Biomedical subjects

S P Didion

Publications and source records attributed to S P Didion.

12 recordsLinked to original sources

PubMed2006

Selective cerebral vascular dysfunction in Mn-SOD-deficient mice.

We tested the hypothesis that the mitochondrial form of superoxide dismutase [manganese superoxide dismutase (Mn-SOD)] protects the cerebral vasculature. Basilar arteries (baseline diameter approximately 140 microm) from mice were isolated, cannulated, and pressurized to measure vessel diameter. In arteries from C57BL/6 mice preconstricted with U-46619, acetylcholine (ACh; an endothelium-dependent vasodilator) produced dilation that was similar in male and female mice and abolished by an inhibitor of nitric oxide synthase. Vasodilation to ACh was not altered in heterozygous male or female Mn-SOD-deficient (Mn-SOD+/-) mice compared with wild-type littermate controls (Mn-SOD+/+). Constriction of the basilar artery to arginine vasopressin, but not KCl or U-46619, was increased in Mn-SOD+/- mice (P<0.05), and this effect was prevented by tempol, a scavenger of superoxide. We also examined responses of cerebral (pial) arterioles (branches of the middle cerebral artery, control diameter approximately 30 microm) to ACh in anesthetized mice using a cranial window. Responses to ACh, but not nitroprusside (an endothelium-independent agonist), were reduced (P<0.05) in cerebral arterioles in Mn-SOD+/- mice, and this effect was prevented by tempol. Thus these are the first data on the role of Mn-SOD in cerebral circulation. In the basilar artery, ACh produced nitric oxide-mediated dilation that was similar in male and female mice. Under normal conditions in cerebral arteries, responses to ACh were not altered but constrictor responses were selectively enhanced in Mn-SOD+/- mice. In the cerebral microcirculation, there was superoxide-mediated impairment of responses to ACh.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2001

Superoxide levels and function of cerebral blood vessels after inhibition of CuZn-SOD.

The goal of this study was to examine the role of endogenous copper/zinc (CuZn)-superoxide dismutase (SOD) on superoxide levels and on responses of cerebral blood vessels to stimuli that are mediated by nitric oxide (acetylcholine) and cyclooxygenase-dependent mechanisms (bradykinin and arachidonic acid). Levels of superoxide in the rabbit basilar artery were measured using lucigenin-enhanced chemiluminescence (5 microM lucigenin). Diethyldithiocarbamate (DDC; 10 mM), an inhibitor of CuZn-SOD, increased superoxide levels by approximately 2.4-fold (P < 0.05) from a baseline value of 1.0 +/- 0.2 relative light units x min(-1) x mm(-2) (means +/- SE). The diameter of cerebral arterioles (baseline diameter, 99 +/- 3 microm) was also measured using a closed cranial window in anesthetized rabbits. Topical application of DDC attenuated responses to acetylcholine, bradykinin, and arachidonate, but not nitroprusside. For example, 10 microM arachidonic acid dilated cerebral arterioles by 40 +/- 5 and 2 +/- 2 microm under control conditions and after DDC, respectively (P < 0.05). These inhibitory effects of DDC were reversed by the superoxide scavenger 4,5-dihydroxy-1,3-benzenedisulfonic acid (10 mM). Arachidonate increased superoxide levels in the basilar artery moderately under normal conditions and this increase was greatly augmented in the presence of DDC. These findings suggest that endogenous CuZn-SOD limits superoxide levels under basal conditions and has a marked influence on increases in superoxide in vessels exposed to arachidonic acid. The results also suggest that nitric oxide- and cyclooxygenase-mediated responses in the cerebral microcirculation are dependent on normal activity of CuZn-SOD.

Acetylcholine↗

PubMed2001

Mechanisms that produce nitric oxide-mediated relaxation of cerebral arteries during atherosclerosis.

BACKGROUND AND PURPOSE: The first goal of the present study was to examine the hypothesis that relaxation of cerebral arteries to nitric oxide in primates is dependent on activation of soluble guanylate cyclase (sGC). The second goal was to determine whether the role of sGC in mediating responses to nitric oxide is altered in atherosclerosis. METHODS: Basilar arteries from normal and atherosclerotic monkeys were studied in vitro. After precontraction with prostaglandin F(2alpha) (0.1 to 1 micromol/L), concentration-response curves to authentic nitric oxide (1 nmol/L to 1 micromol/L), sodium nitroprusside (10 nmol/L to 10 micromol/L; a nitric oxide donor), and papaverine (10 nmol/L to 10 micromol/L; a non-nitric oxide, non-sGC-dependent stimulus) were generated in the presence and absence of 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 and 10 micromol/L; an inhibitor of sGC). The effect of ODQ on basal tone of basilar arteries from normal and atherosclerotic monkeys was also examined. RESULTS: Nitric oxide, sodium nitroprusside, and papaverine produced relaxation that was similar (P:>0.05) in normal and atherosclerotic monkeys. ODQ produced marked inhibition (P:<0.05) of vasorelaxation in response to nitric oxide and nitroprusside but not papaverine. For example, relaxation of the basilar artery in response to nitric oxide (0.1 micromol/L) was inhibited by approximately 85% and 73% by ODQ (1 micromol/L) in normal and atherosclerotic monkeys, respectively. ODQ produced contraction of the basilar arteries, and the increase in tension to ODQ was greater in normal (2.7+/-0.3 g; mean+/-SE) than in atherosclerotic monkeys (1.4+/-0.4 g; P:<0.05). In contrast, contraction to prostaglandin F(2alpha) was similar in the basilar artery from normal and atherosclerotic monkeys. CONCLUSIONS: These findings suggest that (1) relaxation of cerebral arteries in primates in response to nitric oxide is normally dependent, in large part, on activation of sGC and (2) the influence of sGC (via reduced production and/or activity of basal nitric oxide) on cerebral vascular tone is reduced in atherosclerosis.

Animals↗

PubMed2000

Impaired endothelial function in transgenic mice expressing both human renin and human angiotensinogen.

BACKGROUND AND PURPOSE: Chronic hypertension is a risk factor for carotid vascular disease and stroke. Mechanisms that account for alterations in carotid and cerebral vascular function during hypertension are poorly defined and based almost exclusively on studies in the spontaneously hypertensive rat, a model in which hypertension has an unknown etiology and in which the genetic background is dissimilar to the most commonly used normotensive control, the Wistar-Kyoto rat. METHODS: In this study we examined vascular function in a defined model of hypertension, double transgenic mice that overexpress both human renin (R+) and human angiotensinogen (A+). We studied vessels in vitro from R+/A+ mice as well as nontransgenic (R-/A-) and single transgenic (R-/A+ or R+/A-) littermate controls. RESULTS: After submaximal precontraction with U46619 or prostaglandin F(2alpha), acetylcholine, which produces relaxation mediated by endothelial nitric oxide synthase, produced marked relaxation of carotid arteries in control mice but was impaired in R+/A+ mice. For example, 1 micromol/L acetylcholine relaxed the carotid artery by 79+/-4% versus 44+/-7% (P<0.01) in control and R+/A+ mice, respectively. Impaired responses to acetylcholine in R+/A+ mice could be restored toward normal with indomethacin (10 micromol/L). In contrast, relaxation of the carotid artery in response to nitroprusside and papaverine was similar in R+/A+ mice and control mice. CONCLUSIONS: These findings indicate that acetylcholine-induced relaxation of carotid artery is impaired selectively in mice made hypertensive by expression of human renin and human angiotensinogen. The mechanism of this impairment may involve production of a cyclooxygenase-derived contracting factor.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1999

Suppressed impact of nitric oxide on renal arteriolar function in rats with chronic heart failure.

We performed experiments to test the hypothesis that experimental heart failure (HF) is associated with altered nitric oxide (NO)-dependent influences on the renal microvasculature, including diminished modulation of constrictor responses to ANG II. Eight to ten weeks after inducing HF in rats by coronary artery ligation, we administered enalaprilat to suppress ANG II synthesis and studied renal arteriolar function using the in vitro blood-perfused juxtamedullary nephron technique. In kidneys from sham-operated rats, NO synthase inhibition [100 microM Nomega-nitro-L-arginine (L-NNA)] reduced afferent arteriolar diameter by 4.1 +/- 0.6 microm and enhanced ANG II responsiveness (10 nM ANG II decreased afferent diameter by 10.1 +/- 1.4 micrometer before and 12.8 +/- 1.6 micrometer during L-NNA treatment; P < 0.05). In kidneys from HF rats, L-NNA did not alter afferent arteriolar baseline diameter or ANG II responsiveness (10 nM ANG II decreased diameter by 12.5 +/- 1.5 micrometer before and 12.5 +/- 2.3 micrometer during L-NNA). The effects of L-NNA on efferent arteriolar function were also abated in HF rats. In renal cortex of HF rats, NO synthase activity was decreased by 63% and superoxide dismutase activity was diminished by 39% relative to tissue from sham-operated rats. Urinary nitrate/nitrite excretion was also reduced in HF rats. Thus both diminished synthesis and augmented degradation are likely to contribute to a decreased renal microvascular impact of endogenous NO during chronic HF, the consequences of which include loss of NO-dependent modulation of ANG II-induced vasoconstriction.

Animals↗

PubMed1997

Effect of chronic myocardial infarction on in vivo reactivity of skeletal muscle arterioles.

The first goal of this study was to test the hypothesis that chronic myocardial infarction alters reactivity of rat skeletal muscle arterioles in vivo. At 4, 8, and 16 wk after induction of chronic myocardial infarction or sham (control) surgery, the spinotrapezius muscle was prepared for direct visualization of the microcirculation. Responses of third-order arterioles (37.9 +/- 0.9 microns) were measured after topical suffusion of acetylcholine (ACh; 0.1, 1.0, and 10 microM), calcitonin gene-related peptide (CGRP; 0.01, 0.1, and 1.0 nM), substance P (SP; 0.01, 0.1, and 1.0 microM), and sodium nitroprusside (SNP; 1.0, 10, and 100 microM). Arteriolar reactivity was impaired after chronic myocardial infarction in response to ACh and CGRP at all time periods examined. In contrast, vasodilatation in response to SP and SNP was preserved after 4, 8, and 16-wk of chronic myocardial infarction. The second goal of this study was to explore the possibility that impaired arteriolar reactivity during chronic myocardial infarction may be related to an altered availability of L-arginine (L-Arg). Suffusion of L-Arg (1.0 mM) partially restored impaired ACh- and CGRP-induced responses in myocardial-infarcted animals toward that observed in controls. Thus the present study demonstrates that impaired reactivity of skeletal muscle arterioles during chronic myocardial infarction appears to be partially related to an alteration in L-Arg availability.

Acetylcholine↗

PubMed1997

Enhanced constrictor responses of skeletal muscle arterioles during chronic myocardial infarction.

The goal of this study was to test the hypothesis that chronic myocardial infarction potentiates agonist-induced constrictor responses of rat skeletal muscle arterioles in vivo. Eight weeks after we performed coronary artery ligation or sham (control) surgery, the spinotrapezius muscle was prepared for direct visualization of the microcirculation. Diameter of third-order arterioles (40.7 +/- 0.5 microns) to topical suffusion of angiotensin II (ANG II; 0.1-10 nM), arginine vasopressin (AVP; 0.1-10 nM), endothelin-1 (ET-1; 1.0-100 pM), and the thromboxane analog U-46619 (1.0-100 nM) was measured in both groups. Myocardial-infarcted rats exhibited enhanced arteriolar constrictor responses to ANG II and AVP compared with the responses in controls. In contrast, ET-1- and U-46619-induced constrictor responses were similar in control and myocardial-infarcted rats. Additional experiments explored the impact of NG-monomethyl-L-arginine (L-NMMA; 0.1 mM) on arteriolar reactivity. In control animals, L-NMMA potentiated ANG II- and AVP-induced vasoconstriction, achieving values similar to those observed in myocardial-infarcted rats. L-NMMA did not alter vasoconstrictor responses in rats with chronic myocardial infarction. These observations suggest that enhanced agonist-induced vasoconstriction during heart failure may reflect a loss of nitric oxide-mediated modulation of arteriolar tone.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1996

L-Arginine does not restore dilatation of the basilar artery during diabetes mellitus.

The goal of this study was to test the hypothesis that administration of L-arginine, a substrate for the synthesis of nitric oxide, restores endothelium-dependent dilatation of the basilar artery during diabetes mellitus. We measured the diameter, of the basilar artery in vivo in nondiabetic and diabetic (streptozotocin; 50-60 mg/kg i.p.) rats in response to endothelium-dependent agonists (acetylcholine and bradykinin) and an endothelium-independent agonist (nitroglycerin) before and during application of L-arginine. Topical application of acetylcholine (1.0 and 10 muM) and bradykinin (1.0 and 10 microM) produced dilatation in nondiabetic rats of the basilar artery which was impaired in diabetic rats. Topical application of nitroglycerin (0.1 and 1.0 microM) produced similar dilatation of the basilar artery in nondiabetic and diabetic rats. Topical application of L-arginine (0.1 and 3 mM) did not enhance dilatation of the basilar artery in response to acetylcholine and bradykinin in diabetic rats. Thus, impairment of dilatation of the basilar artery in diabetic rats in response to acetylcholine and bradykinin appears to be related to a mechanism unrelated to the availability of L-arginine for nitric oxide synthase.

Acetylcholine↗

PubMed1996

Effect of chronic alcohol consumption on responses of cerebral arterioles.

The goal of this study was to determine whether chronic ingestion of alcohol alters dilatation of cerebral arterioles in response to agonists that produce activation of adenylate cyclase and activation of ATP-sensitive potassium channels. Rats were fed liquid diets with or without ethanol for 2 to 2.5 months. In vivo diameter of pial arterioles was measured in alcohol-fed and nonalcohol-fed rats during superfusion with isoproterenol, forskolin, cromakalim, and nitroglycerin. Dilatation of pial arterioles in response to activation of adenylate cyclase via stimulation of beta-adrenergic receptors using isoproterenol was impaired in alcohol-fed rats. Isoproterenol (1.0 microM) dilated cerebral arterioles by 15 +/- 3% in nonalcohol-fed rats, but by only 7 +/- 2% in alcohol-fed rats. In contrast, dilatation of pial arterioles in response to forskolin was similar in nonalcohol-fed and alcohol-fed rats. Dilatation of pial arterioles in response to activation of ATP-sensitive potassium channels was impaired in alcohol-fed compared with nonalcohol-fed rats. Cromakalim (1.0 microM) dilated pial arterioles by 22 +/- 5% in nonalcohol-fed rats, but by only 5 +/- 2% in alcohol-fed rats (p < 0.05). In contrast, dilatation of pial arterioles in response to nitroglycerin was similar in alcohol and nonalcohol-fed rats. The findings of the present study suggest that chronic alcohol ingestion impairs dilatation of cerebral resistance arterioles in response to activation of adenylate cyclase via stimulation of beta-adrenergic receptors and in response to activation of ATP-sensitive potassium channels. We suggest that impaired vasodilator mechanisms during chronic alcohol consumption may have important implications for the pathogenesis of cerebrovascular abnormalities observed during chronic alcoholism.

Adenosine Triphosphate↗

PubMed1996

Glutamate-induced disruption of the blood-brain barrier in rats. Role of nitric oxide.

BACKGROUND AND PURPOSE: The first goal of this study was to determine the effect of glutamate on permeability and reactivity of the cerebral microcirculation. The second goal of this study was to determine a possible role for nitric oxide in the effects of glutamate on the cerebral microcirculation. METHODS: We examined the pial microcirculation in rats with intravital microscopy. Permeability of the blood-brain barrier was quantified by the clearance of fluorescent-labeled dextran (molecular weight, 10 000 D; FITC-dextran-10K) before and during application of glutamate (0.1 and 1.0 mmol/L). In addition, we examined the permeability of the blood-brain barrier during application of a nitric oxide donor, S-nitroso-acetyl-penicillamine (SNAP; 10 mumol/L). Diameter of pial arterioles was measured before and during application of glutamate or SNAP. To determine a potential role for nitric oxide in glutamate-induced effects on the cerebral microcirculation, we examined the effects of NG-monomethyl-L-arginine (10 mumol/L). RESULTS: In control rats, clearance of FITC-dextran-10K from pial vessels was minimal, and the diameter of pial arterioles remained constant during the experimental period. Topical application of glutamate (0.1 and 1.0 mmol/L) and SNAP (10 mumol/L) produced an increase in clearance of FITC-dextran-10K and in diameter of pial arterioles. In addition, NG-monomethyl-L-arginine (10 mumol) attenuated glutamate-induced increases in permeability of the blood brain barrier and glutamate-induced dilatation of cerebral arterioles. CONCLUSIONS: The findings of the present study suggest that glutamate, a major neurotransmitter in the brain, increases permeability of the blood-brain barrier to low-molecular-weight molecules and dilates cerebral arterioles via a nitric oxide-dependent mechanism.

Animals↗

PubMed1995

Activation of protein kinase C does not participate in disruption of the blood-brain barrier to albumin during acute hypertension.

The blood-brain barrier minimizes the entry of macromolecules into brain tissue. During acute increases in arterial blood pressure, disruption of the blood-brain barrier occurs primarily in cerebral venules and veins. Mechanisms by which increases in cerebral venous pressure produce disruption of the blood-brain barrier during acute hypertension are not clear. The goal of this study was to determine the role of activation of protein kinase C in disruption of the blood-brain barrier during acute hypertension. We examined the microcirculation of the cerebrum in vivo. Permeability of the blood-brain barrier was quantitated by the formation of venular leaky sites and clearance of fluorescent-labeled albumin (FITC-albumin) before and during phenylephrine-induced acute hypertension. In addition, we examined changes in pial arteriolar and pial venular pressure before and during phenylephrine-induced acute hypertension. We compared responses of the blood-brain barrier to acute hypertension in control (untreated) rats and in rats treated with inhibitors of protein kinase C; calphostin C (0.1 microM) or sphingosine (1.0 microM). Under control conditions, no venular leaky sites were visible and clearance of FITC-albumin was minimal in all groups. Phenylephrine infusion increased systemic arterial, pial arteriolar and pial venular pressures, and increased the formation of venular leaky sites and clearance of FITC-albumin by a similar magnitude in all groups. The findings of the present study suggest that inhibition of protein kinase C does not significantly alter the formation of venular leaky sites and/or clearance of FITC-albumin during acute hypertension. Thus, disruption of the blood-brain barrier during acute hypertension does not appear to be influenced by activation of protein kinase C.

Acute Disease↗

PubMed1995

Acute effects of ethanol on responses of cerebral arterioles.

BACKGROUND AND PURPOSE: Previous studies have suggested that acute exposure of large peripheral arteries to ethanol impairs endothelium-dependent relaxation. The goal of the present study was to determine the acute effects of ethanol exposure on responses of cerebral resistance arterioles in vivo. METHODS: We prepared a cranial window in rats to expose the cerebral (pial) microcirculation. We measured the diameter of pial arterioles in vivo in response to agonists that presumably stimulate the synthesis/release of nitric oxide from the endothelium (ADP, acetylcholine, and histamine) or neurons (N-methyl-D-aspartate [NMDA]) before and after topical application of various concentrations of ethanol added to the cerebrospinal fluid (20, 40, 60, 80, and 100 mmol/L). In addition, we examined responses of pial arterioles to nitroglycerin before and 1 hour after topical application of ethanol. RESULTS: Before application of ethanol, ADP, acetylcholine, histamine, NMDA, and nitroglycerin produced dose-related dilatation of pial arterioles. Application of the various concentrations of ethanol did not alter the baseline diameter of pial arterioles. However, application of 80 and 100 mmol/L ethanol inhibited dilatation of pial arterioles in response to agonists that stimulate the synthesis/release of nitric oxide. Dilatation of pial arterioles in response to nitroglycerin was not altered by application of ethanol. CONCLUSIONS: The findings of the present study suggest that acute exposure of cerebral arterioles to modest-to-moderate concentrations of ethanol (20 to 60 mmol/L) does not alter responses of cerebral arterioles. In contrast, exposure of cerebral arterioles to higher concentrations of ethanol (80 and 100 mmol/L) can produce specific impairment of dilatation to agonists that stimulate the synthesis/release of nitric oxide from endothelium and neurons.

Animals↗