bluuebunny/crossref_metadata_2025 huggingface dataset:
Sampling interstitial fluid from rat skeletal muscles by intermuscular wicks
Authors: Wiig H. , Sibley L. , DeCarlo M. , Renkin E. M.
Published: December 2017

A modification of the implanted wick method (K. Aukland and H. O. Fadnes. Acta Physiol. Scand. 88: 350-358, 1973) was devised to sample interstitial fluid from rat muscles. Dry nylon wicks were inserted postmortem into intermuscular spaces between leg muscles by means of a plastic catheter, which was subsequently withdrawn. Inserting the wicks postmortem avoids contaminating wick fluid with proteins extravasated as a result of local inflammatory reactions; placing them intermuscularly avoids contamination by fluid and proteins from damaged muscle cells. Wick fluid protein concentrations (mg/ml) averaged 24.1 +/- 1.1 and 28.5 +/- 1.5 (means +/- SE) in medial and lateral hindlimbs muscles, respectively. The corresponding albumin concentrations were 13.0 +/- 0.7 and 13.9 +/- 0.7 mg/ml. Total protein and albumin concentrations in plasma were 54.1 +/- 0.8 and 22.5 +/- 0.3 mg/ml. Electrophoresis of wick fluid showed a pattern of peaks similar to that of plasma, with albumin relatively high and larger molecules relatively low. Proteins from muscle cells were not detected. Isotope studies (125I-labeled albumin, 51Cr-EDTA) showed that less than 2% of the albumin in wick fluid came directly from plasma and that wick fluid was not concentrated by cell swelling postmortem. Wick fluid from intermuscular wicks implanted in anesthetized rats in vivo had nearly the same total protein concentration as fluid from postmortem wicks, but albumin-to-globulin (A/G) ratios were slightly lower (1.22 +/- 0.07 vs. 1.53 +/- 0.21 measured by gel electrophoresis), and more significantly, nearly 50% of the albumin leaked to wick fluid from plasma as a result of wick implantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of phorbol esters on canine coronary artery constriction and dilation in vitro
Authors: Sheridan F. M. , Horwitz L. D. , McMurtry I. F.
Published: December 2017

The influence of protein kinase C (PKC) activation on canine coronary vasoreactivity was assessed in vitro. Activation of PKC by phorbol 12,13-dibutyrate (PDBu) or phorbol 12-myristate 13-acetate (PMA) caused slow sustained constriction of isolated coronary artery rings. PDBu was a more potent and efficacious constrictor than PMA (169 +/- 21 vs. 81 +/- 7% of maximum KCl constriction). Constriction to PDBu was reduced slightly by deendothelialization and by meclofenamate. Pretreatment with threshold concentrations of PDBu increased constriction to serotonin from 3 +/- 1 to 48 +/- 4% of maximum KCl constriction whether or not the endothelium was present but had no effect on response to the thromboxane analogue U-46619. In addition, in arteries constricted with PDBu, dilations to ADP, thrombin, acetylcholine, and sodium nitroprusside were impaired when compared with arteries constricted with U-46619. These results suggest that activation of PKC in coronary arteries 1) produces potent constriction mediated only in small part by the endothelium and by cyclooxygenase products, 2) potentiates markedly the constrictor response to serotonin by an endothelium-independent mechanism, and 3) attenuates both endothelium-dependent and endothelium-independent vasodilation.
Left ventricular-arterial coupling in conscious dogs
Authors: Little W. C. , Cheng C. P.
Published: December 2017

We investigated the criteria for the coupling of the left ventricle (LV) and the arterial system to maximize LV stroke work (SW) and the transformation of LV pressure-volume area (PVA) to SW. We studied eight conscious dogs that were instrumented to measure LV pressure and determine LV volume from three ultrasonically determined dimensions. The LV end-systolic pressure (PES)-volume (VES) relation was determined by caval occlusion. Its slope (EES) was compared with the arterial elastance (EA) and determined as PES per stroke volume. At rest, with intact reflexes, EES/EA was 0.96 +/- 0.20 EES/EA was varied over a wide range (0.18-2.59) by the infusion of graded doses of phenylephrine and nitroprusside before and during administration of dobutamine. Maximum LV SW, at constant inotropic state and end-diastolic volume (VED), occurred when EES/EA equaled 0.99 +/- 0.15. At constant VED and contractile state, SW was within 20% of its maximum value when EES/EA was between 0.56 and 2.29. The conversion of LV PVA to SW increased as EES/EA increased. The shape of the observed relations of the SW to EES/EA and SW/PVA to EES/EA was similar to that predicted by the theoretical consideration of LV PES-VES and arterial PES-stroke volume relations. We conclude that the LV and arterial system produce maximum SW at constant VED when EES and EA are equal; however, the relation of SW to EES/EA has a broad plateau. Only when EA greatly exceeds EES does the SW fall substantially. However, the conversion of PVA to SW increases as EES/EA increases. These observations support the utility of analyzing LV-arterial coupling in the pressure-volume plane.
Effect of skin concavity on subcutaneous tissue fluid pressure
Authors: Adair T. H. , Vance G. A. , Montani J. P. , Guyton A. C.
Published: December 2017

We tested the hypothesis that mechanical factors associated, with a skin concavity can cause the local tissue fluid pressure to become more negative. Perforated Teflon collars, 26 mm in diameter and having various heights (5, 10, 13, and 16 mm), were implanted into the fascial plane of the inguinal and abdominal areas of six sheep. After several weeks, visible signs of edema were no longer apparent, and the skin formed a concavity within the center of each collar. The depth of each concavity was measured using an electronic micrometer, and the tissue fluid pressure beneath the concavity was measured using a needle method. Over the entire range of collar heights, the average depth of the concavities ranged from 1.1 to 4.7 mm in the abdominal tissues and from 1.8 to 5.5 mm in the inguinal tissues. The respective values of tissue fluid pressure averaged -4.6 to -13.0 and -5.7 to -12.8 mmHg. The results therefore indicate that implanting deeper collars leads to the formation of deeper concavities in the skin and also to greater negativity in the free tissue fluid pressure beneath the skin. Linear regression extrapolation to a collar height of 0 mm corresponded to a tissue fluid pressure of -1.0 mmHg in the abdominal tissue and -2.4 mmHg in the inguinal tissues. A model based on excessive pumping of the lymphatic system in the vicinity of a concavity is provided to explain this newly described phenomenon. We conclude that mechanical factors associated with the formation of a skin concavity cause or permit the tissue fluid pressure to reach levels of negativity far greater than those that exist in the absence of a concavity.
Influence of hyperglycemia on cerebral adenosine production during ischemia and reperfusion
Authors: Hsu S. S. , Meno J. R. , Zhou J. G. , Gordon E. L. , Winn H. R.
Published: December 2017

We hypothesized that systemic hyperglycemia would alter cerebral adenosine concentrations during ischemia and reperfusion. In the present study, we analyzed brain tissue and cerebrospinal fluid (CSF) from hyperglycemic and normoglycemic rats before ischemia, after 15 min of incomplete forebrain ischemia, and during 60 min of reperfusion. Hyperglycemic rats received 3 g/kg of 17% D-glucose intraperitoneally, which increased blood glucose to 357 +/- 23 mg/100 ml compared with 128 +/- 12 mg/100 ml in normoglycemic rats. Brain tissue was sampled by the freeze-blow technique, and CSF was obtained by collecting cortical perfusate from the closed cranial window. Tissue and CSF were analyzed for adenosine and its metabolites inosine and hypoxanthine, and tissue was also analyzed for adenine nucleotides. Hyperglycemia significantly attenuated the increase in brain tissue and CSF adenosine and its metabolites during ischemia while preserving adenine nucleotide concentrates. This attenuation of ischemic adenosine production persisted after 5 min of reperfusion in tissue and throughout 60 min of reperfusion in CSF. Because adenosine, a cerebral vasodilator, can inhibit the release of neuronal excitotoxins as well as affect neutrophil-endothelial interactions, adenosine has been proposed as an endogenous neuroprotector. Thus the attenuation of adenosine and its metabolites may be a factor in the pathogenesis of increased ischemic brain injury associated with systemic hyperglycemia.
Evidence of a role for compounds derived from arginine in coronary response to serotonin in vivo
Authors: Cappelli-Bigazzi M. , Nuno D. W. , Lamping K. G.
Published: December 2017

Recent studies have demonstrated that a nitroso compound derived from L-arginine (Arg) may be the endothelium-derived relaxing factor (EDRF) released from vascular endothelium. Synthesis of EDRF from L-Arg is inhibited by analogues of Arg such as NG-monomethyl-L-arginine (L-NMMA) and N omega-nitro-L-arginine (L-NNA). We tested the role of compounds derived from Arg in the constriction of the proximal left anterior descending coronary artery (LAD) to serotonin in vivo by measuring responses before and during infusion of L-NMMA or L-NNA. In open-chest anesthetized dogs the LAD was perfused at constant pressure (80 mmHg) from a reservoir. Large-artery diameter was measured with piezoelectric crystals, and coronary flow was measured with an in-line electromagnetic flow probe. Intracoronary serotonin (5 and 50 micrograms/min) caused a dose-dependent constriction of the proximal LAD and increase in coronary flow. Intracoronary L-NMMA (2 mg/min) or L-NNA (2 mg/min) augmented the constriction to serotonin, whereas the increase in coronary flow was blunted only by L-NNA. L-Arg (10 mg/min, intracoronary) alone did not alter either the large-artery constriction or the increase in flow to serotonin; however, it prevented the enhanced constriction to serotonin following L-NMMA. Constriction to the endothelium-independent agent prostaglandin F2 alpha was not affected by L-NMMA. We conclude that a metabolite of L-Arg modulates the large coronary artery response to serotonin in vivo.
Vasoactive intestinal polypeptide enhances automaticity of supraventricular pacemakers in anesthetized dogs
Authors: Rigel D. F. , Lathrop D. A.
Published: December 2017

Effects of the cardiac neuropeptide vasoactive intestinal polypeptide (VIP) and isoproterenol (ISO) were compared on sinus nodal, subsidiary atrial, and atrioventricular junctional pacemaker automaticity in pentobarbital sodium-anesthetized dogs (n = 14). Autonomic cardiac nerves were decentralized by bilateral vagotomy and stellectomy. VIP and ISO (30, 100, and 300 pmol/kg iv) were administered during sinus rhythm and either after crushing the sinus node to unmask a latent subsidiary atrial pacemaker (n = 7 dogs) or after injecting pentobarbital sodium into the sinus node artery to elicit an atrioventricular junctional pacemaker (n = 7). Spontaneous sinus nodal, subsidiary atrial, and atrioventricular junctional pacemaker rates (after autonomic nerve decentralization) were 142 +/- 4, 114 +/- 3, and 79 +/- 4 beats/min (means +/- SE), respectively. Both VIP and ISO dose dependently increased the rates of all three pacemaker sites. Combined muscarinic-cholinergic (atropine; 0.11 mg/kg iv) and beta-adrenergic receptor blockade (nadolol; 0.5 mg/kg iv) abolished the stimulatory effects of ISO on subsidiary atrial and atrioventricular junctional pacemakers but did not affect the responses to VIP. We conclude that exogenous VIP enhances the automaticity of sinus nodal, subsidiary atrial, and atrioventricular junctional pacemakers independently of muscarinic-cholinergic and beta-adrenergic receptors. Based on the previous demonstration of VIP-immunoreactive nerves throughout the heart, our findings also suggest that endogenous VIP may be involved in cardiac pacemaker regulation.
Efficacy of Cushing response during development in sheep
Authors: Backofen J. E. , Koehler R. C. , Harris A. P. , Rogers M. C. , Traystman R. J. , Jones M. D.
Published: December 2017

Mean aortic pressure (MAP) increases (Cushing response) when intracranial pressure (ICP) approaches MAP. We elevated ICP to levels equivalent to normal baseline MAP with infusion of mock cerebrospinal fluid (CSF) into the lateral cerebral ventricles and contrasted responses in near-term fetal sheep, 1-wk-old lambs, and adult sheep anesthetized with pentobarbital sodium. With CSF infusion 1-wk-old lambs and adults produced sustained increases in MAP of 16 +/- 1 and 22 +/- 2 mmHg, respectively, over a 40-min period. However, cerebral blood flow fell 66 and 57%, and cerebral O2 uptake fell 34 and 37%, respectively. In the near-term fetus, MAP increased by 11 +/- 1 mmHg and cerebral blood fell 49% at 3 min of elevated ICP. However, by 15 min MAP had increased further (+17 +/- 2 mmHg) and cerebral blood flow was nearly restored. In contrast to postnatal sheep, cerebral O2 uptake was maintained throughout in the fetus. The mechanism of increased MAP differed among groups. In adults total peripheral resistance fell significantly, whereas in the fetus and lamb it remained constant. Cardiac output increased in each group, but, because of the fall in peripheral resistance, increased cardiac output was relatively more important to the rise in MAP in adults. In addition, marked vasoconstriction occurred in intestines and skin in the fetus. The Cushing response is well-developed in near-term fetal sheep. After birth it may lose its effectiveness in providing for the basal metabolic demand of the brain.
Rate of oxygen loss from arterioles is an order of magnitude higher than expected
Authors: Popel Aleksander S. , Pittman Roland N. , Ellsworth Mary L.
Published: December 2017

Pages H921–H924: Aleksander S. Popel, Roland N. Pittman, and Mary L. Ellsworth. “Rate of oxygen loss from arterioles is an order of magnitude higher than expected.” Page H922: Table 1 should appear as the following:

(See PDF)
Two mechanisms mediate relaxation by bradykinin of pig coronary artery: NO-dependent and -independent responses
Authors: Cowan C. L. , Cohen R. A.
Published: December 2017

The role of nitric oxide and guanosine 3',5'-cyclic monophosphate (cGMP) accumulation in the endothelium-dependent relaxation of the porcine coronary artery to bradykinin was investigated by comparing relaxation and cGMP accumulation in the presence or absence of NG-monomethyl-L-arginine (L-NMMA) and methylene blue. Rings were treated with indomethacin to eliminate the effects of prostaglandins. Relaxation to bradykinin of rings contracted with the thromboxane A2 mimetic U-46619 was not affected by L-NMMA and was only minimally inhibited by methylene blue. Rings contracted with elevated potassium (25 mM) also relaxed completely to bradykinin. However, L-NMMA or methylene blue effectively inhibited relaxation to bradykinin in rings contracted with potassium. cGMP accumulation was stimulated by bradykinin and inhibited by L-NMMA or methylene blue in rings contracted with either U-46619 or potassium. These results suggest that in the absence of nitric oxide-induced cGMP accumulation, a nonprostanoid mechanism exists that is capable of completely relaxing U-46619-contracted coronary artery. This mechanism is either inhibited in or unable to relax potassium-contracted rings. These results also demonstrate that nitric oxide mediates the bradykinin-induced cGMP accumulation that is largely responsible for the relaxation during contraction with potassium.
Enhanced synthesis of epoxyeicosatrienoic acids by cholesterol-fed rabbit aorta
Authors: Pfister S. L. , Falck J. R. , Campbell W. B.
Published: December 2017

Arachidonic acid metabolism via cyclooxygenase, lipoxygenase, and cytochrome P-450 epoxygenase was investigated in thoracic aortic tissue obtained from rabbits fed either standard rabbit chow or chow containing 2% cholesterol. Aortic strips were incubated with [14C]arachidonic acid and A23187. Metabolites from extracted media were resolved by high-pressure liquid chromatography (HPLC). Normal and cholesterol-fed rabbit aortas synthesized prostaglandins (PGs) and hydroxyeicosatetraenoic acids (HETEs). The major cyclooxygenase products were 6-keto-PGF1 alpha and PGE2. Basal aortic 6-keto-PGF1 alpha production was slightly reduced in cholesterol-fed compared with normal rabbits. 12(S)- and 15(S)-HETE were the major aortic lipoxygenase products from both normal and cholesterol-fed rabbits. The structures were confirmed by gas chromatography-mass spectrometry (GC-MS). Only cholesterol-fed rabbit aortas metabolized arachidonic acid via cytochrome P-450 epoxygenase to the epoxyeicosatrienoic acids (EETs). 14,15-, 11,12-, 8,9-, and 5,6-EET were identified based on comigration on HPLC with known 14C-labeled standards and typical mass spectra. Incubation of normal aorta with 14,15-EET decreased the basal synthesis of 6-keto-PGF1 alpha. The other EETs were without effect. The four EET regioisomers relaxed the norepinephrine-precontracted normal and cholesterol-fed rabbit aorta. The relaxation response to 14,15-EET was greater in aortas from cholesterol-fed rabbits. These studies demonstrate that hypercholesterolemia, before the development of atherosclerosis, alters arachidonic acid metabolism via both the cyclooxygenase and epoxygenase pathways.
Bicarbonate conservation during incomplete cerebral ischemia with superimposed hypercapnia
Authors: Hurn P. D. , Koehler R. C. , Norris S. E. , Schwentker A. E. , Traystman R. J.
Published: December 2017

We superimposed extreme hypercapnia (arterial Pco2 400-450 mmHg) immediately before and during incomplete cerebral ischemia to distinguish the role of intracellular pH (pHi) and bicarbonate [( HCO3-]i) in postischemic metabolic and electrophysiological recovery. Incomplete global ischemia was produced in seven anesthetized dogs by 30 min of intracranial hypertension followed by 4 h of reperfusion. ATP, phosphocreatine (PCr), and pHi were measured with 31P magnetic resonance spectroscopy, and [HCO3-]i was calculated from the Henderson-Hasselbalch equation using the measured pHi and sagittal sinus Pco2. Cerebral blood flow was reduced to 7 +/- 1 ml.min-1.100 g-1 (+/- SE) during ischemia with extreme hypercapnia, and pHi decreased to 5.72 +/- 0.09. During normocapnic reperfusion, pHi rapidly returned to near baseline values by 14 min. [HCO3-]i fell from 12.1 +/- 0.9 to 6.0 +/- 1.2 mM by the midpoint of ischemia and recovered by 30 min of reperfusion. ATP, PCr, and O2 consumption also recovered rapidly and completely. Somatosensory-evoked potentials (SEP) recovered to 43 +/- 10% of control amplitude. These results are in marked contrast to the poor metabolic and SEP recovery previously observed in hyperglycemic dogs in which pHi decreased to the same range as with hypercapnic ischemia, but in which [HCO3-]i was much lower (1.1 +/- 0.5 mM). Therefore, [HCO3-]i depletion during hyperglycemic ischemia may be a more important factor in recovery than end-ischemic pHi per se. We speculate that higher [HCO3-]i may improve glial cell buffering capacity or decrease iron availability for hydroxyl radical production.
Role of H+ and alpha 2-receptors in escape from sympathetic vasoconstriction
Authors: Chen L. Q. , Shepherd A. P.
Published: December 2017

In a previous study, we noted that mesenteric venous pH falls during the reductions in intestinal blood flow caused by sympathetic stimulation and that alpha 2-receptor antagonists enhanced autoregulatory escape (the partial recovery that blood flow undergoes despite sustained sympathetic stimulation). In addition, other studies indicated that increased [H+] selectively inhibits the responsiveness of postjunctional alpha 2-receptors to norepinephrine (NE). Therefore, we investigated the role of H+ in escape by 1) measuring the rate of unbuffered H+ release during sympathetic stimulation in isolated loops of canine small bowel, 2) infusing acidic buffer intra-arterially and determining the effects of acidosis on sympathetic vasoconstriction and escape, 3) ascertaining the effects of acidosis on the release rate of endogenous NE during sympathetic stimulation, and 4) determining whether acidosis exerts effects in vivo on post-junctional responses to the selective alpha 1- and alpha 2-agonists, phenylephrine and clonidine, respectively. Our findings were that 1) the rate at which the gut released H+ into blood increased during sympathetic stimulation, 2) infusing acidic buffer to lower venous pH from 7.3 to 7.1 attenuated the initial vasoconstrictor response after 30 s of stimulation, 3) acidosis caused blood flow to return further toward control despite continued stimulation and thus enhanced escape, 4) acidosis did not impair NE release at either 30 s or 6 min of stimulation, and 5) acidosis inhibited the intestinal vasoconstrictor effects of selective alpha 2- but not alpha 1-agonists. The results support the hypothesis that escape from sympathetic vasoconstriction occurs, in part, because increased [H+] inhibits alpha 2-mediated postjunctional responses to neuronally released NE.
Heart rate reduction improves myocardial ischemia in swine: role of interventricular blood flow redistribution
Authors: Indolfi C. , Guth B. D. , Miyazaki S. , Miura T. , Schulz R. , Ross J.
Published: December 2017

Regional myocardial blood flow (MBF) distribution and function upon slowing the heart rate (HR) during ischemia were studied in anesthetized swine, a species without coronary collaterals. Perfusion of the left anterior descending artery by a pump allowed controlled production of regional ischemia. Slowing tachycardia by electrical pacing (127 to 87 beats/min) caused marked improvement of regional dysfunction [% wall thickening (WTh) from 9 to 27%] and increased subendocardial MBF [from 0.31 to 0.55 ml.min-1.g-1 (P less than 0.001)] without change of subepicardial MBF. Total left ventricular (LV) MBF increased, whereas right ventricular (RV) MBF fell by 18% (P less than 0.02). The mechanism of MBF changes during slowed HR was assessed by surgically excluding the RV and comparing findings with previous experiments with RV intact when HR was slowed from 96 to 60 beats/min. A similar improvement of regional LV function occurred (8% vs. 30% WTh) with the RV excluded, but without a change in total flow to the LV bed, whereas subendocardial MBF increased and subepicardial MBF fell, indicating transmural redistribution only. These findings show that the RV vascular bed can contribute to LV perfusion in swine during ischemia, and they document the potential for “reverse RV steal” during slowed heart rate in this setting.
Chronic exposure to neuropeptide Y determines cardiac alpha 1-adrenergic responsiveness
Authors: Sun L. S. , Ursell P. C. , Robinson R. B.
Published: December 2017

The onset of sympathetic innervation induces a developmental change in the cardiac alpha 1-adrenergic chronotropic response from an increase to a decrease in rate. The mechanism by which innervation induces this alteration is unknown. Neuropeptide Y (NPY), which is found abundantly in cardiac sympathetic nerve terminals, was considered as a possible mediator for this effect. Chronic conditioning by NPY in noninnervated myocyte cultures stimulated the effect of sympathetic innervation in inducing the alpha 1-inhibitory chronotropic response. Chronic conditioning by the NPY antagonist PYX-2 blocked the effect of innervation. Thus endogenous NPY may modulate alpha 1-adrenergic responsiveness during the ontogeny of cardiac sympathetic innervation.
Ca2+-ATPase and function of sarcoplasmic reticulum during cardiac hypertrophy
Authors: Levitsky Dmitri , Bastie Diane De La , Schwartz Ketty , Lompré Anne-Marie
Published: December 2017

The properties of the calcium pump system of sarcoplasmic reticulum (SR) were studied in a series of 34 rats subjected to cardiac overload and 19 sham-operated animals. Total homogenates of left ventricle were analyzed by measuring the oxalate-supported Ca2+ uptake rate, the steady-state level of the phosphorylated intermediate of Ca2+-adenosine triphosphatase (Ca2+-ATPase) (E-P), and the amount of Ca2+-ATPase mRNA. All three parameters decreased gradually as a function of the relative left ventricular weight increase. The calcium-sensitivity curves showed that the velocity of Ca2+ transport in SR from the hypertrophied heart is diminished at low as well as optimal Ca2+ concentrations, with the dissociation constant (Kd) value for Ca2+ unchanged from that of the control preparation. Taken together with the results presented in our recent publication (De la Bastie, Levitsky, Mercadier, Marotte, Wisnewsky, Brovkovivh, Schwartz, and Lompré, Circ. Res. 66: 554–564, 1990), these data strongly indicate that differences in the Ca2+ pump activities of SR from normal and hypertrophied rat hearts are due to quantitative rather than qualitative changes of the Ca2+-ATPase protein.

calcium ion uptake; calcium ion adenosine triphosphatase messenger ribonucleic acid; cardiac hypertrophy; monoclonal antibody
Thyroid control over membrane processes in rat heart
Authors: Seppet Enn K. , Kadaya Lumme Y. , Hata Tomoji , Kallikorm Ants P. , Saks Valdur A. , Vetter Roland , Dhalla Naranjan S.
Published: December 2017

We have studied the effects of hypo- and hyperthyroidism on sarcolemmal (SL) and sarcoplasmic reticular (SR) ion transport processes and mitochondrial energy production in rat heart. The following conclusions were derived. 1) Compared with euthyroid state, hyperthyroidism led to increased SR Ca2+-accumulation. In SL, the activities of Ca2+-stimulated adenosine triphosphatase (ATPase), ATP-dependent Ca2+ pumping, and Na+-Ca2+ exchanger were not affected; but ouabain-sensitive Na+-K+-ATPase activity was enhanced. 2) Hypothyroidism resulted in depressed activities of Ca2+ pumps both in SL and SR. In SL, the Na+-K+-ATPase activity was decreased, but Na+-Ca2+ exchange was unaltered. 3) Thus slower relaxation of the hypothyroid myocardium may be attributed to depressed functioning of Ca2+ pumps in SR and SL, whereas faster relaxation of the hyperthyroid heart may be based on increased Ca2+-pumping activity of SR. 4) Hyperthyroidism and hypothyroidism, respectively, led to enhanced and decreased rates of mitochondrial phosphocreatine synthesis. The thyroid state appears to control the functional coupling between mitochondrial creatine kinase and ATP-ADP translocase: the energy of oxidative phosphorylation was transformed into phosphocreatine more effectively in mitochondria from hypothyroid hearts than in those from hyperthyroid hearts.

euthyroid; hyperthyroid; hypothyroid; mitochondrial creatine kinase; myocardium; oxidative phosphorylation; phosphocreatine synthesis; sarcolemma; sarcoplasmic reticulum
Na+-K+-ATPase-G protein coupling in myocardial sarcolemma: separation and reconstitution
Authors: Danilenko Mikhail P. , Turmukhambetova Vera C. , Yesirev Oleg V. , Tkachuk Vsevolod A. , Panchenko Mikhail P.
Published: December 2017

The cholinergic agonist carbachol produces a concentration-dependent (half-maximum inhibitory concentration = 0.9 μM) decrease in the Na+-K+-adenosine triphosphatase (ATPase) activity of rabbit cardiac sarcolemma that occurred only in the presence of guanosine 5'-[-thio]triphosphate (0.1 μM GTPS) and reached 40% inhibition. The inhibition is blocked by the muscarinic receptor antagonist atropine (10 μM) and is abolished in sarcolemma treated with pertussis toxin (20 μg/ml) in the presence of 100 μM NAD. GTPS alone reduces Na+–K+-ATPaseactivity by 45% (half-maximum inhibitory = 1 μM). The apparent affinity of the enzyme for GTPS is increased 10-fold in the presence of 1 μM carbachol. In sarcolemma solubilized with the zwitterionic detergent 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS, 10 mM), the GTPS-dependent inhibition of the Na+-K+-ATPase is also observed. Gel filtration of a CHAPS extract of sarcolemma on a Sepharose CL–6B column resulted in a separation of Na+-K+-ATPase and pertussis toxin-sensitive Gi activities. Na+-K+-ATPase activity that was separated on the column lost its sensitivity to the inhibitory action of guanine nucleotides. Inhibitory effects (20–30%) of guanosine 5'-triphosphate analogues [Gpp(NH)p, GTPS, or Gpp(CH2)p] at micromolar concentrations were restored when the Na+-K+-ATPase activity was recombined with fractions that contained the pertussis toxin-sensitive Gi protein(s). Similar concentrations of guanosine 5'-triphosphate, guanosine 5'-diphosphate, guanosine-5'-[β-thio]diphosphate, or App(NH)p were unable to induce the Gi protein-mediated attenuation of Na+-K+-ATPase activity in the reconstitution system. These results suggest that a pertussis toxin-sensitive Gi protein may act as a transducer of the inhibitory hormonal signals on Na+-K+-ATPase in the sarcolemma.

cardiac sarcolemma
LV-arterial coupling: interactive model to predict effect of wave reflections on LV energetics
Authors: Fitchett D. H.
Published: December 2017

The interaction between the left ventricle (LV) and the arterial system was simulated using sequential convolution of the flow output generated by a time-varying elastance model of the LV with an impulse response calculated from a 128-element model of the arterial system. The model illustrates the effect of independent changes of components of the arterial load on LV performance and energetics. This report studies the response of the model LV to an increase in arterial resistance, a decrease in arterial compliance, and an increase in discrete vascular reflections. Although arterial resistance exerts the greatest effect on ventricular stroke output, a reduction of arterial compliance or an increase in early reflections resulted in less optimal coupling of the heart to the arteries and less efficient energy utilization by the LV. In addition, the earlier the reflections return, the greater the disturbance of ventricular arterial coupling.
Adrenergic influences on cardiac function during ventricular fibrillation in isolated rat hearts
Authors: Derad I. , Funk I. , Pauschinger P. , Born J.
Published: December 2017

Effects of norepinephrine (NE, 10(-6) M), epinephrine (E, 10(-6) M), and vehicle on coronary blood flow (CF), oxygen consumption, and lactate release were compared in 32 isolated rat hearts during 5 min of ventricular fibrillation (VF). After VF, tissue concentrations of ATP, AMP, creatinine phosphate (CP), and lactate were measured. Perfusion of treatments started 30 s after onset of VF and was maintained throughout VF. CF during VF was greater (P less than 0.005) during perfusion of E (mean +/- SE, 5.73 +/- 0.15 ml/min) than NE (5.06 +/- 0.32 ml/min) or vehicle (5.11 +/- 0.18 ml/min). Oxygen consumption during VF was higher during perfusion of E (29.5 +/- 0.9 microliters.min(-1).g wet heart wt(-1)) than vehicle (27.3 +/- 0.7 microliters.min(-1).g(-1); P less than 0.05); average oxygen consumption during NE (27.6 +/- 1.4 microliters.min(-1).g(-1)) and vehicle were comparable. After NE, but not E, tissue AMP concentrations were significantly increased, and CP concentrations were reduced compared with vehicle (P less than 0.05). Enhanced consumption of high-energy phosphates during NE suggests that there is also an enhanced demand for oxygen. However, unlike during E, during NE this demand is not met by an augmented CF. Thus, compared with E, NE treatment during VF may increase the risk of hypoxic damage.
Equivalent pressure-volume area accounts for oxygen consumption of fibrillating heart
Authors: Yaku H. , Goto Y. , Futaki S. , Ohgoshi Y. , Kawaguchi O. , Suga H.
Published: December 2017

We attempted to find cardiac mechanical parameters to account for myocardial O2 consumption (VO2) during ventricular fibrillation (VF). We fully utilized the concept of pressure-volume (P-V) area (PVA), which is equivalent to the total mechanical energy generated by a ventricular contraction. We also utilized a multicompartment model consisting of multiple asynchronously contracting compartments, which we previously proposed to simulate the mechanics of a fibrillating ventricle. The model analysis had already validated the application of PVA to VF in terms of "equivalent PVA" (ePVA). ePVA is the area surrounded by the end-systolic and end-diastolic P-V relations in beating state and the isobaric P-V line at the VF pressure. ePVA is supposed to represent the total mechanical energy generated by single contractions of each compartment (or myocyte) in a fibrillating ventricle. We determined ePVA and correlated it with measured VO2 per minute (mVO2) at various ventricular volumes in electrically induced fibrillating left ventricles of the excised cross-circulated canine heart preparation. Correlation coefficient (r) of the mVO2-ePVA relation during VF was high (r = 0.95, P less than 0.01). Comparing mVO2 during VF with that in beating state at an unloaded ventricular volume, we calculated equivalent heart rate (eHR) as an estimate of the frequency of contractions of individual compartments (myocytes). With the use of both ePVA and eHR, mVO2 during VF at various ventricular volumes was estimated. The relation between estimated mVO2 and directly measured mVO2 was highly linear (r = 0.88, P less than 0.01), and the regression line almost agreed with the identity line (regression coefficient = 1.05). We conclude that the new ePVA and eHR concepts can reasonably account for VO2 during VF.
Cardiovascular responses to graded reductions in leg perfusion in exercising humans
Authors: Rowell L. B. , Savage M. V. , Chambers J. , Blackmon J. R.
Published: December 2017

Our objective was to determine whether the chemoreflex from human muscle is elicited by small graded reductions in muscle blood flow (MBF) during mild exercise or whether this reflex has an obvious threshold associated with large changes in femoral venous lactate and H+ levels (i.e., as in dogs with high muscle oxidative capacity). Seven subjects exercised supine at 40, 87, and 142 W; lower body positive pressure (LBPP) was applied in 3-min steps at 25, 35, 45, and 50-60 mmHg with the lower body and the cycle ergometer in a sealed box. Estimated MBF (Fick) fell by 5.3 +/- 4.3 to 19.9 +/- 3.8% at four levels of LBPP over three work rates. Mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine (NE) concentration rose with increasing LBPP. MAP was significantly correlated with femoral venous pH, lactate, O2 tension, and O2 content during moderate and heavy exercise, without an apparent threshold. Percentage decreases in muscle vascular conductance exceeded the decreases in MBF twofold, indicating significant opposition to reduction in MBF by the chemoreflex. Approximately 50% of the correction of MBF back toward control (i.e., at 0 LBPP) could be explained by increased cardiac output, calculated from the rise in HR; the remaining correction could be attributed to both sympathetic vasoconstriction (indicated by high NE levels) and to mechanical effects of partial occlusion. Results suggest that in humans stepwise reductions in MBF gradually elicit muscle chemoreflexes with no apparent threshold at these levels of exercise.
Activation in the region of parabrachial nucleus elicits neurogenically mediated coronary vasoconstriction
Authors: Miller F. J. , Marcus M. L. , Brody M. J. , Gutterman D. D.
Published: December 2017

A role for parabrachial nucleus in cardiovascular regulation is suggested by evidence that electrical stimulation in this region elicits increase in heart rate and arterial pressure. We hypothesized that parabrachial nucleus may also be involved in control of coronary vasomotor tone. After beta-adrenergic receptor blockade in anesthetized cats, electrical stimulation in the region of parabrachial nucleus produced no change in heart rate, an increase in arterial pressure (34 +/- 6 mmHg), and a transient reduction in coronary blood flow velocity (-21 +/- 2%). Coronary resistance (72 +/- 9%) and femoral resistance (189 +/- 31%) increased markedly. The decrease in coronary blood flow velocity was abolished by stellate ganglionectomy or alpha 1-adrenergic blockade without altering pressor or femoral responses. Injection of the neurotransmitter L-glutamate or kainic acid into parabrachial nucleus also elicited coronary vasoconstriction. We conclude that electrical or chemical activation in the region of parabrachial nucleus elicits coronary vasoconstriction as part of a generalized sympathetic activation. The fact that the coronary response is elicited by chemical activation suggests that cell bodies in the region of medial parabrachial nucleus and subceruleus, as opposed to fibers of passage, are involved in this central neural coronary vasoconstriction.
Calcium and cardioplegia in neonates: dose-response and time-response studies in rats
Authors: Riva E. , Hearse D. J.
Published: December 2017

Isolated Langendorff-perfused rat hearts (n = 6/group) were subjected to 60, 90, 120, or 180 min of ischemia with or without a 2-min preischemic infusion with St. Thomas' Hospital cardioplegic solution that had been modified to contain concentrations of calcium of 0, 0.5, 0.8, 1.0, 1.2, 1.8, or 2.4 mM. In general, irrespective of the calcium concentration, hearts in the cardioplegia group recovered better than those in the noncardioplegia group. There was no consistent relationship between calcium content and postischemic recovery of function or enzyme leakage after any of the durations of ischemia studied. However, as expected, there was a strong inverse relationship between recovery and duration of ischemia. The recovery of function correlated with enzyme leakage but not with the time to onset or magnitude of ischemic contracture. In conclusion, although the neonatal rat heart benefits from cardioplegia the protection is less impressive than that reported for adult hearts. Nonetheless, the neonatal heart appears to be very resistant to ischemia. We propose that many of these differences can be explained on the basis of differences in myocardial calcium handling between neonate and adult.
In vivo monitoring of myocardial interstitial norepinephrine by dialysis technique
Authors: Akiyama T. , Yamazaki T. , Ninomiya I.
Published: December 2017

To estimate local sympathetic nerve activity of the heart in vivo, we applied a dialysis technique to the heart and attempted to monitor norepinephrine levels in local myocardial interstitial fluid. The dialysis probe consisted of an 18 x 0.31 mm dialysis fiber with a 50,000-mol wt cutoff. When the probe was perfused at 5 microliters/min in vitro, the average relative recovery rate of norepinephrine was 31.3 +/- 0.6%. Dialysis probes were implanted in the left ventricular lateral wall of the beating heart in anesthetized cats and perfused with Ringer solution at 5 microliters/min. Dialysate norepinephrine concentration was measured using high-performance liquid chromatography with electrochemical detection. 1) After probe implantation, dialysate norepinephrine concentration decreased over the first 120 min and then reached an almost steady level (41.1 +/- 4.7 pg/ml). 2) Electrical stimulation of the left stellate ganglion increased dialysate norepinephrine concentration significantly, from control level of 39.0 +/- 5.8 to 82.0 +/- 7.7 pg/ml (P less than 0.01). After stimulation, dialysate norepinephrine concentration returned to the prestimulation level. The dialysis technique using high-performance liquid chromatography permits monitoring of norepinephrine levels in local myocardial interstitial fluid and detection of changes in local cardiac sympathetic nerve activity in vivo.
Interaction of pressure- and flow-induced responses in porcine coronary resistance vessels
Authors: Kuo L. , Chilian W. M. , Davis M. J.
Published: December 2017

Pressure-induced myogenic responses and flow-induced vasodilatory responses have been documented in coronary resistance arterioles, but the interaction of these two mechanisms and the nature of the flow-mediated response are not well understood. Experiments were designed to quantitatively study the interaction of pressure- and flow-induced responses and to characterize the nature of the substance responsible for flow-mediated dilation in isolated coronary arterioles. Subepicardial arterioles (40-80 microns) were isolated from pigs and cannulated with two glass micropipettes and then pressurized via independent reservoir systems. Flow was initiated by simultaneously moving the reservoirs in equal and opposite directions thus generating a pressure gradient (delta P) without changing the mean intraluminal pressure (IP). IP was changed by moving both reservoirs in the same direction to alter myogenic tone in the absence of flow (delta P = 0). Flow-mediated dilation competed with myogenic constriction when flow and pressure were elevated. Also, flow potentiated myogenic dilation when IP was decreased. The magnitude of flow-induced dilation was greatest at an intermediate level of vascular tone (IP = 60 cmH2O) but was attenuated at higher and lower levels of tone. In the presence of flow (delta P = 4 cmH2O), pressure-diameter relationships were shifted upward, and the magnitude of myogenic responsiveness was attenuated. Double-vessel bioassay studies indicated that a transferable substance was released from intact endothelium in response to flow. Flow-induced dilation was not affected by indomethacin but was abolished by NG-monomethyl-L-arginine or by mechanical removal of endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)
Behavioral arousal enhances inducibility and rate of ventricular tachycardia
Authors: Kirby D. A. , Pinto J. M. , Hottinger S. , Johnson D. A. , Lown B.
Published: December 2017

Behavioral arousal may trigger malignant cardiac arrhythmias. To study the effect of arousal on ventricular tachycardia, pigs were instrumented with catheters to measure mean arterial pressure and sample plasma catecholamines and left anterior descending coronary artery snares for occlusion 1 wk later. Bipolar pacing catheters were placed in the right ventricular apex to induce ventricular tachycardia. One week after occlusion, electrophysiological testing was repeated before and immediately after arousal caused either by restraining and lifting the pig in a canvas sling or by bringing a stall mate into the room. The number of stimuli needed to induce monomorphic ventricular tachycardia was reduced by both types of arousal (P less than 0.05) compared with control conditions. Ventricular tachycardia rate was increased 60 +/- 17 beats/min after lifting stimulation (P less than 0.05). When beta 1-receptor blockade was induced by metoprolol, inducibility of ventricular tachycardia and rate were not different from control. Thus, in pigs, arousal may facilitate arrhythmogenesis. This effect may be mediated by sympathetic neural activity in the heart because it was annulled by beta 1-adrenergic blockade.
Serotonergic responses in rabbit ophthalmic artery: a pharmacological characterization
Authors: Zschauer A. , van Breemen C. , Uusitalo H.
Published: December 2017

The contractile effect of serotonin (5-HT) on rabbit ophthalmic artery was studied. In a solution containing 20 mM K+ 5-HT induced a biphasic dose-response curve (DRC) in intact arteries. At normal extracellular K+ concentration ([K+]o), only high concentrations of 5-HT (greater than or equal to 1 microM) were able to induce contraction. In endothelium-denuded arteries 5-HT induced a DRC at normal [K+]o, which resembled that in intact arteries at 20 mM [K+]o. The high-potency portion of the 5-HT DRC was inhibited only by metitepine, whereas the low-potency portion was blocked by metitepine, methysergide, spiperone, and ketanserin, indicating that in this preparation the 5-HT1 receptor subtypes are more sensitive to 5-HT than the 5-HT2 receptor subtypes. Cyanopindolol had no effect on 5-HT-induced contraction. 8-Hydroxy-2-(di-n-propylamino)tetralin gave a contraction at high concentrations (greater than or equal to 0.1 microM), which was not blocked by cyanopindolol. The contractile response to 5-methoxytryptamine was similar to that for 5-HT. The results indicate that the 5-HT1 receptors of the ophthalmic artery belong either to 1C or 1D subtypes. 2-Methylserotonin, an agonist for 5-HT3 receptor, had no contractile effect on rabbit ophthalmic artery. The effect of prior exposure to 5-HT on norepinephrine (NE)-induced contraction was also studied. In intact arteries prior exposure to a low 5-HT concentration (10 nM) induced attenuation and prior exposure to a high 5-HT concentration (1 microM) gave potentiation of the NE-induced contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
Cholinergic regulation of adrenal medullary blood flow
Authors: Kennedy J. G. , Breslow M. J. , Tobin J. R. , Traystman R. J.
Published: December 2017

To determine the relative role of nicotinic and muscarinic mechanisms in splanchnic nerve stimulation (NS)-induced adrenal catecholamine secretion and medullary vasodilation, 12 pentobarbital-anesthetized dogs were subjected to three identical stimulations. The first NS was performed before drug administration and served as a control. The second NS was performed after administration of either the muscarinic antagonist, atropine 0.5 mg/kg (group 1), or the nicotinic antagonist, hexamethonium 20 mg/kg (group 2). The third NS was performed after administration of both drugs. NS in the absence of drug resulted in 4-fold and greater than 200-fold increases in medullary blood flow (Q, measured with radiolabeled microspheres) and catecholamine secretion (assayed by high-pressure liquid chromatography), respectively. Atropine, when administered alone (group 1), had no effect on these responses. Subsequent administration of hexamethonium to group 1 animals resulted in complete blockade of NS-induced changes in medullary Q and secretion. Hexamethonium alone (group 2) reduced the catecholamine response to NS by 95% but had no effect on the medullary Q response. Addition of atropine further attenuated the increase in catecholamine secretion induced by NS and completely blocked the medullary Q increase. These data suggest the presence of redundant mechanisms to increase medullary Q during NS. One mechanism likely involves neurally released acetylcholine-stimulating vascular muscarinic receptors, whereas the second requires either chromaffin cell degranulation or nicotinic ganglionic transmission.
Protein kinase C and phospholipase C in adenosine receptor-mediated relaxation in coronary artery
Authors: Cushing D. J. , Makujina S. R. , Sabouni M. H. , Mustafa S. J.
Published: December 2017

The effect of adenosine, 2-chloroadenosine (CAD), and 5'-(N-ethylcarboxamido)-adenosine (NECA) on the contraction produced by phorbol 12,13-dibutyrate (PDB) was investigated in porcine coronary artery in vitro to determine whether adenosine receptor-mediated relaxation was linked to protein kinase C. Also, the coronary relaxation produced by adenosine and NECA in KCl-contracted coronary rings was investigated before and after treatment with the phospholipase C inhibitor neomycin to examine a possible link between phospholipase C and adenosine receptor-mediated relaxation. Ring segments of coronary artery were suspended in organ baths for measurement of isometric force. PDB (10 nM-1 microM) caused concentration-dependent contraction, and this response was significantly attenuated by pretreatment with the protein kinase C inhibitor staurosporine (200 nM) but not 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (10 microM). Treatment of rings with either adenosine, CAD, or NECA (100 microM) significantly attenuated the PDB-induced contraction, whereas treatment with either sodium nitroprusside (SNP; 1 microM) or isoproterenol (Isop; 1 microM) did not affect the contraction produced by PDB. The attenuation of the PDB-induced contraction by adenosine and its analogues was blocked by prior treatment of the coronary rings with 8-phenyltheophylline (10 microM). In a separate series of experiments, pretreatment of rings with the phospholipase C inhibitor neomycin (1 mM) resulted in a significant attenuation of the relaxing response to both adenosine and NECA while having no significant effect on the relaxation-response to SNP or Isop. These results provide indirect evidence that adenosine receptor-mediated relaxation in porcine coronary artery may be linked to modulation of protein kinase C and phospholipase C.