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.

5-Hydroxytryptamine-induced contraction of the marmoset aorta is mediated by a 5-HT1-like receptor.

1. 5-Hydroxytryptamine (5-HT) exerts both contractile and relaxant effects in the marmoset isolated aorta, actions that are unaffected by the 5-HT2 antagonist ketanserin. The aim of the present study was to define the receptors mediating the contractile activity of 5-HT in the marmoset aorta. 2. Contractile responses were elicited in aortic rings that were either: (i) precontracted submaximally with the thromboxane A2 agonist U44069 in order to amplify the responses; or (ii) exposed to N(omega)-nitro-L-arginine (100 micromol/L) plus LY 53857 (0.1 micromol/L; a 5-HT2 receptor antagonist shown previously to inhibit relaxation). The effect of 5-HT on adenosine 3',5'-cyclic monophosphate (cAMP) formation was also investigated. 3. The effects of agonists and antagonists comprised: (i) agonist potencies in the order 5-carboxamidotryptamine > 5-HT > sumatriptan > 8-hydroxy-2-(di-n-propylamino)tetralin; (ii) inhibition of contractile action of 5-HT by the 5-HT1D antagonist GR 127935; (iii) a contractile response to methysergide; (iv) a lack of effect of tropisetron, an antagonist of 5-HT3 and 5-HT4 receptors; and (v) inhibition of forskolin-stimulated cAMP formation by 5-HT (in the presence of LY 53857), indicative of negative coupling to adenylate cyclase. 4. The above effects fulfill the criteria for a 5-HT1-like receptor. In view of the previous finding that this contractile response is insensitive to ketanserin, it is concluded that the contractile effects of 5-HT in the marmoset aorta are mediated exclusively by a 5-HT1-like receptor.

Functional tolerance to alpha-adrenergic receptor blockade in the spontaneously hypertensive rat highlights the multifunctional role of vascular angiotensin II in the development of hypertension.

Treatment of spontaneously hypertensive rats (SHR) with alpha-adrenoceptor antagonists failed to alter the development of hypertension in this animal model. However, agents such as captopril (CAP) and losartan (LOS) which interfere with the renin-angiotensin system effectively prevented the development of hypertension. When tolerance occurred in the presence of doxazosin (DOX) or phenoxybenzamine, there was an enhanced sensitivity to the blood pressure lowering influence of LOS. In the presence of CAP, at a dose that did not retard the development of blood pressure in the SHR, DOX treatment significantly offset the development of hypertension in this strain. These results suggest that a functional tolerance to agents that interfere with the sympathetic nervous system is mediated by the renin-angiotensin system. Angiotensin-converting enzyme inhibition was associated with a normalization of the enhanced contraction of the mesenteric vascular bed seen in preparations from the SHR and a suppression in the development of the vascular amplifier. The results suggest that the sympathetic nervous system is unable to maintain an elevated blood pressure in the SHR during interference with the functioning of the renin-angiotensin system. Conversely, under conditions of alpha-adrenoceptor blockade, angiotensin II can maintain an elevated blood pressure in the SHR.

The influence of the renin angiotensin system on abnormal expression of nerve growth factor in the spontaneously hypertensive rat.

1. The levels of the neurotrophic factor, nerve growth factor (NGF) in the mesenteric vascular bed of the spontaneously hypertensive rat (SHR) were greater than those in the corresponding vascular bed of normotensive Wistar-Kyoto rats (WKY). 2. Administration of angiotensin II (200 ng/kg per min, by minipump) for 2 weeks to juvenile WKY rats increased the levels of NGF in the mesenteric vasculature to those seen in untreated SHR. 3. Administration of the angiotensin II receptor antagonists losartan (30 mg/kg per day, p.o.) or PD144277 (10 mg/kg per day, p.o.) to juvenile SHR for 4 weeks reduced the levels of NGF such that they were indistinguishable from the values obtained for normotensive WKY rats. 4. The results confirm the elevated level of NGF in the mesenteric vasculature of the SHR and suggest that angiotensin II may play a role in regulating the abnormal concentrations of the protein in this tissue.

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.

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.

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.

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.

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.

Identification of a nonendothelial cell thromboxane-like constrictor response and its interaction with the renin-angiotensin system in the aorta of spontaneously hypertensive rats.

Aortic ring preparations from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were treated with N omega-nitro-L-arginine (NOLA, 10(-4) M). This produced a sustained contraction in preparations from SHR but not WKY rats. A similar contraction in aortic ring preparations from the SHR was produced with methylene blue (10(-5) M) and NG-monomethyl-L-arginine (10(-5) M). The NOLA-induced contraction was reversed with indomethacin (8 x 10(-6) M), ridogrel (10(-5) M) and SQ 29548 (10(-6) M) thus confirming the involvement of thromboxane A2/prostaglandin H2 processes. Subsequent experiments demonstrated that the thromboxane-like contraction was not dependent upon the presence of endothelial cells and occurred in preparations from young, prehypertensive (5 week) and older (17 week) SHRs. The thromboxane-like contraction was markedly suppressed with chronic captopril treatment and reinstated 4 weeks after withdrawal from captopril. The addition of saralasin (10(-6) M) or captopril (10(-6) M) to aortic ring preparations did not suppress the thromboxane-like contractions. The foregoing findings support the presence of a nonendothelial cell thromboxane-like constrictor agent in the aorta of the SHR that is revealed after impairment of nitric oxide production. The activity of the thromboxane-like constrictor process is not tightly linked to prevailing blood pressure, but is reduced with chronic in vivo inhibition of the angiotensin-converting enzyme.

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.

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.

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.

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.

Responses to cholecystokinin octapeptide in patients with functional abdominal pain syndromes.

Clues to the pathogenesis of functional pain syndromes may be derived from the study of stimuli that precipitate or aggravate symptoms. In this study, cholecystokinin octapeptide (CCK-8, 0.06 microgram/kg) and placebo were given by intravenous infusion (5 min) in random order to control subjects and four groups of patients with unexplained abdominal pain. Induction of pain and nausea were assessed by linear analogue scales while sympathoadrenomedullary responses were assessed by serial changes in plasma concentrations of noradrenaline, adrenaline and dopamine. Scores for pain and nausea were low after infusion of placebo. After infusion of CCK-8, pain scores were significantly higher in patients with spontaneous pain than in control subjects, but significant increases in nausea were restricted to patients with irritable bowel syndrome and a subgroup of patients with pain after cholecystectomy. Although some groups showed increases in plasma concentrations of catecholamines after the infusion of CCK-8, the size of these increases was neither consistent among patients within each group nor predictive of scores of pain and nausea in individual subjects. Pain during the infusion of CCK-8 was a feature common to patients with diverse functional pain syndromes, and did not appear to be attributable to activation of the sympathetic nervous system.

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.

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)

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.

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.