bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural and hormonal control of blood pressure in conscious monkeys
Authors: Cornish K. G. , Barazanji M. W. , Iaffaldano R.
Published: December 2017

The contribution of the autonomic nervous system, angiotensin II (ANG II), and arginine vasopressin (AVP) to the control of blood pressure (BP) was examined in 12 chronically instrumented tethered monkeys. The vasopressin antagonist, [d(CH2)5AVP] (Manning Compound, MC), the ANG II antagonist, saralasin (SAR), and the ganglionic blocking drug, hexamethonium (Hx), were injected in a random sequence into the left atrium (LA) while BP and heart rate (HR) were monitored. When given as the first antagonist, MC caused a slight decrease in BP; SAR did not significantly decrease BP regardless of the sequence of administration, whereas Hx caused a consistent decrease in blood pressure of 35–50 mmHg. Seven (4 intact and 3 with renal denervation) additional animals were involved in hemorrhage experiments. Blood pressure was reduced to 50–60 mmHg by hemorrhage and then allowed to return spontaneously. Ten to 15 min after the end of the hemorrhage, MC was given. When blood pressure had stabilized, SAR was given. Blood pressure returned to 80–90 mmHg after the hemorrhage. MC did not affect the blood pressure recovery; however, saralasin reduced it to the post-hemorrhage levels. We would conclude that the sympathetic nervous system is the primary controlling mechanism for BP in the conscious primate, with AVP making a minor contribution. The release of renin would appear to be primarily under the control of the sympathetic nervous system.
Protection by benzamil against dysfunction and damage in rat myocardium after calcium depletion and repletion
Authors: Pierce G. N. , Maddaford T. G. , Kroeger E. A. , Cragoe E. J.
Published: December 2017

Perfusion of the rat right ventricular wall muscle for 4 min with a Ca2(+)-free medium followed by perfusion with a Ca2(+)-containing solution resulted in a 42% recovery of developed tension, contracture, and a massive release of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) from the muscle. High concentrations (1–5 mM) of amiloride partially protected the ventricular wall from Ca2+ paradox-induced dysfunction. The inclusion of benzamil, an amiloride analogue, 2 min before and during the Ca2(+)-free perfusion period prevented contracture development, restored force development, and almost totally eliminated the release of CPK and LDH from the muscle. Contractile function was best protected by 10–50 microM benzamil. The results demonstrate the efficacy of benzamil as a protective agent against Ca2+ paradox-induced myocardial dysfunction and damage. In view of the known capacity of benzamil to block transsarcolemmal Na(+)-Ca2+ exchange, this study supports the involvement of elevated intracellular Na+ and a stimulation of Na(+)-Ca2+ exchange in this model of cardiac pathology.
Preload does not affect relaxation rate in normal, hypoxic, or hypertrophic myocardium
Authors: Zile M. R. , Conrad C. H. , Gaasch W. H. , Robinson K. G. , Bing O. H.
Published: December 2017

To determine whether isolated changes in preload (end-diastolic force) can influence myocardial relaxation rate in normal or abnormal (hypoxic or hypertrophic) hearts, isolated LV papillary muscles from normal Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were studied using physiologically sequenced contractions. While total (systolic) load and late (lengthening) load were held constant, maximum isometric force decline (peak -dT/dt) and maximum isotonic lengthening rate (peak +dL/dt) were measured at seven levels of preload that varied from 115 to 55% of the resting tension at maximum length-tension curves (Lmax). Muscles from normal rats were studied in the oxygenated state (95% O2-5% CO2) and in the hypoxic state (95% N2-5% CO2). Preload did not effect peak -dT/dt or peak +dL/dt in either oxygenated or hypoxic muscles. During hypoxia, peak -dT/dt and peak +dL/dt were 9.5 +/- 1.0 g.mm-2.s-1 and 0.3 +/- 0.1 muscle length/s, respectively, at a preload of 115% compared with 9.0 +/- 1.2 g.mm-2.s-1 and 0.2 +/- 0.1 at a preload of 55%. In separate experiments, the effect of preload on relaxation rate was studied in WKY and SHR rats. In neither group did preload have an independent effect on relaxation rate. In the SHRs, peak -dT/dt and peak +dL/dt were 24.3 +/- 5.3 g.mm-2.s-1 and 0.7 +/- 0.1 muscle length/s, respectively, at a preload of 115% compared with 24.7 +/- 6.6 and 0.8 +/- 0.1 at a preload of 55%. Thus, in hypoxic and hypertrophic myocardium, as in normal muscle, an acute isolated change in preload did not influence the rate of force decline or muscle lengthening.
Mechanisms leading to adenosine-stimulated proliferation of microvascular endothelial cells
Authors: Meininger C. J. , Granger H. J.
Published: December 2017

This study investigated the mechanisms by which adenosine stimulates proliferation of microvascular endothelial cells. The metabolic byproducts of adenosine, inosine and hypoxanthine were unable to stimulate proliferation. When adenosine uptake was prevented, the stimulation of proliferation was unchanged, suggesting that uptake of adenosine with subsequent incorporation into the nucleotide pool is not the mechanism for increasing proliferation. Treatment of endothelial cells with adenosine analogues, presumably selective for either the A1 or A2 receptor, stimulated proliferation equally. This suggested that adenosine 3', 5'-cyclic monophosphate (cAMP) might not mediate the proliferative response to adenosine. However, radioimmunoassay of cell extracts after treatment with either analogue showed an increase in cAMP. In addition, adenylate cyclase blockade with 2', 5'-dideoxyadenosine prevented the proliferative response brought about by these analogues. These data suggest that the proliferative response to adenosine depends on an increase in cAMP. A 2-h pulse of cholera toxin stimulated endothelial cell proliferation, further supporting a role for cAMP. Pretreatment of endothelial cells with pertussis toxin blocked the stimulation of proliferation, indicating that a Gi or similar G protein is also involved in proliferation. We conclude that the proliferative response to adenosine involves a pertussis toxin-sensitive substrate as well as an increase in cAMP.
Role of extracellular calcium on heart muscle energetics: effects of verapamil
Authors: Ponce-Hornos J. E. , Musi E. A. , Bonazzola P.
Published: December 2017

The mechanical and energetic effects of verapamil (VER) and reduction of extracellular Ca concentration ([Ca]o) were studied in the interventricular rabbit septa and the dog papillary muscle. Even though the negative inotropic effects of VER [i.e., decrease in developed tension (T), maximal rates of contraction (+T) and relaxation (-T), and tension time integral] qualitatively resemble [Ca]o reduction, VER also elicited an anti-relaxant effect (decrease in -T/T and prolongation of the last phase of relaxation) that was not found with [Ca]o reduction. Resting heat production was similar in both preparations and remained unaffected either by changes in [Ca]o or by the presence of VER. The ratio between T and active heat production per beat (H'a) under constant fiber length decreased with VER, and this decreased economy of contraction was more marked with the increase in contraction frequency. Conversely, the T/H'a remained unaltered with changes in [Ca]o. Tension-independent heat decreased in the presence of VER and, although muscle economy can be improved by increasing muscle length in a VER-treated muscle, it is not possible to achieve either the maximal T or the maximal contraction economy that can be obtained by stretching a nontreated muscle. It may be concluded that at constant fiber length and frequency of contraction VER decreases myocardial contractile force, impairs relaxation, and decreases contraction economy. Neither the mechanical nor the energetic effects of VER can be explained solely on the basis of a reduced extracellular Ca availability, so that either the density of the Ca that enters through the channel is different from that of other sources of Ca or VER has an effect on the cross-bridge cycling mechanism.
Time course of recovery of arterial pressure control after carotid denervation
Authors: O'Leary D. S. , Scher A. M.
Published: December 2017

We examined the recovery of arterial pressure control after carotid sinus baroreceptor denervation in conscious dogs with atrioventricular block. Strength of control was assessed by measuring changes in peripheral resistance and atrial rate after step changes in cardiac output. One day after carotid denervation, arterial pressure was significantly elevated (+13.7 mmHg), and the strength of control of peripheral resistance and atrial rate were significantly decreased to 46.1 and 36.6% of control, respectively. Over 4–7 days, the strength of control of both peripheral resistance and atrial rate and the mean arterial pressure returned to the levels observed before denervation. After carotid denervation, the pressor response to bilateral carotid artery occlusion was abolished, and thus the recovery of arterial pressure control was not caused by inadequate carotid denervation or regeneration of carotid baroreceptors. The recovery of arterial pressure control after carotid denervation is probably caused by an increase in the reflex responses to pressure changes at the aortic baroreceptors and may reflect plasticity within the baroreflex pathway.
Determination of capillary perfusion pattern in rat brain by timed plasma labeling
Authors: Vetterlein F. , Demmerle B. , Bardosi A. , Gobel U. , Schmidt G.
Published: December 2017

The pattern of capillary perfusion was studied in the brain of anesthetized rats. Two plasma labels were used to demonstrate the density of capillaries perfused during a 10-min period [fluorescein isothiocyanate (FITC) globulin], as well as during a 10-, 3-, or 1-s period [lissamine-rhodamine B 200 (RB200) globulin, infused into the left heart chamber], respectively. A special biopsy cutting-freezing system was used to withdraw brain tissue via a cranial window for histological analysis of dye distribution at the end of the infusion period. Complete labeling of all capillaries was already found after 10 s of dye circulation. However, intra-arterial dye infusion for 3 and 1 s led to reduced filling of capillaries: cortex 86.6 +/- 5.2 and 6.8 +/- 1.8%, hippocampus 95.0 +/- 1.6 and 9.9 +/- 2.1%, and thalamus 97.9 +/- 1.0 and 11.7 +/- 1.8%, respectively. The period of 1 s was found to be the circulation time from left heart chamber to brain capillaries. It can thus be concluded that in the studied brain areas greater than 85% of capillaries are reached by a plasma flow within 2 s and that the remaining small fraction completely fills within 10 s.
Mechanism underlying responses to histamine of isolated monkey and human cerebral arteries
Authors: Toda N.
Published: December 2017

Cerebral artery strips obtained from Japanese monkeys partially contracted with prostaglandin F2 alpha responded to histamine with a relaxation that was attenuated by treatment with cimetidine or chlorpheniramine and was abolished by their combined treatment. Endothelium denudation suppressed the relaxation; the remaining relaxation was not influenced by the H1 antagonism but was abolished by the H2 antagonism. Treatment with methylene blue slowed the development of relaxation and, in the presence of cimetidine, depressed the magnitude of relaxation. Indomethacin did not alter the response. In the main trunk of human middle cerebral arteries obtained during autopsy, histamine predominantly caused contractions, whereas third and fifth branches responded exclusively with a dose-dependent relaxation. The contraction was abolished by chlorpheniramine, and the relaxation was attenuated by either chlorpheniramine or cimetidine. Removal of endothelium suppressed or reversed the relaxation to a contraction. It appears that the histamine-induced relaxation is mediated by endothelial H1 receptors responsible for the release of endothelium-derived relaxing factor and also by H2 receptors in smooth muscle, whereas the contraction is associated with activation of smooth muscle H1 receptors. Involvement of the receptor subtypes in the observed response of monkey and human cerebral arteries quantitatively differs. Physiological and pathophysiological roles of endogenous histamine acting on the large cerebral arteries may be postulated.
Hemodynamic actions of intravenous endothelin in rats: comparison with sodium nitroprusside and methoxamine
Authors: Rohmeiss P. , Photiadis J. , Rohmeiss S. , Unger T.
Published: December 2017

We investigated hemodynamic actions of endothelin (ET) in conscious rats. Intravenous injections of ET produced dose-dependent biphasic blood pressure (MAP) responses: initial decreases of up to 84 +/- 11 s were followed by increases of up to 1-h duration. Corresponding responses in cardiac output (CO), heart rate, and efferent splanchnic nerve activity were reciprocal to changes in MAP. Mesenteric blood flow showed an immediate and sustained decrease. Compared with equidepressor doses of sodium nitroprusside (NNP), ET produced a markedly different regional hemodynamic response pattern during the initial depressor phase. Compared with equipressor doses of the alpha-adrenoceptor agonist methoxamine, ET produced significantly greater vasoconstriction in hindlimb and renal vascular bed during pressor phase. ET-induced changes in CO were significantly greater than the respective CO responses to NNP and methoxamine in intact animals and following cardiac autonomic blockade with atenolol and methscopolamine. ET has vasodilator and vasoconstrictor properties that induce a unique hemodynamic response pattern on intravenous injection. Persistence of ET-induced changes in CO following cardiac autonomic blockade suggests direct cardiostimulatory actions of the peptide during depressor phase as well as direct cardiodepressant actions during pressor phase.
Effect of human recombinant superoxide dismutase on canine myocardial infarction
Authors: Patel B. S. , Jeroudi M. O. , O'Neill P. G. , Roberts R. , Bolli R.
Published: December 2017

To determine whether human recombinant superoxide dismutase (h-SOD) produces sustained reduction of infarct size, anesthetized dogs underwent a 2-h coronary occlusion followed by either 48 or 4 h of reperfusion. In the 48-h study, dogs were randomized to three intravenous treatments: 1) “low-dose” h-SOD (2 mg/kg bolus 2 min before reperfusion followed by 4 mg/kg over 45 min), 2) “high-dose” h-SOD (8 mg/kg bolus 2 min before reperfusion followed by 8 mg/kg over 45 min), or 3) equivalent volumes of saline. In the 4-h study, dogs were randomized to high-dose h-SOD or saline. Occluded bed size was measured by postmortem perfusion and infarct size by triphenyl tetrazolium chloride staining and planimetry. Investigators performing the study and measuring infarct size were blinded to the treatment given. High plasma concentrations of h-SOD were present in the arterial blood of treated dogs in the early phase of reperfusion (greater than 60 and greater than 180 micrograms/ml in low- and high-dose groups, respectively). In both studies, control and treated groups were similar with respect to occluded bed size, collateral blood flow, and rate-pressure product during ischemia. In the 48-h study, infarct size, expressed as percent of occluded bed size, was 41.3 +/- 7.6% (mean +/- SE) in the control group, 37.1 +/- 7.2% in the low-dose h-SOD group, and 48.0 +/- 7.1% in the high-dose h-SOD group. In the 4-h study, infarct size was 30.6 +/- 4.9% in the control group and 31.5 +/- 9.6% in the high-dose h-SOD group. Analysis of the flow-infarct relationships confirmed that h-SOD did not reduce infarct size at any level of collateral flow in either the 48- or 4-h study. Recovery of regional myocardial function after reperfusion was also unaffected by h-SOD in both studies. Thus in this randomized blinded study, large doses of h-SOD given at the time of reperfusion failed to limit infarct size or enhance recovery of function, both early (4 h) and late (48 h) after reperfusion following a 2-h coronary occlusion.
Heterogeneity of myocardial blood flow under normal conditions and its dependence on arterial PO2
Authors: Wolpers H. G. , Hoeft A. , Korb H. , Lichtlen P. R. , Hellige G.
Published: December 2017

We studied the heterogeneity of myocardial blood flow in nine anesthetized closed-chest dogs using an indicator-dilution technique that allows the stochastic description of transport characteristics for three inert gases (helium, argon, and xenon) from the coronary inflow to outflow. The results show that under normal conditions the transcoronary transport of the tracers is spatially heterogeneous. Heterogeneity is strongly dependent on the arterial oxygen tension over a range of 40–200 Torr. This could be similarly observed with each tracer gas despite different physicochemical properties and was largely independent from the magnitude of coronary blood flow. The results are interpreted to mean that the arteriolar or intratissue PO2 influences myocardial blood flow over a broad range and possibly acts as an important integrating factor in the local regulation of coronary blood flow and flow reserve.
Opposite effects of substance P on conductance and resistance coronary vessels in conscious dogs
Authors: Nakamura Y. , Parent R. , Lavallee M.
Published: December 2017

The effects of substance P (SP) on epicardial coronary diameter (CD) and coronary blood flow (CBF) were examined in conscious dogs. SP (5.0 ng/kg) induced transient increases (P less than 0.01) in CBF by 139 +/- 19% from 26.5 +/- 1.5 ml/min followed by sustained decreases (P less than 0.01) averaging 22 +/- 2% when mean arterial pressure had returned to preinjection base line. CD increased (P less than 0.01) by 6.7 +/- 1.4% from 3.47 +/- 0.35 mm. After ganglionic blockade with hexamethonium (35 mg/kg), the transient increases (P less than 0.01) in CBF (95 +/- 10% from 28.6 +/- 1.9 ml/min) were smaller (P less than 0.05), but the late decreases (P less than 0.01) in CBF averaged 23 +/- 3%, similar to responses before ganglionic blockade. Increases (P less than 0.01) in CD (4.1 +/- 0.7% from 3.49 +/- 0.35 mm) were smaller (P less than 0.05) than before ganglionic blockade. During steady-state effects of SP (5.0 ng.kg-1.min-1) under ganglionic blockade, CBF fell (P less than 0.01) by 39 +/- 3% from 26.4 +/- 2.3 ml/min, but CD increased (P less than 0.01) by 6.6 +/- 1.6% from 3.45 +/- 0.40 mm. Additional experiments indicated that coronary sinus blood oxygen content fell and myocardial arteriovenous O2 difference increased during steady-state effects of SP under ganglionic blockade. Cyclooxygenase inhibition did not alter coronary responses to SP. Endothelial denudation abolished increases in CD after SP. Therefore, under steady-state conditions and in the absence of autonomic reflexes, SP is a potent endothelium-dependent dilator of conductance coronary vessels but paradoxically a constrictor of resistance coronary vessels.
Positive pleural pressure decreases coronary perfusion
Authors: Fessler H. E. , Brower R. G. , Wise R. , Permutt S.
Published: December 2017

Pressure surrounding the heart (PSH) rises with maneuvers that increase pleural pressure. This may decrease left ventricular (LV) oxygen demand by reducing LV afterload. However, positive PSH may also directly impede coronary flow. To study the effects of positive PSH on coronary perfusion, PSH was increased in 10-mmHg increments from 0 to 60 mmHg in an isolated canine heart-lung preparation with constant venous return, arterial pressure, and lung volume. Increased PSH caused a rapid significant (P less than 0.001) fall in left atrial transmural pressure (PLATM) of up to 1.28 +/- 0.31 mmHg. With constant venous return and lung volume, this was interpreted to reflect decreased LV afterload. However, at levels of PSH greater than 30 mmHg, initial decreases in PLATM were followed by sustained increases, suggesting that there was a deterioration in cardiac function despite the lower level of afterload. Increased PSH was also associated with decreases in circumflex coronary artery flow [flow (ml/min) = 52.4 - 0.4PSH, P less than 0.01]. Moreover, when the circumflex coronary artery was maximally dilated with adenosine, the effects of PSH were amplified [flow (ml/min) = 137.9 - 1.78PSH, P less than 0.001], indicating that positive PSH mechanically impeded coronary flow. When PSH was raised to 60 mmHg for 90 s, the aortic-coronary sinus lactate concentration difference fell from 0.71 +/- 0.09 to 0.10 +/- 0.21 mM (mean +/- SE, P less than 0.001, n = 8), suggesting myocardial ischemia. We conclude that positive PSH directly decreases myocardial perfusion. This may lead to ischemic cardiac dysfunction, especially in patients with low arterial pressure or coronary artery disease.
Chemotactic peptide FMLP contracts human coronary arteries via cyclooxygenase products
Authors: Bode S. M. , Kuhn M. , Forstermann U.
Published: December 2017

The chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) is a constrictor of bronchial smooth muscle. Recently it has also been shown to contract rabbit coronary arteries by an unknown mechanism. This prompted us to investigate whether the chemotactic peptide has an effect on the tone of human coronary arteries obtained during heart transplantation. FMLP was found to be a potent and efficacious myotropic agent on strips of human coronary artery. Contractions were generally transient and subject to tachyphylaxis. The FMLP-induced vasoconstriction was not dependent on the presence of endothelial cells. The response was unaffected by the histamine H1-antagonist diphenhydramine or the antagonist of peptido-leukotrienes FPL 55712. However, the contractions were completely abolished in the presence of the fatty acid cyclooxygenase inhibitors aspirin or indomethacin. Stimulation of rings of human coronary artery with FMLP resulted in a marked production of prostaglandin (PG)F2 alpha, a smaller production of PGD2, and a slight increase in thromboxane B2. All these prostanoids constricted the artery, but the stable thromboxane mimetic U44069 was 100 times more potent than PGF2 alpha or PGD2. These data indicate that FMLP activates cells of unknown identity in the adventitia or media of human coronary arteries to produce a mixture of vasoconstrictor cyclooxygenase products. These compounds are likely to mediate the myotropic effect of FMLP on this artery. The mechanism may participate in the pathogenesis of some forms of coronary vasospasm.
Platelet activation by polymorphonuclear leukocytes exposed to chemotactic agents
Authors: Del Maschio A. , Evangelista V. , Rajtar G. , Chen Z. M. , Cerletti C. , De Gaetano G.
Published: December 2017

Human platelets were loaded with aequorin, a Ca2(+)-sensitive photoprotein, and tested in the platelet-ionized calcium aggregometer for simultaneous recording of platelet aggregation and intraplatelet Ca2+ levels both in the presence and in the absence of autologous polymorphonuclear leukocytes. Cells were exposed to one of three chemotactic stimuli: platelet-activating factor (PAF), N-formyl-methionyl-leucyl-phenylalanine (FMLP), or leukotriene B4 (LTB4). Platelets alone aggregated and showed intracellular Ca2+ movement only when exposed to PAF. Amplification of both platelet aggregation and intraplatelet Ca2+ movement was induced by PAF in the presence of leukocytes. Aggregation and intraplatelet Ca2+ mobilization were also observed in the presence of leukocytes activated by either FMLP or LTB4. Both parameters increased with the concentration of the stimuli and/or the number of leukocytes. Platelet thromboxane B2 production was also significantly increased in the presence of leukocytes. Addition of platelets at different times after leukocyte activation resulted in progressively reduced cytoplasmic Ca2+ increase. Cell-free supernatants prepared from FMLP-stimulated leukocytes were able to induce platelet aggregation, thromboxane B2 generation, and Ca2+ mobilization, although at a reduced degree as compared with intact leukocyte addition. The activity of leukocyte supernatants was stable at 37 degrees C for up to 30 min and was suppressed by trypsin inhibitor. Our study indicates that stimulated leukocytes release a soluble enzymatic activity able to activate platelets; cell-to-cell interaction may also play a role in this phenomenon. Platelet-leukocyte interaction could have physiopathological relevance and constitutes a new model for studying old and new platelet inhibitory drugs.
Human cardiac sodium channels expressed in Xenopus oocytes
Authors: Tomaselli G. F. , Feldman A. M. , Yellen G. , Marban E.
Published: December 2017

We report the expression of voltage-dependent Na+ channels in Xenopus oocytes injected with total RNA isolated from explanted human hearts. The expressed channels demonstrate characteristic voltage-dependent gating, inhibition by tetrodotoxin, and selectivity for Na+. Oocytes injected with sterile water or intentionally degraded RNA had no similar channel activity. The antiarrhythmic agent lidocaine (20 microM) inhibits current flow through the channel in a voltage-dependent fashion. Na+ channels expressed by injection of human cardiac RNA into Xenopus oocytes qualitatively resemble channels in the native tissue.
Heterogeneities in regional volumes of distribution and flows in rabbit heart
Authors: Gonzalez F. , Bassingthwaighte J. B.
Published: December 2017

The heterogeneity of volumes of distribution in the heart influences the rates of uptake and washout of substrates and metabolites; thus it is important to evaluate their variability in the normal heart. Several tracers were injected intravenously into anesthetized adult closed-chest rabbits, and time was allowed for equilibration in the heart. Tracer microspheres were injected into the left ventricular cavity at the apex for the measurement of regional flows, the chest was opened, another set of microspheres was injected, and the heart was frozen rapidly in situ with liquid nitrogen-cooled Freon-22. Each heart was divided into 72 pieces of less than 0.1 g weight, and the tracer content of each was determined by multichannel gamma-counting and the water content by desiccation. The regional myocardial flows were (closed chest) 0.62 +/- 0.16 ml.g-1.min-1 and (open chest) 0.63 +/- 0.37 ml.g-1.min-1. The volumes of distribution (ml/g) for the 432 pieces for six rabbits, given as mean +/- SD (% coefficient of variation), were as follows: for plasma, VP = 0.11 +/- 0.03 (26%); erythrocytes, VRBC = 0.041 +/- 0.015 (37%); vascular space, VV = 0.15 +/- 0.04 (26%); extracellular space, VECF = 0.33 +/- 0.05 (15%); interstitial space, VISF = 0.21 +/- 0.03 (15%); and water space, VW -0.79 +/- 0.022 (2.8%). Regional hematocrits were 77% +/- 9% of the large-vessel hematocrits.
Cardiac chemical reflex control of preload in conscious dogs
Authors: Nganele D. M. , Hintze T. H.
Published: December 2017

The purpose of our study was to determine the effects of cardiac chemical reflexes on left ventricular (LV) preload in conscious dogs. Adult mongrel dogs were instrumented to measure LV pressure and, with ultrasonic dimension crystals, to measure LV internal diameter. A catheter was inserted in the left circumflex coronary artery for the administration of increasing doses of veratridine, arachidonic acid (AA), and prostacyclin (PGI2). LV end-diastolic diameter (EDD) and end-diastolic pressure (EDP) were used as indexes of preload. Veratridine (0.4 micrograms/kg) reduced EDD 3.0 +/- 0.5% from 36.6 +/- 1.7 mm and EDP 24 +/- 5.0% from 6.1 +/- 0.5 mmHg (P less than 0.05). AA (100 micrograms/kg) reduced EDD by 3.7 +/- 0.5% from 37 +/- 1.1 mm and EDP by 25 +/- 4.4% from 7.0 +/- 0.6 mmHg (P less than 0.05). PGI2 (0.5 micrograms/kg) also reduced EDD by 3.3 +/- 0.5% from 37 +/- 0.5 mm and EDP by 25 +/- 6.0% from 7.8 +/- 0.3 mmHg (P less than 0.05). Although holding heart rate constant by pacing or combined beta-adrenergic and muscarinic receptor blockades did not reduce the preload responses to veratridine, AA, or PGI2, alpha 1-adrenergic blockade or vagotomy abolished them. Systemic arterial barodenervation markedly potentiated the reduction in myocardial size after stimulation of cardiac chemical receptors. Stimulation of inhibitory cardiac receptors, therefore, reduces preload via a vagal reflex by withdrawing peripheral alpha-adrenergic tone to capacitance vessels in the conscious dog.
Microvascular occlusions promote coronary collateral growth
Authors: Chilian W. M. , Mass H. J. , Williams S. E. , Layne S. M. , Smith E. E. , Scheel K. W.
Published: December 2017

The objective of this study was to examine whether myocardial ischemia without alterations in pressure gradients between large epicardial coronary arteries was a sufficient stimulus to produce coronary collateral growth and development. To accomplish this aim, we partially embolized the circumflex coronary perfusion territory with 25-microns diameter microspheres to produce multiple microvascular occlusions, sufficient to abolish or greatly attenuate coronary vasodilator reserve. The embolization procedure was performed in two groups of dogs during aseptic surgery. After the dogs recovered for 1-3 wk (short-term embolization) or 6-8 wk (long-term embolization), indexes of vascular growth were compared with a group of control animals in which all operative procedures were performed, except embolization. Retrograde blood flow, an index of collateral blood flow and coronary vascular resistance, was determined in an isolated beating empty heart preparation during coronary vasodilation with adenosine. Circumflex retrograde blood flow from the left anterior descending artery was increased from 0.09 ml.min-1.g-1 (sham) to 0.21 and 0.17 ml.min-1.g-1 in the short-term and long-term groups, respectively (P less than 0.05). Collateral blood flow from the septal artery was also increased from 0.03 ml.min-1.g-1 (sham) to 0.08 ml.min-1.g-1 (P less than 0.05) in the short-term group. Collateral contribution from the right coronary artery was not significantly altered in either group of embolization animals. The contributions of epicardial and intramyocardial collaterals to the total retrograde flow were also determined and were found to be different among the three experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Regional circulatory responses to intestinal work in developing swine
Authors: Buckley N. M. , Frasier I. D.
Published: December 2017

Circulatory effects of intraduodenal feeding with 2 and 5% glucose were studied in 29 fasted swine (1 day to 1 mo old) anesthetized with pentobarbital. Recordings included aortic and intestinal venous pressures and intestinal, renal, and femoral blood flows. Calculations included vascular resistances, arterial and intestinal venous O2 contents, and intestinal O2 consumption. Observations were made before and at 15 and 30 min after a feeding and at end of experiments. Blood flow autoregulation was evaluated before and after feedings. Glucose induced increases in intestinal O2 consumption and blood flow at all ages, but intestinal blood flow autoregulation was enhanced only in 2 wk olds. Blood flow was redistributed to the working gut from the hindlimb, but not the kidney, at all ages. Renal blood flow autoregulation was sustained in 2-wk-old and 1-mo-old animals and became significant in 1 wk olds during intestinal hyperemia. We concluded that basic mechanisms governing blood flow redistribution from hindlimb to working gut are available at birth in swine and that maintenance of renal blood flow depends only partly on autoregulatory capability.
Effects of aging on responses of cerebral arterioles
Authors: Mayhan W. G. , Faraci F. M. , Baumbach G. L. , Heistad D. D.
Published: December 2017

Our goal was to determine whether responses of cerebral arterioles are altered in aged rats. We examined responses of cerebral arterioles in adult (6-8 mo old) and aged (22-24) mo old) Wistar rats to superfusion of acetylcholine and bradykinin, which presumably produce dilatation by releasing an endothelium-derived relaxing factor (EDRF), and to nitroglycerin, which produces dilatation by a direct effect on vascular muscle. In adult rats, cerebral arterioles dilated by 11 +/- 2% (SE) to acetylcholine (10(-5) M) and by 21 +/- 3% to bradykinin (10(-7) M). In contrast, arterioles in aged rats dilated by only 3 +/- 1% to acetylcholine and by 7 +/- 3% to bradykinin. Vasodilatation in response to nitroglycerin was similar to adult and aged rats. We also examined responses of cerebral arterioles to products released by platelets (ADP, serotonin, and thromboxane). ADP (10(-4) M) increased pial arteriolar diameter by 26 +/- 5% in adults rats and only 12 +/- 3% in aged rats. Serotonin (10(-5) M) produced modest vasodilatation in adult rats (7 +/- 1%) but modest vasoconstriction in aged rats (-5 +/- 2%). Vasoconstriction in response to a thromboxane A2 analogue (U 46619) was similar in adult and aged rats. Indomethacin (10 mg/kg iv) did not affect responses to acetylcholine, serotonin, and ADP in aged rats. Thus dilator responses of cerebral arterioles to agonists that may release EDRF are altered in aged compared with adult rats. Impaired vasodilatation in aged rats does not appear to be related to production of a cyclooxygenase constrictor substance.
Myocardial adaptation to creatine deficiency in rats fed with beta-guanidinopropionic acid, a creatine analogue
Authors: Mekhfi H. , Hoerter J. , Lauer C. , Wisnewsky C. , Schwartz K. , Ventura-Clapier R.
Published: December 2017

A creatine analogue, beta-guanidinopropionic acid (GPA), was fed to 12 young rats for several weeks. Another 12 animals were kept in the same conditions and age matched. Six pairs of animals were used to measure some energetic and mechanical parameters of the isovolumic perfused heart and to measure the accumulation of the phosphorylated form of GPA (GPAP) by 31P-nuclear magnetic resonance (NMR) spectroscopy. As a result of GPAP accumulation, phosphocreatine and ATP content decreased by 90 and 40%, respectively, and mechanical performance was impaired. Six other pairs of animals were used to assess the mechanical performances of Triton X-100-skinned fibers and the myosin isoenzyme distribution. It was found that the maximal force, Ca and ATP sensitivities, and myofibrillar creatine kinase efficacy of creatine-depleted hearts were similar to control values. There was, however, a decrease in the rate of cross-bridge cycling, and the isoenzymic expression of myosin was changed from the fast myosin V1 to the slower forms V2 and V3. In all animals, hypertrophy was observed in both right and left ventricles. We conclude that rat hearts subjected to a slow and persistent decrease in creatine and phosphocreatine respond with both quantitative and qualitative changes. These alterations, which most probably lead to an improvement in the economy of cardiac contraction, are nonetheless not sufficient to maintain maximal force.
Atrial tachycardia causes hydrops in fetal lambs
Authors: Gest A. L. , Hansen T. N. , Moise A. A. , Hartley C. J.
Published: December 2017

The purpose of this project was to study mechanisms responsible for edema formation in fetuses with hydrops. We produced hydrops fetalis in 28 fetal sheep [gestational age of 125 +/- 5 days (mean +/- SD)] by pacing their atria at 300-320 beats/min for 68 +/- 40 (SD) h. All fetuses developed peripheral edema and ascites [volume of ascitic fluid was 134 +/- 75 (SD) ml; total protein concentration was 3.10 +/- 0.6 (SD) g/dl, and total albumin concentration was 1.68 +/- 0.3 (SD) g/dl]. Pacing did not affect aortic pressure but increased venous pressure from 4 +/- 1 to 8 +/- 1 (SE) Torr. Pacing did not affect pH, arterial partial pressure of O2 (PaO2), or Na+ but increased PaCO2 from 53 +/- 1 to 55 +/- 1 (SE) Torr and K+ from 3.9 +/- 0.1 to 4.3 +/- 0.1 (SE) meq/l. Hematocrit increased from 29 +/- 1 to 32 +/- 1 (SE)% acutely with pacing but returned to base line by the last day of the experiment. Plasma protein concentration decreased slightly from 3.7 +/- 0.1 to 3.5 +/- 0.1 (SE) g/dl by the last day of the experiment; plasma albumin concentration did not change. Plasma volume decreased acutely from 271 +/- 19 to 238 +/- 16 (SE) ml and then remained decreased throughout the experiment. Red blood cell mass and the turnover time for albumin were not affected by pacing. We found no consistent relationship between edema formation and changes in arterial blood gas tensions, plasma protein concentrations, or the turnover time for albumin.2
Calcium-sensitive delayed rectifier potassium current in guinea pig ventricular cells
Authors: Tohse N.
Published: December 2017

The calcium sensitivity of the delayed rectifier K+ current (IK) was investigated in guinea pig single ventricular cells using the whole cell configuration of the patch-clamp technique with a cell dialysis method. The concentration-response curve of IK for intracellular Ca2+ indicated that IK started to increase at intracellular Ca2+ concentration [Ca2+]i of 10(-8) M (pCa 8) and it increased threefold at pCa 7. At lower [Ca2+]i than pCa 9, IK remained unchanged. A shift of the activation curve of IK by the elevation of [Ca2+]i was not observed. Although [Ca2+]i had little effect on time constants of the activation and deactivation of IK, it predominantly increased the amplitudes of the fast components in the activation process and the slow component in the deactivation process. In the ensemble noise analysis, the elevation of [Ca2+]i increased the number and open probability of functional IK channels but not the unit amplitude of IK channel. These results suggest that the elevation of [Ca2+]i enhances IK, probably by increasing the number and open probability of functional IK channels. Ca2(+)-sensitive IK in cardiac cells is a class of current different from Ca2(+)-activated K+ current in other tissue because the activation curve of Ca2(+)-sensitive IK was not shifted by the [Ca2+]i elevation, and the single channel conductance of IK was smaller than the one of Ca2(+)-activated K+ current.
Elevated body temperature and increased blood vessel sensitivity in spontaneously hypertensive rats
Authors: Price J. M. , Wilmoth F. R.
Published: December 2017

Body temperature (BT) was significantly greater in spontaneously hypertensive rats (SHR) than in Wistar-Kyoto (WKY) rats regardless of the time of day, length of rectal probe, sex, age, or commercial vendor. Bath temperature (theta) for excised aortic rings was controlled by a thermoelectric Peltier module with an accuracy of 0.1 degree C. At peak force in individual contractions of norepinephrine (NE) dose-response experiments, theta was changed from 37 to 39 degrees C. Active and resting wall tension (Tw) were increased, and the mean effective dose (ED50) was decreased in the SHR aorta with and without endothelium. For the WKY aorta, active and resting Tw were increased, but ED50 was the same with and without endothelium. These results were supported by experiments where theta was decreased from 39 to 37 degrees C and by experiments on Sprague-Dawley rats. Potassium dose-response experiments with aorta from SHR and WKY rats show an increase in sensitivity at 39 degrees C, but active Tw is the same at 39 and 37 degrees C. When compared at the BT of each rat, the NE ED50 was lower and resting Tw was higher in the SHR aorta than in the WKY aorta, but active Tw was the same.(ABSTRACT TRUNCATED AT 250 WORDS)
Prevention of salt angiotensin II hypertension by servo control of body water
Authors: Krieger J. E. , Cowley A. W.
Published: December 2017

An automated servo-control system to maintain total body weight constant was used to investigate the role of fluid volume expansion in the development of salt-dependent hypertension in dogs continuously infused with subpressor doses of angiotensin II. Dogs maintained on a fixed salt and water intake were studied in metabolic scale cages, which enabled continuous 24 h/day monitoring of changes in body weight as an index of changes in total body water. Beat-by-beat hemodynamics were determined 24 h/day. Daily fluid and electrolyte balances and hormonal profile were determined. Blood volume was periodically measured by injection of 51Cr red blood cells. After a 3-day control period, salt intake was increased from 8 to 120 meq/day. In contrast to the rise of arterial pressure that was observed in our previous nonservo-controlled volume studies, average 24-h mean arterial pressure, cardiac output, and total peripheral resistance remained unchanged during a 4-day high-salt period. Total body weight was maintained within 7 +/- 17 g of the original weight. Blood volume was unchanged by day 2 as indicated by direct measurement (51Cr red blood cells) or by analysis of plasma protein concentration. There was a retention of 82 +/- 5 meq (P less than 0.05) of sodium on day 1 of high-salt period. Plasma sodium concentration increased approximately 7 meq/l (P less than 0.05) above control levels. Plasma renin activity and aldosterone decreased to undetectable values, whereas vasopressin and atrial natriuretic peptide increased significantly. These results confirm that elevations of blood volume and cardiac output normally observed when salt intake was increased in dogs infused with angiotensin II are secondary to water retention and that this salt-dependent model of hypertension is dependent on fluid volume expansion.
Differences in endothelium-dependent cerebral dilation by bradykinin and acetylcholine
Authors: Kontos H. A. , Wei E. P. , Kukreja R. C. , Ellis E. F. , Hess M. L.
Published: December 2017

We compared the mechanism of action of acetylcholine and bradykinin, two agents that cause endothelium-dependent relaxation, on cerebral arterioles of cats equipped with cranial windows for the observation of the cerebral microcirculation. The vasodilation caused by bradykinin was eliminated by cyclooxygenase inhibition with topical indomethacin, it was reduced by topical deferoxamine, an agent that scavenges iron and thereby inhibits the production of hydroxyl radical via the Haber-Weiss reaction, and it was eliminated by 3-amino-1,2,4-triazole, an agent that inhibited superoxide production by cyclooxygenase. The vasodilation from acetylcholine was not affected by these agents. Acetylcholine induced a transferable, short-lived vasodilator material in bioassay experiments, whereas bradykinin did not. Bradykinin or acetylcholine, when applied topically by themselves, induced arteriolar dilation; when applied together, they did not. The findings are consistent with the view that the cerebral arteriolar dilation from bradykinin is caused by oxygen radicals generated in association with accelerated arachidonate metabolism via cyclooxygenase, whereas the dilation from acetylcholine is caused by an endothelium-derived relaxing factor (EDRF) similar to that generated by this agent in large vessels in vitro. The EDRF from acetylcholine and the radicals from bradykinin interact and inactivate each other.
Energy substrate utilization by isolated working hearts from newborn rabbits
Authors: Lopaschuk G. D. , Spafford M. A.
Published: December 2017

The ability of newborn rabbit hearts to utilize fatty acids as an energy substrate was determined. Isolated working hearts from 1- or 7-day-old rabbits were perfused with Krebs-Henseleit buffer containing either 11 mM glucose or 0.4 mM palmitate as carbon substrates. One-day-old rabbit hearts were perfused at a 11.5-mmHg filling pressure via the inferior vena cava and at a combined aortic and pulmonary arterial hydrostatic afterload of 20 mmHg. In these hearts, addition of insulin was necessary to maintain mechanical function. Function was maintained in the presence of glucose or glucose plus palmitate but not in the presence of palmitate alone. Measurement of glucose and palmitate oxidation rates in hearts perfused with glucose, palmitate, and insulin showed that 57% of ATP production from exogenous substrates was provided by glucose. Substrate use was also measured in 7-day-old rabbit hearts perfused in the Neely working heart mode at a 7.5-mmHg preload and 30-mmHg afterload. In these hearts, function could be maintained in the presence of either glucose alone or palmitate alone. Insulin addition was not necessary to maintain function. Measurement of glucose and palmitate oxidation in 7-day-old rabbit hearts perfused with glucose, palmitate, and insulin showed that only 10% of ATP production from exogenous substrates was provided by glucose. These data demonstrate that between 1 and 7 days of life in the rabbit the heart switches to using predominantly fatty acids as an energy substrate.
Postsynaptic alpha- and beta-adrenergic supersensitivity of recovery properties in the canine ventricle
Authors: Van Why K. J. , Lund D. D. , Martins J. B.
Published: December 2017

We studied postsynaptic manifestations of adrenergic supersensitivity in the canine left ventricle (LV) regionally denervated by phenol in 14 dogs. Measurements were performed from 17 to 23 days later under alpha-chloralose anesthesia after sinoaortic denervation and vagotomy. After the sternum was split, multipolar pacing and recording electrodes were placed in both innervated and denervated LV. With isoproterenol infusion at 0.1, 1, and 10 micrograms/min, there was no change in activation times or pacing threshold. However, supersensitivity was manifested by a parallel left shift in the isoproterenol dose to effective refractory period (ERP) response curve (greater than or equal to 5.7 ms) in the denervated endocardium and epicardium compared with the respective innervated LV (P less than 0.05). In addition, local repolarization in the denervated area shortened more than the innervated area with isoproterenol infusion and correlated (r = 0.56) with the change in ERP. Postsynaptic supersensitivity of Purkinje to isoproterenol was also manifested by a parallel left shift (greater than or equal to 10 ms) in the dose to relative refractory period response curve in the denervated compared with the innervated area (P less than 0.05). In addition, a greater prolongation of Purkinje refractoriness was observed with phenylephrine only at 50 micrograms.kg-1.min-1. We conclude that postsynaptic supersensitivity occurred with the beta-agonist isoproterenol in both muscle and Purkinje. However, only Purkinje in the denervated area demonstrated an enhanced response to the alpha-agonist phenylephrine.
Release of EDRF from canine renal artery by leukotriene D4
Authors: Pawloski J. R. , Chapnick B. M.
Published: December 2017

The goal of the present investigation was to determine whether leukotriene D4 (LTD4) was capable of releasing endothelium-derived relaxing factor (EDRF) from perfused renal arterial (RA) segments and to begin to characterize any released mediator. To detect EDRF, a bioassay was used in which a prostaglandin (PG) F2 alpha precontracted, endothelium-denuded coronary artery (CA) ring was superfused either directly or with effluent from a perfused RA segment. Addition of LTD4 or acetylcholine (ACh) to the perfusate proximal to the RA segment resulted in CA ring relaxation, the degree of which was inversely related to transit time. Calculated half-life (t1/2) for the CA relaxing substance released by LTD4 and ACh from the RA segment was 7.5 +/- 1.4 and 7.4 +/- 0.9 s, respectively. Pretreatment of the RA segment with collagenase prevented relaxation of the CA ring evoked by RA effluent in response to either ACh or LTD4 that was administered into the perfusate proximal to the RA segment. Addition of superoxide dismutase (SOD) to the effluent distal to the RA segment markedly enhanced both ACh and LTD4-evoked relaxation of the CA ring, whereas reduced hemoglobin (Hb) virtually abolished these responses. When either LTD4 or ACh was superfused directly over the CA, no change in tone of the bioassay ring was observed. These data indicate that, similar to ACh, LTD4 has the ability to release a labile substance(s), presumably EDRF, from the endothelium-intact RA segment that evokes relaxation of the endothelium-denuded CA ring. Although apparently similar, further studies are required to confirm whether or not the mediator(s) released by LTD4 is identical to that which is released by ACh.