bluuebunny/crossref_metadata_2025 huggingface dataset:
Nature of [Ca2+]i transients during ventricular fibrillation and quinidine treatment in perfused rat hearts
Authors: Kojima S. , Wikman-Coffelt J. , Wu S. T. , Parmley W. W.
Published: December 2017

We studied intracellular Ca2+ concentration ([Ca2+]i) and the electrocardiographic signals during pacing-induced ventricular fibrillation (VF) and quinidine treatment (0.4 mg/min) using surface fluorometry in indo 1-acetoxymethyl ester (AM)-loaded perfused rat hearts. [Ca2+]i was evaluated as the indo 1 fluorescence ratio (F400/F510) and expressed as a percentage of the control amplitude of F400/F510 transients. F400/F510 increased to approximately 250% during 2- (n = 14) or 20-min (n = 9) VF. Quinidine significantly decreased F400/F510 by 60% after 2-min VF; however, this effect was blunted after 20-min VF. After 2-min VF, F400/F510 and left ventricular pressure recovered almost to the control level. However, recovery of F400/F510 and ventricular function was poor after 20-min VF. The relationship between [Ca2+]i and the electrocardiogram (ECG) during VF was evaluated by power spectrum analysis of F400/F510 and ECG signals. During VF (25 +/- 3 Hz) with high irregularity, there were no clear [Ca2+]i transients (n = 110). When the cardiac rhythm (22 +/- 3 Hz) was regular, including ventricular tachycardia, there were recognizable [Ca2+]i signals with dominant frequencies that were the same (n = 2), one-half (n = 12), or one-third (n = 1) of the ECG frequencies. The highest frequency of the [Ca2+]i transients was 19 Hz. During quinidine treatment, the VF rate decreased significantly, and clear [Ca2+]i transients were noted in all records responding to every one or two ECG signals. The conclusions were the following: 1) [Ca2+]i responds to electrical signals rapidly (up to 19 Hz) during VF. This fast [Ca2+]i response is a probable cause of high [Ca2+]i during VF. 2) Quinidine decreased [Ca2+]i after 2-min VF possibly in part by slowing the VF and [Ca2+]i transients rates. 3) 20-min VF caused [Ca2+]i overload and poor functional recovery after defibrillation.
Effects of myocardial hypertrophy on transient outward current
Authors: Li Q. , Keung E. C.
Published: December 2017

In the one-clip, two-kidney model of hypertensive rat, a gradual chronic pressure overload is imposed on the heart. Myocardial hypertrophy resulting from such pressure overload is associated with an increased but slower inactivating L-type calcium current and prolongation of action potential duration. Voltage clamp experiments in a variety of excitable tissues indicate that a 4-aminopyridine-sensitive transient outward current (Ito) plays an important role in regulating the action potential duration. Accordingly, we studied Ito in single adult cardiac myocytes enzymatically isolated from hypertrophied left ventricles of the renovascular hypertensive (HBP) rat hearts using the whole cell patch-clamp method. The current densities (normalized to cell capacitative surface area) measured at the early transient peak Ito, at the steady state, and as the difference between the transient peak and the steady state were larger in HBP cells (n = 23) than in control (Ctrl) cells (n = 20) (P < 0.05). There was no difference in the Ito reversal potential between Ctrl (-60.9 +/- 1.9 mV, mean +/- SE; n = 16) and HBP (-63.7 +/- 2.6 mV; n = 19) cells. The observed increase in Ito amplitude was not due to an increase in the number of channels available for activation or in the fraction of channels activated because there were no statistical differences in the membrane potential at which one-half of the Ito channels are activated (V0.5) for the steady-state activation and inactivation curves between Ctrl and HBP cells. The time course of inactivation of Ito was described by a double-exponential function.(ABSTRACT TRUNCATED AT 250 WORDS)
Calcium is involved in both positive and negative modulation of the secretory system for ANP
Authors: Doubell A. F. , Thibault G.
Published: December 2017

The calcium dependence of the atrial natriuretic peptide (ANP) secretory system is controversial. Some studies clearly support a stimulatory role, whereas others favor an inhibitory role for calcium in this endocrine system. We demonstrate that calcium is involved in both a positive modulatory role and a negative modulatory role, thereby providing some explanation for the seemingly irreconcilable findings previously published. The negative modulatory role performed by calcium is evident during basal secretion, whereas the positive modulatory role is especially evident in the sustained phase of the secretory response to stimulation. Furthermore, we demonstrate the calcium dependence of processing of the prohormone to the mature circulating form in a cell culture system. This supports the concept that processing is a function of the atrial myocyte rather than of the mesenchymal cells of the atrium. We have demonstrated previously that calcium is important for packaging of the prohormone into secretory granules. Together these findings support a multifaceted role for calcium in the regulation of the secretory apparatus for ANP.
Vasomotor tone affects diastolic coronary flow and flow impediment by cardiac contraction similarly
Authors: Bouma P. , Sipkema P. , Westerhof N.
Published: December 2017

We studied the effect of cardiac contraction on coronary arterial flow with vasomotor tone (control) and during maximal vasodilation with adenosine in the isolated blood-perfused rat heart at constant perfusion pressure (105 mmHg) with a left ventricular balloon (n = 6). Ventricular pressure was changed by volume changes and contractility via postextrasystolic potentiation. Contractility was expressed as the slope of the end-systolic pressure-volume ratio, elastance. Constant vasomotor tone was judged from stable diastolic flow. Coronary flow reduction (diastolic minus systolic flow, delta CBF, ml.min-1.g-1) due to contraction was related to developed ventricular pressure (devPLV) and developed elastance (devELV, systolic minus diastolic elastance) by multiple regression: delta CBF = SP.devPLV+SE.devELV+I, where SP and SE represent changes in coronary blood flow due to changes in devPLV and devELV, respectively, and I is intercept. In control, delta CBF = (0.016 +/- 0.008).devPLV + (0.0022 +/- 0.0009).devELV + (0.29 +/- 0.77); during vasodilation, delta CBF = (0.046 +/- 0.011).devPLV + (0.009 +/- 0.0053).devELV + (2.50 +/- 2.56). Diastolic flow increased by a factor of 4.06 +/- 1.57 (SD) during vasodilation. The increases in diastolic flow, SP, and SE were not different. We conclude that vasodilation has similar effects on diastolic flow and flow amplitude without affecting the relative contributions of ventricular pressure and contractility.
Effects of heat stress on vascular capacitance
Authors: Deschamps A. , Magder S.
Published: December 2017

In dogs and humans, heat stress is associated with an increase in cardiac output that sustains blood flow to heat-dissipating organs. Because cardiac output and venous return are equal in the steady state, the circulation must also adjust in heat stress to allow the venous return to increase. To analyze these adjustments, we measured blood volumes, unstressed volumes, blood flow distribution, venous compliance, venous resistance, and the time constant of venous drainage of the splanchnic and extrasplanchnic vascular beds in dogs anesthetized with alpha-chloralose at normal and at high core temperatures. We repeated the measurements at high core temperatures with ganglionic blockade, alpha-adrenergic receptor blockade, or beta-adrenergic receptor blockade to determine the efferent neurohumoral pathway. When core temperature was increased from 37.8 +/- 0.2 to 41.9 +/- 0.1 degrees C, total splanchnic blood volume decreased 23% (4.6 +/- 1.4 ml/kg) and splanchnic unstressed volume decreased 38.5%. None of the other determinants of venous return changed. Ganglionic blockade shifted the total and unstressed splanchnic blood volume during heat stress back to normothermic values. However, beta- and alpha-blockade did not affect splanchnic volumes. We conclude that a decrease in splanchnic unstressed volume is an important factor for the increased venous return during heat stress. Although mediated through sympathetic ganglions, this decrease is not abolished by alpha- or beta-receptor blockade.
Oxyradical-induced antioxidant and lipid changes in cultured human cardiomyocytes
Authors: Li R. K. , Shaikh N. , Weisel R. D. , Williams W. G. , Mickle D. A.
Published: December 2017

Because the chronically cyanotic myocardium is thought to be more susceptible to oxyradical injury than the noncyanotic myocardium during cardiovascular surgery, we studied the oxyradical susceptibility of human ventricular cardiomyocytes cultured at high and low oxygen tension (PO2) levels. Passage 4 tetralogy of Fallot cardiomyocytes were cultured at PO2 levels of 150 and 40 mmHg for 14 days and then exposed for 10 min to superoxide radicals. The cellular levels of ATP, phospholipid fatty acids, phospholipid conjugated dienes, alpha-tocopherol, and activities of superoxide dismutase, catalase, and glutathione peroxidase were measured. ATP levels decreased more markedly in the low-PO2 group. Although the decrease in alpha-tocopherol levels was similar for both groups, phospholipid conjugated diene formation and phospholipid unsaturated fatty acid loss was greater in the low-PO2 cells. Glutathione peroxidase activity was rapidly inhibited. Superoxide dismutase activity was unaffected, and catalase activity was inhibited by no more than 50%. Although extracellular superoxide dismutase with catalase did not inhibit phospholipid conjugated diene formation and phospholipid breakdown, extracellular glutathione peroxidase with reduced glutathione did limit phospholipid damage. With the occurrence of membrane lipid peroxidation, the decreased glutathione peroxidase activity in the cyanotic tetralogy of Fallot myocardium determines cardiomyocyte membrane susceptibility to oxidant injury.
Inward diastolic motion: a normal component of isovolumic relaxation and rapid refill
Authors: McInerney J. J. , Aronoff R. D. , Blasko S. H. , Copenhaver G. L. , Herr M. D.
Published: December 2017

Many reports note expansive events occurring in the left ventricle during isovolumic relaxation. Expansions during isovolumic relaxation require compensatory inward displacements elsewhere in the ventricle. The location and character of such compensatory displacements have been a continuing source of speculation. Using a high-precision Compton backscatter imaging (CBI) technique, we have detected an early diastolic inward motion that initiates during isovolumic relaxation on the right and left epicardial free walls of the heart in 100% of the 14 normal canines we have studied. This inward motion is first detected 20–30 ms after left ventricular maximal rate of pressure decrease over time (-dP/dtmax), lasts into the early rapid filling phase with a mean duration of 92 +/- 5 (SE) ms, and ends approximately 30 ms after opening of the mitral valve. Maximum wall velocities during this time period (approximately 20 mm/s) exceed those occurring in the same regions during systole. Inward surface displacements in the areas undergoing inward motion average 1.1 +/- 0.2 and 0.9 +/- 0.2 mm on the left and right side of the heart, respectively.
Sodium depletion in conscious cynomolgus monkeys attenuates baroreflex sensitivity independently of prostaglandins
Authors: Panzenbeck M. J. , Harrison P. C. , Madwed J. B. , McFarland M. L. , Winquist R. J. , Frei P. , Weldon S. , Desai S. N.
Published: December 2017

We tested the hypothesis that baroreflex attenuation during sodium depletion is due to increased prostaglandin (PG) levels. We studied baroreflex sensitivity before and after PG synthesis inhibition in conscious cynomolgus monkeys. Arterial pressure and pulse interval (PI) were measured during intravenous infusions of phenylephrine (1–20 micrograms.kg-1.min-1, n = 6) and nitroprusside (1–10 micrograms.kg-1.min-1, n = 7). Infusions were repeated 30 min after indomethacin (Indo, 6 mg/kg iv). The slope (in ms/mmHg) of the mean arterial blood pressure-PI plot was used as an index of baroreflex sensitivity. Plasma renin activity (PRA) was elevated (47.9 +/- 9.7 vs. 8.8 +/- 3.3 ng angiotensin I.ml-1.h-1) after sodium depletion (P < 0.05). Baroreflex sensitivity to hypotension and hypertension was significantly (P < 0.05) attenuated by sodium depletion (3.69 +/- 0.9 vs. 0.9 +/- 0.1 ms/mmHg and 7.38 +/- 0.6 vs. 5.04 +/- 0.9 ms/mmHg, respectively). Indo decreased PRA to 28.6 +/- 5.7 ng angiotensin I.ml-1.h-1 (P < 0.05) in sodium-depleted monkeys and decreased heart rate -21 +/- 3.7 from a baseline of 166 +/- 9.40 beats/min in normal monkeys and -22 +/- 2.9 from a baseline of 191 +/- 7.9 beats/min in low-sodium monkeys (P < 0.05). Indo did not significantly change baroreflex sensitivity in either group. Thus the baroreflex was attenuated in conscious nonhuman primates during sodium depletion; acute PG synthesis blockade did not improve baroreflex sensitivity. Indo decreased heart rate without changing arterial pressure; suggesting that PGs caused a downward resetting of the pressure-heart rate relationship.
Hypertrophic growth of cultured neonatal rat heart cells mediated by type 1 angiotensin II receptor
Authors: Miyata S. , Haneda T.
Published: December 2017

Primary cultures of neonatal cardiac myocytes were used to determine the identity of second messengers that are involved in angiotensin II (ANG II) receptor-mediated effects on cardiac hypertrophy and the type of ANG II receptor that is involved in ANG II-induced cell growth. Treatment of myocytes with ANG II significantly increased the protein-to-DNA and the RNA-to-DNA ratios. ANG II accelerated rates of protein synthesis by 24.9%. Intracellular free calcium was transiently increased after ANG II exposure. The activity of protein kinase C in particulate fractions was transiently increased after exposure to ANG II but returned to control level. The activity of protein kinase C in the cytosol was significantly decreased at all times after exposure to ANG II. After ANG II treatment, the content of c-Fos mRNA was increased. The stimulatory effects of ANG II on these parameters were inhibited by the type 1 angiotensin II receptor (AT1) antagonist, losartan. These studies demonstrate that ANG II-induced hypertrophic growth is, at least in part, mediated through AT1 receptors.
WB4101- and CEC-sensitive positive inotropic actions of phenylephrine in rat cardiac muscle
Authors: Williamson A. P. , Seifen E. , Lindemann J. P. , Kennedy R. H.
Published: December 2017

This study was designed to determine the role of the alpha 1-adrenergic receptor (AR) subtypes in the positive inotropic action of alpha 1-adrenergic agonists in rat myocardium. Isolated left atrial and papillary muscle were suspended in oxygenated Krebs-Henseleit buffer (37 degrees C) containing 3 microM nadolol and paced at 3.3 Hz. Isometric tension was continuously monitored. Cumulative concentration-response curves for phenylephrine (3 x 10(-7) to 3 x 10(-4) M) were obtained in the presence and absence of WB4101 (4 and 10 nM) and with and without treatment with chloroethylclonidine (CEC; 10, 100, and 300 microM). WB4101 antagonized the effect of phenylephrine in both tissues, increasing half-maximal effective concentration (EC50) values in a concentration-dependent manner. CEC pretreatment also increased EC50 values in both tissues, and 300 microM CEC reduced the maximal positive inotropic effect of phenylephrine by approximately 48 and 38% in left atrial and papillary muscle, respectively. CEC alone elicited significant increases in contractile force that were not readily reversible. These data suggest that the positive inotropic effect of alpha 1-adrenergic agonists in rat atrial and ventricular myocardium results from stimulation of both WB4101- and CEC-sensitive alpha 1-ARs.
ANG II receptor blockade prevents ventricular hypertrophy and ANF gene expression with pressure overload in mice
Authors: Rockman H. A. , Wachhorst S. P. , Mao L. , Ross J.
Published: December 2017

There is increasing evidence that the renin-angiotensin system may play a important role in cardiac hypertrophy. To assess the role of angiotensin II in the induction of cardiac hypertrophy, three groups of adult mice were subjected to left ventricular pressure overload by transverse aortic constriction (TAC). For the next 7 days the groups received either the specific angiotensin II subtype 1 receptor (AT1) antagonist (losartan, 1.05 g/l; n = 17), an angiotensin enzyme inhibitor (captopril, 2 g/l; n = 17), or no treatment (n = 22) administered in the drinking water and compared with three similarly treated sham-operated groups (n = 7 each). TAC resulted in a significant increase in heart weight-to-body weight ratio (0.634 +/- 0.087 vs. 0.525 +/- 0.039, g/g x 100, P < 0.05), which was prevented by losartan (0.506 +/- 0.069, g/g x 100, P < 0.0001) despite similar hemodynamic load (proximal systolic pressure 146 +/- 31 vs. 136 +/- 32 mmHg, untreated vs. losartan, P = NS). Proximal systolic pressure was positively correlated with the development of ventricular hypertrophy. In the presence of AT1-receptor blockade, the increase in heart weight-to-body weight ratio at any given systolic pressure was significantly attenuated compared with untreated TAC mice. The increase in heart weight-to-body weight ratio was also significantly attenuated by captopril compared with untreated banded controls (0.542 +/- 0.091, g/g x 100, P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Stimulation of the nigrostriatal dopamine system produces hypertension and tachycardia in rats
Authors: Lin M. T. , Yang J. J.
Published: December 2017

To test for the ability of the nigrostriatal dopamine (DA) system to influence cardiovascular function, experiments were carried out to assess the effects of electrical or chemical stimulation of the nigrostriatal DA system on arterial blood pressure, heart rate, and striatal DA release in anesthetized rats. Electrical stimulation of the substantia nigra pars compacta (SNC), in addition to enhancing the DA release in the corpus striatum (CS), elicited proportional hypertension and tachycardia. This could be mimicked by microinjection of two excitatory amino acids, kainic acid and glutamate, into the SNC area of rat brain. The SNC stimulation-induced hypertension, tachycardia, and increased striatal DA release were attenuated by prior destruction of the nigrostriatal DA system produced by intramedial forebrain bundle injection of 6-hydroxydopamine and by prior blockade of postsynaptic DA receptors produced by intra-CS injection of DA receptor antagonists, haloperidol or pimozide. The SNC stimulation-induced hypertension was attenuated by spinal transection, whereas the SNC stimulation-induced tachycardia was attenuated by bilateral vagotomy. The data suggest that stimulation of the nigrostriatal DA system produces both hypertension and tachycardia in rats.
Pressor and endocrine responses to lesions of canine rostral ventrolateral medulla
Authors: Stith R. D. , Dormer K. J.
Published: December 2017

To understand the mechanism(s) of reduction in arterial pressure (AP) after kainic acid cytotoxic lesions in the rostral ventrolateral medulla (RVLM), recordings of AP, cardiac output (CO), heart rate (HR), plasma catecholamines, and cortisol were obtained from awake relaxed dogs. Mongrels (n = 12) were instrumented with a solid-state pressure transducer in the descending aorta and a pulse transit-time ultrasonic flowmeter on the aortic arch. After the dogs recovered from thoracotomy, AP, CO, HR, and plasma levels of epinephrine, norepinephrine, and cortisol were recorded periodically or measured at rest over 2–3 wk followed by unilateral, cytotoxic lesion placement in the rostral C1 area of the RVLM. After the dogs recovered from lesion surgery, the measurements were repeated, and, compared with prelesion control values, they showed significantly decreased AP (-23.1 mmHg) and total peripheral resistance (-0.014 peripheral resistance units) but no significant changes in CO or HR. The reduction in AP may be caused partially by significant reductions in plasma epinephrine (-47%), norepinephrine (-34%), and cortisol (-66%) levels. Lesion sites corresponded to the rostral C1 area, immunocytochemically positive for phenylethanolamine-N-methyltransferase (PNMT). These observations support the concept that a discrete site in the RVLM, demarcated by a rostral subgroup of PNMT-immunoreactive cell bodies, contributes to direct sympathoexcitatory support of resting AP. The neurotransmitter responsible for vasomotor tone, however, remains unknown. This study also provides new information suggesting a role for catecholamine and cortisol regulation from this putative vasomotor center.
Central cholinergic modulation of the exercise pressor reflex in anesthetized cats
Authors: Ally A. , Meintjes A. F. , Mitchell J. H. , Wilson L. B.
Published: December 2017

Effects of central administration of a cholinesterase inhibitor, physostigmine, on cardiovascular responses to static contraction and passive stretch of the triceps surae were studied using anesthetized cats. Contraction increased mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) by 44 +/- 5 mmHg, 18 +/- 1 beats/min, and 86 +/- 6%, respectively. MAP, HR, and RSNA increased during stretch by 44 +/- 5 mmHg, 15 +/- 1 beats/min, and 61 +/- 4%, respectively. Administration of physostigmine (100 micrograms; 5 microliters) into the third ventricle decreased resting MAP by 22 +/- 3 mmHg and RSNA by 32 +/- 4%, with no effect on HR. Physostigmine attenuated the contraction-evoked responses as MAP, HR, and RSNA increased by 17 +/- 2 mmHg, 3 +/- 1 beats/min, and 31 +/- 6%, respectively. Also, physostigmine blunted MAP, HR, and RSNA responses to stretch (16 +/- 2 mmHg, 4 +/- 1 beats/min, and 9 +/- 6%, respectively). Posterior hypothalamic stimulation increased MAP by 39 +/- 3 mmHg, which was unaffected by physostigmine, despite a lower baseline. Cardiovascular and RSNA responses to contraction and stretch returned to control 90-120 min after physostigmine. Preadministration of the muscarinic antagonist, atropine sulfate (100 micrograms; 5 microliters), blocked the effects of physostigmine. Results suggest central cholinergic stimulation can inhibit the exercise pressor reflex in anesthetized cats.
Acute tamponade alters subendo- and subepicardial pressure-flow relations differently during vasodilation
Authors: Kingma J. G. , Martin J. , Rouleau J. R.
Published: December 2017

Instantaneous diastolic left coronary artery pressure-flow relations (PFR) shift during acute tamponade as pressure surrounding the heart increases. Coronary pressure at zero flow (Pf = 0) on the linear portion of the PFR is the weighted mean of the different myocardial waterfall pressures, the distribution of which varies across the left ventricular wall during diastole. However, instantaneous PFR measured in large epicardial coronary arteries cannot be used to estimate Pf = 0 in the different myocardial tissue layers. During coronary vasodilatation in a capacitance-free model, myocardial PFR differs from subendocardium to subepicardium. Therefore, we studied the effects of acute tamponade during maximal pharmacology induced coronary vasodilatation on myocardial PFR in in situ anesthetized dogs. Tamponade reduced cardiac output, aortic pressure, and coronary blood flow. Results demonstrate that different mechanisms influence distribution of myocardial blood flow during tamponade. Subepicardial vascular resistance is unchanged and the extrapolated Pf = 0 is increased, thereby shifting PFR to a higher intercept on the pressure axis. Subendocardial vascular resistance is increased while the extrapolated Pf = 0 remains unchanged. Results indicate that in the setting of acute tamponade with coronary vasodilatation different mechanisms regulate the distribution of myocardial blood flow: in the subepicardium only outflow pressure increases, whereas in the subendocardium only vascular resistance increases.
Alpha- and beta-adrenergic mechanisms in the control of vascular capacitance by the carotid sinus baroreflex system
Authors: Shigemi K. , Brunner M. J. , Shoukas A. A.
Published: December 2017

We examined the active and passive contributions of the alpha- and beta-adrenergic receptor mechanisms to the changes in systemic vascular capacitance caused by the carotid sinus baroreflex system in anesthetized, vagotomized dogs. The carotid sinuses were isolated from the systemic circulation and perfused with controlled pressures. To determine the changes in vascular capacitance, a constant flow, constant venous pressure cardiopulmonary bypass was used. The changes in unstressed vascular volume were calculated when carotid sinus pressure was reduced from 200 to 50 mmHg without any adrenergic receptor antagonist, with either an alpha- (phentolamine) or a beta- (propranolol) antagonist and then with both. The reflex change in unstressed vascular volume in the systemic circulation (22.6 +/- 9.0 ml/kg without any antagonist) was reduced by 72% with phentolamine, by 35% with propranolol, and by 73% with both antagonists. Our results suggest that the alpha-adrenergic mechanisms contribute significantly to active changes in systemic venous capacity. In addition, the beta-adrenergic system has very little effect on active changes in venous vessels but does contribute to the overall capacity changes by dilating the hepatic outflow resistance when the carotid sinus baroreflex system is activated.
Reappraisal of effective refractory period testing
Authors: Fan W. , Gotoh M. , McCullen A. , Karagueuzian H. S. , Chen P. S.
Published: December 2017

To test the hypothesis that effective refractory period (ERP) testing is an accurate and reproducible measure of the cardiac refractory period, 4 pigs and 12 dogs were studied. We define the conventional ERP as the longest S1–S2 interval associated with noncapture and the triplicate ERP as the average of three ERP values determined by the up-down algorithm. We also determined the probability curve for noncapture after testing multiple S1–S2 intervals. The results showed that the difference between the coupling intervals associated with a 0 and a 100% probability of noncapture was 13 +/- 1 (range 12–16) ms for pigs and 9 +/- 2 (range 4–12) ms for dogs. The conventional and the triplicate ERP were associated with a 71 +/- 20% (range 26–100%) and a 60 +/- 21% (range 12–100%) probability of noncapture, respectively. We conclude that the ERP is a probability function. Therefore a single ERP determination cannot be used as an accurate and reproducible measure of cardiac refractory period unless it is used to detect potential differences in ERP that exceed 16 ms in pigs or 12 ms in dogs. A probability function curve determination will be needed if smaller differences in the ERP are to be detected.
Sustained paradoxical vasodilation during orthostasis in heart failure: a factor in the edema pathogenesis?
Authors: Wroblewski H.
Published: December 2017

Baroreceptor-induced peripheral reflex vasoconstriction during upright posture is an important edema-prevention mechanism in humans. Congestive heart failure (CHF) has been associated with blunted baroreceptor control of regional blood flow during short-term head-up tilt. The effect of prolonged unloading of baroreceptors on subcutaneous blood flow of the calf was investigated in 12 healthy subjects and in 13 patients with severe idiopathic dilated cardiomyopathy (New York Heart Association functional class III or IV). The subjects were studied both supine and sitting for 3-h periods. When sitting, subcutaneous vascular resistance decreased -26 +/- 19% in CHF patients and increased 90 +/- 69% in control subjects (P < 0.0001). The corresponding subcutaneous blood flow increased 43 +/- 29% in patients with CHF compared with the decrease of -42 +/- 17% in control subjects (P < 0.0001). I conclude that patients with CHF secondary to idiopathic dilated cardiomyopathy have an abnormal baroreceptor-mediated peripheral vasodilation during orthostatic stress that is sustained for hours. This extended paradoxical vasodilation may participate as an additional pathophysiological mechanism contributing to lower extremity edema in patients with CHF.
Enhanced bradycardia but not renal sympathoinhibition during hemorrhage in rats with area postrema lesions
Authors: Edwards G. L. , Johnson A. K. , Peuler J. D.
Published: December 2017

Hypotensive hemorrhage inhibits renal sympathetic nerve activity (SNA) and heart rate (HR) in rats. The area postrema (AP) is reported to modulate autonomic responses to arginine vasopressin (AVP) and may be a site where circulating AVP influences SNA and HR during hypotensive hemorrhage. We found a similar renal sympathoinhibition in AP-lesioned (APX) and sham-lesioned (Sham) rats during hypotensive hemorrhage and a greater bradycardia in APX compared with Sham rats. Further inhibition of renal SNA with AVP infusion was not observed in APX rats, although the bradycardic action of AVP infusion was comparable to that in Sham rats. Thus the AP attenuates bradycardia but not renal sympathoinhibition during hypotensive hemorrhage in normal rats. Nonetheless, an intact AP permits further reduction in renal SNA during infusion of AVP. If AVP contributes to hypotensive hemorrhage-induced renal sympathoinhibition, its action may occur at sites other than the AP or at the AP where such action is counterbalanced by sympathoexcitatory factor(s) also activated during hypotensive hemorrhage. Finally, enhanced bradycardia during hypotensive hemorrhage in APX rats suggests it may not be the site of action for AVP-induced bradycardia in intact rats.
Hypertonic saline is a negative inotropic agent in normovolumic dogs
Authors: Constable P. D. , Muir W. W. , Binkley P. F.
Published: December 2017

The inotropic effects of hypertonic saline (HS) and hyperosmotic dextrose (HD; 2,400 mosmol/l, 4 ml/kg) were determined in normovolumic, chloralose-anesthetized, intact (n = 14) and autonomically blocked (n = 8) dogs. Solutions were infused intravenously over 3 min. HS and HD rapidly increased preload in both intact and autonomically blocked dogs, as assessed by significant (P < 0.05) increases in plasma volume, end-diastolic volume, and end-diastolic pressure. In intact dogs, HS produced a nonsignificant decrease in end-systolic elastance (Ees) and a nonsignificant increase in the maximal rate of change of left ventricular pressure (dP/dtmax) and cardiac output, whereas HD produced a significant increase in Ees, dP/dtmax, and cardiac output. In autonomically blocked dogs, HS significantly decreased Ees and significantly increased dP/dtmax but did not alter cardiac output, whereas HD significantly increased Ees, dP/dtmax, and cardiac output. We conclude that in normovolumic animals, HS is a negative inotropic agent, HD is a positive inotropic agent, and the in vivo effect of an ionic hyperosmotic agent (HS) differs from that of a nonionic hyperosmotic agent (HD).
Hypothermia modifies anesthetic effect on contractile force and Ca2+ transients in cardiac Purkinje fibers
Authors: Sprung J. , Stowe D. F. , Kampine J. P. , Bosnjak Z. J.
Published: December 2017

Mild hypothermia enhances cardiac contractility, and volatile anesthetics depress contractility. Contractile force (tension) and Ca2+ transients were measured in canine Purkinje fibers at 35 and 25 degrees C with and without halothane and isoflurane to examine how anesthetics attenuate the positive inotropic effect of mild hypothermia. Isometric tension and light emitted from the photoprotein aequorin were used to assess contractility and intracellular Ca2+ transients in fibers stimulated at 40–60 pulses/min. At 35 degrees C, each anesthetic depressed peak tension and peak Ca2+ transients and decreased contractile force duration but, for halothane, increased Ca2+ transient duration. Decreases in tension by both anesthetics at 35 degrees C were converted to marked increases in tension at 25 degrees C, whereas Ca2+ transients were little changed. Removal of anesthetics at 25 degrees C greatly increased tension with a small increase in Ca2+ transients that was much lower than that at 35 degrees C. The curve relating peak contractile force as a function of Ca2+ transients at 25 degrees C during stepwise increases in extracellular CaCl2 was shifted steeper and leftward of the curve at 35 degrees C. These studies suggest that the positive inotropic effect of mild hypothermia is due primarily to increased myofibrillar Ca2+ sensitivity and that anesthetics decrease tension during hypothermia by decreasing myofibrillar Ca2+ sensitivity. Reduced influx of transsarcolemmal or sarcoplasmic reticular Ca2+ may also play a role during mild hypothermia.
Analysis of responses to bradykinin: effects of Hoe-140 in the hindquarters vascular bed of the cat
Authors: Santiago J. A. , Garrison E. A. , Kadowitz P. J.
Published: December 2017

The mechanisms and receptor subtype mediating vasodilator responses to bradykinin were investigated in the hindquarters vascular bed of the cat under constant flow conditions. Intraarterial injections of bradykinin in doses of 10–1,000 ng into the hindquarters vascular bed caused dose-related decreases in perfusion pressure that were inhibited by Hoe-140, a bradykinin B2-receptor antagonist. Injections of des-Arg9-bradykinin (in doses 10-fold higher than for bradykinin) caused smaller dose-related decreases in hindquarters perfusion pressure that were not blocked by Hoe-140. Administration of atropine, glibenclamide, or cyclooxygenase inhibitors did not alter vasodilator responses to bradykinin, suggesting that activation of muscarinic receptors, ATP-sensitive K+ channels, or prostaglandin release is not involved in the response to the peptide. Administration of N omega-nitro-L-arginine and its methyl ester reduced vasodilator responses to bradykinin, acetylcholine, and substance P, whereas responses to endothelium-independent vasodilator agents were not attenuated. Decreases in systemic arterial pressure and in hindquarters perfusion pressure in response to bradykinin were enhanced by the angiotensin-converting enzyme inhibitors captopril and enalaprilat. These results suggest that hindquarters vasodilator responses to bradykinin are mediated by activation of kinin B2 receptors and in part by the release of nitric oxide. These data also suggest the presence of bradykinin B1 receptors, mediating vasodilation in the hindquarters vascular bed. These results indicate that bradykinin is rapidly inactivated by angiotensin-converting enzyme in the lung and in the hindquarters vascular bed of the cat.
Calcium entry and myogenic phenomena in skeletal muscle arterioles
Authors: Hill M. A. , Meininger G. A.
Published: December 2017

Studies were conducted to examine Ca2+ entry in several vasomotor situations related to myogenic properties of arterioles (basal tone, vasomotion, and responsiveness to alterations in intravascular pressure). In vivo studies were performed on small cremaster muscle arterioles of anesthetized rats. Intravascular pressure was increased using the pressure-box technique. Voltage-operated Ca2+ channel (VOC) activity was inhibited by nifedipine or methoxyverapamil and was stimulated with BAY K 8644. To examine the effect of hyperpolarization, studies were performed in the presence of pinacidil. Nifedipine and methoxyverapamil exhibited a trend toward dose-dependent dilation; however, neither agent caused dilation comparable to adenosine (10(-4) M). BAY K 8644 produced a biphasic effect, constriction below 10(-8) M, and dilation at higher levels. These data indicate that basal tone can be modulated by agents acting on VOCs; however, as high concentrations of nifedipine do not abolish tone, other mechanisms contribute. At similar concentrations, the Ca2+ channel antagonist significantly inhibited vasomotion, abolishing vasomotion at concentrations above 5 x 10(-6) M. In contrast, BAY K 8644 caused a dose-dependent increase in vasomotion amplitude (e.g., 269 +/- 52% of basal at 10(-7) M). Thus vasomotion appears highly dependent on VOCs. Experiments performed in the presence of the antagonists/agonists indicated that VOCs are not the prime determinant of constrictor responses to acute increases in intravascular pressure. Exposure to pinacidil resulted in dose-dependent vasodilatation and inhibition of vasomotion while showing little effect on acute myogenic responses. Similar effects of pinacidil were observed in isolated, cannulated, cremaster arterioles.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of ATP on ligand recognition of platelet fibrinogen receptor on GPIIb-IIIa
Authors: Gawaz M. P. , Mayinger P. , Neumann F. J.
Published: December 2017

The recent discovery of 8-azido-ATP binding sites on the platelet fibrinogen receptor glycoprotein complex GPIIb-IIIa suggests that extracellular ATP may directly modulate function of GPIIb-IIIa. In this study we investigated the effect of ATP on ligand binding to GPIIb-IIIa. Fibrinogen-mediated aggregation of washed platelets was inhibited by ATP and 8-azido-ATP in a dose-dependent manner, independent of the agonist (thrombin, collagen, epinephrine, phorbol 12-myristate 13-acetate) used to induce platelet activation. In addition, 8-azido-ATP and ATP inhibited binding of 125I-labeled fibrinogen to thrombin- and phorbol ester-activated platelets. Interaction of nonstimulated platelets with solid-phase fibrinogen was also reduced by 8-azido-ATP and ATP. Moreover, fibrinogen mimetic peptide-induced conformational change of GPIIb-IIIa on resting platelets was reduced in the presence of both nucleotides. Finally, photoincorporation of 8-azido-[gamma-32P]ATP into GPIIb-IIIa was suppressed by GRGDSP but not by the biologically inactive GRGESP peptide. Thus interaction of ATP with 8-azido-ATP binding sites present on GPIIb-IIIa modulate receptor function, which may play a role in regulation of in vivo platelet aggregation.
Leukocyte sequestration in the microvasculature in normal and low flow states
Authors: Eppihimer M. J. , Lipowsky H. H.
Published: December 2017

Techniques of indicator dilution were applied to determine the relative transit times (TTs) of fluorescently labeled leukocytes (TTWBC), red blood cells (TTRBC), and plasma (TTpl) between functionally paired arterioles and venules in hamster cremaster muscle in normal and low flow states. In the normal flow state, paired measurements of TTWBC/TTpl in arteriovenous (A-V) pairs bounding the true capillaries averaged 0.75 +/- 0.08 (SE) s and were not significantly different from an average TTRBC/TTpl of 0.78 +/- 0.06 (SE) s as WBCs appeared to traverse the capillary segment through more centralized preferential pathways. In larger-diameter A-V pairs, significantly larger (10%) values of TTWBC/TTpl were found compared with TTRBC/TTpl due to margination of WBCs in postcapillary venules. To assess the relative effects of WBC-capillary plugging and WBC adhesion in venules on flow resistance, TTWBC was measured in normal and low flow states, with the latter induced by systemic administration of sodium nitroprusside, which resulted in an increase in TTpl from a norm of 1.08 +/- 0.16 to 2.62 +/- 0.44 (SE) s (P < 0.05). With onset of the low flow state, TTWBC/TTpl, the number of plugged capillaries, and the duration of capillary plugs did not change significantly from the norm. In contrast, the rate at which WBC-endothelium (-EC) adhesion increased with successive bolus injections increased approximately eight-fold during hypoperfusion. Estimates of the percentage increase in segmental resistance at the capillary level (due to plugging) and in postcapillary venules (due to EC adhesion) revealed that venous resistance may increase at a threefold greater rate due to WBC sequestration with each successive bolus infusion. Inasmuch as hemodynamic resistance in capillary and venular segments is of the same order of magnitude in the normal flow state, it appears that WBC adhesion in venules may have a far greater deleterious effect on microvascular blood flow in the low flow state.
Reduced collateral perfusion is a direct consequence of elevated right atrial pressure
Authors: Manor D. , Williams S. , Ator R. , Bryant K. , Scheel K. W.
Published: December 2017

In the present study we determined quantitatively the effects of increased right atrial pressure (RAP) on coronary and collateral flows. In an isolated, blood-perfused, maximally vasodilated dog heart preparation in which the left ventricle was vented, we used the retrograde flow method to assess collateral flow. When RAP was elevated from 5 +/- 1 (control) to 13 +/- 1 and 23 +/- 1 mmHg, retrograde flow from the left circumflex coronary artery (which was open to atmospheric pressure) increased 29 +/- 8 and 97 +/- 21% relative to control while left anterior descending flow decreased 5 +/- 1 and 14 +/- 2%, respectively (P < 0.01; n = 7). The increase in retrograde flow could be due to 1) an increase in collateral flow due to increased pressure at the origin of the collaterals or 2) the elevated RAP (venous outflow pressure), which forces the antegrade collateral flow component in the retrograde direction. To distinguish between these possibilities we embolized the circumflex with 30-microns spheres to eliminate the antegrade flow component. After embolization there was no significant change in retrograde flow with elevated RAP, indicating that the second supposition was correct. We conclude that increased RAP 1) results in a reduction of flow to the collateral-dependent myocardium and 2) reduces perfusion of the unoccluded coronary vessel. Furthermore, we found that under conditions of varying venous outflow pressure, retrograde flow may not serve as a reliable index of collateral flow.
Cardiopulmonary bypass impairs vascular endothelial relaxation: effects of gaseous microemboli in dogs
Authors: Feerick A. E. , Johnston W. E. , Steinsland O. , Lin C. , Wang Y. , Uchida T. , Prough D. S.
Published: December 2017

Gaseous microemboli during hypothermic cardiopulmonary bypass (CPB) may injure the vascular endothelium and interfere with intrinsic vasomotion. We tested whether gaseous microemboli reduced the vasodilator response to acetylcholine (ACh, 10(-9)-10(-6) M) and potentiated the vasoconstrictor response to norepinephrine (NE, 3 x 10(-8)-10(-4) M). Arteries from 18 dogs were excised before and after 120 min 28 degrees C CPB using membrane (n = 9) and bubble (n = 9) oxygenators to produce microemboli, which were quantitated by Doppler. Five nonbypassed dogs were controls. In isolated vessel rings, the 50% effective dose (ED50) values for ACh (10(-8) M) and NE (10(-7) M) responses were calculated. Mean microemboli count per minute was 0 +/- 0 in the control group, 1.0 +/- 0.4 in the membrane group (P < 0.05 vs. controls), and 46.9 +/- 8.4 in the bubble group (P < 0.05 vs. control and membrane groups). ACh ED50 values did not change in controls but increased in the membrane group from 4.01 +/- 1.52 to 5.66 +/- 1.39 (P < 0.05) and in the bubble group from 2.32 +/- 0.56 to 7.21 +/- 1.90 (P < 0.05). The change in ED50 was greater for bubble than for membrane animals (P < 0.05) but did not correlate with microemboli number (bubble: r = 0.392, P = 0.297; membrane: r = 0.058, P = 0.802). NE responses were similar in all groups. Hypothermic CPB reduces ACh-induced dilation of the canine femoral artery independent of the incidence of gaseous microemboli.(ABSTRACT TRUNCATED AT 250 WORDS)
Spinal cord excitatory amino acids and cardiovascular autonomic responses
Authors: West M. , Huang W.
Published: December 2017

The excitatory amino acid subtype receptor agonists, N-methyl-D-aspartate (NMDA) and (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA, a non-NMDA agonist), produce specific dose-related heart rate and vasoconstrictor responses when given by injection into the upper thoracic or lumbar intrathecal space of the conscious rabbit. The responses are inhibited by prior intrathecal injection of the specific excitatory amino acid subtype receptor antagonist, 2-amino-5-phosphonovaleric acid (AP-5) or 6,7-dinitroquinoxaline-2,3-dione (DNQX), respectively. Baroreceptor heart rate reflex function is inhibited by AP-5 and by DNQX applied to the upper thoracic spinal cord. In contrast baroreflex vasoconstrictor function is blocked by AP-5 but not by DNQX given in the lumbar intrathecal space. The experiments support previous evidence that spinal excitatory amino acids are important as neurotransmitters at the level of the sympathetic preganglionic neuron and as such exert tonic and reflex control of autonomic cardiovascular function. It is concluded that 1) intrathecal activation of NMDA and non-NMDA subtype receptors has similar but independent effects on heart rate and on blood pressure and 2) NMDA receptors alone participate in mediation of baroreflex vasoconstrictor function, whereas both sets of receptors determine reflex sympathetic heart rate effects.
Human basilar and middle cerebral arteries exhibit endothelium-dependent responses to peptides
Authors: Onoue H. , Kaito N. , Tomii M. , Tokudome S. , Nakajima M. , Abe T.
Published: December 2017

We examined the activities of bradykinin, substance P, and vasopressin in isolated human cerebral arteries to better understand humoral control of cerebrovascular tone. Basilar and middle cerebral arteries were isolated from human cadavers during autopsy, and isometric tension was measured in helical strips of the arteries. Both bradykinin and substance P relaxed strips of both arteries precontracted with prostaglandin F2 alpha to similar extents. The relaxations induced by both peptides were abolished by removal of the vascular endothelium and were markedly reduced by pretreatment with NG-nitro-L-arginine, an inhibitor of endothelium-derived relaxing factor. Treatment with indomethacin, a cyclooxygenase inhibitor, did not attenuate the relaxations. These results indicate that the responses of human cerebral arteries to bradykinin and substance P are mediated by endothelium-derived relaxing factor. In contrast, vasopressin primarily produced endothelium-independent contractions in human cerebral arteries. Contractions of basilar arteries induced by vasopressin were much less than those of middle cerebral arteries. Two of eighteen basilar arteries, but none of the middle cerebral arteries, responded to vasopressin with endothelium-dependent relaxation. This suggests that the function of vasopressin receptors differs in basilar and middle cerebral arteries.
Pertussis toxin-sensitive G proteins in regenerated endothelial cells of porcine coronary artery
Authors: Shibano T. , Codina J. , Birnbaumer L. , Vanhoutte P. M.
Published: December 2017

Endothelium-dependent, pertussis toxin-sensitive relaxations are impaired selectively after regeneration of endothelial cells following balloon denudation of the porcine coronary artery. The present study was designed to examine the hypothesis that there is a difference in G proteins modified by pertussis toxin between regenerated and intact endothelial cells. Yorkshire pigs, fed a high-cholesterol diet, underwent balloon denudation of the endothelium of the left anterior descending coronary arteries (LAD). Four weeks after the denudation the animals were killed to detect G proteins by ADP ribosylation catalyzed with pertussis toxin and [32P]NAD, separated on a urea gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In membrane fractions of endothelial cells obtained from previously denuded LAD, G alpha i-1/G alpha i-3 (41 kDa) and G alpha 1-2 (40 kDa) proteins were labeled. The two bands revealed on the gel were the same as those obtained from intact left circumflex coronary arteries (LCX). However, the intensity of the bands was less prominent in the LAD than the LCX. These results suggest that either a decreased amount or a reduced functionality of Gi proteins in the regenerated endothelial cells may account for the impairment in the pertussis toxin-sensitive relaxations after balloon injury of coronary arteries in the pigs.