bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct actions of cocaine on cardiac cellular electrical activity.
Authors: Przywara D A , Dambach G E
Published: June 2012

The hypothesis that cocaine has Class I-type antiarrhythmic drug effects was tested in tissues isolated from rabbit heart with standard microelectrode methods. Propranolol (1 microM) was used to block beta-adrenergic effects. The actions of cocaine on cellular electrophysiology were concentration- and time-dependent and were reversible. In paced right atrial (RA) and right ventricular papillary (RVP) tissues, cocaine produced a profound prolongation of the effective refractory period (ERP) assessed by either premature stimulation or minimum pacing interval. ERP was increased up to eightfold in RA tissue and doubled in RVP tissue by 60 microM cocaine. This concentration of cocaine depressed action potential phase 0 depolarization 80% in RA tissue and 53% in RVP tissue but had no effect on resting membrane potentials. Automaticity was moderately depressed in sinus node (34% decrease in rate) but not in tricuspid valve cells. Phase 0 depolarization was not altered in these spontaneously active slow-response cells. Repolarization was depressed in RA, tricuspid valve, and sinus node cells leading to a twofold increase in action potential duration during exposure to cocaine. Evidence from the effects on cellular action potentials suggests that cocaine affects both fast Na+ channels and repolarizing K+ but not Ca2+ channels. We conclude that cocaine has Class I-type activity and the effects on ERP are extreme.
Mechanism of action of EDRF on pressurized arteries: effect on K+ conductance.
Authors: Kauser K , Stekiel W J , Rubanyi G , Harder D R
Published: June 2012

Experiments were performed to study the cellular mechanism of endothelium-derived relaxing factor (EDRF) on vascular smooth muscle. Rat femoral arteries were cannulated and pressurized to 100 mm Hg. Vascular smooth muscle membrane potential (Em) and diameter responses to perfusion with 5 x 10(-6) M acetylcholine (ACh) were measured in vessels precontracted with 5 x 10(-6) M norepinephrine (NE). Hyperpolarization (-35 +/- 1.2 to -66 +/- 2.0 mV) and dilation were observed during ACh administration. Both responses were abolished on removal of the endothelium with collagenase. A bioassay was developed in which two vessel segments from the same artery were connected in series. The downstream vessel was deendothelialized while the endothelium of the upstream vessel remained intact. The protocol used was the same as in the first set of measurements. Hyperpolarization and dilation were observed in both vessels during ACh perfusion. However, when the direction of the perfusate flow in the bioassay system was reversed so that the deendothelialized vessel was upstream, only the "endothelium-intact" vessel demonstrated vascular smooth muscle hyperpolarization. To examine the ionic mechanism underlying the hyperpolarization presumably by released EDRF, the Em was measured as a function of increasing extracellular potassium ([K+]o). In the presence of ACh (but not NE) the maximum depolarization produced by a decade increase of [K+]o (10-100 mM) was 50 mV. In the deendothelialized vessel, this depolarization was decreased significantly to 39 mV. Addition to the superfusate of 10 mM tetraethylammonium, a K+ channel blocker, significantly reduced the hyperpolarization caused by ACh-induced EDRF release.(ABSTRACT TRUNCATED AT 250 WORDS)
Cholinergic constriction in the general circulation and its role in coronary artery spasm.
Authors: Kalsner S
Published: June 2012

The release of acetylcholine from autonomic nerves in those tissues that receive a cholinergic innervation is widely believed to dilate blood vessels. Exogenously administered acetylcholine in vivo does dilate vascular beds and produce hypotension; however, this latter effect is indirect and probably the result of liberation of endothelium-derived relaxing factor (EDRF) from endothelial cells. Some blood vessels contain a substantial population of medial constrictor receptors for acetylcholine, and the implications of this presence for vascular control systems has been largely ignored, although it needs to be considered. A survey of the evolution of vasomotor control systems indicates that acetylcholine serves principally as an excitatory transmitter to blood vessels. Neurally mediated cholinergic constriction and not dilation is found in fish, amphibians, reptiles, and birds, with responses initiated by medial muscarinic receptors. Acetylcholine constricts many vascular preparations from these lower animals, but some vessels relax, reflecting the emergence of an EDRF responsive to acetylcholine. An examination of cholinergic responses in mammalian vessels reveals that cholinergic (neurogenic) dilation is limited to a very few vascular beds and to only a few species. Both experimental evidence and evolutionary considerations support the likelihood that cholinergic (neural) constriction operates in some vascular regions in mammals and, in particular, in the coronary circulation of some species, including humans. In fact, constriction, and not dilation, may be the dominant vascular response to activation of the cholinergic axis in most mammals, including humans. The complications and contradictions introduced by the simultaneous presence of both EDRF and a cholinergic constrictor innervation involving medial muscarinic receptors are discussed. A variety of evidence is also presented that implicates cholinergic constriction in at least some instances of coronary artery spasm and sudden death.
Developmental changes in the electrophysiological properties and the beta-adrenergic receptor-effector complex in atrial fibers of the canine coronary sinus.
Authors: Horn E M , Johnson N J , Bilezikian J P , Rosen M R
Published: June 2012

beta-Adrenergic stimulation induced delayed afterdepolarizations and triggered activity in atrial fibers of adult but not young canine coronary sinus. However, sensitivity to beta-adrenergic agonists with respect to maximum diastolic potential was identical at both ages, and delayed afterdepolarizations and triggered activity did occur in response to ouabain. Age-dependent lengthening of the action potential duration and plateau also were seen and were greater in the adult than the young. beta-Adrenergic receptor density and affinity and the stimulatory guanine nucleotide regulatory protein (Gs) were similar in adult and young tissues. In contrast, the inhibitory guanine nucleotide regulatory protein (Gi) was 2.5-fold greater in adult (15 fmol/mg) than in young (6.0 fmol/mg) tissues. Basal- and forskolin-stimulated adenylate cyclase activities were greater in adult than young coronary sinus although the increment in isoproterenol-stimulated adenylate cyclase activity in young tissue was greater when compared either with basal levels or expressed as a percentage of maximal catalytic activity. Both the traditional effector pathway of beta-adrenergic action, involving the stimulation of adenylate cyclase activity, and developmental changes in the action potential plateau may contribute to the developmental changes in delayed afterdepolarizations and triggered activity.
Coronary angiogenesis during long-term hypertension and left ventricular hypertrophy in dogs.
Authors: Tomanek R J , Schalk K A , Marcus M L , Harrison D G
Published: June 2012

Many studies have documented that during the development of left ventricular hypertrophy (LVH) coronary vascular growth lags behind that of cardiac muscle. To ascertain whether significant growth of coronary resistance vessels occurs with long-standing hypertension and LVH, we studied dogs with Goldblatt (one-kidney, one-clip) hypertension seven months after surgery. Left ventricular minimal coronary vascular resistance (LV MCVR) was derived from adenosine-induced maximal flow measured with 15 microns microspheres. Morphometric data were based on perfuse-fixed hearts arrested in diastole. Hypertension and LVH were associated with a 46% increase in left ventricular weight/body weight ratio (LVH, 6.73 +/- 0.31; control, 4.62 +/- 0.30), no significant change in LV MCVR/100 g, and a reduction in total LV MCVR (LVH, 0.11 +/- 0.02 mm Hg/ml/min; control, 0.15 +/- 0.02 mm Hg/ml/min). Arterial and arteriolar wall/lumen ratios were virtually identical in the two groups. Arteriolar (lumen diameter less than 200 microns) numerical densities (arteriolar profiles/mm2) were also similar for the two groups even when analyzed according to lumen diameter size class and by ventricular location (epimyocardium, midmyocardium, and endomyocardium). Moreover, the relative frequency distribution of any arteriolar size class was similar for both groups. Because MCVR and arteriolar density were normal, this study provides new evidence that angiogenesis during long-term LVH in this model is of sufficient magnitude to enable the cross-sectional area of the coronary resistance vessels to increase in proportion to the increase in left ventricular mass.
Differential effect of physical exercise routines on ventricular myosin and peripheral catecholamine stores in normotensive and spontaneously hypertensive rats.
Authors: Rupp H
Published: June 2012

The influence of the adrenergic system on the population of ventricular myosin isoenzymes under physiological conditions was assessed by subjection of normotensive and spontaneously hypertensive rats (SHR) to different types of physical exercise that increased the activity of the peripheral adrenergic system to varying degrees. The routines, which were 5-6 weeks in duration, involved the mild exercise of enforced swimming (2 x 90 min/day), spontaneous running (daily, about 15 km/10-12 hr) that resulted in absolute ventricular hypertrophy, and enforced running of low intensity (daily, 2 x 1.8 km/3 hr) but associated with marked stressors. Swimming and spontaneous running reduced the high blood pressure of SHR, whereas enforced running increased it. In both strains, the myosin isoenzymes were redistributed in the direction of V1 after swimming but not after running. In SHR, therefore, reduction of pressure load seems insufficient for induction of a higher proportion of V1. The unique and, until now, unexplained effect of swimming was attributed to the pronounced activation of the peripheral adrenergic system as judged from catecholamine stores of ventricles and adrenal glands. Only swimming increased the norepinephrine content of ventricles and adrenal glands in normotensive rats. Swimming also had the strongest influence in SHR. Further evidence for the influence of the adrenergic system came from the effect of selective cardiac beta-blockade with atenolol (50 mg/kg/day). The diminished adrenergic drive of the heart reduced the proportion of V1 to a greater extent in the swimming rats than in the sedentary rats. Taken together, the data demonstrate that substantial changes in adrenergic activity occur under physiological conditions associated with an altered myosin heavy-chain expression.
Enhancement of potassium-sensitive current in heart cells by pinacidil. Evidence for modulation of the ATP-sensitive potassium channel.
Authors: Arena J P , Kass R S
Published: June 2012

Pinacidil belongs to a novel group of compounds that enhance the potassium permeability of vascular smooth muscle. Evidence also exists that this drug enhances the potassium permeability of cardiac tissue. The purpose of the present investigation was to determine if pinacidil alters potassium-channel activity in heart and, if so, which potassium channel is the target. We used the whole-cell arrangement of the patch voltage clamp to record membrane currents from isolated guinea pig ventricular cells. In solutions designed to isolate potassium currents, pinacidil enhances a time-independent current positive to the potassium equilibrium potential. Current measured at voltages negative to the potassium equilibrium potential are essentially unaltered by the drug. The potassium sensitivity of outward current indicates that the target for the drug is a potassium channel. Experiments designed to test for voltage-dependent channel gating strongly suggest that the pinacidil-sensitive current is not voltage gated. Pinacidil-sensitive current is blocked by externally applied Ba2+, Cs+, and tetraethylammonium ion. In addition, it is potently blocked after external application of 100 nM glibenclamide. Taken along with the time- and voltage-independent properties of pinacidil-sensitive current, this pharmacology strongly suggests that the target for pinacidil in heart is the ATP-sensitive potassium channel.
Biochemical kinetics of porcine cardiac subfragment-1. II. Pre-steady-state studies of the initial phosphate burst.
Authors: Stein L A , White M P , Annis D T
Published: June 2012

The actin dependence of the rate and magnitude of the initial phosphate burst was measured using both quench-flow and stopped-flow kinetic techniques. These studies revealed that even at high actin concentrations the magnitude of the phosphate burst was a significant fraction of the magnitude that exists in the absence of actin. Furthermore, it was shown that the rate of the burst rises rapidly as a function of the actin concentration. Detailed modeling with the four-state model revealed that if the predicted Vmax is constrained to be approximately equal to the extrapolated value (double reciprocal plot) and if the apparent dissociation constant of subfragment-1 to actin divided by the apparent activation constant of the actin-activated myosin ATPase activity (Kbinding/KATPase) is constrained to be considerably different from one, then the model is unable to simultaneously account for the ATPase activity and the rate and magnitude of the initial inorganic phosphate burst.
Prostaglandin E receptors in cardiac sarcolemma. Identification and coupling to adenylate cyclase.
Authors: Lopaschuk G D , Michalak M , Wandler E L , Lerner R W , Piscione T D , Coceani F , Olley P M
Published: June 2012

Purified cardiac sarcolemmal membrane vesicles were used to determine if specific prostaglandin (PG) receptors are present on the myocyte. Two binding sites for PGE2 were identified in isolated bovine sarcolemmal membranes: a high-affinity site with a dissociation constant (Kd) of 0.32 nM and a maximum binding (Bmax) of 376 fmol/mg of protein and a lower-affinity site with a Kd of 3.41 nM and a Bmax of 2,112 fmol/mg of protein. In competition experiments, unlabeled PGE1 displaced [3H]PGE2 from its membrane receptor at concentrations similar to those of unlabeled PGE2. Both PGF2 alpha and PGD2 displaced [3H]PGE2 from the membrane, but only at high concentrations (greater than 10(-6) M and greater than 10(-5)M, respectively). Digestion of sarcolemmal membrane with trypsin resulted in a threefold decrease in specific [3H]PGE2 binding. Phosphorylation of the membrane with protein kinase A also decreased specific [3H]PGE2 binding. At concentrations of PGE2 that occupy the high-affinity site, sarcolemmal adenylate cyclase activity was inhibited in the presence of 5'-guanylylimidodiphosphate [Gpp(NH)p]. We conclude that the isolated cardiac sarcolemmal membrane contains a high-affinity binding site for PGE2 that is functionally coupled to adenylate cyclase. The binding site is stereospecific and probably recognizes the 9-keto,11-hydroxyl portion of the ring structure of these prostaglandins.
Intracoronary injections of salbutamol demonstrate the presence of functional beta 2-adrenoceptors in the human heart.
Authors: Hall J A , Petch M C , Brown M J
Published: June 2012

To demonstrate the presence of functional cardiac beta 2-adrenoceptors in man, we studied the responses to intracoronary injections of salbutamol in three groups of six patients. We injected salbutamol, a selective beta 2-adrenoceptor agonist, into the right coronary artery to avoid peripheral vasodilator action and to stimulate the sinoatrial node directly. Salbutamol injections caused a sinus tachycardia. The same doses of salbutamol injected into the aortic root caused no change in heart rate, ruling out a systemic effect. The mean dose required to cause an increase in heart rate of 30 beats/min (IHR30) was 2.6 micrograms in the first group of six patients. In 12 other patients salbutamol was given after beta-blockade to confirm the beta 2-selectivity of the responses. Doses of practolol (beta 1-selective blockade) and of propranolol (beta 1- and beta 2-blockade) that had equal beta 1-blocking activity were used. In six patients who were given practolol, the mean IHR30 dose was 2.1 micrograms. In six patients who were given propranolol, the mean IHR30 dose was significantly greater at 64 micrograms (p less than 0.001, practolol vs. propranolol). This study demonstrates that direct cardiac beta 2-adrenoceptor stimulation in man has a positive chronotropic effect.
Enkephalinase inhibition increases plasma atrial natriuretic peptide levels, glomerular filtration rate, and urinary sodium excretion in rats with reduced renal mass.
Authors: Lafferty H M , Gunning M , Silva P , Zimmerman M B , Brenner B M , Anderson S
Published: June 2012

To investigate the in vivo effects of inhibition of endopeptidase 24.11, an enkephalinase enzyme shown to be involved in atrial natriuretic peptide (ANP) breakdown in vitro, we infused phosphoramidon, a specific inhibitor of endopeptidase 24.11, into rats with reduced renal mass (and chronic extracellular volume expansion) and into normal rats. Relative to baseline values in rats with remnant kidneys, phosphoramidon led to elevations of plasma ANP levels and concomitant increases in urinary sodium excretion, fractional excretion of sodium, glomerular filtration rate, filtration fraction, and urinary cyclic GMP excretion. Similar changes in renal function and urinary cyclic GMP excretion were obtained with thiorphan, another endopeptidase 24.11 inhibitor. These enhanced ANP levels and renal actions were not observed with phosphoramidon in normal rats. These results show that plasma ANP levels can be modulated in rats with reduced renal mass by inhibition of endopeptidase 24.11.
Natural course of the impairment of endothelium-dependent relaxations after balloon endothelium removal in porcine coronary arteries. Possible dysfunction of a pertussis toxin-sensitive G protein.
Authors: Shimokawa H , Flavahan N A , Vanhoutte P M
Published: June 2012

The purposes of the present study were to examine the natural course of the impairment of endothelium-dependent relaxations during a regeneration and tissue repair process after balloon endothelium removal and to elucidate the cellular mechanism(s) underlying it. Twenty-three male Yorkshire pigs underwent balloon endothelium removal along the proximal portion of either the left anterior descending or circumflex coronary artery and were then maintained on a regular chow for 4, 8, 16, or 24 weeks. Endothelium-dependent responses were examined in vitro in rings taken from the control and previously denuded arteries studied in parallel. Morphometric analysis revealed that intimal thickening developed only at the previously denuded area. In the previously denuded arteries with regenerated endothelium, the endothelium-dependent relaxations to UK 14304 (a selective alpha 2-adrenergic agonist), serotonin, and aggregating platelets were impaired 4 weeks after endothelium removal and remained so throughout the study. The endothelium-dependent relaxations to thrombin and adenosine diphosphate became depressed 8 weeks after endothelium removal and those to bradykinin became depressed 16 weeks after endothelium removal, while those to the calcium ionophore A23187 were maintained throughout the study. Endothelium-dependent relaxations to all vasoactive agents were unaltered in the control arteries. In the control arteries, pertussis toxin, an inhibitor of certain G proteins, markedly inhibited the endothelium-dependent relaxations to UK 14304 and serotonin and partially inhibited those to thrombin and aggregating platelets. The responses inhibited by the toxin in control arteries were significantly reduced in the reduced in the previously denuded arteries with regenerated endothelium. The inhibitory effect of pertussis toxin was markedly reduced in those arteries with regenerated endothelium. In quiescent rings, the presence of normal endothelium inhibited the contractions caused by serotonin and aggregating platelets; this endothelium-dependent depression was markedly impaired in the previously denuded arteries throughout the study. Direct relaxation of the coronary smooth muscle to nitric oxide or sodium nitroprusside or direct contraction to KCl or serotonin were comparable between the control and previously denuded arteries. These experiments indicate that endothelium-dependent relaxations progressively worsen after regeneration of the endothelium and that the dysfunction of a pertussis toxin-sensitive G protein partly account for the endothelial dysfunction in the chronic regenerated state.
Immunological identification of five troponin T isoforms reveals an elaborate maturational troponin T profile in rabbit myocardium.
Authors: Anderson P A , Oakeley A E
Published: June 2012

Myocardium is generally thought to express no more than two isoforms of troponin T (TnT). We have recently reported that TnT purified from rabbit myocardium is resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis into five proteins (TnT1, TnT2, TnT3, TnT4, and TnT5). In this study, these proteins are characterized immunologically and a novel elaborate maturational profile is described. Myocardium was obtained from 23 days of gestation fetal rabbits and 2-day, 6-week, 3-month, and 6-month postnatal rabbits. The major species in the adult myocardium, TnT4, was identified on sodium dodecyl sulfate-polyacrylamide gels and excised. The protein was electroeluted and purified. An amino acid microsequence of a cleaved fragment of this protein was found to be virtually identical to residues 86-99 from adult rabbit cardiac TnT. The protein, TnT4, was used to raise a polyclonal antibody. This antibody recognized all five isoforms from purified cardiac TnT, but none of the TnT isoforms from fast skeletal muscle. A monoclonal antibody, Mab JLT-12, raised against a highly conserved epitope of rabbit fast skeletal muscle, recognized all five cardiac as well as five skeletal muscle isoforms. Western blots performed on intact myocardial preparations demonstrated that TnT1, the cardiac isoform with the slowest electrophoretic mobility, was expressed prominently in the immature hearts, in addition to TnT2, TnT3, and TnT4, but TnT1 was not evident in the 3-month and 6-month postnatal hearts. The expression of TnT2 also decreased with maturation. Thus, the number of TnT isoforms expressed in the rabbit decreases with maturation.(ABSTRACT TRUNCATED AT 250 WORDS)
Tissue- and species-specific expression of inhibitory guanine nucleotide-binding proteins. Cloning of a full-length complementary DNA from canine heart.
Authors: Holmer S R , Stevens S , Homcy C J
Published: June 2012

Three different isoforms of the inhibitory guanine nucleotide-binding protein alpha-subunit (Gi alpha) have been cloned. However, little information on the cardiac-specific expression of these isoforms is available. The deduced amino acid sequence of a full-length Gi alpha 2 complementary DNA from a canine ventricular library displays several unique residues compared with those from other species. In contrast to previously described complementary DNA clones for Gi alpha 2, this complementary DNA has a complete 3'-untranslated region with the expected consensus sequence for polyadenylation. Gi alpha 2 is the predominant isoform in the heart, and its message level of 14.7 +/- 4.9 pg/10 micrograms total ventricular RNA is about fourfold lower than that of the stimulatory guanine nucleotide-binding protein.
Metabolic recovery of acidotic rabbit cardiac muscle: effects of low pH and oxygen shortage.
Authors: Mast F , Elzinga G
Published: June 2012

Heat production during and after contraction of isolated rabbit papillary muscles was measured at 20 degrees C with metal-film thermopiles. Under control conditions (0.2 Hz, pH 7.4) total heat and steady-state force production due to 120 twitches were 1.0 +/- 0.4 J/g and 29.5 +/- 5.1 mN/mm2 (mean +/- SD; n = 5), respectively. Increasing the CO2 of the bicarbonate-buffered superfusate from 5% (pH 7.4) to 24% (pH 6.6) led to a decrease of force and heat production, 54% and 72%, respectively, of the control value. The recovery heat-time constant, reflecting the time course of oxidative phosphorylation, increased from 23.0 +/- 5.1 seconds at pH 7.4 to 69.5 +/- 34.7 seconds at pH 6.6. The ratio of recovery and initial heat equaled 1.06 under both conditions. Enhancing the metabolic rate by increasing the stimulation frequency to 1.0 Hz led, after an initial maximum, to a decline of force and heat presumably as the consequence of shortage of oxygen in the muscle core. The recovery phase in this case was characterized by a double exponential function having time constants of 7.6 and 64.4 seconds. When pH was lowered to 6.6 together with the enhancement of the stimulation frequency to 1 Hz, an additional exothermal process, unrelated to force production, was observed during contraction and for some time thereafter. It was concluded that severe acidosis slows down the rate of oxidative phosphorylation and may reduce the economy of contraction. However, it does not change the nature of recovery and initial heat processes.(ABSTRACT TRUNCATED AT 250 WORDS)
Rabbit polymorphonuclear neutrophils elicit endothelium-dependent contraction in vascular smooth muscle.
Authors: Ohlstein E H , Nichols A J
Published: June 2012

The present studies were designed to investigate the interaction between activated polymorphonuclear neutrophils (PMNs) and endothelial regulation of vascular smooth muscle function. Rabbit peritoneal PMNs (4 x 10(3)-4 x 10(5) cells/ml) added to muscle bath chambers containing phenylephrine-precontracted rabbit isolated aortic rings produced no effect on vascular tone. However, when PMNs were activated with the chemotactic peptide, f-met-leu-phe (0.1 microM), PMNs produced concentration-dependent vascular contraction, which was dependent on the presence of the endothelium. Aortic rings denuded of endothelium were unaffected by activated PMNs. Superoxide dismutase (100 units/ml) treatment of tissues blocked completely PMN-induced vascular contraction, whereas mannitol (20 mM) had no significant effect on PMN-induced vascular contraction. Pyrogallol (a generator of superoxide anion) produced a response that was similar to that observed with activated PMNs. Superoxide anion production was measured separately, and the time of peak rate of superoxide anion production corresponded to the time of the maximal vascular contractile responses. Activated PMNs added to vascular tissues undergoing endothelium-dependent relaxation mediated by either acetylcholine or A23187 produced a reversal of vascular relaxation. Furthermore, activated PMNs did not have any effect on endothelium-independent vascular relaxation produced by either isoproterenol or nitroglycerin. The present investigation reveals that activated PMNs can release superoxide anion and produce endothelium-dependent contraction. The endothelium-dependent contraction may be the result of superoxide anion inactivation of endothelium-derived relaxing factor.
Air trapping in the lungs during cardiopulmonary resuscitation in dogs. A mechanism for generating changes in intrathoracic pressure.
Authors: Halperin H R , Brower R , Weisfeldt M L , Tsitlik J E , Chandra N , Cristiano L M , Fessler H , Beyar R , Wurmb E , Guerci A D
Published: June 2012

To test the hypothesis that during cardiopulmonary resuscitation, chest compression with an unobstructed trachea raises and maintains intrathoracic pressure by collapsing airways and trapping air in the lung, we studied 11 dogs (20-32 kg). An inflatable vest compressed the thorax after induction of ventricular fibrillation. First, tracheal airflow was measured by a pneumotachometer during vest inflation and deflation in nine of the dogs. As expected, during the initial phase of vest inflation of cycles after ventilation, air moved out of the lungs, but then airflow stopped. After vest deflation, however, more air moved out of the lungs in eight of the nine dogs; this occurrence indicated that a portion of the inspired tidal volume was trapped during vest inflation. During cycles without prior ventilation, the amount of air expired by chest compression decreased, paradoxically, at higher peak vest pressure (p less than 0.002); this occurrence indicated that air was trapped at the higher vest pressures. The change in right atrial pressure was higher on cycles after ventilation than on cycles without prior ventilation (79 +/- 12 vs. 67 +/- 12 mm Hg [mean +/- SEM], p less than 0.005), and lung volume was higher on cycles after ventilation (p less than 0.001). Next, a 5-Fr micromanometer was advanced down the airway in eight of the dogs. With the tip of the micromanometer 5-8 cm distal to the carina, a zone of high pressure was noted in seven dogs; this high pressure suggested a zone of airway collapse distal to the carina.(ABSTRACT TRUNCATED AT 250 WORDS)
Electrophysiology and ultrastructure of canine subendocardial Purkinje cells isolated from control and 24-hour infarcted hearts.
Authors: Boyden P A , Albala A , Dresdner K P
Published: June 2012

Ventricular arrhythmias that accompany myocardial infarction in dogs may be secondary to the altered electrophysiological properties of the subendocardial Purkinje fibers that survive 24 hours after the coronary occlusion. To better understand the ionic mechanisms that underlie the altered electrical activity of these fibers, we have dispersed, using an enzymatic technique, Purkinje cells from the subendocardium of the infarcted ventricle (IZPCs) and compared their electrical and structural properties to Purkinje cells dispersed from fiber strands (SPCs) and from the subendocardium of the noninfarcted ventricle (NZPCs). Ultrastructural analysis of these cells shows that IZPCs contain an increased number of lipid droplets when compared with the SPCs and NZPCs. In addition, transmembrane action potentials of IZPCs have reduced resting potentials, action potential amplitudes, and upstroke velocity and are increased in duration when compared with either SPCs or NZPCs. Input resistance of IZPCs is increased over that measured in control cells (SPCs and NZPCs). Furthermore, the time course of the process of electrical restitution of action potential duration is altered in IZPCs with long action potentials. Finally, using K+-sensitive microelectrode techniques, we have determined that intracellular free K+ activity (aKi) in IZPCs (93.7 +/- 15 mM) is not significantly different from control aKi measurements (SPC, 106 +/- 13 mM; NZPC, 103 +/- 12 mM). Thus a reduction in aKi does not provide a basis for the reduced resting potentials observed in IZPCs. By studying the relation between the resting potential and log [K+]o we determined that in IZPCs with reduced resting potentials, there is a significant increase in the PNa/PK ratio when compared with control. In summary, to better understand the cellular basis of ventricular arrhythmias postinfarction, we have developed a single cell model that will allow for more rigorous electrophysiological studies of the specific ionic currents that underlie the abnormal electrophysiology.
Subendomyocardial exhaustion of blood flow reserve and increased fibrosis in conscious dogs with heart failure.
Authors: Hittinger L , Shannon R P , Bishop S P , Gelpi R J , Vatner S F
Published: June 2012

The effects of near-maximal coronary vasodilation were examined in conscious dogs with left ventricular (LV) failure after pressure overload hypertrophy induced by either aortic banding alone or aortic banding plus a peripheral arteriovenous shunt. The findings were compared with results in littermates with compensated LV hypertrophy and with a third group of normal dogs. At rest, there was a marked difference in the intramyocardial distribution of coronary flow, measured with radiolabeled microspheres. The endocardial/epicardial (endo/epi) flow ratio in the LV failure dogs was 0.96 +/- 0.08 as compared with control dogs (1.28 +/- 0.06, p less than 0.05) or dogs with compensated LV hypertrophy (1.23 +/- 0.08, p less than 0.05). During near-maximal coronary vasodilation with adenosine, all groups showed similar increases in subepimyocardial (epi) flow. While significant increases in subendomyocardial (endo) flow during adenosine infusion were seen in the control group (0.88 +/- 0.10 to 3.53 +/- 0.24 ml/min/g) and in dogs with compensated LV hypertrophy (1.12 +/- 0.14 to 3.60 +/- 0.16 ml/min/g), there was no change in endo flow in the LV failure dogs (1.55 +/- 0.20 to 1.71 +/- 0.47 ml/min/g) and a further significant reduction in the endo/epi flow ratio was observed (0.30 +/- 0.06, p less than 0.01). These hemodynamic changes were associated with chronic multifocal interstitial or discrete areas of fibrosis observed preferentially in endo layers. Thus, endo flow reserve is nearly exhausted in dogs with decompensated pressure overload LV hypertrophy, which may induced periodic episodes of endo ischemia resulting in myocyte necrosis and fibrosis, which in turn results in exacerbation of LV failure.
Degree and time sequence of hypothermic protection against experimental ischemic acute renal failure.
Authors: Zager R A , Gmur D J , Bredl C R , Eng M J
Published: June 2012

The purpose of this study was to assess the degree, time sequence, and biochemical correlates of hypothermic protection against ischemic acute renal failure. Rats subjected to 40 minutes of bilateral renal artery occlusion (RAO) were made mildly hypothermic (32 degrees-33 degrees C, by cold saline peritoneal lavage) during the following time periods: 1) RAO only, 2) reperfusion only (beginning at 0, 15, 30, or 60 minutes after RAO and maintained for 45 minutes), or 3) during and after (0-45 minutes) RAO. Continuously normothermic (37 degrees C) RAO rats served as controls. The control rats developed severe acute renal failure (blood urea nitrogen [BUN], 95 +/- 4 mg/dl; creatinine, 2.2 +/- 0.1 mg/dl; and extensive tubular necrosis at 24 hours). Hypothermia confined to RAO was highly protective (BUN, 33 +/- 5 mg/dl; creatinine, 0.62 +/- 0.07 mg/dl; and minimal necrosis). Hypothermia partially preserved ischemic renal adenylate high-energy phosphate (ATP and ADP), increased AMP and inosine monophosphate concentrations, and lessened hypoxanthine/xanthine buildup (assessed at end of RAO). Hypothermia confined to the reflow period (beginning at 0, 15, and 30 minutes) was only mildly protective (e.g., BUN, 58-63 mg/dl); the degree of protection did not differ according to the time of hypothermic onset. Lowering reflow temperature to 26 degrees C had no added benefit. Hypothermia that started at 60 minutes after RAO conferred no protection. Combining ischemic and postischemic hypothermia abolished all renal failure (assessed at 24 hours). This study offers the following conclusions: Mild hypothermia can totally prevent experimental ischemic acute renal failure. Hypothermia is highly effective during ischemia, and it is mildly protective during early reflow; these benefits are additive. During early reflow, hypothermic protection is not critically time dependent. By 60 minutes of reflow, no effect is elicited; this absence of effect possibly signals completion of the reperfusion injury process. Hypothermia's protective effects may be mediated, in part, by improvements in renal adenine nucleotide content and, possibly, by decreasing postischemic oxidant stress.
Protection by superoxide dismutase from myocardial dysfunction and attenuation of vasodilator reserve after coronary occlusion and reperfusion in dog.
Authors: Mehta J L , Nichols W W , Donnelly W H , Lawson D L , Thompson L , ter Riet M , Saldeen T G
Published: June 2012

Previous studies indicate impairment of coronary arterial ring relaxation and loss of coronary vasodilator reserve after coronary artery occlusion and reperfusion. These changes are mediated in part through loss of endothelium-derived relaxing factor (EDRF) and/or myocardial neutrophil accumulation. To examine if superoxide dismutase (SOD), a scavenger of superoxide radicals, would modify the diminished coronary vasodilator reserve after temporary coronary occlusion in the intact animal, open-chest mongrel dogs were subjected to 1 hour of circumflex (Cx) coronary artery occlusion followed by 1 hour of reperfusion and treated with saline or SOD. Before Cx occlusion, coronary blood flow increased, and vascular resistance decreased (both p less than 0.01) in response to EDRF-dependent vasodilator acetylcholine as well as EDRF-independent vasodilator nitroglycerin. After Cx reperfusion, resting Cx coronary blood flow and vascular resistance were similar to the preocclusion values. In the saline-treated animals, there was evidence of myocardial dysfunction, which was measured by segmental shortening (-6 +/- 2% vs. 10 +/- 2%). Furthermore, increase in Cx coronary blood flow and reduction in vascular resistance in response to both vasodilators were significantly (p less than 0.01) impaired; these occurrences suggested loss of coronary vasodilator reserve. Myocardial histology showed extensive capillary plugging by neutrophils in the Cx-supplied myocardium. Myocardial myeloperoxidase activity, an index of neutrophil infiltration, was also increased in the Cx compared with the left anterior descending coronary artery region (p less than 0.02). Treatment of dogs with SOD, started at the end of Cx occlusion and continued during reperfusion, exerted significant (p less than 0.01) protective effect against reperfusion-induced attenuation of coronary vasodilator reserve in response to both acetylcholine and nitroglycerin. Loss of myocardial function (segmental shortening 5 +/- 1% vs. 10 +/- 1%) was less than in the saline-treated animals (p less than 0.01). Cx region-myocardial neutrophil accumulation and myeloperoxidase activity were also less (p less than 0.02) in the SOD-treated than in the saline-treated dogs. These observations suggest that coronary reperfusion impairs coronary vasodilator reserve in intact dogs. This impairment can be modified by treatment of animals with SOD before reperfusion. Capillary plugging by neutrophils may contribute to the altered coronary vasodilator reserve observed in the immediate postreperfusion period, and SOD modifies this reperfusion-induced impairment.
Mathematical model of the changes in heart rate elicited by vagal stimulation.
Authors: Dexter F , Levy M N , Rudy Y
Published: June 2012

We developed a mathematical model of the underlying cellular mechanisms responsible for the changes in sinus cycle length (SCL) elicited by vagal stimulation in intact animals. The model incorporated a stimulation-mediated depletion of the releasable pool of acetylcholine (ACh) in the nerve endings, the in vitro reaction kinetics of acetylcholinesterase, and the electrical activity of a pacemaker cell with six membrane ionic currents. SCL increased linearly with the frequency of simulated vagal stimulation, as it does in animal experiments, because the concentration of ACh in the neuroeffector junction [( ACh]) saturated as the frequency of stimulation was increased and because SCL increased geometrically in response to increases in [ACh]. The dependence of SCL on the timing of vagal stimulation in the cardiac cycle resulted, in part, from the dependence of [ACh] on SCL. Simulated vagal stimulation entrained the sinus node because the rate of activation and inactivation of ACh-activated K+ channels depended only weakly on membrane potential during diastolic depolarization. SCL increased geometrically with [ACh], because 1) during diastolic depolarization, the amplitude of the ACh-activated K+ current was approximately equal to the amplitude of the sum of the other ionic currents, 2) [ACh] was low enough to saturate neither acetylcholinesterase nor the cellular system that activates the ACh-activated K+ channels, 3) the pacemaker cell membrane behaved electrotonically like a capacitor, and 4) the sum of all the ionic currents increased linearly with the amplitude of the ACh-activated K+ current.
Central nervous system mechanisms involved in inhibition of renal sympathetic nerve activity induced by arginine vasopressin.
Authors: Suzuki S , Takeshita A , Imaizumi T , Hirooka Y , Yoshida M , Ando S , Nakamura M
Published: June 2012

Previous studies have suggested that intravenous infusion of arginine vasopressin (AVP) inhibits sympathetic nerve activity (SNA) in rabbits by its action at the brainstem. This study aimed to determine, first, whether this action of AVP depended on functioning baroreflex mechanisms. The second aim was to determine the role of the nucleus tractus solitarii (NTS) in mediating this action of AVP. Experiments were performed in rabbits anesthetized with alpha-chloralose. Intravenous infusions of AVP (1, 3, and 10 mU/kg/min) resulted in progressive inhibition of renal SNA in rabbits with intact arterial baroreceptors and vagal afferents as well as in rabbits with sinoaortic denervation and bilateral vagotomy. The magnitudes of renal SNA inhibition evoked with AVP were comparable in the two groups. Renal SNA inhibition evoked with AVP at doses of 1 and 3 mU/kg/min in rabbits after sinoaortic denervation and vagotomy was totally blocked by chemical lesions with kainic acid of the bilateral NTS or the area postrema. Lesions of the NTS or the area postrema markedly attenuated (by about 60%) but did not totally block the response evoked with AVP at a dose of 10 mU/kg/min. AVP microinjected directly into the NTS did not evoke changes in renal SNA or arterial pressure, whereas AVP microinjected into the area postrema suppressed renal SNA. These results suggest that intravenous AVP at lower doses inhibited renal SNA by causing excitation of the NTS neurons, and this action of AVP did not depend on functioning baroreflex mechanisms. The second suggestion is that the NTS was unlikely to be the site where AVP directly interacted but instead received a neural connection, presumably from the area postrema, where AVP might directly interact.
Contribution of the baroreflex afferent nerves to the production of vasoconstricted hypertension in volume-expanded dogs.
Authors: Otsuka A , Ogihara T , Mikami H , Kohara K , Katahira K , Tsunetoshi T , Kumahara Y
Published: June 2012

Dextran in lactated Ringer's solution (20 ml/kg) was infused for 1 hour into anesthetized dogs with sinoaortic denervation and vagotomy (deafferentation; n = 10) and dogs treated with hexamethonium (de-efferentation; n = 13) to compare with our previous observation in dogs with an intact autonomic nervous system (control, n = 34). During the infusion, increase in blood pressure associated with increase in cardiac output was observed in all three groups. The increases in blood pressure were larger in the two groups with an impaired autonomic nervous system. In the recovery period, the control dogs and the hexamethonium-treated dogs showed gradual increases in total peripheral resistance and in vasoconstricted hypertension 3 hours after stopping the infusion. In contrast, the dogs with sinoaortic denervation and vagotomy did not show any increase in total peripheral resistance. The vasoconstricted groups showed peaks of natriuresis soon after the infusion, not 3 hours after the infusion when vasoconstriction was observed, although the dogs with deafferentation did not show a significant increase in natriuresis. Norepinephrine (0.5 micrograms/kg) was administered intravenously before and after volume expansion, and the pressor responses in the three groups after volume expansion were enhanced similarly (143%, 128%, and 136%, respectively). These results indicate that the afferent signals from peripheral vessels to the brain contribute to the production of vasoconstricted hypertension after acute volume expansion and that the vasoconstriction is independent of pressor hypersensitivity and is dissociated in time from the natriuresis.
Pressure-induced vasoconstriction of renal microvessels in normotensive and hypertensive rats. Studies in the isolated perfused hydronephrotic kidney.
Authors: Hayashi K , Epstein M , Loutzenhiser R
Published: June 2012

The capacity of small arteries to respond to increased intravascular pressure may be altered in hypertension. In the kidney, hypertension is associated with a compensatory shift in the autoregulatory response to pressure. To directly determine the effects of established hypertension on the renal microvascular response to changes of perfusion pressure, we evaluated pressure-induced vasoconstriction in hydronephrotic kidneys isolated from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Vessel diameters of interlobular arteries (ILAs) and afferent and efferent arterioles were determined by computer-assisted videomicroscopy during alterations in renal arterial pressure (RAP) from 80 to 180 mm Hg. Increased RAP induced a pressure-dependent vasoconstriction in preglomerular vessels (afferent arterioles and ILAs), but not in postglomerular vessels (efferent arterioles). The calcium antagonist nifedipine prevented pressure-induced afferent arteriolar vasoconstriction with a similar half-maximal inhibitory concentration (IC50) (WKY, 63 +/- 27 vs. SHR, 60 +/- 32 nM). The pressure-activation curves for ILAs in SHR and WKY were similar. In contrast, the pressure-activation curve for afferent arterioles in SHR kidneys exhibited a rightward shift, which was observed at every segment of the afferent arteriole (i.e., near ILA, at midportion, and near glomerulus). These findings demonstrate that the ILA and the afferent arteriole both possess the ability to constrict in response to increased pressure, whereas this property is lacking in the efferent arteriole. Hypertension was associated with a compensatory shift in the pressure response of the afferent arteriole, such that higher RAPs were required to elicit vasoconstriction in this vessel.