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Biomedical subjects

D B Frewin

Publications and source records attributed to D B Frewin.

At least 19 recordsLinked to original sources

The preoperative management of phaeochromocytoma.

Although the preoperative use of alpha-receptor antagonist drugs is generally accepted for patients with phaeochromocytoma, evidence on the most appropriate treatment and its timing is scarce. In this retrospective study, the effectiveness of the preoperative preparation of fourteen patients who required surgical excision of a phaeochromocytoma was examined in the light of their operative stability. A simple score was developed of blood pressure stability by scoring the need for additional antihypertensive agents intraoperatively before, and blood pressure support after, tumour removal. A higher score indicated greater instability. Twelve patients received phenoxybenzamine and their stability was superior to the two patients treated with labetalol and with prazosin. There was no correlation between the duration of treatment with phenoxybenzamine and the operative stability (r = 0.18 P = 0.55 Spearman). The five patients who were treated with phenoxybenzamine for longer than 10 days did not have better perioperative blood pressure stability than the five patients who had treatment for less than a week. Predictive factors for intra-operative blood pressure stability were also sought. The degree of postural hypotension after treatment with phenoxybenzamine did not predict operative stability (r = -0.31, P = 0.33 Spearman). However, the peak total catecholamine level found during surgery correlated quite well with more operative instability (r = 0.65, P = 0.031, Spearman), suggesting that patients with phaeochromocytomas with high production of catecholamines are more likely to show cardiovascular instability.

Adolescent↗

Phaeochromocytoma: intraoperative changes in blood pressure and plasma catecholamines.

The aim of this study was to assess the relationship between changes in plasma catecholamine concentrations and intra-arterial blood pressure (BP) measured simultaneously during resection of phaeochromocytoma (n = 14). Arterial plasma concentrations of noradrenaline (NA), adrenaline (A) and dopamine (DA) were measured by a radio-enzymatic method. Arterial NA concentrations (pmol/ml; median and Wilcoxon 95% CI) were 71.8 (46,162) before induction of anaesthesia, 113.0 (79,231) after intubation, 375.0 (285,931) during tumour handling and 32.5 (18,88) following tumour removal. Simultaneous mean BP values (mmHg; Mean +/- SEM) were 119 +/- 8, 114 +/- 7, 159 +/- 7 (p = 0.0001) and 72 +/- 6 (p < 0.0001) respectively. At the time of tumour handling there was a weak correlation between plasma NA and A combined and mean BP (r = 0.583, p = 0.029) and a stronger correlation between log plasma NA and A combined and pulse pressure (r = 0.749, p = 0.008). The very large rises in plasma catecholamine concentrations and in BP are likely to have been causally related. Individual patients maintained a constant ratio of NA to A in plasma from pre-induction to tumour handling (r = 0.916, p < 0.0001). The maintenance of a constant NA:A ratio suggests that the pattern of catecholamine synthesis and release may be a characteristic of the individual tumour.

Adolescent↗

Sympathetic suppression attenuates anomalous responses to morphine in unexplained pain after cholecystectomy.

Anomalous responses to morphine are common in patients with unexplained pain in the upper abdomen after cholecystectomy and may be linked to activation of the sympathetic nervous system. The hypothesis that sympathetic suppression would attenuate anomalous responses to morphine was tested by a randomized, cross-over trial using a standard challenge with morphine, with and without pretreatment with clonidine (300 micrograms orally, 1 h prior to the administration of morphine). In 13 of the 15 patients who completed the study, pre-treatment with clonidine decreased plasma concentrations of noradrenaline, dopamine and adrenaline by 56, 15 and 25% respectively. This was associated with a significant reduction in morphine-induced pain (p = 0.02) and nausea (p = 0.04) and attenuated increases in plasma aspartate aminotransferase (AST) activity (p = 0.03). Clonidine attenuates anomalous responses to morphine, perhaps through effects on sympathetic nervous activity or plasma concentrations of catecholamines.

Adult↗

Interactions between 5-hydroxytryptamine, noradrenaline and the thromboxane-A2 mimetic U44069 in the marmoset isolated aorta.

1. The effects of 5-hydroxytryptamine (5-HT) in the absence and presence of noradrenaline (NA) or the thromboxane-A2 mimetic, U44069, were investigated in ring preparations of marmoset aorta. 2. 5-HT (0.001-10 mumol/L) produced little or no contractile response in preparations at basal tone. When the tone was elevated to 50% of maximum with NA the predominant response to 5-HT was relaxation. The 5-HT2 receptor antagonist LY53857 (0.1 mumol/L) unmasked a contractile response to low concentrations of 5-HT (0.01-1.0 mumol/L) and reduced relaxation to high concentrations of 5-HT (1.0-10 mumol/L) in vessels precontracted with NA. 3. In U44069-contracted vessels, 5-HT was contractile in the range 0.01-1 mumol/L and relaxant in concentrations of 6.0-10.0 mumol/L. Ketanserin (1.0 mumol/L) had no effect on the contraction or relaxation to 5-HT. 4. The relaxant response to 5-HT was not significantly diminished in endothelium-impaired arteries. 5. In conclusion, 5-HT exerts complex inhibitory and excitatory actions on the marmoset aorta. The inhibitory actions are not endothelium-dependent and the excitatory actions do not appear to involve the 5-HT2 receptor.

Animals↗

The expression and localisation of the angiotensin-converting enzyme mRNA in human adipose tissue.

Recent evidence in rats has indicated that angiotensinogen may be synthesised in adipose tissue surrounding blood vessels and that a local renin-angiotensin system may regulate adipose tissue blood supply and the efflux of fatty acids from fat in that species. This hypothesis is critically dependent on the local expression of the angiotensin converting enzyme gene in adipocytes. Thus the current study set out to examine whether the angiotensin converting enzyme gene was expressed in human adipose tissue and, if it was present, to localise the individual sites of that expression. Northern analysis indicated the presence of mRNA for angiotensin converting enzyme in both subcutaneous and extraperitoneal adipose tissue. In situ hybridisation showed that the gene was expressed in adipocytes. The foregoing results therefore suggest that components of the renin-angiotensin cascade are also present in human adipose tissue and support the hypothesis that adipose tissue may play a role in the local production of Angiotensin II and hence participate in vascular function and blood pressure control in the human.

Adipose Tissue↗

The effect of captopril treatment and its withdrawal on the gene expression of the renin-angiotensin system.

The mRNA expression of renin, angiotensinogen and angiotensin converting enzyme (ACE) was determined in the kidneys and livers from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) during chronic treatment with captopril and following its withdrawal. Chronic captopril treatment was associated with a dramatic rise in renin mRNA in the kidney and an elevation in mRNA for ACE in the liver. The release from captopril treatment was associated with a reversal of the increase in kidney renin mRNA but no reversal of the sustained elevation of ACE mRNA in the liver. In situ hybridisation revealed a localisation of renin to the area of the juxtaglomerular apparatus in the kidneys from untreated animals, but recruitment of vascular sites of renin expression in kidneys from captopril-treated animals. In kidneys from released animals, renin mRNA expression was once again confined to the juxtaglomerular apparatus. ACE mRNA was expressed in hepatocytes throughout the livers from animals in all treatment groups. The results highlight a differential effect of captopril withdrawal upon the gene expression of the components of the renin-angiotensin system in kidney and liver.

Animals↗

Plasma catecholamine levels during exposure to an environment of hyperbaric oxygen.

Plasma catecholamine levels were measured before, during and after hyperbaric oxygen therapy in nine subjects. Adrenaline levels were elevated immediately prior to hyperbaric oxygen therapy, but then fell and stabilized once treatment commenced. No significant fluctuations in plasma dopamine or noradrenaline levels were noted during the treatment period. This study does not support the premise that there is a suppression of endogenous plasma catecholamine levels during hyperbaric oxygen as has been previously reported. The observed initial increase in adrenaline can be attributed to stress/anxiety and the subsequent decline in this stress, rather than the result of the hyperbaric oxygen treatment itself.

Adult↗

Influence of alpha 1- and alpha 2-adrenoceptor antagonist therapy on the development of hypertension in spontaneously hypertensive rats.

There is general agreement that the sympathetic nervous system is involved in the development of hypertension in spontaneously hypertensive rats (SHR). However, in a previous study we established that chronic administration of the selective alpha 1-adrenoceptor antagonist terazosin to SHR failed to prevent this phenomenon. In the present study, we extended that investigation further by examining the effects of another selective alpha 1-antagonist (doxazosin), an alpha 2-adrenoceptor antagonist (yohimbine), and a combination of these agents. Chronic administration of doxazosin and yohimbine produced receptor blockade, as determined by their effect on blood pressure (BP) responses to norepinephrine (NE) and phenylephrine. Chronic administration of either antagonist alone or the two in combination failed to prevent the development of hypertension in SHR, however. These findings suggest that although there may be a need for involvement of the sympathetic nervous system in the development of hypertension in SHR, its influence on this process is not mediated through activation of alpha-adrenoceptors.

Adrenergic alpha-Antagonists↗

Angiotensin II-mediated facilitation of sympathetic neurotransmission in the spontaneously hypertensive rat is not associated with neuronal uptake of the peptide.

Evidence suggests that angiotensin II (AII) can modulate neuroeffector responses in the vasculature of spontaneously hypertensive rats (SHR). Included in this modulation is an action of AII in facilitating release of neurotransmitter from sympathetic nerves by a mechanism involving prejunctional angiotensin receptors. In addition, AII may be a substrate for the carrier processes that operate within sympathetic nerves. Therefore, we examined the influence of AII on the responses to sympathetic nerve stimulation in the isolated perfused mesenteric vascular bed preparation and determined whether AII was incorporated into neuronal tissue in blood vessels. AII (10(-8) M) shifted the frequency-response curves to the left, and this shift was reversed with addition of the AII receptor type 1 (AT1) antagonist losartan (10(-6) M). AII uptake into mesenteric artery, thoracic aorta, kidney, and skeletal muscle was determined in tissues taken from SHR and normotensive Wistar-Kyoto rats (WKY). Additional tissues were taken from animals that had been subjected to chemical sympathectomy with 6-hydroxydopamine (6-OHDA). Although AII accumulation was evident in all tissues examined, in no case was this accumulation diminished by 6-OHDA treatment. Subsequent studies using segments of kidney and skeletal muscle demonstrated that a large proportion of AII accumulation was temperature sensitive and was also sensitive to the metabolic inhibitor 2-4-dinitrophenol (DNP 10(-3) M). The results confirm the role of AII in potentiating the responses to sympathetic nerve stimulation through a process involving AT1 receptors, but this process is not associated with neuronal accumulation of the peptide.

Angiotensin II↗

Antihypertensive efficacy and safety of perindopril in mild-to-moderate essential hypertension: results of a double-blind multicenter study versus atenolol.

A 3-month double-blind multicenter trial compared the efficacy and safety of perindopril, a new angiotensin-converting enzyme (ACE) inhibitor, with atenolol in mild-to-moderate essential hypertension. A total of 190 patients, 49 of whom were diabetic, entered the perindopril-atenolol comparison. Of these, 163 had been previously treated and had a 4-week run-in period on placebo; 27 had previously been untreated and received placebo for 2 weeks. At entry, all patients who had a supine diastolic blood pressure (DBP) of 95-115 mm Hg were randomized to receive perindopril 2 mg or atenolol 25 mg, once daily. Patients were assessed at 2 weekly intervals for the first month and then monthly for 2 more months. If supine DBP was greater than 90 mm Hg, treatment was increased by stepwise doubling of dose up to 8 mg perindopril or 100 mg atenolol once daily, and later by the addition of hydrochlorothiazide 25 mg, (indapamide 2.5 mg in diabetic patients) once daily. The two groups were homogeneous prior to treatment except for supine and erect heart rate, which were higher in the perindopril group than in the atenolol group (p less than 0.05). Mean supine DBP was 101.1 +/- 0.6 mm Hg in the perindopril group (n = 94) and 99.9 +/- 0.6 mm Hg in the atenolol group (n = 96). After 3 months' active treatment, 74% of patients in the perindopril group achieved a supine DBP of less than or equal to 90 mm Hg and 73% of patients in the atenolol group achieved the same goal. Monotherapy controlled supine DBP in 67% of the perindopril group and 63% of the atenolol group. The decrease in supine DBP was not significantly different between the two groups (-12.9 +/- 0.9 versus -14.7 +/- 0.9 mm Hg) but the decrease in erect DBP was lower in the perindopril group (-10.3 +/- 0.9 versus - 13.4 +/- 1.0 mm Hg, p less than 0.02). Heart rate was reduced in the atenolol group (p less than 0.001). Sixteen patients withdrew from the study; nine were attributed to adverse events, two in the perindopril group and seven, including one death, in the atenolol group. Cough was spontaneously reported by 13% patients of the perindopril group and 1% patients of the atenolol group. In 5% of the perindopril cases this was mild and associated with upper respiratory tract infection. The nature and incidence of other symptoms were similar with both drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

Effect of alpha 1-adrenoceptor blockade on the development of hypertension in the spontaneously hypertensive rat.

There is a large body of evidence to suggest that the sympathetic nervous system plays a critical role in the development of hypertension and vascular medial hypertrophy in the spontaneously hypertensive rat (SHR). The synthesis of a water soluble, specific alpha 1-adrenoceptor antagonist (terazosin) has permitted an examination of the influence of alpha 1-adrenoceptors on those two phenomena. Thus, in the present study, terazosin (43 mg/kg per day) was administered to SHR and Wistar-Kyoto (WKY) rats from 4.5 to 12 weeks of age, and a number of assessments made in vitro and in vivo. In the SHR, the development of hypertension was not prevented by terazosin. The drug did not influence blood pressure in the WKY. This was despite the fact that animals which had been chronically treated with terazosin displayed marked alpha-adrenoceptor blockade in vivo. The response of systolic blood pressure to tyramine and noradrenaline was significantly reduced in animals which had been chronically treated with terazosin. In both the SHR and WKY, chronic administration of terazosin did not influence vascular concentrations of 3-methylhistidine, a biochemical marker for contractile proteins and vascular medial hypertrophy. The results therefore argue against a role of alpha 1-adrenoceptors in the development of hypertension and vascular medial hypertrophy in the SHR.

Adrenergic alpha-Antagonists↗

A comparison of the effect of lisinopril and hydrochlorothiazide on electrolyte balance in essential hypertension.

The effects of lisinopril 10-20 mg or hydrochlorothiazide 25-50 mg (each given once daily) on blood pressure, serum sodium, potassium and magnesium concentrations, total body potassium and urinary cation excretion were compared in a group of hypertensive patients using a double blind randomised crossover design. Each active treatment phase lasted six weeks and a total of sixteen patients completed the study. Both lisinopril and hydrochlorothiazide produced clinically significant decreases in blood pressure. However, lisinopril treatment produced a mean reduction of 14 mmHg in sitting diastolic pressure compared with a 7 mmHg reduction for hydrochlorothiazide treatment. This difference was statistically significant. The decrease in the concentration of serum potassium during hydrochlorothiazide treatment was greater than that during lisinopril treatment (0.53 vs 0.01 mmol.1). The absolute value of serum potassium was significantly lower on hydrochlorothiazide than on lisinopril therapy. Neither treatment had an effect on serum magnesium concentrations, nor was there any significant effect of either treatment on urine volume or urinary excretion of sodium, potassium or magnesium. There was a trend towards increased total body potassium concentration on lisinopril compared with a decrease in total body potassium on hydrochlorothiazide. However, this difference was just outside the range of statistical significance. Both treatments were equally well tolerated. The results indicate slight superiority of lisinopril over hydrochlorothiazide with regard to control of diastolic blood pressure with a better effect on overall electrolyte balance.

Adolescent↗

The relationship between the concentration of temazepam in cerebrospinal fluid and sedation in man.

Twenty-six patients received oral temazepam and subsequently spinal anaesthesia. Blood and lumbar cerebrospinal fluid temazepam levels were measured together with the degree of sedation. The plasma and cerebrospinal fluid concentrations correlated well with the temazepam dose but even better with the weight standardised dose (r = 0.65, p = 0.0003 and r = 0.75, p = 0.00001 respectively). Both the plasma and cerebrospinal fluid concentrations of temazepam were correlated with the patient's sedation (r = 0.42 p = 0.037, and r = 0.46 p = 0.021 respectively), but neither was strong. Thus, although the drug concentration at the receptor may be a major factor in producing sedation, other factors, possibly the receptor population or their responsiveness, are also important contributors.

Administration, Oral↗

The influence of chronic captopril treatment and its withdrawal on endothelium-dependent relaxation.

The current experiments were designed to explore the relationship between the renin angiotensin system (RAS) and prostanoid formation in aortic ring preparations from spontaneously hypertensive rats (SHR). A further aim was to examine the mechanisms responsible for the reversal of the impaired acetylcholine (ACh) mediated relaxation induced by chronic administration of the angiotensin converting enzyme inhibitor captopril and the relationship of the ACh response to blood pressure. Rats were administered captopril (100 mg/kg/day) and their blood pressures monitored from 5 to 17 weeks of age. ACh-mediated relaxation was determined in aortic ring preparations from untreated and treated rats, and drug withdrawn rats. The influence of indomethacin, saralasin, SQ29548 and captopril on ACh-mediated responses was determined. It was found that chronic captopril treatment produced a marked suppression of the development of hypertension in the SHR. After the withdrawal of the drug the blood pressure remained significantly lower than in untreated animals for 4 weeks. ACh relaxation was impaired in SHR ring segments; this was reversed with captopril treatment and returned to the impaired state upon withdrawal of the drug. In vitro inhibition of the RAS did not significantly influence ACh relaxation. In contrast, impairment of the prostanoid system in vitro reversed the impaired relaxation. The results suggest that the influence of captopril on enhancing ACh relaxation in the SHR does not involve an acute interaction of local angiotensin II synthesis with prostanoid mechanisms. Importantly, the results highlight a dissociation between the impaired ACh relaxation and elevated blood pressure in the SHR.

Analysis of Variance↗

A comparison of the efficacy of captopril and enalapril given once daily for the treatment of hypertension: a study using 24-hour ambulatory blood pressure monitoring.

Sixteen patients who had essential hypertension were stabilized on either captopril or enalapril monotherapy and had 24-hour blood pressure profiles monitored by using one of two automatic, non-invasive ambulatory systems: Spacelabs 5300 (Squibb, Princeton, NJ) or PAR Physioport II (Kardiotec, Mannheim). In four subjects (group 1), ambulatory pressures were repeated 4 to 6 weeks later using the same equipment and the same drug. In four subjects (group 2), the drug was changed (dose ratio: captopril:enalapril, 5:1) after the first measurement, but the monitoring equipment was not changed. In four subjects (group 3), the drug was constant, but the equipment was changed for the second measurement of ambulatory pressure. In four subjects (group 4), both drug and equipment were reversed after the first measurement. The results showed that both drugs (given once daily) controlled blood pressure during the 24-hour period, with no clinically significant difference between them.

Adult↗

Felodipine in combination with a beta-adrenoceptor blocker as an effective substitute for triple therapy in severe hypertension. The Australian Felodipine Multicentre Study Group.

We have studied the efficacy and tolerability of felodipine plus a beta-adrenoceptor blocker in 79 patients with essential hypertension previously treated with a combination of three or more anti-hypertensive agents, one of which was a beta-adrenoceptor blocker. After a 4-week run-in period on the same beta-blocker plus placebo (as a substitute for the other agents in the regimen), felodipine was added and its dose titrated to achieve a supine diastolic blood pressure or less than 90 mm Hg. This was followed by a 12-week maintenance phase in all patients, and 47 patients entered an optional long-term follow-up for an additional 9 months. The mean supine blood pressure was 149/88 mm Hg at entry and 174/108 mm Hg after the run-in phase. Felodipine significantly reduced the blood pressure to 142/85 mm Hg after dose titration and to 141/84 mm Hg after 12 weeks, 94% of patients achieving a supine diastolic blood pressure of 90 mm Hg or below. This reduction was maintained in the patients who were followed for 12 months. The adverse events recorded were usually mild, transient, and typical for an effective precapillary vasodilator. Nine of 74 patients (11%) were withdrawn in the first phase of the study because of adverse events and 5 of 47 patients were withdrawn during the long-term follow-up. These results show that the efficacy and tolerability of a combination of felodipine with a beta-blocker allow a simplified regimen for hypertensive patients who were previously taking three or more drugs for satisfactory blood pressure control.

Adolescent↗

Morphine responders with unexplained pain after cholecystectomy may have sympathetic overactivity.

In patients with unexplained pain after cholecystectomy, morphine often induces pain and may increase plasma aspartate aminotransferase activity because of exaggerated or prolonged rises in pressure within the biliary system. Previous studies have demonstrated that patients showing increases in aspartate aminotransferase have increases in plasma concentrations of noradrenaline and dopamine prior to and soon after induction of pain. The purpose of this study was to assess sympathetic activity under basal conditions in patients with (responders) and without (non-responders) increases in aspartate aminotransferase after challenge with morphine. When compared to non-responders, morphine responders had higher plasma concentrations of noradrenaline (p = 0.0001) and dopamine (p = 0.02) and higher urinary excretion of noradrenaline over 24 h (p = 0.03). Plasma and urinary levels of adrenaline were similar in the two groups. These observations indicate higher basal levels of sympathetic activity in the subgroup of patients showing increases in aspartate aminotransferase after challenge with morphine.

Aspartate Aminotransferases↗