Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020440 (hypercapnia)
 7,939 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experiments were performed in isolated non-working guinea pig hearts perfused according to the Langendorff technique (95% O2, 5% CO2), to evaluate the relative contribution of the coronary endothelium to the formation of cardiac adenosine during hypoxia, hypercapnia, and acetylcholine infusion. For this purpose the adenine-nucleotides of the coronary endothelium were prelabeled by perfusion of isolated hearts with 3H-adenosine (10(-8) M) for 35 min. Changes in the relative specific radioactivity (RSA) of adenosine released into the coronary effluent perfusate were used to assess changes in the relative contribution of the coronary endothelium and cardiomyocytes to total cardiac adenosine release. Hypoxic perfusion (15% O2) doubled coronary flow and increased total adenosine release by about two orders of magnitude and in addition, substantially increased the release of 3H-adenosine. The RSA of adenosine, however, was consistently depressed. During hypercapnic acidosis (9% CO2) the increase in coronary flow was associated with only a small and transient rise in cardiac adenosine release, and did not influence the formation of 3H-adenosine. In the unpaced heart, acetylcholine (10(-7) and 2 X 10(-6) M) dose-dependently increased coronary flow and the release of both adenosine and 3H-adenosine. Within the first minute, the RSA of adenosine was increased, but thereafter was decreased relative to control. In the paced heart, the effects of acetylcholine (2 X 10(-6) M) were greatly attenuated. Increasing coronary flow by bradykinin and isosorbide dinitrate or decreasing heart rate by (-)N6-phenylisopropyl-adenosine did not significantly affect effluent perfusate concentration of adenosine or its RSA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contribution of coronary endothelial cells to cardiac adenosine production. 308 33

1. Exposure to glass of whole blood from anaesthetized foetal lambs (at 0.6-0.95 of term) causes the rapid development of a potent pulmonary vasodilator agent.2. The formation of the vasodilator agent on exposure to glass, its disappearance with time, and the inhibition of its production by soya bean trypsin inhibitor, suggest that it is bradykinin.3. Small doses of bradykinin ( approximately 1 ng/kg) cause pulmonary vasodilatation on close arterial injection. Neither this, nor the vasodilatation caused by glass-exposed whole blood, are affected by agents which block the vasodilator actions of acetylcholine, isoprenaline or histamine.4. Exposure of foetal plasma and/or red cells to glass rarely caused the development of a pulmonary vasodilator agent. Maternal plasma was always active. Injection of the buffy coat from foetal blood caused pulmonary vasodilatation.5. The capacity of plasma from sheep at different ages to produce kinin(s) was examined by assay on the isolated rat's uterus. In the foetus activity was very low; it increased with age.6. In adolescent lambs 5-14 weeks after birth injection of approximately 10 ng/kg bradykinin into the pulmonary artery caused only a trifling vasodilatation; this was greater when pulmonary vasoconstriction was induced by lung collapse, hypoxaemia and hypercapnia.7. The possible physiological consequences of these findings are discussed.
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PMID:The release of a bradykinin-like pulmonary vasodilator substance in foetal and new-born lambs. 563 4

Cerebral blood flow (CBF) and cerebral O2 metabolism (CMRO2) changes were measured in these studies during treatment with three reputed cerebral vasodilators: bradykinin, adenosine triphosphate (ATP) and increased arterial PCO2. Intracerebrovascular bradykinin infusions increased CMRO2 and CBF to a similar degree. Intramaxillary ATP infusions increased CBF to an extent greater than that required for increases seen in CMRO2. Hypercapnia increased CBF without a significant change in CMRO2. Results suggest that increases in cerebral metabolism may mediate most, some and none of the cerebrovascular changes produced by bradykinin, ATP or hypercapnia, respectively.
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PMID:Cerebrovascular and metabolic effects of bradykinin, ATP and hypercapnia in the goat. 687 30

The prostanoid-synthesizing enzyme cyclooxygenase-2 (COX-2) is expressed in selected cerebral cortical neurons and is involved in synaptic signaling. We sought to determine whether COX-2 participates in the increase in cerebral blood flow produced by synaptic activity in the somatosensory cortex. In anesthetized mice, the vibrissae were stimulated mechanically, and cerebral blood flow was recorded in the contralateral somatosensory cortex by a laser-Doppler probe. We found that the COX-2 inhibitor NS-398 attenuates the increase in somatosensory cortex blood flow produced by vibrissal stimulation. Furthermore, the flow response was impaired in mice lacking the COX-2 gene, whereas the associated increase in whisker-barrel cortex glucose use was not affected. The increases in cerebral blood flow produced by hypercapnia, acetylcholine, or bradykinin were not attenuated by NS-398, nor did they differ between wild-type and COX-2 null mice. The findings provide evidence for a previously unrecognized role of COX-2 in the mechanisms coupling synaptic activity to neocortical blood flow and provide an insight into one of the functions of constitutive COX-2 in the CNS.
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PMID:Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. 1063 5

Transgenic mice overexpressing the amyloid precursor protein (APP) have a profound impairment in endothelium-dependent cerebrovascular responses that is counteracted by the superoxide scavenger superoxide dismutase (SOD). The authors investigated whether the amyloid-beta peptide (A beta) is responsible for the cerebrovascular effects of APP overexpression. Cerebral blood flow (CBF) was monitored by a laser-Doppler flowmeter in anesthetized-ventilated mice equipped with a cranial window. Superfusion of A beta1-40 on the neocortex reduced resting CBF in a dose-dependent fashion (-29% +/- 7% at 5 micromol/L) and attenuated the increase in CBF produced by the endothelium-dependent vasodilators acetylcholine (-41% +/- 8%), bradykinin (-39% +/- 9%), and the calcium ionophore A23187 (-37% +/- 5%). A beta1-40 did not influence the CBF increases produced by the endothelium-independent vasodilators S-nitroso-N-acetylpenicillamine and hypercapnia. In contrast, A beta1-42 did not attenuate resting CBF or the CBF increases produced by endothelium-dependent vasodilators. Cerebrovascular effects of A beta1-40 were reversed by the superoxide scavengers SOD or MnTBAP. Furthermore, substitution of methionine 35 with norleucine, a mutation that blocks the ability of A beta to generate reactive oxygen species, abolished A beta1-40 vasoactivity. The authors conclude that A beta1-40, but not A beta1-42, reproduces the cerebrovascular alterations observed in APP transgenics. Thus, A beta1-40 could play a role in the cerebrovascular alterations observed in Alzheimer's dementia.
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PMID:Exogenous A beta1-40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice. 1112 82

Cyclooxygenase (COX) is a prostanoid-synthesizing enzyme present in 2 isoforms: COX-1 and COX-2. Although it has long been hypothesized that prostanoids participate in cerebrovascular regulation, the lack of adequate pharmacological tools has led to conflicting results and has not permitted investigators to define the relative contribution of COX-1 and COX-2. We used the COX-1 inhibitor SC-560 and COX-1-null (COX-1(-/-)) mice to investigate whether COX-1 plays a role in cerebrovascular regulation. Mice were anesthetized (urethane and chloralose) and equipped with a cranial window. Cerebral blood flow (CBF) was measured by laser Doppler flowmetry or by the (14)C-iodoantipyrine technique with quantitative autoradiography. In wild-type mice, SC-560 (25 micromol/L) reduced resting CBF by 21+/-4% and attenuated the CBF increase produced by topical application of bradykinin (-59%) or calcium ionophore A23187 (-49%) and by systemic hypercapnia (-58%) (P<0.05 to 0.01). However, SC-560 did not reduce responses to acetylcholine or the increase in somatosensory cortex blood flow produced by vibrissal stimulation. In COX-1(-/-) mice, resting CBF assessed by (14)C-iodoantipyrine was reduced (-13% to -20%) in cerebral cortex and other telencephalic regions (P<0.05). The CBF increase produced by bradykinin, A23187, and hypercapnia, but not acetylcholine or vibrissal stimulation, were attenuated (P<0.05 to 0.01). The free radical scavenger superoxide dismutase attenuated responses to bradykinin and A23187 in wild-type mice but not in COX-1(-/-) mice, suggesting that COX-1 is the source of the reactive oxygen species known to mediate these responses. The data provide evidence for a critical role of COX-1 in maintaining resting vascular tone and in selected vasodilator responses of the cerebral microcirculation.
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PMID:Cyclooxygenase-1 participates in selected vasodilator responses of the cerebral circulation. 1128 94

Cardiac sympathetic afferents are known to reflexly activate the cardiovascular system, leading to increases in blood pressure, heart rate, and myocardial contractile function. During myocardial ischemia, these sensory nerves also transmit the sensation of pain (angina pectoris) and cause tachyarrhythmias. The authors' laboratory has been interested in defining the mechanisms of activation of this neural system during ischemia and reperfusion. During these periods, reactive oxygen species, particularly hydroxyl radicals, are produced from the breakdown of purine metabolites and lead to stimulation of sympathetic (and vagal) ventricular chemosensitive nerve endings. For example, stimulation with hydrogen peroxide leads to a small reflex increase in blood pressure from the predominant sympathetic afferent activation that is reduced by simultaneous activation of cardiac vagal afferents (known to exert predominantly depressor reflexes). Central integration of these two opposing reflexes likely occurs at several regions of the brain stem, including the nucleus tractus solitarii, where neural occlusion occurs during simultaneous cardiac sympathetic and vagal-afferent stimulation. Activation of platelets also appears to play a role during myocardial ischemia, leading to local release of serotonin (5HT), which, through a 5HT3 mechanism, stimulates sympathetic afferents. Finally, regional changes in pH from lactic acid (but not hypercapnia), stimulate ventricular afferents and may activate kallikrein to increase bradykinin (BK), which, in turn, breaks down arachidonic acid to form prostaglandins. Prostaglandins sensitize cardiac sympathetic afferents to BK. Thus, stimulation of cardiac sympathetic afferents during ischemia and reperfusion and the resulting reflex events form a multifactorial process resulting from activation of a number of chemical pathways in the myocardium.
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PMID:Cardiac sympathetic afferent activation provoked by myocardial ischemia and reperfusion. Mechanisms and reflexes. 1145 9

In the recent years it has been recognized that nitric oxide is an important regulator of ocular blood flow. Nitric oxide is involved in the control of basal blood flow in the choroid, optic nerve and the retina. In addition, nitric oxide mediates a number of vasodilator responses in ocular vessels to agonists such as acetylcholine, bradykinin, histamine, substance P and insulin. Nitric oxide also plays a role in hypercapnia-induced vasodilation in the choroid and is a modulator of pressure autoregulation in this vascular bed. Abnormalities of the L-arginine/nitric oxide system have been observed in a variety of ocular diseases including glaucoma, diabetic retinopathy and retinopathy of prematurity. This makes the L-arginine/nitric oxide pathway an attractive target for therapeutic interventions. Additional research is required, particularly in characterizing the role of the three nitric oxide synthase isoforms in the control of ocular perfusion, to implement this concept into the clinical management of ocular diseases.
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PMID:Role of nitric oxide in the control of ocular blood flow. 1158 19

We hypothesize that inhibitory effects exist between prostanoids and nitric oxide (NO) in their contributions to cerebral circulation. Piglets (1-4 days old) were divided into three chronically treated (6-8 days) groups: control piglets, piglets treated with indomethacin (75 mg/day), and piglets treated with N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg x kg(-1) x day(-1)). Pial arterioles dilated in response to hypercapnia similarly among the three groups (41 +/- 4, 40 +/- 6, and 45 +/- 11%). Cerebrospinal fluid cAMP increased in control piglets, while cGMP increased in indomethacin-treated piglets. L-NAME, but not 7-nitroindazole, inhibited the response to hypercapnia only in indomethacin-treated piglets (40 +/- 6 vs. 17 +/- 5%). Topical sodium nitroprusside or iloprost restored dilation in response to hypercapnia. Similar results were obtained when the dilator was bradykinin. Pial arterioles of control and L-NAME-treated piglets constricted in response to ACh (-24 +/- 3%). However, those of indomethacin-treated piglets dilated in response to ACh (15 +/- 2%). This dilation was inhibited by L-NAME. NO synthase activity, but not endothelial NO synthase expression, increased after chronic indomethacin treatment. These data suggest that chronic inhibition of cyclooxygenase can increase the contribution of NO to cerebrovascular circulatory control in piglets.
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PMID:Compensatory role of NO in cerebral circulation of piglets chronically treated with indomethacin. 1179 49

N-methyl-D-aspartate (NMDA) elicits pial arteriolar dilation that has been associated with neuronal nitric oxide (NO) production. However, endothelial factors or glial P-450 epoxygenase products may play a role. We tested whether NMDA-induced pial vasodilation 1) primarily involves NO diffusion from the parenchyma to the surface arterioles, 2) involves intact endothelial function, and 3) involves a miconazole-sensitive component. Arteriolar diameters were determined using closed cranial window-intravital microscopy in anesthetized piglets. NMDA (10-100 microM) elicited virtually identical dose-dependent dilations in paired arterioles (r = 0.94, n = 15). However, NMDA- but not bradykinin (BK)-induced dilations of arteriolar sections over large veins were reduced by 31 +/- 1% (means +/- SE, P < 0.05, n = 4) compared with adjacent sections on the cortical surface. Also, 100 microM NMDA increased cerebrospinal fluid levels of NO metabolites from 3.7 +/- 1.0 to 5.3 +/- 1.2 microM (P < 0.05, n = 6). Endothelial stunning by intracarotid injection of phorbol 12,13-dibutyrate did not affect NMDA-induced vasodilation but attenuated vascular responses to hypercapnia and BK by approximately 70% (n = 7). Finally, miconazole (n = 6, 20 microM) pretreatment and coapplication with NMDA did not alter vascular responses to NMDA. In conclusion, NMDA appears to dilate pial arterioles exclusively through release and diffusion of NO from neurons to the pial surface in piglets.
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PMID:N-methyl-D-aspartate-induced vasodilation is mediated by endothelium-independent nitric oxide release in piglets. 1189 77


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