Biomedical subjects

W M Armstead

Publications and source records attributed to W M Armstead.

123 records · Page 7Linked to original sources

PubMed1989

Influence of intraarterial norepinephrine on cerebral hemodynamics of newborn pigs.

Effects of intraarterial norepinephrine on cerebral hemodynamics were investigated in conscious newborn pigs. Intracarotid infusion of norepinephrine (100 ng/min) increased cerebral blood flow from 72 +/- 5 to 82 +/- 8 ml/100 g.min. The norepinephrine-induced increase in cerebral blood flow was accompanied by an increase in cerebral oxygen consumption from 2.75 +/- 0.17 to 3.11 +/- 0.29 ml O2/100 g.min. Both the increase in cerebral oxygen consumption and the increase in cerebral blood flow were blocked by propranolol and unchanged by combined prazosin and yohimbine treatment. These data show that intraarterial norepinephrine increases cerebral blood flow and cerebral oxygen consumption in newborn pigs. beta-Adrenergic stimulation increases cerebral oxygen consumption. This increase may produce the increase in cerebral blood flow caused by the norepinephrine.

Animals↗

PubMed1989

Permissive role of prostanoids in acetylcholine-induced cerebral vasoconstriction.

The present study was designed to test the hypothesis that prostanoids play a permissive role in acetylcholine-induced cerebral constriction. Pial arterioles of newborn pigs were observed using a closed cranial window. Pial arteriolar constriction induced by topical acetylcholine (10(-5) M) was blocked by indomethacin (5 mg/kg i.v.), but was restored when acetylcholine was coadministered with topical prostaglandin (PG) F2 alpha (1 ng/ml), U46619 (1 ng/ml) or PGH2 (100 ng/ml). The restored acetylcholine response was blocked by topical pirenzepine (10(-3) M), a muscarinic-1 antagonist. Constriction and ability of all three prostanoids to restore acetylcholine-induced constriction was blocked by SQ 29,548 (10(-4) M), a purported thromboxane A2/PGH2 receptor antagonist. Subthreshold concentrations of U46619 and PGF2 alpha (0.1 ng/ml) restored acetylcholine-induced constriction, whereas threshold and subthreshold concentrations of PGE2, platelet-activating factor and norepinephrine had no effect. Therefore, activation of the thromboxane A2/PGH2 receptor appears to be necessary for acetylcholine-induced constriction to occur. Thus, prostanoids appear to play a permissive role in acetylcholine-induced pial arteriolar constriction in newborn pigs.

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

PubMed1988

Effect of 15-HETE on cerebral arterioles of newborn pigs.

Effects of topical application of 15-HETE on pial arteriolar diameter and cortical periarachnoid cerebrospinal fluid (CSF) prostanoid concentrations were investigated in chloralose-anesthetized newborn pigs. Pial arteriolar diameters were measured using a closed cranial window, and CSF samples from under the window were collected for prostanoid analysis after applying artificial CSF without drug and CSF containing 15-HETE (1, 10, 100, 10000 ng/ml). 15-HETE caused significant dose-related constriction from 162 +/- 17.0 microns (control diameter) to 136 +/- 14.5 and 129 +/- 18.7 microns (100 and 1000 ng/ml, respectively). The concentration of PGE2 (but not of PGF2 alpha or 6-keto-PGF1 alpha) increased in CSF at 100 and 1000 ng/ml of 15-HETE. Pial arteriolar responses to 15-HETE were determined before and after indomethacin treatment (5 mg/kg, i.v.). 15-HETE (100 ng/ml) constricted pial arterioles before indomethacin (diameter change, -15 +/- 10%); after indomethacin, constriction was potentiated in response to the same dose (diameter change, -26 +/- 7%). These data support the hypothesis that, in newborn piglets, 15-HETE exerts a vasoconstrictor effect on pial arterioles, which appears to be attenuated by 15-HETE-induced stimulation of dilator prostanoids.

Animals↗

PubMed1988

Adrenergic and prostanoid mechanisms in control of cerebral blood flow in hypotensive newborn pigs.

The interaction between adrenergic and prostanoid mechanisms in the control of cerebral hemodynamics in the conscious, hypotensive newborn pig was investigated. Pretreatment with the selective alpha 1- and alpha 2-adrenoceptor antagonists prazosin and yohimbine, respectively, had no effect on cerebral blood flow, calculated cerebral vascular resistance, or cerebral metabolic rate either before or after hemorrhagic hypotension. Indomethacin treatment (5 mg/kg ia) of piglets following hemorrhage caused a significant decrease in blood flow to all brain regions within 20 min. This decrease in cerebral blood flow resulted from increased cerebral vascular resistances of 54 and 177%, 20 and 40 min after treatment, respectively. Cerebral oxygen consumption was reduced from 2.42 +/- 0.28 to 1.45 +/- 0.28 ml.100 g-1.min-1 and to 1.0 +/- 0.28 ml.100 g-1.min-1 20 and 40 min after indomethacin, respectively, in hemorrhaged piglets. Decreases in cerebral blood flow and metabolic rate and increases in vascular resistance on treatment with indomethacin were the same as in animals pretreated with vehicle, prazosin, or yohimbine. These data are consistent with the hypothesis that the prostanoid system contributes to the maintenance of cerebral blood flow and cerebral metabolic rate during hypotension in the newborn, as reported previously. These data do not implicate removal of sympathetic modulation by prostanoids as a mechanism for indomethacin-induced cerebral vasoconstriction in hypotensive newborn piglets.

Animals↗

PubMed1988

Histamine dilates pial arterioles of newborn pigs through prostanoid production.

To test the hypothesis that histamine would dilate pial arterioles via a prostanoid mechanism, histamine was placed on the brain surface of anesthetized newborn pigs via a closed cranial window. Pial arteriolar diameters were measured after topical application of 10(-7), 10(-6), 10(-5), 10(-4), and 10(-3) M histamine. In addition, cortical cerebrospinal fluid (CSF) was collected for radioimmunoassay of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), thromboxane B2 (TxB2), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), and prostaglandin F2 alpha (PGF2 alpha). The animals were then randomized to receive either indomethacin trihydrate (5 mg/kg, iv) or an equal volume of saline (vehicle). The protocol then was repeated. Histamine (before indomethacin or vehicle infusion) caused concentration-dependent vasodilation. This vasodilation was accompanied by a significant increase in cortical CSF 6-keto-PGF1 alpha and PGE2. Concentrations of TxB2, PGD2, and PGF2 alpha were not altered significantly by histamine application. Pretreatment with indomethacin blocked the histamine-induced cerebral vasodilation, but vasodilation after vehicle was intact. These data imply that histamine dilates the pial arterioles of newborn pigs by stimulating the synthesis of vasodilator prostanoids.

Animals↗

PubMed1988

Postischemic generation of superoxide anion by newborn pig brain.

Cerebral superoxide anion generation during reperfusion after total cerebral ischemia was measured in newborn pigs. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined using two closed cranial windows inserted over the parietal cortices. Twenty minutes of total cerebral ischemia was produced by increasing intracranial pressure, and SOD-inhibitable NBT reduction was determined during 20 min of reperfusion. SOD-inhibitable NBT reduction (8.7 +/- 1.5 pmol.mm-2.20 min-1) was greater in piglets subjected to cerebral ischemia followed by reperfusion than in control piglets not exposed to ischemia (1.6 +/- 1.3 pmol.mm-2.20 min-1). Pretreatment with indomethacin (5 mg/kg iv) markedly reduced postischemia SOD-inhibitable NBT reduction (2.8 +/- 1.1 pmol.mm-2.20 min-1). We conclude that superoxide anion radical is produced by newborn pig brain during postischemic reperfusion. Furthermore, cyclooxygenase metabolism of arachidonic acid appears to be a major source of this activated oxygen during reperfusion of ischemic piglet brain.

Animals↗

PubMed1988

Platelet activating factor: a potent constrictor of cerebral arterioles in newborn pigs.

This study characterized the nature of the response to platelet activating factor (PAF) in the cerebral microcirculation of the newborn pig. Pial arterioles were observed directly using a closed cranial window in chloralose-anesthetized piglets. Topical application of 10-100 ng/ml PAF produced dose-dependent decreases in pial arteriolar diameter; diameters were 193 +/- 27 microns for control, 167 +/- 25 microns at 10 ng/ml, and 129 +/- 21 microns at 100 ng/ml. Topical application of 30-300 ng/ml norepinephrine and 3-30 ng/ml U46619, a purported thromboxane A2 receptor agonist, also produced dose-dependent decreases in pial arteriolar diameter. After topical administration of U66985 (1 microgram/ml), a putative PAF antagonist, responses to PAF were attenuated significantly, but responses to norepinephrine and U46619 were unchanged. Moreover, intravenously administered U66985 (0.1 mg/kg) antagonized PAF responses as well. Responses to PAF were unchanged after cyclooxygenase and leukotriene receptor inhibition. Further, PAF did not increase cortical subarachnoid cerebrospinal fluid prostaglandin or leukotriene levels. These data indicate that PAF is a potent constrictor of cerebral arterioles in newborn pigs and that its mechanism of action is independent of formation of cyclooxygenase and lipoxygenase products of arachidonic acid metabolism. These data also suggest that U66985 may be a selective PAF antagonist that crosses the blood-brain barrier. Since PAF is an endogenous lipid released from a variety of tissues and may be an important mediator of inflammation and allergic reaction, PAF could be involved in the pathophysiology of the cerebral circulation in the perinatal period.

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

PubMed1988

Acetylcholine produces cerebrovascular constriction through activation of muscarinic-1 receptors in the newborn pig.

This study was designed to characterize the nature of responses to selective muscarinic (M)-1 and M-2 agonists and to determine the receptor subtype which mediates the vascular response to acetylcholine in the cerebral circulation of the newborn pig. Pial arterioles of anesthetized newborn pigs were observed using the closed cranial window method. Topical McN-A-343 (10(-7), 10(-4) M), an M-1 agonist, produced pial arteriolar constriction (diameters were 140 +/- 8, 127 +/- 9 and 111 +/- 8 microns for control, 10(-7) and 10(-4) M McN-A-343) that was blocked by topical pirenzepine (10(-3) M), an M-1 antagonist. Topical bethanachol (10(-7), 10(-4) M), an M-2 agonist, produced pial arteriolar dilation (diameters were 148 +/- 8, 169 +/- 10 and 181 +/- 10 microns for control, 10(-7) and 10(-4) M bethanachol) that was blocked by 4-DAMP 4-diphenylacetoxy-N'-methylpiperidine methiodide (10(-3) M), an M-2 antagonist. Responses to McN-A-343 were unchanged after 4-DAMP, and responses to bethanachol were unchanged after pirenzepine. Topical McN-A-343 and bethanachol elicited modest increases in cortical periarachnoid cerebrospinal fluid levels of 6-keto-prostaglandin F1 alpha, prostaglandin E2, thromboxane B2 and prostaglandin F2 alpha. Topical acetylcholine (10(-7), 10(-4) M) elicited pial arteriolar constriction and large increases in cerebrospinal fluid prostanoid levels which were blocked by atropine (0.5 mg/kg i.v.) and topical pirenzepine (10(-3) M), but not by topical 4-DAMP. These data demonstrate the existence of M-1 and M-2 receptors in the cerebral circulation of the newborn pig and indicate that acetylcholine elicits cerebrovascular constriction and increased cerebrospinal fluid prostanoid synthesis via activation of M-1 receptors.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMed1988

Inhibitory effects of diltiazem on vasoconstrictor responses in the cat.

The effect of diltiazem on vasoconstrictor responses was investigated in the feline mesenteric vascular bed under conditions of controlled blood flow. Diltiazem inhibited vasoconstrictor responses to sympathetic nerve stimulation, tyramine and norepinephrine suggesting that responses to both nerve-released and exogenous norepinephrine are dependent in part on an extracellular source of calcium. The calcium entry antagonist inhibited vasoconstrictor responses to alpha 1 and to alpha 2 adrenoceptor agonists over a wide range of concentration. Diltiazem also inhibited mesenteric vasoconstrictor responses to angiotensin II, vasopressin, prostaglandin F2 alpha and KCl. The inhibitor effects of diltiazem on vasoconstrictor responses to nerve stimulation and the pressor agents were reversible, and all responses returned to control value 30 to 45 min after the infusion of the calcium entry antagonist. The present data suggest that the inhibitory effects of diltiazem on responses to sympathetic nerve stimulation are postjunctional in nature, as responses to nerve-released and exogenous norepinephrine and nonadrenergic pressor agents are reduced to a similar extent. The present results suggest that vasoconstrictor responses to neuronally released and exogenous norepinephrine, as well as agents which activate membrane receptors or depolarize vascular smooth muscle in the feline mesenteric vascular bed, are dependent in part on an extracellular source of calcium. The inhibitory effects of diltiazem on vasoconstrictor responses to sympathetic nerve stimulation and pressor hormones may be relevant to the antihypertensive actions of this calcium entry antagonist.

Adrenergic alpha-Agonists↗

PubMed1988

The role of prostanoids in the mediation of responses to KC-404, a novel cerebrovasodilator.

The purpose of this study was to characterize the nature of the response to KC-404 in the cerebral microcirculation of the newborn pig. Pial arterioles were observed directly using a closed cranial window in chloralose-anesthetized piglets. Topical application of 100, 300, 1000, 3000 and 10,000 ng/ml of KC-404 produced concentration-dependent increases in pial arteriolar diameter. Diameters were 168 +/- 18, 190 +/- 19 and 238 +/- 21 mu for control, 100 ng/ml and 10,000 ng/ml of KC-404, respectively. Responses to KC-404 (3-isobutyryl-2-isopropylpyrazolo-[1,5a]-pyridine) were blocked by indomethacin (5 mg/kg i.v.). Moreover, KC-404, topically applied to the cerebral cortex, produced small but significant increases in cortical subarachnoid cerebrospinal fluid levels of 6-keto-prostaglandin (PG) F1 alpha and PGE2, whereas thromboxane B2 levels were unchanged. Similar to topical application, i.v. KC-404 (0.5 mg/kg) produced pial arteriolar dilation without significantly altering arterial blood pressure. Intravenous KC-404 also increased cerebrospinal fluid levels of 6-keto-PGF1 alpha and PGE2, whereas thromboxane levels were unchanged. Further, topically applied KC-404 (1 microgram/ml) potentiated dilator responses to PGE2 and PGI2, whereas responses to isoproterenol were unchanged. These data indicate that KC-404 is a potent dilator of cerebral arterioles in newborn pigs. These data also suggest that KC-404 produces cerebral vasodilation predominantly by potentiating prostanoid-mediated dilation.

Animals↗

PubMed1987

Characterization of the vasoconstrictor activity of indomethacin in the mesenteric vascular bed of the cat.

The effects of indomethacin on vascular resistance were investigated in the feline mesenteric vascular bed under conditions of constant blood flow. Indomethacin produced mesenteric vasoconstriction that was dose-dependent but was less active than U46619, the thromboxane mimic, angiotensin II, PGF2 alpha and norepinephrine. The vasoconstrictor response to indomethacin was not altered by meclofenamate and phenoxybenzamine. Indomethacin, in a dose that blocked the systemic vasodepressor response to arachidonic acid, did not alter mesenteric vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine, angiotensin II, U46619, and U44069. The present data suggest that in the feline intestinal vascular bed indomethacin has marked vasoconstrictor activity that occurs independent of activation of alpha-adrenoceptors and formation of cyclooxygenase products possessing pressor activity. The present data suggest that cyclooxygenase products do not modulate vasoconstrictor responses as well as the sympathetic nervous system in the intestinal vascular bed of the cat.

Angiotensin II↗

PubMed1987

Influence of nisoldipine on vascular resistance and vasoconstrictor responses in cats.

The influence of nisoldipine, a calcium entry antagonist, on vascular resistance and vasoconstrictor responses was investigated in the anesthetized cat. Nisoldipine, a dihydropyridine calcium entry blocking agent, decreased total peripheral resistance and dilated the intestinal vascular bed. This calcium antagonist blocked intestinal vasoconstrictor responses to BAY K 8644, a nifedipine analogue, which promotes calcium entry. The calcium entry antagonist decreased intestinal vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine, and tyramine. Nisoldipine also reduced intestinal vasoconstrictor responses to potassium chloride and agonists that elicit vasoconstriction by specific receptor-mediated actions including stimulation of alpha 1- and alpha 2-adrenoceptors. The vasodilator and inhibitory effects of nisoldipine on vasoconstrictor responses were reversible, and responses returned to control value over a 60-min period. The present data suggest that an extracellular source of calcium is required for maintenance of tone and for vasoconstriction induced by neuronally released or exogenous norepinephrine as well as a diverse group of agents that act through specific receptor mechanisms or depolarize vascular smooth muscle. The present results suggest that similar sources of calcium are required for vasoconstriction elicited by alpha 1- and alpha 2-adrenoceptor agonists in the feline intestinal vascular bed.

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

PubMed1987

Influence of calcium-entry blockade on vasoconstrictor responses in feline mesenteric vascular bed.

The subtypes of postjunctional alpha-adrenoceptors activated by neuronally released and exogenous norepinephrine and the source of calcium used for vasoconstrictor responses were investigated in the feline mesenteric vascular bed. Under constant flow conditions, intra-arterial injections of phenylephrine and UK14304, alpha 1- and alpha 2-adrenoceptor agonists, increased mesenteric arterial perfusion pressure in a dose-related manner. Prazosin, an alpha 1-antagonist, reduced vasoconstrictor responses to phenylephrine without altering responses to UK14304. Yohimbine, an alpha 2-antagonist, reduced responses to UK14304 without altering responses to phenylephrine. The same pattern of blockade was observed in animals pretreated with 6-hydroxydopamine to destroy the integrity of adrenergic terminals. Responses to phenylephrine and UK14304 were reduced by nitrendipine, a calcium-entry blocking agent, and this agent decreased vasoconstrictor responses to sympathetic nerve stimulation, tyramine, and norepinephrine. Responses to sympathetic nerve stimulation were selectively blocked by prazosin, but responses to norepinephrine were selectively blocked by yohimbine. Vasoconstrictor responses to tyramine were reduced by both prazosin and yohimbine. Nitrendipine also reduced responses to angiotensin II, U46619, a prostaglandin endoperoxide analogue, Bay K 8644, and potassium chloride. These data suggest the presence of alpha 1- and postjunctional alpha 2-adrenoceptors and support the hypothesis that norepinephrine released by nerve excitation acts mainly on alpha 1-receptors but that exogenous norepinephrine acts primarily on alpha 2-receptors. However, norepinephrine released by tyramine acts on both receptor subtypes. Nitrendipine inhibited responses to the alpha 1- and alpha 2-adrenoceptor agonists as well as those to nerve released and exogenous norepinephrine, the calcium agonist, Bay K 8644, and to other vasoconstrictor agents. These data suggest that in the feline mesenteric vascular bed, an extracellular source of calcium ions is required for vasoconstriction induced by a variety of mechanisms including activation of alpha 1- and postjunctional alpha 2-adrenoceptors.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1984

Vasoconstrictor effects of leukotrienes C4 and D4 in the feline mesenteric vascular bed.

The effects of leukotriene C4 (LTC4) and leukotriene D4 (LTD4) in the feline mesenteric vascular bed were investigated under conditions of controlled blood flow so that changes in perfusion pressure directly reflect changes in vascular resistance. Intra-arterial injections of LTC4 and LTD4 (0.3-3.0 micrograms) increased perfusion pressure in a dose-related fashion. Vasoconstrictor responses to LTC 4 and LTD4 were similar to norepinephrine (NE) whereas mesenteric vasoconstrictor response to the thromboxane analog, U46619, was markedly greater than were responses to LTC4 and LTD4. Meclofenamate in a dose that greatly attenuated the systemic depressor response to arachidonic acid was without effect on vasoconstrictor responses to LTC4 and LTD4, NE and U46619 in the mesenteric vascular bed. The present data show that LTC4 and LTD4 possess significant vasoconstrictor activity in the feline mesenteric vascular bed. In addition, the present data suggest that products of the cyclooxygenase pathway do not mediate vasoconstrictor responses to LTC4 and LTD4 in the intestinal circulation of the cat.

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

PubMed1984

Analysis of adrenergic responses in the mesenteric vascular bed of the cat; evidence that vascular beta 2-adrenoceptors are innervated.

Responses to sympathetic nerve stimulation and pressor hormones were investigated in the feline mesenteric vascular bed under conditions of controlled blood flow. Sympathetic nerve stimulation and norepinephrine produced frequency- and dose-dependent increases in mesenteric vascular resistance. However, when alpha-receptors were blocked with the non-equilibrium alpha-receptor antagonist, phenoxybenzamine, nerve stimulation and norepinephrine produced frequency- and dose-dependent decreases in mesenteric vascular resistance. These reductions in mesenteric vascular resistance were unchanged after indomethacin or atropine, whereas propranolol converted the mesenteric vasodilator responses to small vasoconstrictor responses. In these studies, responses to a variety of vasoconstrictor agents were enhanced after administration of propranolol. Sotalol, a nonselective beta blocker with little membrane stabilizing activity, also enhanced vasoconstrictor responses. The present data suggest that both alpha- and beta-adrenergic receptors are innervated in the feline mesenteric vascular bed, and that vasodilator responses to norepinephrine and sympathetic nerve stimulation are independent of activation of muscarinic receptors or formation of products in the cyclooxygenase pathway. These data also demonstrate that there is a nonspecific potentiation of intestinal vasoconstrictor responses after beta-adrenergic receptor blockade that is independent of a membrane-stabilizing or receptor-mediated mechanism.

Animals↗