ischemia and collateral artery development.

Arterial compliance increases after moderate-intensity cycling

Abstract: Exercise training elevates arterial compliance at rest, but the effects of acute exercise in this regard are unknown. This study investigated the effects of a single, 30-min bout of cycling exercis...

Sleep and circadian influences on cardiac autonomic nervous system activity

Abstract: To assess the separate contributions of the sleep and circadian systems to changes in cardiac autonomic nervous system (ANS) activity, 12 supine subjects participated in two 26-h constant routines, which were counterbalanced and separated by 1 wk. One routine did not permit sleep, whereas the second allowed the subjects to sleep during their normal sleep phase. Parasympathetic nervous system activity was assessed with respiratory sinus arrhythmia as measured from the spectral analysis of cardiac beat-to-beat intervals. Sympathetic nervous system activity was primarily assessed with the preejection period as estimated from impedance cardiography, although the 0.1-Hz peak from the spectral analysis of cardiac beat-to-beat intervals, the amplitude of the T wave in the electrocardiogram, and heart rate were also measured. Respiratory sinus arrhythymia showed a 24-h rhythm independent of sleep, whereas preejection period only showed a 24-h rhythm if sleep occurred. Thus the findings indicate that parasympathetic nervous system activity is mostly influenced by the circadian system, whereas sympathetic nervous system activity is mostly influenced by the sleep system.

Formation of nitric oxide, superoxide, and peroxynitrite in myocardial ischemia-reperfusion injury in rats

Abstract: In the present study, the contribution of nitric oxide (NO), superoxide, and peroxynitrite to the inflammatory response induced by myocardial ischemia-reperfusion (MI/R) was investigated. Male Sprague-Dawley rats were anesthetized, and the left main coronary artery was ligated for 20 min and reperfused for 5 h. MI/R induced severe arrhythmias, indicated by a significantly elevated arrhythmia score in the MI/R group compared with that in the sham control group. Creatine kinase activity in the left ventricular free wall of the MI/R group was significantly reduced by 38%. In contrast, myeloperoxidase activity in the left ventricular free wall of the MI/R group was increased by 140%. Similarly, superoxide and tissue NO levels in the ischemic region of the heurt were increased by 140 and 90%, respectively. Superoxide and NO values in the nonischemic regions were similar to the sham control group. Total NO synthase (NOS) activity was elevated by 212%; moreover, inducible NOS (iNOS) activity increased 6.7-fold in the ischemic vs. nonischemic regions. MI/R also induced both systemic and remote organ (lung) inflammatory responses. Circulating neutrophils and plasma NO levels were increased by 163 and 138%, respectively, in MI/R rats compared with sham control animals. NO levels and superoxide generation were increased by 90 and 176%, respectively, in the lung tissues. The expression of iNOS and peroxynitrite generation were demonstrated by immunohistochemical staining with polyclonal anti-iNOS and monoclonal anti-nitrotyrosine antibodies, respectively. Sections of both the ischemic area of the ventricular wall and the lung tissue of MI/R animals exhibited a marked immunoreactivity with anti-iNOS and anti-nitrotyrosine antibodies, indicating the presence of iNOS and nitrotyrosine. Our data indicate that NO, superoxide, and peroxynitrite formation are elevated after reperfusion of the ischemic heart, suggesting that these inflammatory mediators may be involved in MI/R injury.

Intracellular calcium-release channels: regulators of cell life and death.

Abstract: Intracellular Ca2+-release channels on the sarcoplasmic reticulum of striated muscle [ryanodine receptors (RyRs)] and on the endoplasmic reticulum of almost all types of cells [inositol 1,4,5-trisphosphate receptors (IP3Rs)] comprise a unique family of molecules that are structurally and functionally distinct from all other known ion channels. These channels play crucial roles in Ca2+-mediated signaling that triggers excitation-contraction coupling, T-lymphocyte activation, fertilization, and many other cellular functions. Three forms of RyR have been identified: RyR1, expressed predominantly in skeletal muscle; RyR2, expressed predominantly in cardiac muscle; and RyR3, expressed in specialized muscles and nonmuscle tissues including the brain. RyR channels are tetramers composed of four subunits each with a molecular mass of approximately 560,000 Da. The tetrameric structures of RyR1 and RyR2 are stabilized by a channel-associated protein known as the FK506 binding protein (FKBP). FKBP is the cytosolic receptor for the immunosuppressant drugs FK506 and rapamycin that inhibit the prolyl isomerase activity of FKBP and can dissociate FKBP from RyRs. Rapamycin and FK506 increase the sensitivity of RyRs to agonists such as caffeine and could be a cause of cardiac dysfunction associated with high-dose immunosuppressant therapy by promoting leakage of Ca2+ from the sarcoplasmic reticulum. The role of prolyl isomerase activity of FKBP in regulating RyR function remains uncertain, and several models have been proposed that could explain how the channel is modulated by its association with FKBP. Three forms of IP3Rs (types 1, 2 and 3) have been characterized by cDNA cloning. Most cells have at least one form of IP3R, and many express all three types. Like RyRs, the IP3R channels are tetramers composed of four subunits (approximately 300,000 Da each). IP3R1 function is regulated by at least two major cellular signaling pathways: the second messenger IP3 activates the channel, and phosphorylation by nonreceptor protein tyrosine kinases (e.g., Fyn) increase its open probability. During end-stage human heart failure, RyR2 mRNA and protein are downregulated, whereas IP3R1 is upregulated, suggesting that altered Ca2+-release channel levels may contribute to defects in Ca2+ homeostasis. Cells that are deficient in IP3R1 exhibit defective T cell-receptor signaling and thus cannot be activated by T cell-receptor stimulation. IP3R1-deficient cells are also resistant to induced apoptosis. Thus RyRs and IP3Rs play critical roles in fundamental and diverse signaling phenomena that include excitation-contraction coupling, T-cell activation, and programmed cell death.

Myocardial ischemia decreases oxidative phosphorylation through cytochrome oxidase in subsarcolemmal mitochondria

Abstract: The effect of myocardial ischemia on mitochondrial oxidative phosphorylation was investigated using isolated, buffer-perfused rabbit hearts. After 45 min of global ischemia, oxidative phosphorylation was decreased only in the subsarcolemmal population of mitochondria with all substrates tested. The oxidation of N,N,N',N' tetramethyl p-phenylenediamine-ascorbate, an electron donor to cytochrome oxidase via cytochrome c, was decreased in subsarcolemmal mitochondria [ischemia (n = 6): 76 +/- 3 vs. control (n = 5): 105 +/- 6 nanoatoms O.min-1.mg-1, P < 0.01] but not in interfibrillar mitochondria. Only minor morphological changes were observed by electron microscopy in the isolated mitochondria after ischemia. Neither cytochrome oxidase activity measured under conditions for maximal activity nor the apparent Michaelis constant and maximum velocity values of the two cytochrome c binding sites were different in subsarcolemmal mitochondria isolated from ischemic and control hearts. The cytochrome c content was decreased in subsarcolemmal mitochondria after ischemia (ischemia: 0.111 +/- 0.013 vs. control: 0.156 +/- 0.007 nmol/mg protein, P < 0.05). Thus ischemia decreased the rate of oxidative phosphorylation through cytochrome oxidase selectively in intact subsarcolemmal mitochondria. Ischemic damage to the terminal segment of the electron transport chain involves a decrease in the content of cytochrome c, whereas the expressible catalytic activity of cytochrome oxidase remains unchanged.

Angiotensin II formation from ACE and chymase in human and animal hearts: methods and species considerations.

Abstract: The current study examined the contributions of angiotensin-converting enzyme (ACE) vs. chymase to angiotensin II (ANG II) generation in membrane preparations from left ventricles of humans, dogs, ...

Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride

Abstract: Cisapride, a gastrointestinal prokinetic agent, is known to cause long Q-T syndrome and ventricular arrhythmias. The cellular mechanism is not known. The humanether-a-go-go-related gene (HERG), whi...

Effects of [Ca2+]i, SR Ca2+ load, and rest on Ca2+ spark frequency in ventricular myocytes

Abstract: In heart, spontaneous local increases in cytosolic Ca2+ concentration ([Ca2+]i) called "Ca2+ sparks" may be fundamental events underlying both excitation-contraction coupling and resting Ca2+ leak from the sarcoplasmic reticulum (SR). In this study, resting Ca2+ sparks were analyzed in rabbit and rat ventricular myocytes with laser scanning confocal microscopy and the fluorescent Ca2+ indicator fluo 3. During the first 20 s of rest after regular electrical stimulation, both the frequency of Ca2+ sparks and SR Ca2+ content gradually decreased in rabbit. When rabbit SR Ca2+ content was decreased by reduction of stimulation rate. the initial resting spark frequency was also decreased, even though resting [Ca2+]i was unchanged. The rest-dependent decrease in spark frequency in rabbit cells was prevented by inhibition of Na+/Ca2+ exchange (which also prevents SR Ca2+ depletion during rest). These results suggest that elevation of SR Ca2+ content can increase Ca2+ spark frequency. In contrast to rabbit cells, 20 s of rest produced a gradual increase in spark frequency in rat cells, although SR Ca2+ content was constant and Ca2+ influx was completely prevented. This indicates that there is a time-dependent increase in spark probability during rest that is independent of [Ca2+]i or SR Ca2+. This effect was also apparent in rabbit cells when SR Ca2+ depletion was prevented by blocking Na+/Ca2+ exchange. Stimulation of Ca2+ extrusion via Na+/Ca2+ exchange in the rat (by Ca2+-free superfusion, which slowly depletes SR Ca2+ content) converted the normal rest-dependent increase in spark frequency to a decrease. The amplitude of individual Ca2+ sparks increased with increasing SR Ca2+ content. In the Ca2+-overloaded state, fusion of sparks or long-lasting localized increases of [Ca2+]i were observed with increased spark frequency. We conclude that the resting frequency of Ca2+ sparks can be independently affected by changes in SR Ca2+ content, [Ca2+]i, or rest period. The latter may reflect recovery of the SR Ca2+ release channels from inactivation or adaptation.

Nitric oxide-mediated vasodilation in human pregnancy

Abstract: The maternal circulation vasodilates during pregnancy. We investigated the contribution of nitric oxide to this vasodilatation. Using venous occlusion plethysmography, we measured the effect of nitric oxide synthase inhibition on hand blood flow during human pregnancy. We compared the response to a brachial artery infusion of the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) with the response to norepinephrine in three groups of women: nonpregnant, early pregnant (9-15 wk), and late pregnant (36-41 wk). Basal hand blood flow increased significantly during late pregnancy compared with nonpregnant and early pregnant subjects (P = 0.007). L-NMMA produced a greater reduction in hand blood flow in both pregnant groups compared with nonpregnant controls (P = 0.0003). Norepinephrine produced an attenuated response in late pregnancy compared with nonpregnant and early pregnant women (P = 0.0029). If other vascular beds respond in the same way as the hand, the gestational increase in vasoconstrictor response to L-NMMA that we observed implicates increased generation of nitric oxide in the fall of peripheral vascular resistance during healthy human pregnancy.

Diabetes rapidly induces contractile dysfunctions in isolated ventricular myocytes.

Abstract: To determine whether diabetes-induced cardiac dysfunction is due to contractile dysfunction at the single-cell level, mechanical properties and Ca2+ transients were evaluated in ventricular myocyte...

Organ-specific endothelial cell uptake of cationic liposome-DNA complexes in mice

Abstract: This study identified the organ and cellular distribution of cationic liposome-DNA complexes injected intravenously into CD-1 mice for gene delivery. DOTIM-cholesterol liposomes were labeled with the fluorescent dye CM-Dil and complexed with plasmid DNA encoding the chloramphenicol acetyltransferase reporter gene. The distribution of the complexes was examined in 29 organs and tissues by fluorescence, confocal, and electron microscopy from 5 min to 24 h after injection. The complexes formed clusters in blood, which were cleared within 20 min. Complexes visible by fluorescence microscopy were taken up by endothelial cells, leukocytes, and macrophages and did not leave the vasculature except in the spleen. At 5 min, the complexes formed a patchy coating on the endothelial surface, but by 4 h, they were internalized into endosomes and lysosomes in organ- and vessel-specific patterns. Uptake by capillary endothelial cells was greatest in the lung, ovary, and anterior pituitary, less in muscle and the heart, and nearly absent in the brain and pancreatic islets. In lymph nodes and intestinal Peyer's patches, the uptake was sparse in capillaries but abundant in high endothelial venules. In the liver and spleen, most of the uptake was in Kupffer cells and macrophages. Measurements of chloramphenicol acetyltransferase reporter gene expression were generally consistent with the pattern of uptake by endothelial cells. The uptake and gene expression were accompanied by a decrease in circulating leukocytes and platelets. Overall, our results showed that the complexes were internalized by endothelial cells in organ- and vessel-specific patterns that did not match any previously identified properties of the microvasculature. The unusual distribution of endothelial cell uptake may be explained by a heterogeneously distributed membrane receptor for which the complexes are ligands.

Limb ischemia preconditions the heart against reperfusion tachyarrhythmia

Abstract: We investigated the hypothesis that a cardioprotective, antiarrhythmic effect might be obtained by brief ischemia of a remote part of the body before ischemia of the heart. Regional ischemia (RI) w...

Cardiovascular indexes in the mouse at rest and with exercise: new tools to study models of cardiac disease

Abstract: Manipulations of the murine genome that alter cardiovascular function have created the need for methods to study cardiovascular physiology in genetically altered animals in vivo. We adapted chronic physiological measurement techniques to the nonanesthetized, nonrestrained murine model, established strain-specific cardiovascular and metabolic norms, and evaluated responses to anesthesia, exercise, and adrenergic stimulation. Anesthesia resulted in alterations in heart rate (HR), blood pressure (BP), and O2 consumption (V(O2)) and CO2 production (V(CO2)) for up to 6 h postoperatively. There were significant interstrain differences in resting values of HR and BP Graded treadmill exercise resulted in linear increases in HR, V(O2), V(CO2), and respiratory exchange ratio (RER) similar to those seen in larger species. Response to beta-adrenergic stimulation showed a classic sigmoidal dose-response curve; however, there was very little tachycardiac response to vagal blockade, indicating low resting vagal tone. This study demonstrates the feasibility of performing chronic cardiovascular measurements in nonanesthetized mice and stresses the importance of allowing for anesthetic recovery and strain variability. Murine cardiovascular responses to exercise can be reliably measured and are qualitatively similar to those in humans.

Low-intensity exercise training decreases cardiac output and hypertension in spontaneously hypertensive rats

Abstract: The decrease in cardiac sympathetic tone and heart rate after low-intensity exercise training may have hemodynamic consequences in spontaneously hypertensive rats (SHR). The effects of exercise tra...

1,25-Dihydroxyvitamin D3 regulation of cardiac myocyte proliferation and hypertrophy

Abstract: We previously demonstrated that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits myocyte maturation (T D O'Connell, D A Giacherio, A K Jarvis, and R U Simpson Endocrinology 136: 482-488, 19

Induction of nitric oxide synthase mRNA in coronary resistance arteries isolated from exercise-trained pigs

Abstract: The purpose of this study was to develop a method by which endothelial cell nitric oxide synthase (ecNOS) mRNA expression could be measured in single coronary resistance arteries and to test the hy...

Cardiac inotropic actions of urocortin in conscious sheep.

Abstract: Urocortin (Ucn) is a recently isolated peptide related to the corticotropin-releasing factor (CRF) family, which can produce hemodynamic and hormonal actions in conscious rats. This study examined in detail the cardiovascular actions of Ucn and CRF after intravenous injection in chronically instrumented, conscious sheep. Injection of Ucn produced dose-dependent changes in cardiac contractility [rate of increase of aortic flow (dF/dt)], maximum aortic flow (Fmax), mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and coronary blood flow (CF). Ucn injected at 100 micrograms produced a potent increase in dF/dt, from 909 +/- 44 to a maximum of 1,849 +/- 901.min-1.s-1, and in Fmax, from 25.5 +/- 0.8 to 36.6 +/- 1.4 l/min. Cardiac contractility increased within 30 min of injection and remained significantly elevated for up to 24 h. MAP increased from 78 +/- 2 to 90 +/- 3 mmHg, and HR increased from 73 +/- 4 to 103 +/- 9 beats/min. CO rose from 5.0 +/- 0.1 to 5.8 +/- 0.2 l/min, whereas central venous pressure, total peripheral conductance, and stroke volume were unchanged. All Ucn-induced cardiovascular effects were inhibited by prior treatment with the CRF antagonist alpha-helical CRF-(9-41). Equimolar doses of CRF produced little change in any hemodynamic parameter. Both peptides increased plasma levels of adrenocorticotropin and cortisol, with Ucn having a more potent effect than CRF. We have shown for the first time that Ucn can produce potent and long-lasting actions to elevate cardiac contractility in conscious animals.

Regional differences in the role of the Ca2+ and Na+ currents in pacemaker activity in the sinoatrial node.

Abstract: The effect of block of the L-type Ca2+ current by 2 microM nifedipine and of the Na+ current by 20 microM tetrodotoxin on the center (normally the leading pacemaker site) and periphery (latent pace...

Cytoskeletal rearrangement mediates human microvascular endothelial tight junction modulation by cytokines

Abstract: The tight junction (TJ) is a specialized intercellular structure responsible for the regulation of ionic and macromolecular flux across cell monolayers. Because plasma leakage is believed to occur mainly across the microvasculature, we hypothesized that microvascular endothelial cells (MVEC) may form more intact, regulatable TJ than other endothelial cell (EC) types, allowing further insight into the control of EC permeability. Primary cultures of MVEC monolayers produced transmonolayer electrical resistances (TER) of 120-155 omega.cm2, approximately 10 times that of large-vessel EC. Treatment with tumor necrosis factor and interferon-gamma caused a 50% decrease in the TER and a striking fragmentation of the basal, continuous interendothelial cell zonula occludens-1 protein (ZO-1) distribution determined by immunofluorescence. Fragmentation was inhibited by cytochalasin D, and confocal microscopy demonstrated a colocalization between F actin and ZO-1. These findings suggest that the F actin cytoskeleton plays a central role in endothelial TJ barrier regulation and that dynamic cytoskeletal alterations may primarily control vascular permeability.

Endothelial vasodilator production by uterine and systemic arteries. II. Pregnancy effects on NO synthase expression

Abstract: Pregnancy is characterized by elevations in uterine but not omental artery nitric oxide synthase (NOS)-specific activity. We hypothesized that increases in NO production during pregnancy are associ...

Arterial expansive remodeling induced by high flow rates

Abstract: The effects of chronic increase in aortic blood flow on arterial wall remodeling were investigated in vivo with the use of an aortocaval fistula (ACF) model in rats. Phasic hemodynamics and aortic ...

Estrogen relaxation of coronary artery smooth muscle is mediated by nitric oxide and cGMP

Abstract: Estrogens are proposed to exert protection against cardiovascular disease, and evidence now suggests that this protection involves a direct vasodilatory effect. We have shown previously that estrog...

Hypercholesterolemia is associated with enhanced angiotensin AT1-receptor expression.

Abstract: Low-density lipoprotein increases the AT1-receptor gene expression in vascular smooth muscle cells. To elucidate whether elevated cholesterol serum levels upregulate the AT1 receptor and its functional response to angiotensin II in vivo, we compared 1) the vasoconstrictive effect of angiotensin II and 2) the level of expression of the vascular AT1 receptor in aortas of normocholesterolemic and hypercholesterolemic rabbits. Contraction experiments on isolated aortic rings showed that the angiotensin II-induced vasoconstriction was increased in hypercholesterolemic New Zealand White rabbits compared with normocholesterolemic New Zealand White rabbits. This difference in the angiotensin II-induced vasoconstriction was caused by a twofold increase in the density of cell surface AT1 receptors in hypercholesterolemic rabbits, as assessed by radioligand binding assays. The enhanced expression of AT1 receptors on the surface of these vascular cells was caused by elevated steady-state levels of the AT1-receptor mRNA to 220 +/- 35% in aortas excised from hypercholesterolemic rabbits compared with levels in aortas from normocholesterolemic rabbits, as measured by Northern blot analysis. These data indicate that hypercholesterolemia is associated with upregulation of expression and function of vascular AT1 receptors in vivo. This suggests a novel mechanism by which hypercholesterolemia could be involved in the onset and progression of chronic vascular diseases such as hypertension and arteriosclerosis if the phenomenon is confirmed in humans.

Microvascular blood flow resistance: role of endothelial surface layer

Abstract: Observations of blood flow in microvascular networks have shown that the resistance to blood flow is about twice that expected from studies using narrow glass tubes. The goal of the present study w...