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Biomedical subjects

J G Collier

Publications and source records attributed to J G Collier.

At least 19 recordsLinked to original sources
PubMed1998

The macrosialin promoter directs high levels of transcriptional activity in macrophages dependent on combinatorial interactions between PU.1 and c-Jun.

Macrosialin is a transmembrane glycoprotein that is highly expressed in macrophages. In the present studies, macrosialin mRNA levels are shown to be markedly up-regulated during macrophage differentiation of bone marrow progenitor cells in response to macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. To investigate the mechanisms responsible for regulation of macrosialin expression, we have isolated the macrosialin gene and performed an initial analysis of its transcriptional regulatory elements. The macrosialin promoter and 7.0 kilobase pairs of 5'-flanking information direct high levels of reporter gene activity in monocyte/macrophage-like cells, but little or no expression in nonmyeloid cells. This pattern of expression is dependent on regulatory elements located between -7.0 and -2.5 kilobase pairs from the transcriptional start site that exhibit strong enhancer activity in macrophages and repressor activity in nonmyeloid cells. Analysis of the proximal macrosialin promoter indicates that combinatorial interactions between at least four classes of transcriptional activators, including PU.1/Spi-1 and members of the AP-1 family are required for basal promoter function. PU.1/Spi-1 and c-Jun act synergistically to activate the macrosialin promoter in a nonmyeloid cell line, suggesting that combinatorial interactions between these proteins are involved in regulating macrosialin expression during macrophage differentiation.

Amino Acid Sequence↗
PubMed1994

Local L-NG-monomethyl-arginine attenuates the vasodilator action of bradykinin in the human forearm.

1. Studies in animals indicate that bradykinin relaxes blood vessels directly through an action on smooth muscle and indirectly through the release of endothelium-derived mediators. Its precise mechanism of action in the human arterial circulation is not yet known. 2. In this study the effects of a specific inhibitor of nitric oxide synthase, L-NG-monomethyl-arginine (L-NMMA) and noradrenaline on the vasodilator responses to bradykinin were examined in the forearm arterial bed of healthy volunteers. Noradrenaline was used as a control for vasoconstriction by L-NMMA; glyceryl trinitrate (GTN) as a control vasodilator acting independently of the NO synthase enzyme. 3. L-NMMA (4 mumol min-1; 5 min) alone reduced resting forearm blood flow by 44% (P < 0.01; n = 6) confirming that nitric oxide plays an important role in regulating vascular tone. 4. Bradykinin (10 and 100 pmol min-1; 3 min each dose) and GTN (2 and 5 nmol min-1; 3 min each dose) increased forearm blood flow in a dose-dependent manner (percentage changes 171 +/- 17% and 398 +/- 35%, and 176 +/- 21% and 268 +/- 42%, respectively; n = 6). 5. The response to bradykinin, but not that to GTN, was attenuated by L-NMMA compared with noradrenaline (P < 0.05; n = 6), suggesting that bradykinin-induced vasodilatation in the forearm is mediated, at least in part, by stimulating release of nitric oxide.

Adult↗
PubMed1991

Angiotensin II augments sympathetically mediated arteriolar constriction in man.

1. In animal studies, angiotensin II facilitates adrenergic neurotransmission by both pre- and post-synaptic mechanisms. We have investigated whether this interaction occurs in forearm resistance vessels in man. 2. The effect of arterial infusion of angiotensin II (320 fmol/min) on sympathetic vasoconstriction produced by lower-body negative pressure (15 mmHg) was studied in six subjects, and that on the response to exogenous noradrenaline (37.5-150 pmol/min) was studied in a further eight subjects. Forearm blood flow was measured by strain-gauge plethysmography. 3. The dose of angiotensin II was chosen to produce no alteration in resting blood flow, and those of noradrenaline were selected to provide a reduction in blood flow equivalent to that produced by lower-body negative pressure. 4. Lower-body negative pressure produced no change in heart rate or diastolic blood pressure, but caused an initial 5 mmHg fall in systolic blood pressure (P less than 0.01). Blood flow was reduced by 21 +/- 6% in both forearms by lower-body negative pressure during saline infusion. During angiotensin II infusion, there was a marked difference in the response to lower-body negative pressure, with blood flow being reduced by 40 +/- 7% in the infused arm, but only by 21 +/- 4% in the control arm (P less than 0.05). Angiotensin II infusion had no effect on resting blood flow or the responses to noradrenaline. 5. We conclude that angiotensin II augments sympathetic vasoconstriction in forearm resistance vessels in man at a concentration that has no direct effect on blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Augmentation of sympathetic venoconstriction by angiotensin II in human dorsal hand veins.

The constriction produced by a single deep breath was measured simultaneously in two adjacent hand veins in normal subjects. One vein was infused with saline or angiotensin II; the other acted as a control. A dose of angiotensin II (1 pmol/min) that did produce venous constriction directly significantly augmented the constriction caused by deep breath in eight subjects (P less than .01). In a further six subjects the same dose had no effect on venoconstriction caused by infused noradrenaline. We conclude that angiotensin II causes venoconstriction indirectly by augmenting sympathetically mediated responses, possibly by a presynaptic mechanism.

Adult↗
PubMed1989

Local inhibition of converting enzyme and vascular responses to angiotensin and bradykinin in the human forearm.

1. The function of angiotensin converting enzyme was investigated in twenty-four healthy men. Forearm blood flow was measured under basal conditions and during administration of enalaprilat (a converting enzyme inhibitor) and/or peptide substrates of converting enzyme into the left brachial artery. Blood flow was compared in the two arms. 2. Enalaprilat had no effect on basal blood flow. The concentration of enalaprilat in venous blood from the control arm was low, and plasma renin activity was not increased, indicating that systemic inhibition of converting enzyme did not occur. 3. Effects of angiotensin and of bradykinin, administered intra-arterially, were limited to the infused arm. Enalaprilat (13 nmol min-1) inhibited converting enzyme in the infused arm, in which it caused approximately a 100-fold reduction in sensitivity to angiotensin I, while having no effect on the vasoconstriction caused by angiotensin II. Enalaprilat increased vasodilatation caused by bradykinin. 4. Aspirin, an inhibitor of cyclo-oxygenase, did not inhibit vasodilatation caused by bradykinin whether infused alone or with enalaprilat, indicating that these responses are not mediated by prostaglandins. 5. We conclude that under basal conditions neither conversion of angiotensin I to angiotensin II nor degradation of bradykinin determines resistance vessel tone in the human forearm. Converting enzyme may affect vascular tone in situations in which intravascular concentrations of peptides are increased over those present under basal conditions.

Adult↗
PubMed1988

Angiotensin II augments sympathetically induced venoconstriction in man.

1. The constriction produced by a single deep breath was measured simultaneously in two adjacent hand veins in normal volunteers. One vein was infused with angiotensin II (ANG II) while the other acted as a control. 2. At a dose lower than that required to produce direct venous constriction (1 pmol/min), ANG II significantly augmented the constriction caused by a deep breath in eight subjects (P less than 0.01). The same dose had no effect on the venoconstriction caused by infused noradrenaline (NA) in a further six subjects. 3. It is concluded that ANG II at low doses may cause venoconstriction indirectly by augmenting sympathetically induced venous tone via a presynaptic mechanism. This observation may help to explain the apparent venodilating property of angiotensin-converting enzyme inhibitors in clinical situations where the renin-angiotensin system is stimulated.

Adult↗
PubMed1988

Sympathetically mediated vasoconstriction is augmented by angiotensin II in man.

In order to determine whether angiotensin II may influence sympathetically mediated arteriolar constriction in man, we have examined the effect of angiotensin II, infused directly into the left brachial artery of normal subjects, on the reduction in forearm blood flow produced by a lower-body negative pressure (LBNP) of 15 mmHg. Angiotensin II (320 fmol/min) caused no reduction in blood flow when given alone but significantly augmented the reduction in blood flow in response to LBNP. The same dose of angiotensin II did not affect a similar reduction in forearm blood flow produced by infused noradrenaline (12.5-50 ng/min). We conclude that angiotensin II augments sympathetically mediated constriction of resistance vessels in man at concentrations with no direct effect on vessel tone. The lack of an effect of angiotensin II on constriction in response to infused noradrenaline suggests the involvement of a presynaptic mechanism.

Angiotensin II↗
PubMed1988

Regulation of regional vascular tone: the role of angiotensin conversion in human forearm resistance vessels.

Inhibition of the action of endothelially-located angiotensin converting enzyme (ACE) in blood vessels of the human forearm was studied using enalaprilat, the active metabolite of the prodrug enalapril. In a dose of 5 micrograms/min enalaprilat inhibits arteriolar vasoconstriction in response to angiotensin I (Ang I) and enhances vasodilation in response to bradykinin. At this dose enalaprilat had no effect on resting forearm blood flow, or on the reduction in forearm blood flow in response to application of lower body negative pressure, in subjects with normal sodium intake. Following sodium depletion, however, enalaprilat produced an increase in resting forearm blood flow compared with the response in the same subjects under normal-sodium conditions. It appears that local ACE within forearm resistance vessels of healthy volunteers is unlikely to play an important role in regulation of local vascular tone in the sodium-replete state. However, in sodium-depleted subjects, and perhaps also in other circumstances where circulating concentrations of Ang I are elevated, local ACE may significantly affect vascular tone.

Adult↗
PubMed1987

Influence of ramipril diacid on the peripheral vascular effects of angiotensin I.

Studies were performed to examine the effect on forearm blood flow of local brachial artery infusions of angiotensin I, angiotensin II and of the converting enzyme inhibitor ramipril diacid (the active metabolite of ramipril). Acute infusions of both angiotensins produced dose-dependent decreases in blood flow (measured by venous occlusion plethysmography). To produce equivalent effects the dose of angiotensin I was 2 to 4 times that of angiotensin II. After ramipril diacid the response to angiotensin II was unchanged, while the dose of angiotensin I required to produce an equipotent response was increased 20-fold. Ramipril diacid given alone produced a small, nonsignificant increase in forearm flow, although the response was significantly related to basal plasma renin. The study confirms the presence of converting enzyme activity within human resistance vessels, and suggests that inhibition of converting enzyme, at sites other than the pulmonary vascular bed, might contribute to the hypotensive action of converting enzyme inhibitors.

Adult↗
PubMed1987

Endogenous vasopressin affects postural control of blood pressure in man.

1. Six healthy volunteers received intravenous infusions of isotonic (0.9% NaCl) and hypertonic (3% NaCl) saline on separate days. There were no significant changes in blood pressure or forearm blood flow, despite an increase in plasma arginine vasopressin (AVP) during hypertonic saline. 2. Immediately and 10 min after passive tilting to 50 degrees, mean forearm blood flow fell by 17.1 and 14.3% compared with the values in the supine position during isotonic saline and by 40.3 and 43.3% during hypertonic saline. Forearm vascular resistance rose by 23.6 and 17.8% with isotonic saline and by 80.2 and 88.2% with hypertonic saline for the two readings in the tilted compared with the supine position. 3. Tilting was associated with a 14.9 and 12.1% rise in diastolic blood pressure immediately and 10 min after assuming this position during hypertonic saline, and a rise of 6.4% in mean arterial pressure. 4. The results from this study are similar to those obtained previously, when small amounts of AVP were infused. They provide further evidence that AVP may have a physiological role in the postural regulation of blood pressure.

Adult↗
PubMed1986

Haemodynamic effects of vasopressin in man are related to posture.

Ten healthy volunteers received intravenous infusions of arginine vasopressin (AVP) at 0.1 m-unit min-1 kg-1 and 5% D-glucose on separate days. AVP caused a small fall in forearm blood flow and small rises in mean arterial pressure and systemic vascular resistance. Cardiac output was unaffected. When subjects were tilted to 50 degrees the fall in forearm blood flow was much greater, mean fall being 44.8% with AVP compared with 18.2% with D-glucose. Cardiac output also fell significantly more with AVP, and diastolic pressure, mean arterial pressure and systemic vascular resistance rose significantly more on tilting during AVP infusion than with D-glucose. Six of the same volunteers were given sequential infusions of 'low dose' (0.0125 m-unit min-1 kg-1) and 'high dose' (0.3 m-unit min-1 kg-1) AVP on a third occasion. Tilting still produced a mean fall in forearm blood flow of 41.2% during low dose infusion, despite a mean plasma AVP level of only 1.9 pg/ml, which is well within the physiological range. When the AVP concentration was increased 24-fold to the high dose, forearm blood flow fell only a further 8.8%. The low dose infusion was also associated with a marked fall in cardiac output on tilting and a rise in systemic vascular resistance. We conclude that AVP has profound haemodynamic effects in man at physiological concentrations. Although these effects are modest in the supine position, they become marked on tilting, suggesting a possible role for AVP in the postural control of blood pressure.

Adult↗
PubMed1986

Vascular angiotensin conversion in humans.

Studies were performed in normotensive volunteers and hypertensive subjects to examine the effect on forearm blood flow (FBF) of brachial artery infusions of angiotensin I (ANG I), angiotensin II (ANG II), and ramiprilat [the active metabolite of the angiotensin converting enzyme (ACE) inhibitor, ramipril]. Ramiprilat (10 mcg/min for 10 min) produced a 71% mean increase in FBF (n = 8; range, 26-130%; p less than 0.001) in vessels preconstricted with ANG I (64-128 pmol/min), with the effect maximal at the end of ramiprilat infusion and subsiding over 30 min. Doses of ANG I required to produce equivalent reductions of FBF were 2 to 4 times those of ANG II before ramiprilat, but after ramiprilat the dose of ANG I required to produce equivalent constriction was increased 20-fold (n = 6; p = 0.01) while that of ANG II was unaltered. Ramiprilat given alone produced only a small nonsignificant increase in FBF of 7 +/- 4% (n = 12; p = 0.29), though this increase did correlate significantly with plasma renin (r = 0.60; p = 0.04). These results confirm the presence of ACE within human resistance vessels and suggest the possibility that inhibition of ACE at sites other than the pulmonary bed might contribute to the hypotensive action of ACE inhibitors.

Adult↗
PubMed1985

The effect of intravenous sodium cromoglycate on the bronchoconstriction induced by sulphur dioxide inhalation in man.

Ten healthy subjects received, on separate occasions, intravenous infusions of 0.9% NaCl solution (saline) and of sodium cromoglycate given in a double-blind cross-over fashion. After 20 min of infusion the specific airway conductance (sGaw) of each subject was measured in a body plethysmograph. The subject then breathed first a low (1-20 p.p.m.) and then a higher (4-40 p.p.m.) concentration of sulphur dioxide (SO2) for 2 min while the infusion continued. Measurements of sGaw were repeated after each inhalation of SO2. Sodium cromoglycate infusion did not affect the sGaw measured before challenge with SO2. During the infusion of sodium cromoglycate, the falls in sGaw in response to both concentrations of SO2 were significantly less than those which occurred during saline infusion. Plasma concentrations of sodium cromoglycate were found to be 209 +/- 22 nmol/l at the end of the drug infusion. This is about one-hundredth of lowest dose required to stabilize mast cells in vitro. We conclude that sodium cromoglycate acted by a mechanism which did not involve mast cells. Other possible modes of action are discussed.

Adult↗
PubMed1984

Capsaicin inhalation in man and the effects of sodium cromoglycate.

The inhalation of capsaicin for 1 min, delivered as an aerosol by nebulising solutions of capsaicin at concentrations of 2-65 mumol 1(-1), caused dose-dependent coughing in normal volunteers and subjects with mild asthma. Capsaicin did not cause a feeling of breathlessness, and had no effect on forced expiratory volume in 1 s (FEV1) measured at the 1st, 5th and 9th min after the challenge was completed. Coughing started within seconds of applying the face mask, continued throughout the minute of capsaicin inhalation, and stopped within seconds of the mask being removed. In any one subject the number of coughs was reproducible when repeated on the same day or after an interval of several days. Experiments using local anaesthesia applied to the buccal mucosa or larynx indicated that the cough was caused by the stimulation of capsaicin-sensitive nerve terminals situated in the larynx. Cough response was not altered by the prior inhalation of sodium cromoglycate.

Aerosols↗
PubMed1984

Sodium cromoglycate and atropine block the fall in FEV1 but not the cough induced by hypotonic mist.

In a group of patients with mild asthma the inhalation of mist derived from ultrasonically nebulised distilled water caused an increase in cough and a fall in FEV1. Double blind administration for five minutes of sodium cromoglycate (from an original solution containing 30 mg/ml) or atropine (2 mg/ml) by inhalation from a Minineb nebuliser, 30 minutes before the mist challenge, caused a significant reduction in the fall in FEV1 (p less than 0.05), but not in cough, by comparison with the protection afforded by placebo (saline). In a second study the fall in FEV1 caused by the inhalation of distilled water was not significantly different from that seen in response to hypotonic sodium chloride (1.7 g/l, 58 mmol/l), but both produced a significantly greater fall than did a similar mist containing sodium cromoglycate at an original concentration of 10 mg/ml (58 mmol/l). The results show that both atropine and sodium cromoglycate can block the fall in FEV1 due to mist and that protection by sodium cromoglycate is immediate. These results suggest that sodium cromoglycate blocks the nervous reflexes concerned in the response to mist, probably in the afferent limb of the reflex.

Aerosols↗