Coupling of neural activity to blood flow in olfactory glomeruli is mediated by astrocytic pathways

Functional neuroimaging uses activity-dependent changes in cerebral blood flow to map brain activity, but the contributions of presynaptic and postsynaptic activity are incompletely understood, as are the underlying cellular pathways. Using intravital multiphoton microscopy, we measured presynaptic activity, postsynaptic neuronal and astrocytic calcium responses, and erythrocyte velocity and flux in olfactory glomeruli during odor stimulation in mice. Odor-evoked functional hyperemia in glomerular capillaries was highly correlated with glutamate release, but did not require local postsynaptic activity. Odor stimulation induced calcium transients in astrocyte endfeet and an associated dilation of upstream arterioles. Calcium elevations in astrocytes and functional hyperemia depended on astrocytic metabotropic glutamate receptor 5 and cyclooxygenase activation. Astrocytic glutamate transporters also contributed to functional hyperemia through mechanisms independent of calcium rises and cyclooxygenase activation. These local pathways initiated by glutamate account for a large part of the coupling between synaptic activity and functional hyperemia in the olfactory bulb.     

Local heating of human skin causes hyperemia without mediation by muscarinic cholinergic receptors or prostanoids.

Local changes in surface temperature have a powerful influence on the perfusion of human skin. Heating increases local skin blood flow, but the mechanisms and mediators of this response (thermal hyperemia response) are incompletely elucidated. In the present study, we examined the possible dependence of the thermal hyperemia response on stimulation of muscarinic cholinergic receptors and on production of vasodilator prostanoids. In 13 male healthy subjects aged 20-30 yr, a temperature-controlled chamber was positioned on the volar face of one forearm and used to raise surface temperature from 34 to 41 degrees C. The time course of the resulting thermal hyperemia response was recorded with a laser-Doppler imager. In one experiment, each of eight subjects received an intravenous bolus of the antimuscarinic agent glycopyrrolate (4 microg/kg) on one visit and saline on the other. The thermal hyperemia response was determined within the hour after the injections. Glycopyrrolate effectively inhibited the skin vasodilation induced by iontophoresis of acetylcholine but did not influence the thermal hyperemia response. In a second experiment, conducted in five other subjects, 1 g of the cyclooxygenase inhibitor aspirin administered orally totally abolished the vasodilation induced in the skin by anodal current but also failed to modify the thermal hyperemia response. The present study excludes the stimulation of muscarinic receptors and the production of vasodilator prostaglandins as essential and nonredundant mechanisms for the vasodilation induced by local heating in human forearm skin.     

Effect of distribution of the stimulation frequency in the volley on post-contraction hyperemia of the gastrocnemius muscle of cats]

The influence of stimulation frequency distribution in a volley on postexercise (postcontraction) hyperemia was studied in acute experiments on cat gastrocnemius muscle. The initial high frequency of the rhythmic volley augmented the postcontraction hyperemia indices (the peak blood flow and an additional blood volume).     

Activity of nitric oxide synthase in the ventilatory muscle vasculature

We evaluated in the in situ vascularly isolated canine diaphragm the role of nitric oxide (NO) in the regulation of basal vascular resistance and vascular responses to increased muscle activity (active hyperemia), brief occlusions of the phrenic artery (reactive hyperemia), and changes in arterial pressure. The vasculature of the left hemidiaphragm was either pump-perfused at a fixed flow rate or autoperfused with arterial blood from the femoral artery. Endothelial nitric oxide synthase (NOS) activity was inhibited by intraphrenic infusion of L-arginine analogues such as N(G)-nitro-L-arginine, N(G)-nitro-L-arginine methyl ester and argininosuccinic acid. Active hyperemia was produced by low (2 Hz) frequency stimulation of the left phrenic nerve. Reactive hyperemia was measured in response to 10, 20, 30, 60, and 120 sec duration occlusions of the left phrenic artery and was quantified in terms of postocclusive blood flow, vascular resistance, hyperemic duration, and hyperemic volume. Infusion of NOS inhibitors into the vasculature of the resting diaphragm increased phrenic vascular resistance significantly and to a similar extent. Reactive hyperemic volume and reactive hyperemic duration were also significantly attenuated after NOS inhibition, however, peak reactive hyperemic dilation was not influenced by NOS inhibition. It was also found that enhanced NO release contribute by about 41% to active dilation elicited by continuous 2 Hz stimulation. In addition, NOS inhibition had no effect on O2 consumption of the resting diaphragm, but significantly attenuated the rise in diaphragmatic O2 consumption during during 2 Hz stimulation. The decline in diaphragmatic O2 consumption was due to reduction in blood flow. These results indicate that NO release plays a significant role in the regulation of diaphragmatic vascular tone and O2 consumption.     

2 phase of the working hyperemia of skeletal muscle]

The dynamics of the working hyperemia of cat m. gastrocnemius was studied by means of an electromagnetic flowmeter. Two phases could be distinguished in the increase in the rate of circulation. There proved to be a rapid increase of the blood flow during the I phase, and an abrupt reduction of this process during the II phase. The duration of the I phase failed to depend on the frequency of stimulation and on the number of the contracting motor units. The II phase was absent when the number of the contracting motor units was few or the frequency of stimulation was low. It is suggested that the dilatation of the precapillary arterioles is responsible for the I phase of the working hyperemia and the II phase is connected with the dilatation of the larger arteries.     

Plasma nitrite reserve and endothelial function in the human forearm circulation

Attenuation of endothelium-derived nitric oxide (NO) synthesis is a hallmark of endothelial dysfunction. Early detection of this disorder may have therapeutic and prognostic implications. Plasma nitrite mirrors acute and chronic changes in endothelial NO-synthase activity. We hypothesized that local plasma nitrite concentration increases during reactive hyperemia of the forearm, reflecting endothelial function. In healthy subjects (n = 11) plasma nitrite and nitrate were determined at baseline and during reactive hyperemia of the forearm using reductive gas-phase chemiluminescence and flow-injection analysis, respectively. Endothelium-dependent dilation of the brachial artery was measured as flow-mediated dilation (FMD) using high-resolution ultrasound. Results were compared to patients with endothelial dysfunction as defined by reduced FMD (n = 11). Reactive hyperemia of the forearm increased local plasma nitrite concentration from 68 +/- 5 to 126 +/- 13 nmol/L (p < 0.01), whereas in endothelial dysfunction nitrite remained unaffected (116 +/- 12 to 104 +/- 10 nmol/L; n.s.), corresponding to nitrite reserves of 94 +/- 21 and -8 +/- 4%. This was accompanied by a significantly greater increase in brachial artery diameter (FMD: 8.5 +/- 0.4% vs 2.9 +/- 0.5%, for healthy subjects and endothelial dysfunction, respectively; p < 0.001). This observation suggests that nitrite changes reflect endothelial function. Assessment of local plasma nitrite during reactive hyperemia may open new avenues in the diagnosis of vascular function.     

Vascular escape from vasoconstriction and post-stimulatory hyperemia in the superior mesenteric artery of the cat

Vascular escape is seen as a partial recovery from initial vasoconstriction despite continued constrictor stimuli. Escape in the feline intestine (superior mesenteric artery) occurred for i.a. norepinephrine (NE) infusions (56% escape for low dose, 40% for high dose NE) and for sympathetic nerve stimulation (SNS) (65% for 1 Hz, 49% for 3 Hz, 44% for 9 Hz). Adenosine infusion or blockade of adenosine receptors (8-phenyltheophylline) did not alter the escape, showing that endogenous adenosine levels are unlikely to play any role in the mechanism of escape. Other aspects of escape were studied: equiconstrictor doses of NE given i.a. or i.v. lead to similar degrees of escape; propranolol and ouabain did not alter escape; the degree of escape was significantly greater for the low dose NE and the 1-Hz SNS than for higher intensities of stimulation, however, escape did not inversely correlate significantly with the initial degree of vasoconstriction when all data were pooled. Post-stimulatory hyperemia occurs upon cessation of vasoconstrictor stimuli, reaches a peak conductance within 1 min, and returns to baseline within about 3 min. Hyperemia was quantitated from the peak vasodilation and from the area under the flow-hyperemia curve. The hyperemias were not related to NE dose or SNS frequency nor did they correlate with initial vasoconstriction or extent of vascular escape. Contrary to the hypothesis that adenosine may mediate hyperemia, adenosine infusions reduced the response and adenosine receptor antagonism tended to elevate the response. Propranolol and ouabain did not produce significant effects on post-stimulatory hyperemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Post pressure hyperemia in the rat

In prior studies in man, we have demonstrated that pressure-induced hyperemia lasts for prolonged periods as compared to the short-term hyperemia created by proximal arterial occlusion. We have analyzed this phenomenon in our well-studied rat model of skin blood flow. Skin blood flow was measured using laser Doppler techniques in Wistar Kyoto rats at the back, a nutritively perfused site, and at the plantar surface of the paw, where arteriovenous anastomotic perfusion dominates. A customized pressure feedback control device was used to vary applied pressures. At the back, pressures in excess of 80 mmHg resulted in occlusion, whereas at the paw 150 mmHg was required. The peak hyperemic flow after release of pressure was comparable to that elicited by proximal arterial occlusion with a blood pressure cuff. However, the post pressure hyperemia peak descended to a plateau value, which was 50-100% greater than baseline and continued for up to 20 min while the peak following proximal arterial occlusion returned to baseline within 4 min. At the back, post pressure hyperemia reached a maximum after application of 100 mmHg pressure. The application of higher pressures than required for occlusion produced no greater hyperemic response. At the paw, maximum post pressure hyperemia occurred at 100 mmHg, although this pressure level was not totally occlusive. Higher pressures resulted in no greater hyperemia. At the back, 10 min of occlusion produced a maximal peak value whereas 1 min was sufficient at the paw. The application of pressure to a heated probe with subsequent release, produced a hyperemic response. Normalized to baseline blood flow, there was no difference between the hyperemic responses at basal skin temperature and at 44 degrees C. There is a prolonged hyperemic response following local pressure occlusion compared to a much shorter period following proximal ischemic occlusion. One can presume two different mechanisms, one related to ischemia and the other a separate pressure related phenomenon. The thermal vasodilatory response is additive, not synergistic with the post pressure hyperemia we have demonstrated. This finding suggests that different mechanisms are involved in thermal vasodilation and post pressure hyperemia.     

Adenosine mediation of mesenteric blood flow.

The mesenteric circulation is regulated by multiple mechanisms, there is sufficient reason to support the suspicion that local metabolic factors are especially important in the control of intestinal vasculature. Of these, adenosine, a purine nucleoside and mesenteric vasodilator, may be the messenger of the intestinal tissue to signal appropriate responses of the intestinal vessels. The evidence supporting the candidacy of the nucleoside as a local regular of mesenteric circulation may be summarized, as follows: Adenoside is present in the tissue of the gut in measurable quantities. Exogenous adenosine is a powerful dilator of mesenteric resistance vessels. Blockade of adenosine receptors in the mesenteric circulation interferes significantly with three autoregulatory phenomena, i.e., postprandial hyperemia, pressure-flow autoregulation, and reactive hyperemia. The evidence which weakens the role of adenosine as mesenteric vasoregulator includes: Findings in several reports that adenosine depressed intestinal oxygen consumption. The failure of adenosine receptors to inhibit some autoregulatory hyperemias of the gut and the rather limited amount of evidence regarding tissue adenosine release in autoregulatory responses of the gut's vasculature.     

Mechanism of the development of functional hyperemia in the palatal salivary glands of the rat

At various regimens of the secretory activity in the palatile salivary glands, changes occurring in the transversal profiles of the postcapillary venules, but not of the blood capillaries, are most noticeable. Under food stimulation of secretion, the former dilate essentially, that can demonstrate certain functional hyperemia developing in the palatine salivary glands. Some previous experiments concerning interpretation of principles on the microcirculatory bed spatial organization give a good reason to suggest that dilatation of the postcapillary venules is connected with an increased blood perfusion in the canals of the preferrable blood stream. The postcapillary dilatation is possible because blood from the precapillaries gets into the capacitance blood microvessels and its volume at that moment is greater than the capacity of the venous microvessels. A suggestion is made that filtrative function of the palatile salivary glands depends on development of the functional hyperemia. It is possible, that this mechanism is universal, since owing to it, reflectory reactions of the salivary glands directed to the immediate secure of the oral cavity with a necessary amount of liquor become possible.     

Clinical studies of vaccine TEOVac under the conditions of remote revaccination

In the clinical trials of vaccine TEOVac in lower and reglamented doses under the conditions of remote vaccination, carried out on 11 volunteers, local reactions in the form of hyperemia, gingival edema (1 vaccinee), faucial hyperemia, enlargement of submaxillary lymph nodes (2 vaccinees) were registered in some of the vaccines; in one vaccinee systemic postvaccinal reaction of medium gravity was observed. Revaccination produced no negative effect on the hematological and biochemical characteristics of the blood, as well as on the urine characteristics. The study of the sensitizing vaccine to the antigens of the accumulation substrate (chick embryo), as well as its influence on the development of autoimmune reactions, revealed the absence of the allergic action of the preparation and its influence on autoimmune processes in the vaccines. The trial of the smallpox vaccine in tablets under the conditions of the primary immunization of adults was the topical and most promising trend in the improvement of smallpox vaccination, as the preparation TEOVac proved to be safe, in contrast to the traditional smallpox vaccine introduced by the scarification method, for both vaccines and nonimmunized persons having contacts with them.     

Role of polyamines in regulation of uterine blood flow of ovariectomized rats.

Polyamines have been shown to relax several types of smooth muscle including vasculature. In the estrogen-treated uterus, uterine blood flow and polyamine levels in the uterus are increased. The relaxant effect of polyamines on blood vessels suggest that polyamines may act on uterine vasculature to cause uterine hyperemia. In this study, we examined the roles of polyamines in regulating uterine blood flow. Ovariectomized rats were administered with polyamines or estrogen. The uterine blood flow was then measured by employing radioactive microspheres. The direct injection of polyamines into systemic circulation caused a 3-fold increase in uterine blood flow within 30 seconds. The polyamine-induced uterine hyperemia was counteracted by increasing extracellular calcium concentration. When rats were treated with estradiol, uterine blood flow increased. However, the treatment with alpha-difluromethylornithine, a polyamine synthesis inhibitor, did not attenuate the estrogen-induced uterine blood flow. Our results suggest that polyamines may affect uterine blood flow via antagonizing the entry of extracellular calcium. However, the detailed mechanisms via which polyamines involved in estrogenic stimulation of uterine hyperemia may require further studies.     

Effect of sympathetic nerve stimulation on myocardial reactive hyperemia

It has been established in experiments on 25 dogs that the peak of reactive hyperemia (RH) of the myocardium cannot be regarded as an absolute criterion of the coronary dilatory reserves. Stimulation of the stellate ganglion under the conditions of arterial blood pressure stabilization increased the peak of RH. After-effect of the sympathetic nerve stimulation also led to a rise in the peak of RH as compared with control.     

Characteristics of coronary vasodilation reserve in partial restriction and subsequent recovery of the coronary blood flow

The studies were performed on anesthetized dogs using the model of partial controlled blood flow restriction in the left circumflex coronary artery with intact thorax. 70% of blood flow restriction were compensated by coronary vasodilation reserve, evaluated in hyperemia reaction. No rapid reperfusion hyperemia reaction was observed in reperfusion period, while moderate reduction in heart contractility was maintained. Alterations in coronary vessel reactivity could have a certain depressing effect on reperfusion hyperemia reaction. The observed changes were reversible, as coronary vessels retained their dilatation ability in response to an additional ischemic stimulus.     

Effect of different prostaglandin synthesis inhibitors on post-occlusive blood flow in human forearm

The vascular relaxation response in the human forearm that follows a short period of arterial occlusion (reactive hyperemia) was investigated with respect to its dependance on an intact PG synthesis. In 10 healthy subjects, five men and five women, forearm blood flow was measured, using venous occlusion plethysmography, in the basal state and during the recovery phase following 5 min of obstructed arterial flow. The subjects were studied at nine different occasions. At six of these they were pre-treated with the highest recommended doses of either of the PG synthesis inhibitors acetyl-salicylic acid, diclofenac, ibuprofen, indomethacin, naproxen or piroxicam; the remaining occasions were controls, performed in the absence of drugs in the beginning, middle, and end of the series.All the drugs significantly decreased the total reactive hyperemia following 5 min of arterial occlusion. Ibuprofen was the most efficient agent, inhibiting the total reactive hyperemia by more than 70%, and naproxen was least active, producing about 35% inhibition. The rest of the drugs diminished the total reactive hyperemia by 55–65%. Basal forearm blood flow was not affected by either of the agents.From these data we conclude that drugs which inhibit PG synthesis in man have in common the capacity to decrease post-occlusive reactive hyperemia. This indicates that an activation of the local release of arachidonic acid, leading to formation of vasodilator PG, is one of the main factors behind the vascular smooth muscle relaxation response to arterial occlusion.     

Evaluation of coronary bed function by positron emission tomography using 13N-ammonium during cold stimulation

The purpose of the present investigation was to study the time course of changes in myocardial blood flow (MBF) in response to cold stimulation. Thirty-eight patients having risk factors of cardiovascular complications were examined. The time course of MBF changes was estimated by positron emission tomography (PET) using 13N-ammonium at rest and during a cold test (CT). Endothelium-dependent vasodilation of the brachial artery was determined from the results of a reactive hyperemia test, by applying ultrasound duplex scanning. No significant MBF increase in response to the cold test was an indicator of coronary arterial endothelial dysfunction at cardiac 13N-ammonium PET. Agreement of the results of brachial arterial ultrasonography during reactive hyperemia and cardiac 13N-ammonium PET in the presence of the cold test suggests that endothelial dysfunction is generalized. Cardiovascular risk factors, such as left ventricular hypertrophy, smoking, dyslipidemia, and diabetes mellitus, substantially affect coronary arterial function. Left ventricular hypertrophy is an independent factor that influences the amount of the coronary reserve and, in combination with endothelial dysfunction, worsens coronary microcirculation.     

Vasomotor control: functional hyperemia and beyond

Historically, functional hyperemia has been viewed largely as an interaction between a parenchymal cell and its associated microvasculature. Locally released metabolites have been thought to produce relaxation of the smooth muscle and a vasodilation that increases blood flow in proportion to metabolic need. This symposium report presents evidence from a variety of disciplines and a number of different types of biological preparations that demonstrates that functional hyperemia is a complex process involving several classes of microvessels including capillaries, arterioles, and small arteries. These vessels do not function independently but are coordinated by a complex set of interrelations involving at least three different modes of interaction between parenchymal cells and the various segments of the vascular bed. These are local metabolic effects, propagated effects extending over long segments of the vasculature, and flow-dependent vasodilation induced by local changes in blood flow. In addition to these acute responses to metabolic demand it appears that tissues may be capable of more long-term structural alterations of the arterial and arteriolar network in response to sustained changes in the relationship between supply and demand. The vascular bed appears to be able to adapt either by increasing the maximal anatomic diameter of the large arteries or by inserting new arterioles into the parenchyma. Thus, classical functional hyperemia appears to be but one manifestation of a multifaceted process leading to highly coordinated responses of many vascular elements, resulting finally in vascular patterns that are optimized to meet parenchymal cell demands.     

Risk Factors of Cardiovascular Diseases and the Capillary Endothelium in Subjects with Different Levels of Normal Blood Pressure

The capillary circulation in the forearm and crus was studied by occlusion plethysmography at rest and upon stimulation with nitric oxide during reactive hyperemia in 249 virtually healthy subjects with different levels of arterial blood pressure lower than 140/90 mm Hg. Specific features of the microcirculation were found in the forearm and crus depending on the blood pressure level. An increase in the blood pressure higher than 120/80 mm Hg was associated with an increased adverse effect of integral risk factors and heredity on parameters of the capillary circulation, especially in women.     

Evaluation of coronary bed function by positron emission tomography using 13N-ammonium during cold stimulation

The present investigation was to study the time course of changes in myocardial blood flow (MBF) in response to cold stimulation. Thirty-eight patients having risk factors of cardiovascular complications were examined. The time course of MBF changes was estimated by positron emission tomography (PET) using 13N-ammonium at rest and during a cold test (CT). Endothelium-dependent vasodilation of the brachial artery was determined from the results of a reactive hyperemia test, by applying ultrasonic duplex scanning. No significant MBF increase in response to the cold test was an indicator of coronary arterial endothelial dysfunction at cardiac 13N-ammonium PET. Agreement of the results of brachial arterial ultrasonography during reactive hyperemia and cardiac 13N-ammonium PET in the presence of the cold test suggests that endothelial dysfunction is generalized. Cardiovascular risk factors, such as left ventricular hypertrophy, smoking, dyslipidemia, and diabetes mellitus, substantially affect coronary arterial function. Left ventricular hypertrophy is an independent factor that influences the size of the coronary reserve and, in combination with endothelial dysfunction, worsens coronary microcirculation.     

The State of the Regional Blood Flow in the Upper Extremity after Dosed Physical Exercise

The effect of local isometric exercise on hand and forearm blood flow was studied. With maximum muscular exercise performed by both males and females, a decrease in hand and forearm blood flow was due to vasoconstriction caused by the mechanical pressure of working muscles. With 75 and 50% loads, marked hyperemia was observed in the main and microcirculatory vessels in the hand and forearm, which was rather long-lasting in the hand because of the difficulty of the forearm venous outflow. The minimum loads affected mainly the microcirculation, and no significant hemodynamic changes in main vessels were observed. The exercise performed at 50% of maximum muscular force was taken as an optimum load in kinesotherapeutic programs.