bluuebunny/crossref_metadata_2025 huggingface dataset:
Ca-antagonistic effects of adenosine in guinea pig atrial cells
Authors: Cerbai E. , Klockner U. , Isenberg G.
Published: December 2017

In atrial myocytes of the guinea pig, the effects of adenosine (Ado) and acetylcholine (ACh) on Ca currents (ICa) were investigated with the patch-electrode whole cell clamp technique. ICa was dissected from net currents by blocking K currents (IK) with intra- and extracellular Cs ions. ICa was considered as "basal" ICa, since it was not prestimulated by beta-agonists (isoproterenol). T-channel Ca currents were insensitive to Ado or ACh. The antagonism of L-channel Ca currents was maximal with 10 microM Ado or 3 microM ACh, which reduced basal ICa by 35%. From the concentration dependence, a dissociation constant (KD) value of 1.1 microM Ado and a Hill coefficient of -3 were obtained. Ado and ACh were not additive but saturative in reducing basal ICa. Reduction of basal ICa did not modify inactivation time-course, steady-state activation or inactivation, suggesting that Ado reduces the number of functional Ca channels. In myocytes with unblocked IK (KCl electrodes), 3 microM Ado (1 microM ACh) reduced ICa by 30% but increased IK by 300%. It is concluded that the K-agonistic rather than the Ca-antagonistic effect accounts for hyperpolarization as well as for most of the shortening of the action potential and the negative inotropy.
Mechanism of adenosine receptor-induced renal vasoconstriction in rats
Authors: Rossi N. , Churchill P. , Ellis V. , Amore B.
Published: December 2017

Adenosine analogues selective for the A1 subclass of adenosine receptors, such as N6-cyclohexyladenosine (CHA), induce vasoconstriction in the isolated rat kidney perfused at constant flow. Presumably, the vasoconstriction is mediated by increased Ca2+ concentration in renal vascular smooth muscle cells, but the mechanism by which A1 adenosine receptor occupation leads to increased Ca2+ is unknown. In the present experiments, the isolated, perfused rat kidney vasoconstricted in response to CHA, to K depolarization, and to BAY K 8644 (a Ca2+ channel agonist). All of these responses were completely blocked by methoxyverapamil, which suggests that CHA, like K depolarization and BAY K 8644, induces renal vasoconstriction by increasing Ca2+ influx through potential operated Ca2+ channels. The mechanism of action of CHA was different, however, in that pertussis toxin treatment blocked the response to CHA without affecting the responses to K depolarization or to BAY K 8644. Therefore, a pertussis toxin-sensitive step must intervene between occupation of A1 adenosine receptors on renal vascular smooth muscle cells and increased Ca2+ influx through potential-operated Ca2+ channels.
Hyperpolarization and increased free calcium in acetylcholine-stimulated endothelial cells
Authors: Busse R. , Fichtner H. , Luckhoff A. , Kohlhardt M.
Published: December 2017

In freshly harvested aortic endothelial cells from rabbits, some cellular events associated with stimulation by acetylcholine (ACh) were analyzed. ACh (3 microM) induced a transient hyperpolarization of 8.3 +/- 2.5 mV, which peaked within 3-5 s and subsequently declined with a similar time course. Hyperpolarization was caused by a transient Ca2+-dependent outward current (IoACh), which was mainly carried by K+. ACh (3 and 10 microM) also evoked transient dose-dependent increases in the intracellular free Ca2+ concentration (Ca2+i). Pretreatment with atropine (1 and 3 microM) abolished both responses to ACh, the increase in Ca2+i as well as the transient outward current. It is concluded that IoACh and the rise in Ca2+i are two manifestations of muscarinic receptor stimulation. The rise in Ca2+i might be the primary event, leading to secondary membrane hyperpolarization.
Isolation of a translation-inhibiting peptide from myocardium
Authors: Havre P. A. , Hammond G. L.
Published: December 2017

We previously reported that an initial response to acute cardiac stress is temporary translational inhibition. Using an in vitro translational assay to follow activity, we purified a translation-inhibiting peptide (TIP) obtained from control canine hearts and hearts acutely stressed by ascending aortic banding and heat shock for 1 h. We isolated a 17-kDa peptide. The amino acid composition was determined and residues 3-20 were sequenced. Treatment of polysome preparations with TIP shifted the polysome distribution profile to that characteristic of the acutely stressed heart in which monosomes predominate. Translational inhibition acted by suppressing formation of the 80S initiation complex. Suppression curves indicate that translation is inhibited by approximately 60%, with the translation of protein over 30 kDa being highly suppressed. We postulate that translational inhibition is an essential initial reaction to acute stress that allows the cell to redirect energy into vita cell functions that permit long-term adaptation to the stress. We believe that translational inhibition is effected by intracellular activator of TIP.
Vascular reactivity and permeability to serotonin in cyclooxygenase-inhibited dog lung
Authors: Hofman W. F. , Ehrhart I. C.
Published: December 2017

We examined the effects of serotonin (5-HT) infusion on hemodynamics, vascular compliance (Cvasc), and the filtration coefficient (Kf) in the isolated canine lower left lung lobe (LLL) perfused at constant flow. In one group (5-HT; n = 8), 5-HT was infused at 55 micrograms/min for 35 min and then at 105 micrograms/min for 15 min before and during a Kf determination. Cyclooxygenase inhibition (COI) was induced by 40 microM indomethacin (n = 4) or 45 microM meclofenamate (n = 4) before 5-HT infusion in a second group (5-HTCOI; n = 8). Control LLLs (n = 8) were given equivalent volumes of saline. The pulmonary arterial pressure (Pa) increase to 55 micrograms/min 5-HT (3.0 +/- 0.6 Torr; 43.7%) was nearly doubled (P less than 0.01) with COI (10.5 +/- 1.5 Torr; 83.3%), while LLL weight decreased 6.2 g/100 g in both groups. With 5-HT infusion, the dose-dependent increase in Pa, lobar vascular resistance, and precapillary resistance was greater (P less than 0.05) in the 5-HTCOI than the 5-HT group, but capillary pressure (Pc) was not increased from base-line values. Kf values did not differ (P greater than 0.05) among groups but Cvasc was reduced (P less than 0.05) in the 5-HTCOI group. We found that 5-HT increases Pa, but does not appear to promote microvessel fluid filtration by increasing Pc or the Kf. The enhanced and sustained pressor response to 5-HT with COI suggests that vasodilatory prostaglandins may modulate pressor responses to 5-HT.
Naloxone alters organ perfusion during endotoxin shock in conscious rats
Authors: Law W. R. , Ferguson J. L.
Published: December 2017

Antagonism of endogenous opioids has been shown to improve survival time, increase blood pressure, and attenuate acidosis during endotoxin shock. However, some of the most severe problems associated with this condition arise from the circulatory disturbances that occur. We investigated the circulatory effects of naloxone during endotoxin shock as they relate to hemodynamic parameters in conscious, unrestrained rats. Blood flow and hemodynamic variables were measured in male, Sprague-Dawley rats (300-400 g) 24 h after surgical preparation. Rats were challenged with either 10 mg/kg Escherichia coli endotoxin (100% lethal dose) or intravenous saline. Measurements were made at 0, 10, 30, and 60 min postchallenge. Naloxone (2 mg/kg) or saline was given as a treatment (intravenous bolus) at 25 min postchallenge. Cardiac output and blood distribution (%CO) and flow were measured with radiolabeled microspheres. Cardiac output was depressed and total peripheral resistance was elevated 10 min into endotoxin shock. Naloxone treatment improved blood pressure significantly during endotoxin shock, as would be expected with the observed increase in total peripheral vascular resistance and no significant change in cardiac output. Improved perfusion of skeletal muscle is a likely explanation for lower serum lactate levels that have been reported to occur in this model after naloxone administration. Our data also indicate that naloxone may improve cardiac efficiency and does not interfere with maintenance of global cerebral blood flow. Collectively, these effects would contribute to the observed improved survival time after naloxone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of phenylephrine on calcium current and contractility of feline ventricular myocytes
Authors: Hartmann H. A. , Mazzocca N. J. , Kleiman R. B. , Houser S. R.
Published: December 2017

Previous studies on numerous cardiac preparations have shown that stimulation of alpha 1-receptors produces a positive inotropic effect. The cellular basis for this effect is not well understood. Isolated feline ventricular myocytes were used in the present study to examine the idea that the increase in contractility induced by stimulation of alpha 1-receptors is produced by an increase in inward Ca2+ current and that this event is caused by the stimulation of protein kinase C (PKC). These experiments showed that phenylephrine (10(-4) M) increased Ca2+ current from 0.56 +/- 0.02 (control) to 1.12 +/- 0.25 nA and increased contractile magnitude by 201 +/- 28%. The effect on Ca2+ current was completely blocked by propranolol (10(-7)M), whereas after beta-receptor blockade, contractile state was still 130 +/- 8% of control levels. alpha 1-Receptor blockade by prazosin eliminated this residual inotropic component of phenylephrine. Lower concentrations of phenylephrine (10(-7)M) were without effect on Ca2+ current and contractility as was stimulation of PCK with 150 nM of a phorbol ester. These results suggest that the positive inotropic effect of alpha 1-receptor stimulation in adult feline ventricular myocytes is not produced by increasing inward Ca2+ current and that this response is also not associated with stimulation of PKC.
Cerebral blood flow and interstitial fluid adenosine during hemorrhagic hypotension
Authors: Van Wylen D. G. , Park T. S. , Rubio R. , Berne R. M.
Published: December 2017

This study was designed to assess the role of adenosine in autoregulation of cerebral blood flow (CBF) with the use of the brain dialysis technique to sample cerebral interstitial fluid (ISF) and hydrogen clearance to measure local CBF in ketamine-anesthetized rats. In group 1 (n = 11), animals were hemorrhaged to reduce mean arterial blood pressure (MABP) from control levels (MABP = 101.1 +/- 2.6) to 80, 70, 60, 50, 40, and 30 mmHg. Cerebral autoregulation was evidenced by no significant decrease in CBF until MABP decreased to 60 mmHg. However, dialysate adenosine concentration did not increase until MABP decreased to 50 mmHg. In group 2 (bilateral dialysis; n = 11), in which the left carotid artery was ligated before reductions in MABP, left-side dialysate adenosine concentration increased at a MABP of 70 mmHg. In group 3 (bilateral dialysis; n = 6), one dialysis probe was perfused with artificial cerebrospinal fluid containing 10(-3) M 8(p-sulfophenyl)theophylline (8-SPT), an adenosine receptor antagonist, during reduction of MABP to 50 mmHg. Although there were similar reductions in CBF with or without adenosine receptor blockade, dialysate adenosine concentration was greater on the side of locally infused 8-SPT at a MABP of 50 mmHg. These data suggest that adenosine is not responsible for cerebral autoregulation at blood pressures greater than 50 mmHg but may contribute to the decrease in cerebral vascular resistance observed at arterial pressures below the autoregulatory range.
Muscarinic regulation of pulmonary intravascular volume in isolated canine lungs
Authors: Bell L. , Rutlen D. L.
Published: December 2017

The influence of acetylcholine on pulmonary intravascular volume has not been clearly identified. In 14 anesthetized dogs, the pulmonary circulation was separately perfused in situ at a constant rate and drained to an extracorporeal reservoir, so that changes in total pulmonary intravascular volume could be recorded as reciprocal changes in reservoir volume. In eight animals, acetylcholine at 100 micrograms/min for 20 min was associated with increases in pulmonary intravascular volume (PIV) and pulmonary arterial pressure of 41 +/- 5 (SE) ml (P less than 0.001) and 2.0 +/- 0.0 mmHg (P less than 0.001; 11 infusions), respectively. These responses were abolished after atropine (6 infusions). In six animals, pulmonary venous pressure was also measured, so that total pulmonary (TPR), pulmonary arterial (PAR), and pulmonary venous (PVR) resistances could be calculated. TPR and PVR increased from 21 +/- 2 to 24 +/- 3 (P less than 0.001) and from 7 +/- 1 to 11 +/- 1 mmHg.min.l-1 (P less than 0.001), respectively, while PAR did not change significantly (6 infusions). In three of the six animals, these changes were abolished by atropine (6 infusions). In the other three animals, PIV increased 56 +/- 11 ml (P less than 0.001) before and 47 +/- 6 ml (P less than 0.001) after indomethacin. The acetylcholine-associated increases in TPR and PVR were also not significantly attenuated after indomethacin. Hence, muscarinic receptor stimulation with acetylcholine is associated with an increase in pulmonary intravascular volume, which is mediated by an increase in resistance to pulmonary venous outflow. These changes are not due to release of prostanoids.(ABSTRACT TRUNCATED AT 250 WORDS)
Coronary dilation with carotid chemoreceptor stimulation in cardiac-denervated dogs
Authors: Nagata Masayoshi , Pichet Robert , Lavallee Michel
Published: December 2017

The coronary vasodilation that is secondary to carotid chemoreceptor stimulation (CCS) was compared in normal (N) and in cardiac-denervated (CD) conscious dogs. Under base-line conditions, CD only differed from N dogs by greater ( P ≤ 0.01) increases in mean arterial pressure (MAP) with CCS. Coronary blood flow (CBF) increased similarly in N (146 ± 18%) and CD (126 ± 15%) dogs, and coronary resistance (CR) fell to a similar extent in N (53 ± 3%) and CD (43 ± 5%) dogs. After muscarinic and β-adrenergic blockade, CCS resulted in similar increases in MAP in N and CD dogs; increases in CBF averaged 122 ± 15 and 115 ± 12% in N and CD dogs, respectively. Decreases in CR with CCS averaged 46 ± 3 and 40 ± 5% in N and CD dogs, respectively. α1-Adrenergic blockade prevented the increases in MAP with CCS and resulted in smaller (P < 0.01) increases in CBF, similar in N (77 ± 13%) and in CD (69 ± 10%) dogs. CR fell to the same extent in N (40 ± 4%) and CD (37 ± 5%) dogs. Additional blockade of agr2-adrenergic receptors further limited the increases in CBF with CCS in N (20 ± 5%) and CD (28 ± 7%) dogs; decreases in CR were attenuated similarly in N (13 ± 5%) and CD (21 ± 5%) dogs. Thus, in conscious dogs, cardiac nerves contribute little to the coronary dilation after carotid chemoreceptor stimulation.

chemoreflex; α-adrenergic receptors; cardiac denervation

Submitted on January 11, 1988

Accepted on July 28, 1988
Demonstration of hysteresis in refractoriness of canine ventricular myocardium
Authors: Giorgi C. , Vermeulen M. , Cardinal R. , Savard P. , Nadeau R. , Shenasa M.
Published: December 2017

The properties and determinants of hysteresis during ventricular effective refractory period (VERP) measurements by an extrastimulus technique were determined in 15 anesthetized open-chest dogs as well as in isolated ventricular muscle (n = 6). VERP was determined both by decreasing the S1-S2 interval and also by increasing S1S2. Hysteresis was then calculated by subtracting the VERP obtained with the decreasing S1S2 from the VERP obtained with the increasing S1S2. The effects of basic cycle length, pulse width, stimulation intensity, and the number of basic drives on VERP and hysteresis were evaluated. VERP was shorter for long pulse width, high stimulation intensities, and shorter basic cycle lengths. These modifications were not associated with significant changes of hysteresis. VERP was shorter during decreasing S1S2 than during increasing S1S2. Hysteresis was greater with 6 basic drive cycles than with 12 (P less than 0.001) in both in vivo and in vitro preparations. The data suggest that 1) hysteresis occurs during VERP measurements; 2) hysteresis is independent of stimulation modality; and 3) hysteresis decreases with the number of basic drive cycles.
Mechanism of inhibition by methacholine of norepinephrine-stimulated ANP secretion
Authors: Schiebinger R. J.
Published: December 2017

We have previously reported that methacholine inhibits norepinephrine-stimulated immunoreactive atrial natriuretic peptide (ANP-IR) secretion by 65% in vitro. In the present study, we examined the mechanism by which methacholine inhibits norepinephrine-stimulated secretion using isolated, paced rat left atria superfused in vitro. Norepinephrine has beta- and alpha-adrenergic properties, both of which stimulate ANP secretion. Thus we separately examined the effect of 10 microM methacholine on ANP-IR secretion stimulated by the beta-adrenergic agonist isoproterenol (0.1 microM) and by the alpha-adrenergic agonist phenylephrine (10 microM). Methacholine lowered isoproterenol-stimulated ANP-IR secretion to base line but did not inhibit phenylephrine-stimulated ANP-IR secretion. Atria were superfused with 0.5 mM dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP) to determine whether inhibition of isoproterenol-stimulated secretion by methacholine occurred by a reduction in adenylate cyclase activity or at a point distal to cAMP. Methacholine inhibited dibutyryl cAMP-stimulated ANP-IR secretion by 50%. This inhibition could not be reversed by 20 microM isobutylmethylxanthine. We conclude that 1) methacholine completely blocks isoproterenol-stimulated ANP-IR secretion; 2) inhibition appears to be primarily due to a decrease in adenylate cyclase activity; however, inhibition occurs at a point(s) distal to cAMP production; 3) methacholine does not inhibit phenylephrine-stimulated ANP-IR secretion; and 4) inhibition by methacholine of norepinephrine-stimulated ANP-IR secretion reflects a block in beta-adrenergic activity.
Calcium currents in normal and hypertrophied isolated feline ventricular myocytes
Authors: Kleiman R. B. , Houser S. R.
Published: December 2017

The magnitude and kinetics of the slow inward calcium current (Isi) were compared in single right ventricular myocytes that were isolated from normal cats and cats with right ventricular hypertrophy. Peak inward current density was greater in hypertrophy than normal myocytes (-20.4 +/- 15.3 vs. -10.4 +/- 8.8 microA/cm2, P less than 0.05). When we blocked early outward currents with intracellular CsCl, however, the peak magnitude of Isi was shown to be similar in hypertrophy and normal myocytes (-16.4 +/- 11.2 vs. -12.7 +/- 3.0 microA/cm2, P = NS). The increased net inward current in hypertrophy was thus due to a decrease in Cs-sensitive early outward current rather than an increase in the magnitude of Isi. The fast component of inactivation of Isi was similar in hypertrophy and normal myocytes, but the slow component was delayed in hypertrophy (slow time constant; tau slow = 75.9 +/- 14.7 ms vs. tau slow = 60.6 +/- 4.9 ms, P less than 0.05). These abnormalities of Isi may contribute to the prolonged duration of the action potential and of contraction in hypertrophied myocardium, but a defect in excitation-contraction coupling distal to Isi appears to produce the diminished magnitude of contraction.
Alpha-adrenergic vasoconstriction and receptor subtypes in large coronary arteries of calves
Authors: Young M. A. , Vatner D. E. , Knight D. R. , Graham R. M. , Homcy C. J. , Vatner S. F.
Published: December 2017

We investigated alpha-adrenoceptor subtype distribution in large coronary arteries from both functional and biochemical perspectives. The effects of intracoronary administration of the selective alpha 1-adrenoceptor agonist phenylephrine (0.1–5.0 micrograms/kg ic), of the selective alpha 2-adrenoceptor agonist B-HT 920 (0.1–5.0 micrograms/kg ic), and of the mixed alpha 1 + 2-adrenoceptor agonist norepinephrine (0.01–0.5 micrograms/kg ic) were examined on measurements of left circumflex coronary artery diameter in conscious calves. After beta-adrenergic blockade, equivalent reductions in large coronary artery diameter were observed with phenylephrine (-6.9 +/- 0.7%), B-HT (-5.9 +/- 0.5%), and norepinephrine (-6.0 +/- 0.4%). Phenylephrine-induced constrictions were abolished by prazosin, an alpha 1-selective antagonist, but unaffected by rauwolscine, an alpha 2-selective antagonist. Conversely, the B-HT-induced constriction was abolished by rauwolscine but unaffected by prazosin. Coronary constriction with norepinephrine was attenuated with either prazosin or rauwolscine and abolished by the two antagonists combined. Ligand-binding studies in which [3H]prazosin and [3H]rauwolscine and sarcolemmal membranes were used revealed an alpha 1-adrenoceptor density of 15 +/- 3.1 fmol/mg protein with a dissociation constant (KD) of 0.7 +/- 0.2 nM and an alpha 2-adrenoceptor density of 68 +/- 5.1 fmol/mg protein, with a KD of 7.4 +/- 1.2 nM. Thus large coronary arteries of the calf contain both alpha 1- and alpha 2-adrenoceptor subtypes, each of which elicits constriction of the large coronary artery in the conscious animal.
Separation of rate of left ventricular relaxation from chamber stiffness in rats
Authors: Momomura S. , Iizuka M. , Serizawa T. , Sugimoto T.
Published: December 2017

To test the hypothesis that the rate of left ventricular relaxation can be dissociated from left ventricular stiffness, indexes of stiffness and relaxation were evaluated during mild hypoxia and hypoxia with isoproterenol or caffeine in isovolumically beating, isolated rat heart preparations. In group 1, the hearts were perfused with mild hypoxic buffer for 30 min. In group 2, 10 min of mild hypoxic perfusion was followed by 20 min of mild hypoxia plus isoproterenol (10(-6) M). In group 3, the hearts were perfused with mild hypoxic buffer for 10 min followed by 20 min of hypoxia plus caffeine (10(-3) M) perfusion. In group 1, left ventricular end-diastolic pressure (LVEDP) was elevated only slightly, and time constant of left ventricular relaxation T was also prolonged slightly. In group 2, LVEDP was higher, but T was much shorter than the corresponding values in group 1 (LVEDP, 18 +/- 4 mmHg; T, 31.4 +/- 3.4 ms). In group 3, T was more markedly prolonged, and LVEDP tended to be higher than in group 1. These results indicate that the determinants of left ventricular relaxation and stiffness are not identical and that in certain conditions relaxation can be separated from left ventricular stiffness.
Effect of adenosine and its analogues on calcium influx in coronary artery
Authors: Ramagopal M. V. , Mustafa S. J.
Published: December 2017

In the present study, we have investigated the changes in calcium influx during the relaxing responses to adenosine and its analogues. Calcium-45 influx was measured in bovine coronary artery rings in the presence of prostaglandin F2 alpha (10(-5) M) and KCl (50 and 100 mM). Prostaglandin F2 alpha and KCl caused increases in calcium influx. Prostaglandin F2 alpha produced a further contraction when added to rings maximally contracted with KCl (100 mM or higher), suggesting two different mechanisms for prostaglandin F2 alpha- and KCl-induced contractions. Similarly, a greater calcium influx was observed when prostaglandin F2 alpha was mixed with KCl (50 or 100 mM). At all the concentrations tested, adenosine and its analogues [5'-(N-ethyl-carboxamidoadenosine, NECA; N6-(L-2-phenylisopropyl)adenosine, L-PIA] significantly inhibited prostaglandin F2 alpha-induced increases in calcium influx. However, only higher concentrations of adenosine, NECA, and L-PIA inhibited 100 mM KCl-induced calcium influx. Previous treatment with 8-phenyltheophylline blocked the inhibitory actions of adenosine, NECA, and L-PIA on calcium influx. The inhibition of calcium influx by adenosine, NECA, and L-PIA correlated well with their relaxing ability in the presence of prostaglandin F2 alpha. The data suggest that prostaglandin F2 alpha-induced calcium influx was more sensitive to the action of adenosine and its analogues than the calcium influx induced by high K+ depolarization.
Magnesium and reperfusion of ischemic rat heart as assessed by 31P-NMR
Authors: Borchgrevink P. C. , Bergan A. S. , Bakoy O. E. , Jynge P.
Published: December 2017

Isolated rat heart perfusion and high-resolution phosphate-31 nuclear magnetic resonance (31P-NMR) spectroscopy were used to elucidate the effects of Mg during reperfusion of the ischemic myocardium. After an ischemic period of 9 min, the hearts were reperfused with 0, 0.6, or 2.4 mM Mg during the entire 24-min reperfusion period or with 15 mM Mg during the first 12 min before returning to the physiological concentration of 0.6 mM during the last 12 min. Free intracellular Mg calculated by 31P-NMR rose during ischemia and fell gradually during reperfusion. The two groups reperfused with 15 mM Mg exhibited a significantly enhanced rate of recovery of adenosine triphosphate, creatine phosphate, intracellular pH, and coronary flow rate than the three other groups. Myocardial potassium was significantly higher, and inorganic phosphate was significantly lower at the end of the reperfusion period in these groups. The hearts reperfused with 0 mM Mg presented a significantly higher frequency of ventricular fibrillation (VF) than the other groups. It is concluded that reperfusion with high Mg improves the postischemic recovery of metabolism and function in the rat heart, whereas a Mg-free reperfusion solution increases the frequency of VF.
Activation of renal sympathetic outflow by intracisternal hypertonic NaCl in dogs
Authors: Abe I. , Averill D. B. , Ferrario C. M.
Published: December 2017

The neurohormonal and sympathetic nervous system responses to injection of hypertonic NaCl (1.5 M) into the cisterna magna were investigated in morphine-pentobarbital-anesthetized dogs (n = 8). Mean arterial blood pressure (MAP), heart rate (HR), and integrated efferent renal sympathetic nerve activity (ERSNA) were recorded, and blood samples were taken for the determination of plasma concentrations of epinephrine (Epi), norepinephrine (NE), arginine vasopressin (AVP), osmolality, plasma renin activity (PRA), and serum sodium and potassium. By 2 min after injection of hypertonic NaCl into the cisterna magna, significant increases were observed for MAP (+47 +/- 5 mmHg, P less than 0.01), HR (+59 +/- 11 beats/min, P less than 0.01), and ERSNA (+47 +/- 16%, P less than 0.01) above base line. The increased activity of the sympathetic nervous system was not accompanied by changes in PRA, Epi, NE, or AVP. Hypertonic NaCl was injected into the cisterna magna of six dogs before and after intravenous administration of the AVP antagonist [d(CH2)5Tyr(Me)]AVP. The time course for increases in MAP, HR, and ERSNA was not affected by AVP blockade. Subsequent administration of hexamethonium chloride abolished the pressor, tachycardic, and ERSNA responses elicited by cisterna magna injection of hypertonic NaCl. These experiments indicate that hypertonic NaCl acts at the lower brain stem to activate the sympathetic nervous system. Further, the pressor and tachycardic responses evoked by hypertonic NaCl acting at the lower brain stem do not appear to involve the hypothalamic-hypophysial-adrenal axis.
Cervical sympathectomy and cerebral microvascular and blood flow responses to hypocapnic hypoxia
Authors: Kissen I. , Weiss H. R.
Published: December 2017

This study evaluated the effects of bilateral superior cervical ganglionectomy on cerebral blood flow (CBF) and utilization of brain capillary reserve in conscious rats during normoxia and hypoxia (8% O2 in N2). Regional CBF was determined in sham-lesioned and ganglionectomized rats with [14C]iodoantipyrine. The percentage of the total volume fraction and number of perfused capillaries was determined by comparing the perfused microvessels, identified by the presence of fluorescein isothiocyanate dextran, with the total microvascular bed, identified by alkaline phosphatase stain. There were no significant differences in regional CBF between control and ganglionectomized rats under normoxic conditions. CBF increased significantly during hypoxia in both control and control ganglionectomized rats. In control, hypoxic flow to caudal structures was significantly higher than to rostral structures and that differential response was prevented by ganglionectomy. There was no significant difference in the number of perfused microvessels between sham-lesioned and ganglionectomized rats during normoxia. The number of perfused arterioles and capillaries was significantly higher under hypoxic conditions than under normoxic conditions in sham and ganglionectomized animals. During hypoxia, the percent of arterioles per squared millimeter perfused increased to 63 +/- 5% in sham-lesioned rats and to a significantly greater extent, 80 +/- 6%, in ganglionectomized rats. The percentage of capillaries per squared millimeter perfused changed similarly. The peripheral sympathetic nervous system appeared to play an important role in the control of cerebral microvascular response to hypoxia.
Canine myocardial creatine kinase isoenzyme response to coronary artery occlusion
Authors: Sharkey S. W. , Elsperger K. J. , Murakami M. , Apple F. S.
Published: December 2017

The response of the myocardial creatine kinase system to acute coronary artery occlusion is not well defined. In the present study, we measured serial changes in myocardial creatine kinase and creatine kinase-MB activities after acute occlusion of the left anterior descending (LAD) coronary artery in 20 open-chest pentobarbital-anesthetized dogs. Tissue samples were obtained from both ischemic and nonischemic left ventricular myocardium at base line and 1-, 3-, and 5-h intervals after LAD occlusion and assayed for total creatine kinase and the isoenzymes creatine kinase-MM, and creatine kinase-MB. Total creatine kinase activity declined significantly in both the ischemic and the nonischemic tissue because of a decline in creatine kinase-MM activity. Concomitantly, creatine kinase-MB activity increased significantly in both the ischemic and the nonischemic tissue. These changes were observed when the duration of the LAD occlusion was 3 h or longer, but not when the duration of the occlusion was 1 h. Thus acute myocardial ischemia causes pronounced changes in the canine myocardial creatine kinase system. These rapid biochemical alterations occur both locally in ischemic tissue and remotely in nonischemic tissue.
Mathematical model of dependence of heart rate on tissue concentration of acetylcholine
Authors: Dexter F. , Saidel G. M. , Levy M. N. , Rudy Y.
Published: December 2017

The change in sinus period elicited by vagal stimulation depends on the rate of acetylcholine (ACh) release from the nerve endings, the rate of ACh degradation in the nodal tissue, and the responsiveness of the sinus node to ACh. Vagal stimulation in anesthetized dogs prolonged sinus period. After cessation of vagal stimulation, the sinus period returned to the prestimulation period. We developed a mathematical model to analyze the dynamics of ACh degradation in the neuroeffector junction and the dependence of sinus period on the concentration of ACh. From the in vitro reaction kinetics of acetylcholinesterase, we derived an analytical expression for the rate of ACh degradation in the intact animal. Our model represents the electrical behavior of the sinus node by the electrical activity of one pacemaker cell with six membrane ionic currents. This model predicts the decline in sinus period of the intact anesthetized dog as acetylcholinesterase degrades ACh in the neuroeffector junction. The half-life of ACh after cessation of vagal stimulation was estimated to be 2.7 s. We conclude that following termination of vagal stimulation, the sinus node of the intact animal responds to ACh as if the sinus node were one oscillator.
Effects of arginine vasopressin on hemodynamics and lung fluid balance in lambs
Authors: Gest A. L. , Moise A. A. , Hansen T. N. , Kaplan S.
Published: December 2017

The purpose of this project was to study the effects of increased plasma concentrations of arginine vasopressin (AVP) on hemodynamics and lung fluid balance in lambs. We studied 16 unanesthetized newborn lambs during a base-line period and while infusing AVP into a hindlimb vein at 1.65 +/- 0.12 and 2.98 +/- 0.15 mU.kg-1.min-1. We measured aortic, pulmonary arterial, and left atrial pressures and heart rate continuously and cardiac output at frequent intervals. In five additional experiments, we collected samples of pure lung lymph during a base-line period and while infusing AVP at 2.02 +/- 0.15 mU.kg-1.min-1. AVP infusion increased plasma concentrations of AVP to 11.3 +/- 5.2 and 19.9 +/- 5.2 microU/ml at the low and high rates of infusion, respectively. Both aortic and left atrial pressures increased at the low rate of infusion (11 and 3 Torr, respectively) but remained unchanged at the higher rate. Systemic vascular resistance increased, and heart rate and cardiac output decreased at each rate of infusion. In fact, at the higher rate of infusion cardiac output decreased 38% when compared with base line. Neither pulmonary artery pressure nor pulmonary vascular resistance was affected by infusion of AVP. Despite the increase in left atrial pressure, the rate of lung lymph flow was not affected by the infusion of AVP, whereas the lymph-to-plasma protein ratio decreased slightly but significantly from 0.64 +/- 0.02 to 0.60 +/- 0.02.(ABSTRACT TRUNCATED AT 250 WORDS)
Pericardial pressure attenuates release of atriopeptin in volume-expanded dogs
Authors: Stone J. A. , Wilkes P. R. , Keane P. M. , Smith E. R. , Tyberg J. V.
Published: December 2017

The role of the pericardium in the release of atriopeptin (AP) was examined, utilizing two separate protocols, in alpha-chloralose-anesthetized dogs. Protocol I consisted of an experimental group (9 dogs), in which the pericardium was incised to allow instrumentation and reapproximated, and a control group (6 dogs), in which the pericardium was left undisturbed. In the experimental group, mean right atrial pressure (Pra) was elevated from a control value of 1.8 +/- 0.9 mmHg (mean +/- SD) to 8.3 +/- 0.8 mmHg for 40 min by volume expansion with isoncotic, lactated Ringer solution. After this period of volume expansion, the pericardium was removed while holding Pra at 8 mmHg. During volume expansion, arterial blood samples for AP analysis were taken at 5, 10, 15, 20, 30, and 40 min, pre- and postpericardiectomy. A similar protocol was followed in the control group. At a Pra of 8 mmHg prepericardiectomy, the plasma AP concentration was 76 +/- 17 pM/l and 74 +/- 38 pM/l in the experimental and control groups, respectively. However, after pericardiectomy, AP levels increased significantly in both the experimental group (136 +/- 41 pM/l; P less than 0.001) and the control group (107 +/- 53 pM/l; P less than 0.025). In protocol II (6 dogs), the pericardium was removed before volume expansion, and Pra was elevated by 2- to 3-mmHg increments and maintained for periods of 13 min at each pressure. AP concentration did not increase until Pra reached 3-4 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)
Cerebral blood flow and evoked potentials during Cushing response in sheep
Authors: Koehler R. C. , Backofen J. E. , McPherson R. W. , Jones M. D. , Rogers M. C. , Traystman R. J.
Published: December 2017

We determined how alterations in systemic hemodynamics, characteristic of the Cushing response, are related to changes in cerebral blood flow (CBF), cerebral metabolic rate of O2 (CMRO2), and brain electrical conductive function, as assessed by somatosensory-evoked potentials (SEP) and brain stem auditory-evoked responses (BAER). In three groups of eight pentobarbital-anesthetized sheep, intracranial pressure was gradually elevated to within 50, 25, or 0 mmHg of base-line mean arterial pressure and then held constant for 40 min by intraventricular infusion of mock cerebrospinal fluid. Microsphere-determined CBF fell when cerebral perfusion pressure was less than 50 mmHg. CMRO2 fell when CBF fell greater than 30-40%. Mean aortic pressure and cardiac output increased when CBF fell greater than 40%, i.e., at approximately the level at which CMRO2 fell. Furthermore, the magnitude of the increase in arterial pressure and cardiac output correlated with the reduction of CMRO2. SEP latency did not increase unless CBF fell greater than 55-65%, corresponding to a 20-30% reduction of CMRO2. Increased latency of BAER wave V was associated with a fall in midbrain blood flow of greater than 65-70%. Thus increase in SEP and BAER latencies required reductions of flow greater than those required to elicit a systemic response. This demonstrates that there is a range of intracranial pressure over which the increase in arterial pressure preserves sufficient CBF to sustain minimal electrical conductive function. The best predictor of the onset and magnitude of the Cushing response in adult sheep is the decrease in CMRO2.
Kinetic analysis of cerebrovascular transport based on indicator diffusion technique
Authors: Sawada Y. , Patlak C. S. , Blasberg R. G.
Published: December 2017

The indicator diffusion method was used for studies of the blood-brain barrier in rats and [131I]iodoantipyrine (IAP) was used as a highly diffusable model test substance. Interlaminar (Taylor) diffusion and effects of red cell carriage were studied with 57Co-diethylene-triaminepentaacetic acid (DTPA), 125I-human serum albumin, and 46Sc-microspheres (15 microns diameter). Vascular shunting from the pterygopalatine artery (PPA) into the torcula sinus was observed in some animals, and ligation of the PPA was required to obtain reliable data. Dilution curve of the reference compound was corrected to compensate for any difference in interlaminar diffusion and red cell plus protein carriage of the test substance. Apparent extraction ratio of IAP was calculated for each torcula sinus sample and found to increase during the initial phase of the dilution curve, reach a peak of approximately 0.85, and fall during the latter portion of the curve. These results suggest a heterogeneity of intravascular transit times in the cerebral circulation and a rapid efflux of IAP from brain into venous blood. Because of the topography of cerebral capillaries, we developed a modification of the distributed model for intravascular transit and capillary exchange proposed by Goresky et al. (J. Clin. Invest. 52: 991-1009, 1973) and Rose and Goresky (Circ. Res. 34:541-554, 1976); this modification included a well-mixed tissue compartment, as suggested by Johnson and Wilson (Am. J. Physiol. 210: 1299-1303, 1966) and is named the tissue homogeneity model. The experimental data was analyzed by both the tissue homogeneity and Goresky models. The estimated mean extraction E (0.95 and 0.94) and the estimated permeability-surface area product of influx (PS)1 (3.1 and 2.8 ml.min-1.g-1) for IAP in a whole blood injectate were similar using the two different models. The efflux rate constant (k2) for IAP was consistently smaller when the tissue homogeneity model was used (0.13 +/- 0.02 s-1) vs. that obtained with the Goresky model (0.18 +/- 0.02 s-1). Model simulations also indicated that the efflux parameter k2 was most sensitive to the choice of kinetic models, but we could not discriminate between the two model analyses on the basis of the "quality of fit." Nevertheless, from anatomical considerations, we suggest that the tissue homogeneity model may be more appropriate fro brain.
Modulation of Ca2+ channel selectivity and cardiac contraction by photorelease of Ca2+
Authors: Nabauer M. , Ellis-Davies G. C. , Kaplan J. H. , Morad M.
Published: December 2017

The effect of rapid increases of extracellular Ca2+ concentration on tension development and Ca2+ channel selectivity has been investigated in frog (Rana pipiens) ventricular myocardium using a novel light-sensitive Ca2+ chelator, dimethoxy-nitrophen. Dimethoxy-nitrophen is a photolabile tetracarboxylate Ca2+ chelator that on photolysis to dicarboxylate fragments alters its affinity (Kd) for Ca2+ from 5 X 10(-9) to 2 X 10(-3) M. A single 160-microseconds ultraviolet light pulse induced the release of approximately 80-100 microM Ca2+ with a half-time of 200 microseconds. In low extracellular Ca2+ concentration, Na+ current through the Ca2+ channel was blocked by photorelease of extracellular Ca2+ in less than 500 microseconds; nevertheless, 60-80 ms were required to activate or enhance tension. Enhancement of tension was more effective when Ca2+ was released during the activation of the Ca2+ channel than during its inactivation. The voltage dependence of enhanced tension, caused by photorelease of Ca2+, was bell shaped and was similar to that of Ca2+ current. These findings suggest that Ca2+ transport through the Ca2+ channel is the primary mechanism for the transport of Ca2+ to activate tension in the frog heart. The use of dimethoxy-nitrophen makes it possible to examine the rapid kinetics of the Ca-dependent processes involved in regulation of channel function and contraction.
Rate of oxygen loss from arterioles is an order of magnitude higher than expected
Authors: Popel A. S. , Pittman R. N. , Ellsworth M. L.
Published: December 2017

The experimental data on oxygen flux from arterioles in the hamster cheek pouch retractor muscle [L. Kuo and R. N. Pittman, Am. J. Physiol. 254 (Heart Circ. Physiol. 23): H331-H339, 1988] were analyzed under the assumption that the permeability to oxygen is the same in both perfused and unperfused tissue; permeability is defined as the product of the diffusion and solubility coefficients. However, our analysis indicated that the observed oxygen flux was inconsistent with this assumption and that permeability to oxygen of a blood-perfused tissue may be an order of magnitude higher than previously assumed.
Inhibition of platelet hemostatic plug formation by trigramin, a novel RGD-peptide
Authors: Cook J. J. , Huang T. F. , Rucinski B. , Strzyzewski M. , Tuma R. F. , Williams J. A. , Niewiarowski S.
Published: December 2017

Trigramin, a cysteine rich, RGD (Arg-Gly-Asp)-containing peptide from Trimeresurus gramineus snake venom (Mr 7,500) has been previously reported to inhibit fibrinogen binding to ADP-activated platelets and platelet aggregation (disassociation constant 10(-8) M). The present study demonstrates that the infusion of trigramin (17-212 micrograms/100 g body wt) significantly prolonged the bleeding time of severed mesenteric arteries in hamsters (anesthetized with 65 mg/kg pentobarbital), whereas the infusion of RGDS (Arg-Gly-Asp-Ser, 0.45-1.0 mg/100 g body wt) failed to increase the bleeding time in this model. The bleeding time immediately returned to normal after cessation of trigramin infusion. The pattern of the disappearance of 125I-labeled trigramin from the circulation fit a two-compartment model with the half-life for the fast component between 0.7 and 2.0 min and with the half-life for the slow component between 31 and 105 min. It appeared that the kidney and liver are major routes of elimination of trigramin from the circulation. The ability of trigramin to prolong bleeding time, as well as its rapid disappearance from the circulation, indicates that this peptide may be a useful compound to transiently prevent the ability of platelets to form thromboemboli without impairing their long-term hemostatic function.
Circulatory and renal control by prostaglandins and renin in low cardiac output in dogs
Authors: Riegger G. A. , Elsner D. , Kromer E. P.
Published: December 2017

Changes of neurohumoral factors including vasodilatory prostaglandins (PGs) were investigated in an experimental model of moderate low-cardiac-output status induced by rapid right ventricular pacing (240 beats/min). After 7 days of pacing, we studied the response of renal, hormonal, and hemodynamic parameters to cyclooxygenase inhibition by indomethacin and the effects of the renin system by converting-enzyme blockade in addition to the inhibition of PG synthesis. Lowering cardiac output increased plasma levels of norepinephrine and atrial natriuretic peptide. Plasma renin concentration was suppressed, despite a fall in cardiac output and blood pressure and a stimulation of sympathetic nerve activity. Urinary excretion of PGE2 was increased (P less than 0.04); plasma levels of PGE2 and 6-keto-PGF1 alpha were unchanged as measured in blood from the renal vein, pulmonary artery, and aorta. During low cardiac output, we found a significant decrease of glomerular filtration rate, whereas renal blood flow and renal and peripheral vascular resistances were unchanged. Administration of indomethacin decreased plasma and urinary PGs significantly, markedly reduced renal blood flow, and increased renal vascular resistance without affecting peripheral vascular resistance. The additional blockade of the renin-angiotensin system by captopril showed mainly a vasodilator effect on peripheral arterial resistance vessels, resulting in an increase of cardiac output. Our results suggest that, in moderate low-cardiac-output status, renal blood flow is maintained by renal vasodilator PGs, which counterbalance vasoconstrictor mechanisms like the activated sympathetic nerve activity. We indirectly showed the importance of angiotensin II in preserving glomerular filtration rate, which declines when renin secretion is suppressed, as it may be the case in moderate heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Characterization of coronary vasoconstrictor site in medullary reticular formation
Authors: Gutterman D. D. , Bonham A. C. , Arthur J. M. , Gebhart G. F. , Marcus M. L. , Brody M. J.
Published: December 2017

The importance of sympathetic neural influences in regulating coronary blood flow has been well established. However, central nervous system pathways responsible for these effects are largely unknown. In a feline model, we have identified a site in medullary reticular formation that may play a role in neural control of the coronary circulation. Changes in heart rate (HR), mean arterial pressure (AP), Doppler coronary flow velocity (CBFV), and femoral flow velocity (FBFV) were measured in 67 anesthetized cats. Electrical stimulation in a specific region of the right medullary lateral reticular formation produced elevations in HR (12 +/- 2% from 156 beats/min), AP (41 +/- 6% from 83 mmHg), CBFV (33 +/- 7%), and femoral vascular resistance index (136 +/- 27%). After beta-adrenergic blockade (propranolol), a transient (5-15 s) stimulus-induced decrease in CBFV was observed in 67% of animals, with a 55 +/- 6% increase in coronary vascular resistance index, not the result of autoregulation. Ipsilateral stellate ganglionectomy or systemic alpha 1-adrenergic blockade abolished the CBFV decrement. Microinjection of L-glutamate into this medullary region failed to elicit either pressor or coronary vasomotor responses. It is concluded that electrical stimulation in a specific site within medullary reticular formation produces neurogenic coronary vasoconstriction as part of a more generalized activation of central sympathetic fibers. This brain stem site may play an important role in reflex or behaviorally mediated coronary responses.