Synchronous sporadic carcinoma and primary hyperplasia of the parathyroid glands: A case report and review of the literature.

Parathyroid carcinoma is the least common endocrine malignancy. Although it has been noted to be associated with certain clinical factors, such as familial hyper-parathyroidism, its etiology remains unknown. In rare instances, particularly in patients with chronic renal failure, it has been proposed that parathyroid carcinoma can arise from malignant transformation of benign lesions. We present a case of synchronous malignant and primary hyperplastic parathyroid disease in a patient with normal renal function. A 46-year-old woman was seen with symptomatic refractory hypercalcemia. Investigations suggested a hyperactive parathyroid gland. Operative findings were of a low-grade parathyroid carcinoma in concurrence with diffuse hyperplasia of the remaining glands. To our knowledge this represents the fifth reported case. The possibility of malignant change in hyperplastic parathyroid tissue has implications for patient management and follow-up, particularly if tissue is left in situ to maintain hormonal function.

Breast carcinoma in diabetic mastopathy.

Diabetic mastopathy, or diabetic fibrous breast disease is a well-characterised benign, fibro-inflammatory condition affecting women with insulin dependent diabetes. To date the relationship between this condition and breast carcinoma has been poorly reported. We describe a case of breast carcinoma arising within a diabetic fibrous breast lesion, in a renal transplant recipient.

Colonic carcinoma after ureterosigmoidostomy.

Urinary carcinogens promote late malignant transformation of the colon after a ureterosigmoidostomy. An unusual case is presented where, despite the early removal of the latter and hence cessation of urine flow, a colonic carcinoma developed at the site of previous anastomosis. The importance of surveillance of all patients who have undergone this procedure to avoid an iatrogenic cancer is emphasised.

The identification of a potent imidazoline-based vascular K(ATP) channel antagonist.

In this study the activity of a number of novel imidazoline-based compounds (IMID series) was assessed by functional and binding studies to determine their actions at K(ATP) channels. The novel compounds, which we synthesised, were methoxy-, methyl-, butyl- and fluorophenyl derivatives of clonidine. In functional studies we determined the potency (by calculating a pK(B) value) of the IMID compounds to antagonise levcromakalim responses in segments of isolated pig coronary artery. The most potent compounds identified (laboratory codes: IMID-1M, IMID-26F and IMID-4F) had apparent pK(B) values of approximately 7 which is similar to that for the sulphonylurea, glibenclamide and the lipophilic quaternary ion, tetraphenylphosphonium. This inhibitory action was specific for levcromakalim since the imidazoline antagonist IMID-1M failed to effect vasorelaxation response-curves to the non-KATP channel opener, sodium nitroprusside. In the spontaneously beating rat right atrium preparation the majority of the compounds were able to cause slowing of heart rate, but with low EC50 values (approximately 10-30 microM). In binding studies, the compounds were unable to displace binding of [3H]P1075 to bovine aortic smooth muscle preparations nor [3H]glibenclamide binding to rat cerebral cortex membranes. These studies show that some imidazoline-based compounds are potent antagonists of levcromakalim-mediated vasorelaxation responses in the pig coronary artery. The compounds displayed only minimal bradycardic activity. The site of action of the imidazoline compounds does not appear to be the same as that used by K(ATP) channel openers or sulphonylurea-based antagonists. It is likely that these compounds interact with the K(ATP) channel pore itself.

Functional and electrophysiological effects of a novel imidazoline-based K(ATP) channel blocker, IMID-4F.

1. The functional and electrophysiological effects of IMID-4F (2-[N-(2, 6-dichlorophenyl)-N-(4-flurorobenzyl)amino]imidazoline), a fluoro-benzyl derivative of clonidine, on vascular K(ATP) channels were investigated. In pig coronary artery, IMID-4F inhibited the vasorelaxation response to the K(ATP) channel opener levcromakalim with a pK(B) value of approximately 7.1. IMID-4F (30 microM) did not affect the vasorelaxation response to sodium nitroprusside (SNP). 2. In rat mesenteric artery smooth muscle cells IMID-4F (1 - 10 microM) caused a concentration-dependent depolarization of membrane potential. IMID-4F (10 microM) abolished the hyperpolarizing effects of levcromakalim (10 microM). 3. In patch clamp experiments using rat mesenteric artery smooth muscle cells, K(ATP) channel currents induced by levcromakalim (10 microM) were inhibited by IMID-4F (0.3 - 3 microM) in a concentration-dependent manner. The calculated IC(50) for IMID-4F inhibiting K(ATP) channel current was approximately 0.8 microM. 4. Radioligand binding studies using bovine aortic smooth muscle cell membranes showed that IMID-4F (30 microM) did not displace binding to the K(ATP) channel opener [(3)H]-P1075. However, both levcromakalim (10 microM) and glibenclamide (10 microM) caused significant displacement of [(3)H]-P1075. 5. These studies show that the imidazoline compound IMID-4F is one of the most potent antagonists of arterial K(ATP) channels identified. Vasorelaxation, hyperpolarization and K(+) currents through K(ATP) channels were all inhibited by IMID-4F at micromolar concentrations. Radioligand binding studies indicate that IMID-4F does not bind to the same site as levcromakalim or as glibenclamide. Considering other evidence, it is likely that IMID-4F acts by interacting directly with the pore of the K(IR) channel, rather than through the sulphonylurea subunit of the K(ATP) channel complex.

The smooth muscle relaxant effects of venom from the inland taipan (Oxyuranus microlepidotus).

Venom (10 microg/ml) relaxed phenylephrine-precontracted aortae. This relaxation was unaffected by removal of the endothelium or a combination of N(G)-nitro-L-arginine (L-NOARG; 0.1 mM), oxyhaemoglobin (10 microM) and indomethacin (10 microM). 4-BPB (0.78 mM), propranolol (1 microM), or a combination of apamin (0.1 microM), charybdotoxin (0.1 microM) and glibenclamide (10 microM) did not effect endothelium-independent relaxation, suggesting a lack of PLA2 activity or an effect at beta-adrenoceptors or K+ channels. Venom (10 microg/ml) reversed Bay K 8644 (0.1 microM)-induced contraction indicating the venom may have an effect on L-type Ca2+ channels.

Interspecies differences in thromboxane A2 receptors are distinguished by glibenclamide.

The ability of the thromboxane A2 receptor antagonist, GR32191 ([1R-[1alpha(Z),2beta3beta,5alpha]]-7-[5-[[(1,1'-biphe nyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid), and the sulphonylurea, glibenclamide, to antagonise contractions to the thromboxane A2 mimetic, U46619 ((15S)-hydroxy-11alpha,9alpha(epoxymethano)prosta-5Z, 13E-dienoic acid), were assessed in rat and guinea-pig isolated large (aorta) and small (mesentery and coronary) arteries. U46619 concentration-response curves were constructed in the absence and presence of GR32191 and glibenclamide and pKB values calculated. GR32191 caused significant rightward shifts in U46619 concentration-response curves and was a more potent antagonist in guinea-pig vessels (pKB approximately 9.4) than rat arteries (pKB approximately 7.9). Conversely, glibenclamide failed to inhibit contractions to U46619 in guinea-pig vessels but antagonised responses to U46619 in rat aorta (pKB = 6.1) and mesenteric artery (pKB = 6.3). In combination, GR32191 and glibenclamide caused a shift in the concentration-effect curve to U46619 in rat aorta that was additive. These results suggest that glibenclamide can discriminate between species differences in thromboxane A2 receptors and may exert its inhibitory effect upon U46619-mediated contractions at the level of the thromboxane A2 receptor.

The electrophysiological effects of tetraphenylphosphonium on vascular smooth muscle.

The effect of the lipophilic quaternary ion, tetraphenylphosphonium, on membrane potential of segments of rat small mesenteric artery and on the current in single voltage-clamped smooth muscle cells from rabbit portal vein was studied. In rat small mesenteric artery, tetraphenylphosphonium (1-30 microM) caused membrane depolarization of approximately 23 mV and decreased or abolished the hyperpolarization induced by the KATP channel opener, levcromakalim (0.1-3 microM). In rabbit portal vein K+ currents induced by levcromakalim (10 microM) or pinacidil (10 microM) were completely inhibited by tetraphenylphosphonium (IC50 0.5 microM). The results show that tetraphenylphosphonium antagonizes the KATP current induced by K+ channel openers in vascular smooth muscle possibly by acting on the KATP channel itself.

Characterization of K(ATP) channels in intact mammalian skeletal muscle fibres.

1. The aim of this study was to characterize the K(ATP) channel of intact rat skeletal muscle (rat flexor digitorum brevis muscle). Changes in membrane currents were recorded with two-electrode voltage-clamp of whole fibres. 2. The K(ATP) channel openers, levcromakalim and pinacidil (10-400 microM), caused a concentration-dependent increase in whole-cell chord conductance (up to approximately 1.5 mScm(-2)). The activated current had a weak inwardly rectifying current-voltage relation, a reversal potential near E(K) and nanomolar sensitivity to glibenclamide--characteristic of a K(ATP) channel current. Concentration-effect analysis revealed that levcromakalim and pinacidil were not particularly potent (EC50 approximately 186 microM, approximately 30 microM, respectively), but diazoxide was completely inactive. 3. The ability of both classical K(ATP) channel inhibitors (glibenclamide, tolbutamide, glipizide and 5-hydroxydecanoic acid) and a number of structurally related glibenclamide analogues to antagonize the levcromakalim-induced current was determined. Glibenclamide was the most potent compound with an IC50 of approximately 5 nM. However, the non-sulphonylurea (but cardioactive) compound 5-hydroxydecanoic acid was inactive in this preparation. 4. Regression analysis showed that the glibenclamide analogues used have a similar rank order of potency to that observed previously in vascular smooth muscle and cerebral tissue. However, two compounds (glipizide and DK13) were found to have unexpectedly low potency in skeletal muscle. 5. These experiments revealed K(ATP) channels of skeletal muscle to be at least 10x more sensitive to glibenclamide than previously found; this may be because of the requirement for an intact intracellular environment for the full effect of sulphonylureas to be realised. Pharmacologically, K(ATP) channels of mammalian skeletal muscle appear to resemble most closely K(ATP) channels of cardiac myocytes.

KATP channel blocking actions of quaternary ions play no role in their antiproliferative action on mouse leukaemia and rat vascular smooth muscle cells in vitro.

1. The aim of the present study was to investigate the possibility that, in the two cell lines examined, alterations in cell growth caused by lipophilic quaternary ions may involve KATP channels. We examined the effect of tetraphenylphosphonium (TPP), tetraphenylboron (TPB), rhodamine 123, dequalinium chloride (DECA) and the non-quaternary ion cisplatin on the proliferation of L1210 mouse leukaemia cells and rat smooth muscle cells in vitro. The KATP channel opener levcromakalim (LKM) and the KATP channel antagonist glibenclamide were also tested. 2. From growth-inhibition studies, the rank order of potency (based on pIC50 values) using L1210 leukaemia cells was: DECA (6.61) > cisplatin (6.09) = rhodamine 123 (6.01) > TPP (5.61) > TPB (4.25). Levcromakalim and glibenclamide were found to be inactive at the maximum concentrations used (100 mumol/L). A different rank order of potency was obtained in rat aortic smooth muscle cells: cisplatin (6.33) > DECA (5.67) > TPP (4.96) > rhodamine 123 (4.1). Tetraphenylboron (30 mumol/L), LKM (100 mumol/L) and glibenclamide (100 mumol/L) were found to be inactive. 3. When the negatively charged TPB (30 mumol/L) was combined with some of the active agents, the potency of the active agents was increased. Thus, in L1210 cells, rhodamine 123, DECA and TPP were all more potent at inhibiting cell growth in the presence of TPB. Tetraphenylboron had no effect on cisplatin in this cell line. In rat smooth muscle cells, TPB (30 mumol/L) potentiated the effect of rhodamine 123 but had no effect on the actions of cisplatin, DECA or TPP. 4. In functional studies, rhodamine 123 was a weak antagonist of the vasorelaxant responses to the KATP channel opener LKM in the porcine right circumflex artery in vitro. The pKB value obtained for rhodamine 123 at 100 mumol/L was 4.95. Dequalinium chloride was inactive. 5. We found no correlation between the actions of the compounds tested to antagonise KATP channels and their ability to inhibit cell proliferation. In addition, compounds known to regulate KATP channel activity failed to influence proliferative rates. These results suggest that KATP channels are not involved in the antiproliferative action of TPP and other quaternary ions in the two cell lines studied.

Antiischemic and antiarrhythmic activities of some novel alinidine analogs in the rat heart.

The antiischemic and antiarrhythmic effects of alinidine and a number of novel alinidine analogs were examined by using perfused rat-heart models. In the isolated working rat heart, the alinidine analog TH91:21 (10 microM; a butyl derivative) significantly increased the postischemic recovery of the heart in terms of both power and efficiency when compared with the control group. In the in situ perfused heart model, this same compound, along with TH91:22 (10 microM; a pentyl derivative) also significantly reduced the severity of both ischemia- and reperfusion-induced arrhythmias in both paced and unpaced hearts. Thus this study is the first to demonstrate the potent antiarrhythmic efficacy of two novel alinidine analogs TH91:21 and TH91:22, with TH91:21 also demonstrated to be a potent antiischemic agent in the isolated working rat heart. Although the mode of action of these compounds remains unclear, results from this study suggest that it is not simply a result of bradycardia or blockade of KATP channels, two actions these compounds possess. These compounds thus possess a novel and beneficial pharmacologic profile worthy of further study.

A prospective survey of patients presenting with abdominal aortic aneurysm.

OBJECTIVES: To define the presentation and management of patients presenting with abdominal aortic aneurysm (AAA) DESIGN AND SETTING: A prospective survey was carried out of all patients presenting to hospitals within the Oxford region. MATERIALS AND METHODS: Data were collected by one surgeon in each hospital. Full details were collected onto data sheets. RESULTS: One hundred and ninety patients presented, 141 electively, 46 with ruptured AAA and three with acute AAAs. In 53 patients presenting electively the aneurysm was small and surveillance started. Fifty-six patients underwent an operation, three patients died. Of 46 patients with a ruptured aneurysm 24 (52%) died. In 11 no operation was carried out and all of these patients died within 24 h. Operative mortality was 13 of 35 patients (37%). More patients with a ruptured AAA were transferred to the teaching hospital compared with a district general hospital (p < 0.05). This was reflected in a lower operative mortality in the teaching hospital. CONCLUSIONS: The presentation of AAA in this study was approximately 15 per 100,000 population. Approximately one-third of patients presenting electively had small AAAs which required surveillance. A further third underwent an operation, the remaining patients being unfit. Approximately one-quarter of patients with a ruptured aneurysm did not undergo an operation. The operative mortality was 37%.

The thromboxane A2 and K(ATP) channel antagonist actions of a series of sulphonylurea derivatives in the pig coronary artery.

The ability of a series of sulphonylurea derivatives to antagonise the vasorelaxant actions of the ATP-dependent K+ channel (K(ATP)) opener, levcromakalim, and the vasoconstrictor responses of the thromboxane A2 mimetic, U46619, were assessed in the pig coronary artery. The sulphonylurea derivatives of glibenclamide caused a rightward shift in the concentration-vasorelaxant response curve obtained to levcromakalim in arterial segments pre-constricted with acetylcholine (0.5 microM). From these shifts pK(B) were calculated to estimate the potency of these compounds as levcromakalim antagonists. Similarly U46619 concentration-vasoconstrictor responses curves were constructed in the absence and in the presence of a sulphonylurea derivative and pK(B) values calculated. Regression analysis of pK(B) values showed that there was a significant correlation between the potency of these compounds in the two systems studied indicating similar structure-activity relationships apply in both cases. That sulphonylureas regulate K(ATP) channel opening is well known and they do so through a specific receptor associated with the channel. The results obtained in this study may indicate that a sulphonylurea receptor may also be associated with thromboxane A2 excitation-contraction coupling.

Structure-activity relationship of quaternary ion antagonism of levcromakalim-induced relaxation in pig coronary artery.

The aim of this study was to investigate the interaction between the K+ channel opener levcromakalim and several quaternary ions. Cumulative vasorelaxant-response curves to levcromakalim were constructed in the absence and in the presence of the quaternary ions, in the pig coronary artery. The most potent compounds (based on 'apparent pKB' values) were: propyltriphenylphosphonium (7.33), butyltriphenylphosphonium (7.04), tetraphenylarsonium (6.86), tetraphenylphosphonium (6.81), ethyltriphenylphosphonium (6.70), and hexyltriphenylphosphonium (6.63). Tetrabutylphosphonium (6.06), tetrabutylammonium (5.12), methyltriphenylphosphonium (5.25), clofilium (5.66) and guanethidine (5.61) were significantly less potent. Tetrapropylammonium, tetrapentyltin and tetraphenylboron were inactive at the maximum concentrations used (30 microM). Tetraphenylboron (10-100 microM) fully reversed tetraphenylphosphonium, tetraphenylarsonium (both at 3 microM), tetrabutylammonium (30 microM) and clofilium (10 microM) and partially reversed guanethidine (10 microM) antagonism of levcromakalim responses indicating a similarity in the mechanism of action of these chemically distinct compounds. The results show that quaternary ions similar in structure to tetraphenylphosphonium, i.e., containing phosphonium ion centre and phenyl side chains, are the most potent antagonists of levcromakalim, in pig coronary artery. It is also apparent that marked changes can be made in the substitution on the phosphonium ion (ethyl to hexyl) with little or no effect on their potency.

Electrophysiological properties of the rat middle cerebral artery at different levels of passive wall tension.

1. Simultaneous measurements of intracellular membrane potential and myogenic tone of proximal segments of the rat middle cerebral artery, mounted in a small vessel myograph, were made at two levels of passive wall tension. 2. At low levels of passive tension (less than 0.25 mN/mm) vessels had a resting membrane potential of approximately -65 mV. Addition of KCl (5-60 mmol/L), BaCl2 (0.01-3 mmol/L) or tetraethylammonium (TEA; 0.1-3 mmol/L) resulted in a concentration-dependent depolarization, to approximately -40 mV, generally associated with a contractile response. After the application of high levels of passive tension (to approximately 2 mN/mm maximum) the resting membrane potential of the smooth muscle cells was -40 to -45 mV. This more positive membrane potential was generally associated with an increase in myogenic tone of the vessel. Under these conditions, addition of 5-20 mmol/L KCl resulted in a strong hyperpolarization of the cell along with a concomitant decrease in myogenic tone of the artery. The hyperpolarization and vasorelaxation induced by KCl (5-20 mmol/L) were blocked by BaCl2 (0.5-1 mmol/L). 3. While the addition of ryanodine (10 mumol/L) to vessels under low tension had no effect, when added to a vessel under high tension, this agent caused a rhythmic oscillation in membrane potential. This oscillation was augmented by BaCl2 (1 mmol/L) and inhibited by nifedipine (10 nmol/L) and 4-aminopyridine (1 mmol/L). 4. This study suggests that the electrophysiological and mechanical properties of the isolated rat middle cerebral artery depend on the passive resting conditions under which the vessel is studied. The depolarization of membrane potential observed with increased passive tension appears to result from the closure of an inward rectifying K+ channel. These results indicate that the inward rectifying K+ channel plays an important role in regulating vascular reactivity due to its functional dependence on the mechanical status of the blood vessel.

Structure-activity relationship of glibenclamide analogs: a comparison of potency as levcromakalim antagonists in rat aorta vs. affinity for [3H]-glibenclamide binding to membranes from rat cerebral cortex.

Glibenclamide and analogs were tested for their ability to antagonize the vasorelaxant actions of the K+ channel opener levcromakalim in rat thoracic aorta, and to displace [3H]-glibenclamide binding from rat cerebral cortex membranes. Aortic ring segments were suspended in organ baths to record isometric tension. Tissues were precontracted with K+ (20 mM), and full concentration-relaxation curves were constructed to levcromakalim (0.01-30 microM) in the absence and presence of glibenclamide or analog. The majority of the amidoethylbenzenesulfonylurea based compounds (exemplified by glibenclamide) caused parallel rightward shifts in the levcromakalim concentration-effect curves without effecting the maximum response to levcromakalim. Sulfonamide based compounds were generally inactive, with the exception of the compound DK#1 (laboratory code), which was unusually active as an antagonist of levcromakalim-mediated responses. The compounds were 1,000 to 10,000 times more potent at displacing [3H]-glibenclamide binding from rat cerebral cortex membranes. There was a strong correlation between the activity of amidoethylbenzenesulfonylurea based compounds as antagonists of the effects of levcromakalim and their ability to displace [3H]-glibenclamide binding. The slope of the regression line indicated that structural modification to these compounds has a more dramatic effect on their actions as levcromakalim antagonists than on their ability to displace [3H]-glibenclamide binding. This relationship of activity for the amidoethylbenzenesulfonylureas did not hold in the case of the sulfonamide derivatives. The results show that, for the processes characterized in this study (vascular levcromakalim antagonism vs. sulfonylurea receptor affinity), there are quantitative differences in their sensitivities to sulfonamide/sulfonylurea based compounds. Such differentiation may be important in the development of tissue-specific compounds.

Potassium channel openers and other regulators of KATP channels.

1. Interest in ATP-sensitive K (KATP) channels first arose when it was shown that hypoglycaemic sulphonylureas, such as glibenclamide, closed these channels in pancreatic beta-cells to cause insulin release. The demonstration that certain smooth muscle relaxants (K channel openers) may exert their actions through opening a similar channel in vascular smooth muscle fueled further investigation of these channels and their physiological role in a variety of tissue types, including various types of smooth muscle, cardiac and skeletal muscle and neural and endocrine organ function. 2. The K channel openers have a variety of potential therapeutic applications, including disorders of smooth muscle hyperreactivity, such as hypertension, and a great deal of research has focused on this field. More recently, attention has turned to the cardiac actions of these compounds and this area is discussed in detail. One of the current problems is the lack of selectivity of KATP channel regulators. However, there have been a number of recent encouraging reports suggesting that, under certain pathophysiological conditions, the action of the K channel openers may be enhanced, conferring upon them some degree of selectivity. 3. A number of endogenous regulators of these channels have been identified, particularly in the category of endogenous openers of these channels. At present though, the physiological role of these channels and the endogenous regulators identified, is unclear. 4. It is evident that, although advances have been made, much work is still required to increase our understanding and ultimately to allow selective pharmacological manipulation of these channels to become a therapeutic reality.