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J P Spiers

Publications and source records attributed to J P Spiers.

15 recordsLinked to original sources
PubMed2001

Myocardial expression of the endothelin system in endotoxin-treated rats.

Although circulating plasma levels of endothelin (ET)-1 are elevated in endotoxemia, little is known about the myocardial expression of the ET system in endotoxic shock. We assessed the temporal mRNA expression pattern of key components of the ET system (pre-pro ET (ppET) -1, -2, ET-converting enzyme-1, ET(A) and ET(B) receptors) by reverse transcription polymerase chain reaction in a rat model of early endotoxic shock. Lipopolysaccharide (5 mg/kg, i.p.) caused a transient increase (p < 0.05) in inducible nitric oxide synthase mRNA expression. ppET-1 mRNA expression was increased at 2 h (approximately 12-fold increase; p < 0.05) in the lipopolysaccharide compared with the saline group and ppET-2 mRNA expression was unaltered. ET-converting enzyme-1, ET(A), and ET(B) receptor mRNA expression was unaltered in the lipopolysaccharide compared with the saline group. While ppET-1 mRNA expression is selectively upregulated in ventricular myocardium of lipopolysaccharide-treated rats, an absence of alteration in ET-converting enzyme-1 mRNA expression suggests an excess capacity of ET-converting enzyme-1 to cope with the increased expression of ET-1. At the level of the receptor, endotoxic shock did not affect the expression of either ET(A) or ET(B) receptor mRNA. These data are consistent with the increased expression of myocardial ET-1 as an acute-phase response due to hemodynamic instability associated with the early stages of endotoxic shock.

Animals↗
PubMed2000

Inotropic response to endothelin-1, isoprenaline and calcium in cardiomyocytes isolated from endotoxin treated rats: effects of ethyl-isothiourea and dexamethasone.

1. The contractile effects of endothelin-1, isoprenaline and extracellular calcium were assessed on ventricular cardiomyocytes isolated from lipopolysaccharide-treated rats. The involvement of nitric oxide was investigated using dexamethasone (in vivo) and ethyl isothiourea (in vitro). 2. Male Wistar rats (n=70) were injected with either saline (1 ml kg(-1)) or lipopolysaccharide (LPS; 5 mg kg(-1)) alone, or following pre-treatment with dexamethasone (DEX+LPS; 5 mg kg(-1)). Ventricular cell shortening was recorded using a video edge detection system, and concentration-response relationships were established for endothelin-1, isoprenaline and calcium, in the absence or presence of ethyl isothiourea (ETU; 10 microM). iNOS expression was assessed using reverse transcription-polymerase chain reaction. 3. iNOS mRNA expression was greater (P<0.001) in the LPS (iNOS/GAPDH ratio: 0.90+/-0.09) treated group compared to saline (iNOS/GAPDH ratio: 0.36+/-0.02). Baseline contractile amplitude was reduced (P<0.05) in the LPS (7.3+/-0.2 microm) and DEX+LPS groups (6.7+/-0.3 microm) compared to saline (8. 0+/-0.2 microm). 4. The concentration-dependent contractile response to endothelin-1 was attenuated (P<0.05) in the LPS group compared to saline (maximum change: 0.45+/-0.2 vs 1.8+/-0.2 microm). Neither ETU nor dexamethasone improved contractile function in the LPS-treated animals. 5. The concentration-dependent increase in the contractile response to isoprenaline was attenuated in the LPS-treated group compared to saline (P<0.05; maximum change: 1.7+/-0.4 vs 3.1+/-0.4 microm). This effect was reversed by ETU (maximum change: 3.7+/-0.6 microm). Pre-treatment with dexamethasone prevented a significant fall in contraction amplitude (maximum change: 2.4+/-0.4 microm). 6. The contractile response to calcium was reduced (P<0.05) in the LPS group compared to saline (maximum change: 8.7+/-0.6 vs 10.7+/-0.8 microm). Neither ETU nor dexamethasone restored contractile function in the LPS-treated group. 7. In conclusion, a nitric oxide-mediated inhibitory pathway is not responsible for the diminished contractile response to either endothelin-1 or extracellular calcium, but contributes to the hyporesponsiveness to isoprenaline in lipopolysaccharide treated rats.

Animals↗
PubMed2000

Endothelin(A) receptor subtype mediates endothelin-induced contractility in left ventricular cardiomyocytes isolated from rabbit myocardium.

Endothelin (ET)-1 is a potent positive inotropic agent, the effects of which are mediated by increases in cytosolic Ca(2+) in the myocardium. The object of this study was to examine 1) the influence of ET(A) and ET(B) receptor subtypes, and 2) the role of the phospholipase C (PLC) pathway in mediating ET-1-induced contraction. Left ventricular cardiomyocytes were isolated from the hearts of New Zealand White rabbits (2-2.5 kg) by the use of Langendorff perfusion with collagenase. Cardiomyocyte function was examined during unloaded, electrically stimulated (0.5 Hz) contractions with a video-edge detection system. ET-1 increased cell shortening with greater potency than ET-3: mean EC(50) values were 1.1 x 10(-11) and 2.6 x 10(-10) M, respectively. With the same order of potency, ET-1 and ET-3 increased (P <.05) velocity of cell shortening. The ET(A) receptor-selective antagonist ABT-627 shifted the ET-1-induced cell shortening response curve to the right with a pA(2) value of 10.3. The ET(B) receptor-selective antagonist A-192621 (10(-8)-10(-7) M) did not alter the concentration-response of ET-1. Moreover, the ET(B) receptor-selective agonist sarafotoxin 6c did not have any effect on cell shortening over the concentration range of 10(-11) to 10(-7) M. ET-1 in the presence of the PLC inhibitor U-73122 did not alter the contractile amplitude. However, ET-1 in the presence of the protein kinase C inhibitor bisindolylmalemide increased cell shortening. These findings indicate that 1) the ET(A) receptor subtype, and not the ET(B) receptor subtype, mediates the positive inotropic effect of ET-1, and 2) the response of ET-1 is mediated by a PLC pathway, but not through protein kinase C, in ventricular cardiomyocytes isolated from rabbit myocardium.

Animals↗
PubMed1998

Stimulation of L-type Ca2+ current by the endothelin receptor A-selective antagonist, BQ-123 in ventricular cardiomyocytes isolated from the rabbit myocardium.

BQ-123 is extensively used as an antagonist at endothelin (ET) receptors, having selectivity at the ET(A) receptor subtype. In this study, the effects of BQ-123 per se on action potentials, L-type calcium currents, and potassium currents, were examined in ventricular cardiomyocytes isolated from adult, male, New Zealand White rabbits, using the patch-clamp technique. BQ-123 (1 microM) increased (P < 0.02) the duration of the action potential to 267 +/- 36 ms from a control duration of 228 +/- 30 ms. BQ-123 did not have any effect on the inward rectifier or transient outward potassium currents, but increased (P < 0.02) the L-type Ca2+ current to -2.76 +/- 0.3 nA from a control value of -2.45 +/- 0.28 nA. The increases in both duration of the action potential and L-type Ca2+ current were reversed upon washout (233 +/- 28 ms and -2.32 +/- 0.31 nA, respectively) and were not different from the control values in the absence of BQ-123. In contrast, the endothelin receptor antagonists, BQ-788, PD155080 and PD145065 (1-10 microM) did not affect the L-type Ca2+ current. These results indicate that, unlike PD155080, BQ-788 and PD145065, the conventional ET(A) receptor-selective antagonist, BQ-123, exerts a unique positive effect on the L-type Ca2+ current in ventricular cardiomyocytes isolated from rabbit myocardium. The mechanism of action of BQ-123, therefore, is not confined to ET receptor antagonism.

Action Potentials↗
PubMed1998

Receptor-mediated effects of endothelin on the L-type Ca++ current in ventricular cardiomyocytes.

The purpose of this study was to establish whether specific receptor subtypes are responsible for mediating the effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on the L-type calcium current (ICa) using a number of receptor-selective antagonists, including PD155080 (ETA), BQ-788, RES-701 and IRL-1038 (ETB) and the ETA/ETB receptor-non-selective antagonist PD145065. Ventricular cardiomyocytes were isolated from adult New Zealand White rabbits using Langendorff perfusion with collagenase. ICa was recorded using a whole-cell patch-clamp technique. ET-1 decreased, whereas ET-3 increased, ICa at equimolar concentrations of 10 nM. The decrease in ICa produced by ET-1 was completely blocked by PD155080 and PD145065 (1 and 10 microM); however, ICa was increased upon washout of PD155080. Although the decrease in ICa produced by ET-1 was partially blocked by BQ-788 (1 and 10 microM), ET-1 in combination with either RES-701 (1 and 10 microM) or IRL-1038 (1 microM) produced a decrease in ICa similar to that produced by ET-1 alone. The increase in ICa by ET-3 was completely abolished by either BQ-788 or IRL-1038 (1 microM). These data indicate that the decrease in ICa produced by ET-1 in rabbit ventricular cardiomyocytes is mediated by the ETA receptor subtype, because PD155080 completely inhibited this response. The ETB receptor-selective antagonists RES-701 and IRL-1038 did not alter the decrease in current produced by ET-1, although the response was partially sensitive to BQ-788, which may lack receptor-subtype selectivity in these cells. In contrast, the increase in ICa produced by ET-3 was mediated by the ETB receptor subtype, because BQ-788 and IRL-1038 abolished this response.

Animals↗
PubMed1996

Endothelin-1 mediated inhibition of the acetylcholine-activated potassium current from rabbit isolated atrial cardiomyocytes.

1. Endothelin-1 is a 21 amino acid peptide with potent inotropic and chronotropic actions in the heart. Relatively little is known about the underlying electrophysiological effects of the peptide. In this study, the effects of endothelin-1 (ET-1) on the acetylcholine-activated potassium current (IK(ACh) were investigated in the absence and presence of the receptor-selective antagonists, PD155080 (ETA receptor-selective) and RES-701 (ETB receptor-selective) in rabbit atrial cardiomyocytes. 2. Cells were obtained from New Zealand White rabbits (2.5-3 kg) by enzymatic dissociation with collagenase. Potassium currents were recorded, in the presence of nifedipine (5 microM), by use of the whole cell ruptured patch-clamp technique. Following stabilization, control recordings were made with standard pulse protocols, and drugs were applied by a gravity fed microperfusion system. 3. Endothelin-1 (10 nM) alone did not affect the "steady state' potassium current. Acetylcholine (1 microM) increased (P < 0.05) the potassium current to-1321 +/- 290 pA, from a control value of -955 +/- 191 pA, at a step potential of -100 mV. Acetylcholine also increased the holding current at -40 mV from +80 +/- 9 pA to +242 +/- 38 pA, and this effect was abolished (P < 0.05) in the presence of endothelin-1 (+44 +/- 13 pA). The responses to acetylcholine were attributed to activation of the atrial muscarinic-activated potassium current (IK(ACh)) as they were blocked by atropine (10 microM). Endothelin-1 (10 nM) in the presence of acetylcholine did not affect the "steady state' potassium current (-882 +/- 88 pA compared to a control value of -870 +/- 98 pA, at -100 mV). 4. The ETA receptor-selective antagonist, PD155080 (1 microM), prevented (P < 0.05) the ET-1 induced inhibition of IK(ACh) at all potentials. PD155080, in the presence of endothelin-1 and acetylcholine, increased the inward component of the "steady state' potassium current to -1030 +/- 210 pA from a control value of -804 +/- 224 pA at a step potential of -100 mV. Also the outward component was increased at a potential of -20 mV from +90 +/- 17 pA to +241 +/- 47 pA. 5. Unlike PD155080, the ETB receptor-selective antagonist, RES-701 (1 microM), only prevented (P < 0.05) the inhibitory effect of endothelin-1 on the inward component of the IK(ACh); at -100 mV, RES-701, in the presence of endothelin-1 and acetylcholine, increased the "steady state' potassium current to -913 +/- 137 pA from -733 +/- 116 pA. Furthermore, RES-701, in contrast to PD155080, failed to sustain this inhibitory effect as, in the presence of endothelin-1 and acetylcholine, the "steady state' potassium current returned to a value of -768 +/- 96 pA, at a step potential of -100 mV. 6. In conclusion, endothelin-1 clearly inhibits the effects of acetylcholine on IK(ACh) in rabbit atrial cardiomyocytes. This effect is primarily mediated by an ETA receptor-subtype, but is transiently and partially mediated by a RES-701-sensitive ETB receptor subtype. Inhibition of the IK(ACh) may account for the positive chronotropic properties of endothelin-1.

Acetylcholine↗
PubMed1994

Evaluation of non-invasive blood pressure measurement by the Finapres method at rest and during dynamic exercise in subjects with cardiovascular insufficiency.

The accuracy and precision of the Finapres in recording rest and exercise blood pressure compared with the intra-arterial (aortic and branchial) and random-zero sphygmomanometer methods was assessed in 84 ischaemic patients in three different studies. Firstly, comparison at rest with the aortic intra-arterial pressure in 50 ischaemic patients demonstrated that the Finapres systolic (136.5 +/- 21.1 vs. 129.3 +/- 19.0 mmHg; p < 0.001) and mean (92.4 +/- 13.4 vs. 90.7 +/- 11.4 mmHg; p < 0.001) arterial pressures were higher and diastolic pressures lower (70.4 +/- 11.5 vs. 71.5 +/- 9.8 mmHg; p < 0.001). The reproducibility of the Finapres and invasive method was similar for systolic (4.6% vs. 4.0%), diastolic (2.8% vs. 2.7%) and mean (3.3% vs. 3.0%) blood pressures. Second, in seven subjects studied twice at rest and during 4 min supine bicycle exercise, the exercise increase in blood pressure was greater on the Finapres compared with the brachial intra-arterial pressure (systolic +10.2 +/- 6.3 vs. +3.6 +/- 9.8 mmHg; diastolic +9.6 +/- 11.1 vs. +0.2 +/- 2.1 mmHg; p = 0.02 for each); however, at steady-state the peak/trough differences in pressure between the methods were similar. Thirdly, compared under rest conditions, to random zero sphygmomanometer (RZO), the Finapres systolic pressure was higher (6.8 +/- 3.5 mmHg) and diastolic pressure lower (-6.0 +/- 1.9 mmHg). During upright bicycle exercise, the difference between the Finapres and RZO in systolic blood pressure increased at each level of exercise (+14.3 +/- 4.2, +17.9 +/- 4.0 and +22.2 +/- 4.1 mmHg respectively at each exercise stage: p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Traumatic hepatic artery pseudoaneurysm with hemobilia.

Hepatic artery pseudoaneurysm (HPA) with hemobilia is an unusual complication of hepatic trauma. Initial operative management can have an impact on the development of HPA, and definitive management is difficult. A total of 482 consecutive patients with liver injury were prospectively analyzed. Six of these (1.2%) developed HPA with hemobilia. Three patients developed HPA after penetrating injuries, and 3 after blunt trauma. All 6 patients had hemobilia with massive upper gastrointestinal hemorrhage; HPA was confirmed by angiography. A total of 80% had bile leaks as revealed by hepatobiliary scans. One patient was nonseptic and had a small intrahepatic cavity, and the patient underwent successful embolization of the HPA. The remaining 5 had unexplained sepsis with large intrahepatic cavities and underwent operation. Two died due to massive blood loss and coagulopathy during attempted cavity débridement prior to gaining vascular control. One had right hepatic artery ligation in lieu of resection and subsequent lobectomy after recurrence of hemobilia; the other 2 had formal hepatic resections. No survivors had further rebleeding. We conclude that (1) HPA with hemobilia is predisposed by bile leak; (2) embolization appears appropriate for patients with small cavities without sepsis; and (3) débridement and drainage, which may require formal resection, are necessary for those with large cavities and/or sepsis after vascular control is obtained either by preoperative embolization or intraoperatively.

Adult↗
PubMed1993

Time and frequency domain assessment of heart rate variability: a theoretical and clinical appreciation.

Non-invasive techniques for assessing heart rate variability can be used either diagnostically, as in identification of autonomic neuropathy associated with diabetes mellitus or tissue rejection following cardiac transplantation, or as a prognostic indicator in coronary artery disease. The methodology is based upon calculation of successive R-R intervals from an electrocardiogram, which can then be plotted as a frequency histogram (time domain analysis), undergo power spectral analysis to yield information in the frequency domain or be applied to chaos theory. In this review, several parameters are discussed which can be derived to quantify heart rate variability in the time and frequency domains; the latter providing information on autonomic balance. In the frequency domain up to three peaks may be observed, with the peak below 0.15 Hz being mediated by sympathetic and parasympathetic activity and peaks above 0.15 Hz being of vagal origin. The effects of different physiological and pathophysiological conditions on various indices of heart rate variability, and the use of heart rate variability analysis as a pharmacological method to assess the impact of drug therapy on sympathovagal balance are discussed.

Animals↗
PubMed1993

Resuscitation of hemorrhagic shock with hypertonic saline/dextran or lactated Ringer's supplemented with AICA riboside.

Anesthetized and ventilated swine were bled 23 ml/kg (34% of calculated blood volume) to a mean arterial pressure < 50 mm Hg. After 60 min, a bolus of either 7.5% hypertonic saline/6% dextran 70 (HSD, 4 ml/kg x 5 min) or lactated Ringer's (LR, 32 ml/kg x 5 min) was infused i.v. LR (25-30 ml/kg) was administered to all animals for the next 60 min. Amino imidazole carboxamide riboside (AICAR), which increases endogenous adenosine in ischemic tissues, was added to the initial bolus and the subsequent LR (10 mg/kg bolus + 0.5 mg/kg x 60 min) in half the study population. At 2 hr post-shock, hematocrit, urine output, arterial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, portal venous O2 saturation, and pulmonary arterial O2 saturation were similar in all groups. With HSD vs. LR, cardiac outputs and stroke volumes were each significantly higher, while right atrial pressures and pulmonary vascular resistances were each significantly lower, which is consistent with augmented cardiac contractility with HSD. Furthermore, systemic oxygen consumptions were significantly higher, and intracranial pressures were each significantly lower with HSD. Nevertheless, no variables were far outside the normal range in either group. The addition of AICAR to LR and HSD eliminated the difference in intracranial pressure, systemic oxygen consumption, reduced heart rate by 30-40 beats/min during the first hour of resuscitation, and increased stroke volume by 20-30%.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoimidazole Carboxamide↗
PubMed1991

Duration of action and effect on baroreflex function of the anti-arrhythmic alpha 1 antagonist UK-52,046.

The effects of acute and chronic oral administration of UK-52,046 (25 micrograms kg-1) on baroreflex function and its duration of action, were studied in conscious dogs. It was found that UK-52,046 had no effect on blood pressure and heart rate following acute and chronic administration. UK-52,046 shifted the phenylephrine dose response curve to the right, and the PE50 (measure of alpha 1-adrenoceptor antagonism) was increased (P less than 0.05) compared to placebo on day 1 (2, 4, 8 and 24 h) and day 8 (2, 4, 8 and 12 h). The antagonism was increased (P less than 0.05) on day 8 (0, 8 and 12 h) compared with day 1. Evaluation of the effects of UK-52,046 on baroreflex function using phenylephrine to increase blood pressure indicated no significant difference from placebo. It was concluded that at an antiarrhythmic dose, UK-52,046 has no effect on blood pressure, heart rate or baroreflex function. The pressor response curve was shifted to the right indicating a duration of action of at least 12 h on chronic oral administration.

Administration, Oral↗
PubMed1990

Acute and chronic effects of rilmenidine on baroreflex function in conscious dogs.

The effects of acute and chronic administration of rilmenidine on blood pressure, heart rate and baroreflex function were assessed in two groups of six conscious dogs. Baroreflex function was evaluated using increasing doses of glyceryl trinitrate and phenylephrine to decrease and increase blood pressure respectfully. Acute administration of rilmenidine (1 mg/kg p.o.) reduced (P less than 0.05) blood pressure and heart rate, and enhanced (P less than 0.05) baroreflex function to increases in blood pressure with phenylephrine, but not to decreases in blood pressure by glyceryl trinitrate. Following chronic administration of rilmenidine, blood pressure remained lowered while heart rate and baroreflex function returned to control values.

Adrenergic alpha-Agonists↗
PubMed1990

UK-52,046 (a novel alpha 1-adrenoceptor antagonist) and the role of alpha-adrenoceptor stimulation and blockade on atrioventricular conduction.

The effects of increasing intravenous (i.v.) doses of prazosin, phenylephrine, flecainide, and UK-52,046 on blood pressure (BP), heart rate (HR) and the specialized conduction system (AH and HV intervals) were investigated in anaesthetized dogs. Results indicated that UK-52,046 (1-8 micrograms/kg) had no effect on BP or HR, but reduced (p less than 0.05) BP at doses of 16 and 32 micrograms/kg; no change occurred in HR. During sinus rhythm (SR) the AH or HV intervals did not change as compared with placebo; on pacing (PA) UK-52,046 (4-16 micrograms/kg) decreased the AH interval. After prazosin BP decreased (p less than 0.05) after 20-40 micrograms/kg; HR increased after all doses (5-40 micrograms/kg). The HV interval was unaltered, but the AH interval decreased after 40 micrograms/kg during SR and PA. After phenylephrine (continuous infusion, 50 micrograms/ml/min) BP increased at 33 min and HR was decreased at 23 and 33 min. The AH interval lengthened during PA (p less than 0.05), but there was no effect on the HV interval. Administration of flecainide (0.5-2.0 mg/kg) had no effect on BP or HR but increased the HV interval during SR and PA (1 and 2 mg/kg, p less than 0.05). The results indicate that the alpha 1-adrenoceptor agonist phenylephrine and the alpha 1-adrenoceptor antagonist prazosin, on PA altered the AH (but not the HV) intervals in opposite directions in association with changes in HR and BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗