Biomedical subjects

D D Heistad

Publications and source records attributed to D D Heistad.

At least 91 records · Page 5Linked to original sources

PubMed1995

Effects of adenosine and 2-chloroadenosine on cerebral collateral vessels.

Adenosine is a potent cerebral vasodilator. We tested the hypothesis that dilatation of collateral vessels in cerebrum, in response to topical adenosine and 2-chloroadenosine (2-CAD), would increase blood flow to collateral-dependent cerebrum. In dogs anesthetized with halothane, a branch of the middle cerebral artery (MCA) was occluded proximally and cannulated distally. The collateral-dependent area at risk for infarction was perfused from a reservoir with microsphere-free blood, and blood flow to normal cerebrum and to cerebrum dependent on collateral flow was measured with radioactive microspheres injected into the left ventricle through a femoral artery catheter. Perfusion through the cannulated MCA branch was stopped, and flow to normal and collateral-dependent cerebrum was measured after adenosine (10(-2) M) or 2-CAD (10(-4) M) was added to the superfusate over the cerebrum. In normal cerebrum, topical application of adenosine increased flow to outer but not inner layers. Topical application of adenosine had little effect on flow to collateral-dependent tissue. In normal cerebrum, 2-CAD increased flow to outer layers, whereas flow to inner layers tended to increase. During 2-CAD, flow to outer cortical layers of collateral-dependent cerebrum increased from 140 +/- 20 ml/100 g/min (mean +/- SD) to 231 +/- 68, whereas flow to the inner collateral-dependent tissue did not change. The findings indicate that, after occlusion of a cerebral artery, topical 2-CAD increases blood flow to outer layers of collateral-dependent and normal cerebrum.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Chloroadenosine↗

PubMed1995

Increases in pulse pressure impair acetylcholine-induced vascular relaxation.

Effects of pulse pressure on acetylcholine-induced endothelium-dependent relaxation were investigated using a cascade bioassay model. Intact carotid arteries from rabbits were perfused at constant flow, and activity of endothelium-derived relaxing factor (EDRF) was assayed by measuring changes in isometric tension in a detector ring without endothelium. When pulse pressure of the donor artery was raised from approximately 2 to 10 mmHg, relaxation to acetylcholine (10(-7) M) was reduced from 31 +/- 3 (means +/- SE) to 20 +/- 2% (expressed as percent relaxation of phenylephrine-induced tone). Responses of the detector ring to nitroprusside were unchanged. Superoxide dismutase (SOD) and indomethacin each prevented impairment of relaxation to acetylcholine at high pulse pressure. When the donor artery was perfused at a higher mean pressure, elevation of pulse pressure also impaired relaxation to acetylcholine, and this impairment was prevented by SOD. These findings suggest that elevation of pulse pressure inhibits acetylcholine-induced, endothelium-dependent relaxation, and this inhibitory effect is mediated by generation of oxygen radicals.

Acetylcholine↗

PubMed1995

Mechanisms of endotoxin-induced dilatation of cerebral arterioles.

Lipopolysaccharide (LPS; endotoxin) produces dilatation of cerebral arterioles in vivo which may be due, in part, to expression of inducible nitric oxide (NO) synthase. We tested the hypothesis that aminoguanidine, an inhibitor of inducible NO synthase, would reduce endotoxin-induced dilatation of cerebral arterioles. Because mechanisms other than expression of inducible NO synthase may contribute to endotoxin-induced dilatation of cerebral arterioles, we also tested the hypothesis that calcitonin gene-related peptide (CGRP) contributes to vascular responses to endotoxin. Cerebral arteriolar diameter was measured using a closed cranial window in anesthetized rabbits under control conditions [77 +/- 3 (SE) microns] and during topical application of endotoxin (100 micrograms/ml). After 4 h, diameter of cerebral arterioles increased by 41 +/- 5%. Coapplication of aminoguanidine (0.3 mM) with endotoxin reduced vasodilatation at all time points (30 min to 4 h). Relative to control values, endotoxin treatment increased guanosine 3',5'-cyclic monophosphate (cGMP) concentration in cerebrospinal fluid (CSF) by approximately 20 fold at 4 h. Aminoguanidine attenuated the endotoxin-induced increased in CSF cGMP concentration. Aminoguanidine (0.3 mM) did not alter acetylcholine-mediated dilatation of cerebral arterioles. Coapplication of CGRP-(8-37) (0.5 microM), a specific blocker of CGRP receptors, with endotoxin significantly reduced vasodilatation in response to endotoxin at 2, 3, and 4 h. Thus 1) aminoguanidine inhibits endotoxin- but not acetylcholine-mediated dilatation of cerebral arterioles, and 2) activation of CGRP receptors mediates a portion of endotoxin-induced dilation of cerebral arterioles.

Acetylcholine↗

PubMed1995

Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase.

We examined effects of NG,NG-dimethyl-L-arginine (asymmetric dimethylarginine, ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, on cerebral vascular responses using cranial windows in anesthetized rats and rabbits. Under control conditions in rats, topical application of 10 and 100 microM ADMA constricted the basilar artery by 9 +/- 2 and 19 +/- 1% (SE; P < 0.05, n = 8), respectively, from a baseline diameter of 213 +/- 19 microns. ADMA (10 and 100 microM) produced marked inhibition of vasodilation in response to acetylcholine without inhibiting vasodilatation in response to nitroprusside. ADMA (1-100 microM) inhibited activity of brain NO synthase (measured as the conversion of L-[14C]arginine to L-[14C]citrulline). In cerebrum and cerebellum, 50% inhibition of activity of NO synthase was produced by 2.3 +/- 0.4 and 1.8 +/- 0.1 microM ADMA, respectively. In rabbits, treatment with ADMA (300 microM) decreased baseline diameter of cerebral arterioles (control diameter = 93 +/- 10 microns) by 11 +/- 2% (P < 0.05, n = 10). In response to 1 microM acetylcholine, cerebral arterioles dilated by 36 +/- 6 and 13 +/- 4% (P < 0.05 vs. control) in the absence and presence of ADMA, respectively. Effects of ADMA were prevented by L-arginine. Thus ADMA inhibits activity of brain NO synthase and relaxation of cerebral blood vessels in response to acetylcholine. Because ADMA is produced in relatively high concentrations in brain, it may be an important endogenous modulator of cerebral vascular tone under resting conditions and in response to vasoactive stimuli.

Animals↗

PubMed1995

Relaxation of the carotid artery to hypoxia is impaired in Watanabe heritable hyperlipidemic rabbits.

We tested the hypothesis that relaxation of the carotid artery during hypoxia is mediated by activation of glibenclamide-sensitive potassium channels and that this response is impaired in hyperlipidemic rabbits. In New Zealand White rabbits (plasma cholesterol, 69 +/- 12 mg/dL, mean +/- SEM) and Watanabe heritable hyperlipidemic (WHHL) rabbits (plasma cholesterol, 677 +/- 99 mg/dL), tension of the carotid artery was measured in an organ bath under control conditions and during two levels of hypoxia. In normal rabbits, mild hypoxia produced 21 +/- 2% relaxation in arteries precontracted with phenylephrine. Removal of endothelium or the nitric oxide synthase inhibitor NG-nitro-L-arginine (10(-4) mol/L) almost abolished relaxation in response to mild hypoxia in normal rabbits. Glibenclamide (10(-6) mol/L), an inhibitor of ATP-sensitive potassium channels, attenuated relaxation during mild hypoxia by almost 60%. In WHHL rabbits mild hypoxia relaxed the carotid artery by only 9 +/- 4% (P < .05 versus normal rabbits). Severe hypoxia produced greater relaxation of the carotid artery in normal than in WHHL rabbits (85 +/- 5% versus 52 +/- 8%, respectively, P < .05). Glibenclamide but not endothelial denudation or NG-nitro-L-arginine attenuated relaxation during severe hypoxia in normal and WHHL rabbits. Relaxation of the carotid artery to sodium nitroprusside was similar in normal and WHHL rabbits. These findings suggest that relaxation of the carotid artery in response to mild and severe hypoxia is impaired in WHHL rabbits and is mediated, in large part, by activation of glibenclamide-sensitive potassium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1995

Adenovirus-mediated gene transfer to normal and atherosclerotic arteries. A novel approach.

Previous studies of gene transfer to blood vessels in vivo have relied on intraluminal, catheter-based methods for delivery of adenoviral and other vectors. In this study, topical application of a replication-deficient adenoviral vector was used as an alternative method of gene transfer to the vessel wall. We administered recombinant adenovirus (1.0 x 1.5 x 10(10) pfu/mL) containing the nuclear targeted bacterial beta-galactosidase gene topically to arteries in normal and atherosclerotic cynomolgus monkeys. Topical administration was achieved by injection of adenoviral suspension within the periarterial sheath. Segments of femoral and carotid arteries were examined histochemically after staining with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside 1 day after treatment with the adenovirus. After topical administration of virus, beta-galactosidase activity was observed in approximately 20% of cells in the adventitia in both normal and atherosclerotic arteries. There was no detectable beta-galactosidase activity in cells of the intima or media. Thus, topical application provides an alternative method for gene transfer to blood vessels in vivo. This approach, which does not require interruption of blood flow and does not disrupt the endothelium, may be useful for studies of vascular biology and perhaps gene therapy in both normal and atherosclerotic vessels.

Adenoviridae↗

PubMed1995

Enhanced responses of the basilar artery to activation of endothelin-B receptors in stroke-prone spontaneously hypertensive rats.

We tested the hypothesis that responses of the basilar artery to selective activation of endothelin-B receptors are altered during chronic hypertension. Using a cranial window in anesthetized rats, we examined responses of the basilar artery to a selective endothelin-B receptor agonist, IRL 1620, in stroke-prone spontaneously hypertensive rats (SHRSP). Under control conditions, baseline basilar artery diameter was smaller in SHRSP (196 +/- 8 microns [mean +/- SEM]) than in normotensive Wistar-Kyoto rats (WKY) (245 +/- 9 microns, P < .05). Topical application of IRL 1620 (10(-8) mol/L) dilated the basilar artery by 27 +/- 5% in WKY and 56 +/- 4% in SHRSP (P < .05). Dilatation of the basilar artery in response to sodium nitroprusside was similar in WKY and SHRSP. In contrast, acetylcholine-induced vasodilatation in SHRSP was markedly impaired. NG-Nitro-L-arginine methyl ester and NG-nitro-L-arginine, inhibitors of nitric oxide synthase, inhibited IRL 1620-induced vasodilatation in WKY. Neither NG-nitro-L-arginine methyl ester nor indomethacin attenuated vasodilatation produced by IRL 1620 in SHRSP. The major finding is that dilator responses of the basilar artery to selective activation of endothelin-B receptors are paradoxically enhanced in SHRSP compared with WKY. Dilator responses of the basilar artery to endothelin-B receptor activation are mediated by endothelium-derived relaxing factor in WKY. In contrast, responses to activation of endothelin receptors in SHRSP do not depend on the production of nitric oxide or prostanoids.

Acetylcholine↗

PubMed1995

Relaxation of the aorta during hypoxia is impaired in chronically hypertensive rats.

We investigated mechanisms by which hypoxia produces relaxation of the aorta and tested the hypothesis that these mechanisms are altered during chronic hypertension. Tension of thoracic aortae from normotensive Wistar-Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP) was measured in an organ bath under control conditions and at two levels of hypoxia. In WKY rats, mild and severe hypoxia produced relaxation of the aortae (precontracted with phenylephrine) by 33 +/- 4% and 82 +/- 3%, respectively (mean +/- SEM). Removal of endothelium or administration of NG-nitro-L-arginine (10(-4) mol/L), an inhibitor of nitric oxide synthase, abolished relaxation of the aortae in response to mild hypoxia but did not affect relaxation during severe hypoxia. Glibenclamide (10(-6) mol/L), an inhibitor of potassium channels, attenuated relaxation of the aortae during mild and severe hypoxia by 49 +/- 16% and 74 +/- 4%, respectively. In SHRSP, mild hypoxia produced little relaxation of the aortae (3 +/- 4%, P < .05 compared with WKY). Indomethacin did not increase relaxation to mild hypoxia in SHRSP, which suggests that a cyclooxygenase-derived contracting factor does not contribute to impaired relaxation. Severe hypoxia relaxed the aortae by 86 +/- 4% in SHRSP, and glibenclamide inhibited this response by 60 +/- 9%. These findings suggest that relaxation of the aorta in response to mild hypoxia in WKY rats is mediated primarily by endothelium-derived relaxing factor, and the response to mild hypoxia is markedly impaired in SHRSP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Sick vessel syndrome. Recovery of atherosclerotic and hypertensive vessels.

This review describes vascular changes in atherosclerotic and hypertensive vessels as well as effects of treatment. Changes in vascular structure in both atherosclerosis and hypertension are characterized by thickening of the vessel wall and vascular "remodeling." Remodeling tends to preserve the size of the lumen in atherosclerotic vessels and results in a smaller lumen in hypertensive vessels. Changes in vascular function are characterized by preservation of smooth muscle relaxation, with the exception of activity of ATP-sensitive potassium channels, and dysfunction of endothelium. Regression of atherosclerosis, by treatment of hyperlipidemia, results in quite rapid removal of lipid from the vessel wall but with inconsistent improvement in maximal vasodilator capacity. In contrast, endothelial function improves during regression of atherosclerosis, and hyperresponsiveness to serotonin subsides rapidly. Effective treatment of hypertension produces regression of vascular hypertrophy, and some approaches (especially angiotensin-converting enzyme inhibitors) are effective in correcting vascular remodeling. Endothelium-dependent relaxation generally improves during antihypertensive treatment. Reduction in pulse pressure may be more important than reduction in mean arterial pressure in reversing the structural and functional abnormalities of hypertensive vessels.

Arteriosclerosis↗

PubMed1995

Dilatation of cerebral arterioles in response to activation of adenylate cyclase is dependent on activation of Ca(2+)-dependent K+ channels.

The role of Ca(2+)-dependent potassium channels in mediating vascular responses to activation of adenylate cyclase in vivo is not known. The goal of this study was to examine the hypothesis that dilatation of cerebral arterioles in response to activation of adenylate cyclase is mediated by activation of Ca(2+)-dependent potassium channels. Diameters of cerebral arterioles were measured in vivo in anesthetized rabbits. Topical application of forskolin (1 and 10 mumol/L), a direct activator of adenylate cyclase, dilated cerebral arterioles by 40 +/- 8% (mean +/- SEM) and 71 +/- 9%, respectively, from a control diameter of 85 +/- 4 microns. Iberiotoxin (50 and 100 nmol/L), a selective inhibitor of Ca(2+)-dependent potassium channels, inhibited dilatation in response to both concentrations of forskolin by 45% to 60%. We obtained similar results by using charybdotoxin (50 nmol/L), another inhibitor of Ca(2+)-dependent potassium channels. Vasodilatation in response to dibutyryl cAMP (a cell-permeable cAMP analogue) was also inhibited by iberiotoxin. In contrast, dilatation of cerebral arterioles in response to sodium nitroprusside and acetylcholine (activators of guanylate cyclase) and aprikalim (activator of ATP-sensitive potassium channels) was not inhibited by iberiotoxin. These findings suggest that dilatation of cerebral arterioles in response to forskolin and increases in intracellular concentrations of cAMP are mediated by activation of Ca(2+)-dependent potassium channels. Thus, activation of Ca(2+)-dependent potassium channels may be a major mechanism of cerebral vasodilatation in response to activation of adenylate cyclase in vivo.

Adenylyl Cyclases↗

PubMed1995

Adenovirus-mediated gene transfer in vivo to cerebral blood vessels and perivascular tissue.

Gene transfer to blood vessels in vivo generally requires interruption of blood flow. Thus, gene transduction to cerebral blood vessels in vivo has not yet been achieved. In this study, we injected replication-deficient adenovirus into cerebrospinal fluid in an attempt to transduce genes to cerebral blood vessels. Recombinant adenovirus (1 x 10(9) infectious units) expressing nuclear-targeted bacterial beta-galactosidase driven by the cytomegalovirus promoter was injected into the cisterna magna of Sprague-Dawley rats. The brains were examined histochemically after staining with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside 1 to 7 days after injection of adenovirus. Leptomeningeal cells overlying the major arteries were efficiently transduced, and adventitial cells of large vessels and smooth muscle cells of small vessels were occasionally stained. beta-Galactosidase was expressed on days 1 and 3 after injection but was undetectable by day 7. Expression of the gene was 'targeted' by altering the position of the head. When viral suspension was injected while the rat was in a nose-down position, the reporter gene was expressed extensively on the ventral surface of the brain, especially along the circle of Willis. When the position was changed to the nose-up or lateral position, the inferior or lateral region of the brain was stained primarily. Administration of the virus into the lateral ventricle provided extensive expression in ependymal cells and leptomeninges with some transduction to cerebral blood vessels. Thus, adenovirus injected into cerebrospinal fluid provides gene transfer in vivo to cerebral blood vessels and, with greater efficiency, to perivascular tissue. Furthermore, cisternal delivery may target specific brain regions by positioning of the head.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoviridae↗

PubMed1995

Evidence that expression of inducible nitric oxide synthase in response to endotoxin is augmented in atherosclerotic rabbits.

Atherosclerotic lesions contain monocytes/macrophages and vascular smooth muscle cells and thus may have an increased capacity for generation of nitric oxide by inducible nitric oxide synthase (NOS). We used three approaches (contractile responses, generation of L-citrulline from L-arginine, and staining with NADPH-diaphorase) to test the hypothesis that after administration of lipopolysaccharide (LPS) in vivo, generation of nitric oxide by inducible NOS is augmented in atherosclerotic arteries. New Zealand White (normal, n = 18) and Watanabe heritable hyperlipidemic (atherosclerotic, n = 21) rabbits were anesthetized and injected intravenously with vehicle or LPS. Contractile responsiveness of aortic segments was examined in vitro 4 hours after injection of LPS in vivo. There was a substantial (approximately fivefold) decrease in contractile sensitivity of aortas from LPS-treated atherosclerotic rabbits and a small (approximately twofold) decrease in normal rabbits. Incubation of aortic segments with aminoguanidine, which inhibits inducible NOS, restored contractile responsiveness after LPS treatment. In vitro assay of conversion of [14C]L-arginine to [14C]L-citrulline by aortic segments demonstrated marked (approximately fivefold) increase in calcium-independent conversion of [14C]L-arginine by LPS-treated atherosclerotic, but not normal, aortas. NADPH-diaphorase staining demonstrated positive cells only in the endothelium of normal rabbits and in the lesions and media of the atherosclerotic aortas in both vehicle- and LPS-treated rabbits. The general distribution of these NADPH-diaphorase-positive cells resembled that of smooth muscle cells and not macrophages. Thus, impairment of contractile responses, generation of L-citrulline, and staining with NADPH-diaphorase suggest that atherosclerotic arteries have increased capacity for generation of nitric oxide by inducible NOS.

Amino Acid Oxidoreductases↗

PubMed1995

Dilatation of cerebral arterioles in response to lipopolysaccharide in vivo.

BACKGROUND AND PURPOSE: Bacterial lipopolysaccharide can increase nitric oxide (NO) production by expression of an inducible form of NO synthase. Bacterial infections of the central nervous system dilate cerebral vessels and increase blood flow. We hypothesized that topical application of bacterial lipopolysaccharide would increase production of NO, causing dilatation of cerebral arterioles. METHODS: Cranial windows were implanted in anesthetized rabbits. Windows were flushed with artificial cerebrospinal fluid, artificial cerebrospinal fluid with lipopolysaccharide, or artificial cerebrospinal fluid with lipopolysaccharide and NG-monomethyl-L- arginine (an inhibitor of NO synthase) for 4 hours. Other rabbits received either dexamethasone or indomethacin intravenously 1 hour before lipopolysaccharide treatment of cranial windows. RESULTS: Application of lipopolysaccharide in cranial windows produced marked, progressive vasodilation, with diameter increased by 58 +/- 7% (mean +/- SEM) after 4 hours. The cerebral vasodilator response was inhibited by NG-monomethyl-L-arginine, dexamethasone, or indomethacin. Excess L-arginine reversed the inhibitory effect of NG-monomethyl-L-arginine. CONCLUSIONS: Inhibition of lipopolysaccharide-induced dilatation of cerebral arterioles by NG-monomethyl-L-arginine and dexamethasone suggests that a portion of the vasodilation was mediated by inducible NO synthase. Indomethacin also inhibited lipopolysaccharide-induced vasodilatation. These findings suggest an important role for both nitric oxide and cyclooxygenase products in lipopolysaccharide-induced cerebral arteriolar dilatation in vivo.

Amino Acid Oxidoreductases↗

PubMed1995

Role of potassium channels in cerebral blood vessels.

BACKGROUND: Hyperpolarization of vascular muscle in response to activation of potassium channels is a major mechanism of vasodilatation. In cerebral blood vessels, four different potassium channels have been described: ATP-sensitive potassium channels, calcium-activated potassium channels, delayed rectifier potassium channels, and inward rectifier potassium channels. SUMMARY OF REVIEW: Activation of ATP-sensitive and calcium activated potassium channels appears to play a major role in relaxation of cerebral arteries and arterioles in response to diverse stimuli, including receptor-mediated agonists, intracellular second messengers, and hypoxia. Both calcium-activated and delayed rectifier potassium channels may contribute to a negative feedback system that regulates tone in large cerebral arteries. The influence of ATP-sensitive and calcium-activated potassium channels is altered in disease states such as hypertension, diabetes, and atherosclerosis. CONCLUSIONS: Activation of potassium channels is a major mechanism of cerebral vasodilatation. Alteration of activity of potassium channels and impairment of vasodilatation may contribute to the development or maintenance of cerebral ischemia or vasospasm.

Adenosine Triphosphate↗

PubMed1995

Sick vessel syndrome: vascular changes in hypertension and atherosclerosis.

Hypertension and atherosclerosis are associated with structural and functional changes that may be collectively described as a 'sick vessel syndrome'. Structural changes in blood vessels (remodelling and hypertrophy) may be protective and adaptive. Functional changes in blood vessels include impairment of endothelium-dependent relaxation and impaired relaxation in response to activation of ATP-sensitive potassium channels. In general, vasorelaxation in response to direct activation of adenylate and guanylate cyclase is preserved in chronic hypertension and atherosclerosis. Vasoconstrictor responses to selected stimuli, such as serotonin, may be greatly potentiated. Impairment of endothelial function in combination with exaggeration of vasoconstrictor responses may predispose to vasospasm particularly during atherosclerosis.

Adaptation, Physiological↗

PubMed1995

Dilatation of the basilar artery in response to selective activation of endothelin B receptors in vivo.

The objective of this study was to examine effects of activation of endothelin (ET) B receptors on tone of the basilar artery in vivo. By using a cranial window in anesthetized rats, we examined the effects of IRL 1620, a selective ETB receptor agonist, on diameter of the basilar artery. Under control conditions, diameter of the basilar artery was 214 +/- 6 microns (mean +/- S.E.). Topical application of IRL 1620 (10(-8) mol/l) for 4 min dilated the basilar artery by 30 +/- 4%. Marked desensitization of vasodilator responses was observed in response to a second application of IRL 1620, but not acetylcholine, which indicates a homologous nature of desensitization. REA/001, an ETA/ETB receptor antagonist, abolished IRL 1620-induced dilatation of the basilar artery. BQ 123, a selective ETA receptor antagonist, inhibited constriction in response to ET-1, but did not affect dilator responses of the basilar artery to IRL 1620. Both NG-nitro-L-arginine methyl ester and NG-nitro-L-arginine, inhibitors of nitric oxide synthase, produced marked inhibition of dilator responses of the basilar artery to IRL 1620 without inhibiting vasodilator responses to sodium nitroprusside. Indomethacin did not inhibit vasodilatation in response to IRL 1620. These findings suggest that activation of ETB receptors produces dilatation of the basilar artery in vivo. Dilator responses of the basilar artery to activation of ETB receptors are dependent on production of nitric oxide.

Animals↗

PubMed1994

Responses of cerebral arterioles to N-methyl-D-aspartate and activation of ATP-sensitive potassium channels in old rats.

The first goal of this study was to examine the hypothesis that aging impairs dilator responses of cerebral arterioles to N-methyl-D-aspartate (NMDA). The second goal was to determine whether aging impairs vasodilatation in response to activation of ATP-sensitive K+ channels. Diameter of cerebral arterioles was measured through a cranial window in anesthetized adult (5 +/- 1 (mean +/- S.E.) months old) and old (26 +/- 1 months old) Fischer 344 rats. In adult rats, NMDA (10 and 100 microM) dilated pial arterioles by 14 +/- 5 and 72 +/- 9%, respectively, from a control diameter of 36 +/- 5 microns. Aprikalim (1 and 10 microM), a direct activator of ATP-sensitive potassium channels, dilated cerebral arterioles in adult rats by 14 +/- 3 and 49 +/- 6%, respectively. Vasodilatation in response to NMDA and aprikalim were similar in old and adult rats. Thus, in contrast to impaired cerebral vasodilator responses to some stimuli, responses of cerebral arterioles to NMDA and activation of ATP-sensitive potassium channels are preserved in old Fischer 344 rats.

Adenosine Triphosphate↗

PubMed1994

Role of platelets and leukocytes in modulation of vascular tone.

Activated platelets and leukocytes release potent vasoactive factors that may modulate vascular tone. Activation of normal platelets produces dilatation of normal arteries. Vasodilatation is mediated by adenosine diphosphate (ADP), which releases endothelium-derived relaxing factor (EDRF) from endothelium. In atherosclerotic arteries, activation of platelets produces constriction and perhaps spasm. The constrictor response of atherosclerotic arteries is related in part to profound changes in vascular function: endothelial dysfunction with impaired endothelium-dependent vasodilator responses to ADP, and augmented vasoconstrictor responses to serotonin. In addition, hypercholesterolemia has a direct effect on platelets, resulting in impaired vasodilator responses. Thus, abnormal platelets and altered vascular function may both predispose to spasm of atherosclerotic arteries. Activation of leukocytes has little effect on resistance of large arteries in normal monkeys. In contrast, activation of leukocytes produces pronounced vasoconstriction in atherosclerotic monkeys. Possible mediators of vasoconstriction include prostaglandin E2, oxygen radicals, thromboxane, and a peptide (perhaps angiotensin II). In addition, leukocytes also alter vascular responses to platelets, in part by ADPase on the leukocyte membrane, which degrades ADP released by activated platelets. Leukocytes also release oxygen radicals, which may inactivate EDRF, thereby impairing ADP-mediated, endothelium-dependent vasodilator responses. Abnormal responses to platelets and leukocytes are largely reversed when atherosclerotic lesions regress in monkeys.

Animals↗