American Journal of Physiology最新文献

This article is intended for instructors who teach cardiovascular physiology. In our physiology course exercise physiology is used as a tool to review and integrate cardiovascular and respiratory physiology. It is assumed that the students already have mastered the fundamentals of cardiovascular and respiratory physiology. Because this paper is part of a cardiovascular refresher course, I have deleted much of the respiratory physiology. The objectives of this presentation are for the student to 1) understand the relationship between maximal oxygen consumption and endurance during sustained exercise and be able to define "maximal oxygen consumption"; 2) understand the determinants of of maximal oxygen consumption; 3) understand the effects of dynamic exercise on the cardiovascular system and mechanisms for these effects; 4) understand the relationships between exercise intensity and major cardiorespiratory parameters, including heart rate, cardiac output, blood flow distribution, left ventricular stroke volume, arterial pressures, total peripheral resistance, and arterial and venous blood oxygen content; 5) be able to compare and contrast the cardiovascular effects of dynamic and isometric exercise in man and the mechanisms responsible for the major differences; and 6) be able to apply knowledge of the cardiovascular effects of exercise to understanding the causes of cardiovascular symptoms in disease and in diagnosis of disease states. This material contains many areas that stimulate discussion with students and allow exploration of concepts that are challenging for the student. This give and take between teachers and student is difficult to summarize in an article of this sort. Therefore, subjects that in my experience often stimulate questions and discussion with the students are indicated in the text.

Crus II is an area of the cerebellar cortex that receives trigeminal afferents from the perioral region. We investigated the mechanisms of functional hyperemia in cerebellum using activation of crus II by somatosensory stimuli as a model. In particular, we sought to determine whether stimulation of the perioral region increases cerebellar blood flow (BFcrb) in crus II and, if so, whether the response depends on activation of 2-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-kainate receptors and nitric oxide (NO) production. Crus II was exposed in anesthetized rats, and the site was superfused with Ringer. Field potentials were recorded, and BFcrb was measured by laser-Doppler flowmetry. Crus II was activated by electrical stimulation of the perioral region (upper lip). Perioral stimulation evoked the characteristic field potentials in crus II and increased BFcrb (34 +/- 6%; 10 Hz-25 V; n = 6) without changing arterial pressure. The BFcrb increases were associated with a local increase in glucose utilization (74 +/- 8%; P < 0.05; n = 5) and were attenuated by the AMPA-kainate receptor antagonist 2, 3-dihydroxy-6-nitro-7-sulfamoylbenzo-[f]quinoxaline (-71 +/- 3%; 100 microM; P < 0.01; n = 5). The neuronal NO synthase inhibitor 7-nitroindazole (7-NI, 50 mg/kg; n = 5) virtually abolished the increases in BFcrb (-90 +/- 2%; P < 0.01) but did not affect the amplitude of the field potentials. In contrast, 7-NI attenuated the increase in neocortical cerebral blood flow produced by perioral stimulation by 52 +/- 6% (P < 0.05; n = 5). We conclude that crus II activation by somatosensory stimuli produces localized increases in local neural activity and BFcrb that are mediated by activation of glutamate receptors and NO. Unlike in neocortex, in cerebellum the vasodilation depends almost exclusively on NO. The findings underscore the unique role of NO in the mechanisms of synaptic function and blood flow regulation in cerebellum.

The influence of the circadian pacemaker and of the duration of time awake on the electroencephalogram (EEG) was investigated in 19 humans during approximately 40 h of sustained wakefulness. Two circadian rhythms in spectral power density were educed. The first rhythm was centered in the theta band (4.25-8.0 Hz) and exhibited a minimum approximately 1 h after the onset of melatonin secretion. The second rhythm was centered in the high-frequency alpha band (10.25-13.0 Hz) and exhibited a minimum close to the body temperature minimum. The latter rhythm showed a close temporal association with the rhythms in subjective alertness, plasma melatonin, and body temperature. In addition, increasing time awake was associated with an increase of power density in the 0.25- to 9.0-Hz and 13.25- to 20. 0-Hz ranges. It is concluded that the waking EEG undergoes changes that can be attributed to circadian and homeostatic (i.e., sleep-wake dependent) processes. The distinct circadian variations of EEG activity in the theta band and in the high-frequency alpha band may represent electrophysiological correlates of different aspects of the circadian rhythm in arousal.

The expression of two members of the ATP-binding cassette family of transport proteins, P-glycoprotein (P-gp) and the canalicular multispecific organic anion transporter (cMOAT or Mrp2), was evaluated in renal brush-border membranes (BBM) and various rat tissues after cisplatin treatment. One administration of cisplatin (5 mg/kg) increased P-gp expression by >200-300% in renal BBM and in crude membranes from liver and intestine. The increase in P-gp expression in the kidney was also detected in photolabeling experiments, suggesting the induction of functional P-gp. cMOAT expression was increased by >10-fold in renal BBM after cisplatin administration, although it had no effect on liver cMOAT expression. The increase in the levels of both proteins was maximal at 2 days after cisplatin treatment and lasted for at least 8 days. These results indicate that a single administration of cisplatin induces overexpression of P-gp and cMOAT in specific tissues. This may be of significant relevance to the design of clinical trials using cisplatin as a single chemotherapeutic agent or in combination with other drugs.

Unlabelled: Prior exercise stimulates muscle and liver glucose uptake. A negative arterial-portal venous glucose gradient (a-pv grad) stimulates resting net hepatic glucose uptake (NHGU) but reduces muscle glucose uptake. This study investigates the effects of a negative a-pv grad during glucose administration after exercise in dogs.

Experimental protocol: exercise (-180 to -30 min), transition (-30 to -20 min), basal period (-20 to 0 min), and experimental period (0 to 100 min). In the experimental period, 130 mg/dl arterial hyperglycemia was induced via vena cava (Pe, n = 6) or portal vein (Po, n = 6) glucose infusions. Insulin and glucagon were replaced at fourfold basal and basal rates. During the experimental period, the a-pv grad (mg/dl) was 3 +/- 1 in Pe and -10 +/- 2 in Po. Arterial insulin and glucagon were similar in the two groups. In Pe, net hepatic glucose balance (mg x kg(-1) x min(-1), negative = uptake) was 4.2 +/- 0.3 (basal period) and -1.2 +/- 0.3 (glucose infusion); in Po it was 4.1 +/- 0.5 and -3.2 +/- 0.4, respectively (P < 0.005 vs. Pe). Total glucose infusion (mg x kg(-1) x min(-1)) was 11 +/- 1 in Po and 8 +/- 1 in Pe (P < 0.05). Net hindlimb and whole body nonhepatic glucose uptakes were similar.

Conclusions: the portal signal independently stimulates NHGU after exercise. Conversely, prior exercise eliminates the inhibitory effect of the portal signal on glucose uptake by nonhepatic tissues. The portal signal therefore increases whole body glucose disposal after exercise by an amount equal to the increase in NHGU.

Cardiac hypothermia alters contractility and intracellular Ca2+ concentration ([Ca2+]i) homeostasis. We examined how left ventricular pressure (LVP) is altered as a function of cytosolic [Ca2+]i over a range of extracellular CaCl2 concentration ([CaCl2]e) during perfusion of isolated, paced guinea pig hearts at 37 degrees C, 27 degrees C, and 17 degrees C. Transmural LV phasic [Ca2+] was measured using the Ca2+ indicator indo 1 and calibrated (in nM) after correction was made for autofluorescence, temperature, and noncytosolic Ca2+. Noncytosolic [Ca2+]i, cytosolic diastolic and systolic [Ca2+]i, phasic [Ca2+]i, and systolic Ca2+ released per beat (area Ca2+) were plotted as a function of 0.3-4.5 mM [CaCl2]e, and indexes of contractility [LVP, maximal rates of LVP development (+dLVP/dt) and relaxation (-dLVP/dt), and the integral of the LVP curve per beat (LVParea)] were plotted as a function of [Ca2+]i. Hypothermia increased systolic [Ca2+]i and slightly changed systolic LVP but increased diastolic LVP and [Ca2+]i. The relationship of diastolic and noncytosolic [Ca2+] to [CaCl2]e was shifted upward at 17 degrees C and 27 degrees C, whereas that of phasic [Ca2+]) to [CaCl2]e was shifted upward at 17 degrees C but not at 27 degrees C. The relationships of phasic [Ca2+]i to developed LVP, +dLVP/dt, and LVP(area) were progressively reduced by hypothermia so that maximal Ca2+-activated LVP decreased and hearts were desensitized to Ca2+. Thus mild hypothermia modestly increases diastolic and noncytosolic Ca2+ with little effect on systolic Ca2+ or released (area) Ca2+, whereas moderate hypothermia markedly increases diastolic, noncytosolic, peak systolic, and released Ca2+ and results in reduced maximal Ca2+-activated LVP and myocardial sensitivity to systolic Ca2+.

A reduction of renal kallikrein has been found in non-insulin-treated diabetic individuals, suggesting that an impaired renal kallikrein-kinin system (KKS) contributes to the development of diabetic nephropathy. We analyzed relevant components of the renal KKS in non-insulin-treated streptozotocin (STZ)-induced diabetic rats. Twelve weeks after a single injection of STZ, rats were normotensive and displayed hyperglycemia, polyuria, proteinuria, and reduced glomerular filtration rate. Blood bradykinin (BK) levels and prekallikrein activity were significantly increased compared with controls. Renal kallikrein activity was reduced by 70%, whereas urinary BK levels were increased up to threefold. Renal kininases were decreased as indicated by a 3-fold reduction in renal angiotensin-converting enzyme activity and a 1.8-fold reduction in renal expression of neutral endopeptidase 24.11. Renal cortical expression of kininogen and B2 receptors was enhanced to 1.4 and 1. 8-fold, respectively. Our data suggest that increased urinary BK levels found in severely hyperglycemic STZ-diabetic rats are related to increased filtration of components of the plasma KKS and/or renal kininogen synthesis in combination with decreased renal kinin-degrading activity. Thus, despite reduced renal kallikrein synthesis, renal KKS is activated in the advanced stage of diabetic nephropathy.

The characteristics and modulation of glucose transport were investigated in skeletal muscles of 5-wk-old Muscovy ducklings (Cairina moschata). Glucose uptake by sarcolemmal vesicles isolated from gastrocnemius muscle followed typical Michaelis-Menten kinetics with a K(m) value (17 mM) similar to that described in equivalent mammalian preparations. Western blot analysis of duckling sarcolemma using antibodies directed against rat GLUT-4 transporter revealed an immunoreactive protein of similar molecular mass (45 kDa) to that present in rats. When ducklings were killed in the postabsorptive state, GLUT-4 homologous protein was located predominantly (80%) in intracellular membranes. Insulin stimulation of a perfused leg muscle preparation in vitro led to the translocation of GLUT-4 homologous proteins from intracellular pools to the sarcolemma, with a subsequent increase in glucose uptake by sarcolemmal vesicles and perfused muscles. Glucose transport was positively controlled by the metabolic needs of skeletal muscle as reflected by the increased glucose uptake of sarcolemmal vesicles isolated from cold-acclimated ducklings. Present results, therefore, demonstrate, for the first time in an avian species, the existence in skeletal muscle of a glucose transporter showing molecular and functional homologies with the mammalian GLUT-4 transporter.

The actin cytoskeleton is an important contributor to the modulation of the cell function. However, little is known about the regulatory role of this supermolecular structure in the membrane events that take place in the heart. In this report, the regulation of cardiac myocyte function by actin filament organization was investigated in neonatal mouse cardiac myocytes (NMCM) from both wild-type mice and mice genetically devoid of the actin filament severing protein gelsolin (Gsn-/-). Cardiac L-type calcium channel currents (I(Ca)) were assessed using the whole cell voltage-clamp technique. Addition of the actin filament stabilizer phalloidin to wild-type NMCM increased I(Ca) by 227% over control conditions. The basal I(Ca) of Gsn-/- NMCM was 300% higher than wild-type controls. This increase was completely reversed by intracellular perfusion of the Gsn-/- NMCM with exogenous gelsolin. Further, cytoskeletal disruption of either Gsn-/- or phalloidin-dialyzed wild-type NMCM with cytochalasin D (CD) decreased the enhanced I(Ca) by 84% and 87%, respectively. The data indicate that actin filament stabilization by either a lack of gelsolin or intracellular dialysis with phalloidin increase I(Ca), whereas actin filament disruption with CD or dialysis of Gsn-/- NMCM with gelsolin decrease I(Ca). We conclude that cardiac L-type calcium channel regulation is tightly controlled by actin filament organization. Actin filament rearrangement mediated by gelsolin may contribute to calcium channel inactivation.

Isolated, cannulated, and pressurized (100 mmHg) middle cerebral arteries from adult cats were perfused intraluminally at rates from 0 to 4 ml/min with heated and gassed physiological saline solution. An electronic system held pressure constant by changing outflow resistance. The arteries constricted 18.1 +/- 0.95% in response to flow and depolarized from -54 +/- 0.51 to -40 +/- 1.26 mV (P < 0.05). Constriction was independent of a functional endothelium but was eliminated by superoxide dismutase or tyrosine kinase inhibitors. Luminal perfusion with a synthetic extracellular matrix Arg-Gly-ASP (RGD) peptide that binds with integrin significantly reduced constriction to flow. Neither reducing intraluminal pressure nor increasing tone or shear stresses altered constriction to flow. Flow-induced constriction did not impede the ability of the arteries to dilate to hypercapnia, and inhibiting flow-induced constriction did not alter contractile responses to other agonists. These data suggest that, in vitro, middle cerebral arteries constrict to flow through a mechanism involving free radicals and tyrosine kinase and that flow shear stresses resulting in constriction are transduced by integrin signaling.