Showing papers in "Clinical and Experimental Pharmacology and Physiology in 1993"

A simple method for estimating 24 h urinary sodium and potassium excretion from second morning voiding urine specimen in adults.

Abstract: SUMMARY 1 An assessment was made of the extent sodium (Na) and potassium (K) intake can be estimated from Na, K and creatinine (Cr) content of a second morning voiding urine (SMU) specimen collected within 4 h after the first voiding upon awakening but before breakfast in 159 clinically healthy, free-living individuals (20–79 years) The SMU and the rest of 24 h urine specimens for a 3–5 day period were collected 2 The following equations for estimating 24 h urinary Na (24HUNaV) and K (24HUKV) excretions were developed, and the accuracy and the reliability of these equations were evaluated Estimated value of 24HUNaV (mEq/day) = 163 √XNa; estimated value of 24HUKV (mEq/day) = 72 √XK, where XNa (or XK) = SMUNa (or SMUK)/SMUCr X predicted 24 h urinary Cr excretion 3 Highly statistically significant correlations were detected between the values estimated and measured for both Na (r= 0728, P < 0001, n= 159) and K (r= 0780, P < 0001, n= 159) 4 These equations were applied to Group 1 subjects, who collected the urine for a single day, and to Group 2, for 3 days The correlation coefficients between the values estimated and measured for Na and K were 0531 and 0443 in Group 1, and 0821 and 0590 in Group 2, respectively No statistically significant differences were observed 5 The SMU specimens provide a satisfactory alternative to both 24HUNaV and 24HUKV in adults for extensive epidemiological surveys but also for clinical application

Evidence that primary aldosteronism may not be uncommon: 12% incidence among antihypertensive drug trial volunteers

Abstract: 1. Six (12%) out of 52 respondents to newspaper advertisements for antihypertensive drug trials had elevated aldosterone to renin ratio, confirmed by repeated measurement. 2. Failure to suppress aldosterone with fludrocortisone acetate administration and oral salt loading confirmed the presence of primary aldosteronism in all six patients. 3. Two of the six patients have already had aldosterone-producing adenomas removed, one has commenced spironolactone, and one has an adrenal mass on computerized tomography but investigation is incomplete. 4. None of the six patients with primary aldosteronism had unprovoked hypokalaemia. 5. Plasma aldosterone levels did not distinguish those patients with subsequently proven primary aldosteronism from the others. Plasma renin activity (PRA) was a better discriminator, but not as good as the aldosterone to renin ratio. 6. The incidence of primary aldosteronism is probably much higher than the 1% currently quoted in texts, with earlier, normokalaemic forms accounting for the majority of cases.

Effect of breathing pattern on blood pressure and heart rate oscillations in humans.

Abstract: 1. The relationships of respiratory sinus arrhythmia (RSA) and respiratory changes in systolic blood pressure (SBP) to tidal volume (VT) and breathing frequency (BF), were quantified during voluntary control of VT and BF in healthy subjects. 2. Respiration was measured non-invasively with a respiratory inductive plethysmograph, which was calibrated prior to each study while breathing through a pneumotachygraph. Finger arterial blood pressure was measured non-invasively by the Finapres. 3. Heart rate (HR) increased during inspiration, with a nearly fixed time delay for most VT and BF approximating 0.9 s. The magnitude of RSA increased with increases in VT and with decreases in BF. SBP decreased during inspiration, with a time delay which increased as BF decreased, resulting in a phase delay approximating 160 degrees. The magnitude of the inspiratory fall in SBP increased with increases in VT. Increased amplitudes of RSA and SBP variation occurred at the lowest BF, consistent with the possibility of interactions between respiratory-related influences and those due to 'slow waves' of vasomotor tone. 4. The present results are consistent with the conclusion that respiratory effects on SBP are caused by a mechanism other that simply changes in HR.

Five year prospective study on blood pressure and maximal oxygen uptake

Abstract: 1. The relationship between physical fitness (maximal oxygen uptake VO2max) and incidence of hypertension was investigated through a prospective study for a total of 16,525 human-years of observation. 2. This study involved 3305 Japanese males whose blood pressure (BP) was normal when they received their first physical examination before the age of 50. They were monitored from 1983 to 1988. The BP of 425 subjects was diagnosed as hypertension in the fifth year. 3. Fitness levels were divided into quintiles according to VO2max levels, and were compared with the changes of BP and relative risk of hypertension after adjustment for age, initial percentage of body fat (PFAT), initial BP, alcohol consumption, cigarette smoking status and familial history of hypertension. The increase in BP of subjects in the least fit group was higher than in any other group. Relative risk was calculated using a multiple logistic regression and was 1.9 x higher in the least fit group compared with the fittest group. 4. The subjects were classified into three groups: the improved VO2max group, the deteriorated VO2max group and the unchanged VO2max group. The increase in BP of the improved VO2max group was significantly lower than the other two groups after adjustment for changes in PFAT, age, initial PFAT, initial BP, fitness level, alcohol consumption, cigarette smoking status and familial history of hypertension. 5. It is concluded that low VO2max level is related to higher incidence of hypertension. An improved VO2max would therefore be able to prevent hypertension.

Atrial and brain natriuretic peptide response to exercise in patients with ischaemic heart disease

Abstract: SUMMARY 1. The response of venous plasma natriuretic peptides (atrial natriuretic peptide, ANP, and brain natriuretic peptide, BNP) plasma cyclic guanosine monophosphate (cGMP) and vasoactive hormones to dynamic exercise has been studied in 16 subjects undergoing diagnostic exercise tolerance for ischaemic heart disease (IHD), and in five healthy control subjects. 2. In patients with IHD, plasma ANP increased 3-fold (mean 16 ± 2.5 pmol/L pre-exercise, 51 ± 11 pmol/L after exercise, P<0.01). Increase in plasma BNP (10.5 ± 1.6 pmol/L pre-exercise, 13 ± 2 pmol/ L after exercise, P<0.01) was proportionately much less than ANP but more sustained. In exercising normal subjects, plasma ANP levels doubled (P<0.01) but there was no significant change in plasma BNP levels. 3. In patients with IHD, there was a significant correlation between levels of plasma ANP and BNP before exercise (r = 0.97, P<0.001) as well as during exercise (r= 0.79, P<0.001). 4. Hormone responses in patients with positive exercise tests did not differ significantly from those with negative tests. 5. Although resting levels of plasma ANP and BNP in IHD are correlated, the findings indicate different mechanisms of secretion. The low BNP/ ANP ratio in response to acute dynamic exercise presumably reflects the predominance of ANP in pre-secretory atrial stores.

Different responses to acetylcholine in the presence of nitric oxide inhibitor in rat aortae and mesenteric arteries

Abstract: SUMMARY 1. This study compared the relaxation induced by acetylcholine (ACh) in aortic and mesenteric arterial rings from Sprague-Dawley (SD) rats in the presence and absence of inhibitors of the known endothelium-derived relaxing factors. 2. ACh-induced relaxations were completely blocked by methylene blue and N”-nitro-L-arginine (LNNA) in aortae, whereas these were only partially attenuated by methylene blue and LNNA in mesenteric arteries. 3. This methylene blue-resistant relaxation of ACh was partly attenuated by potassium channel blockers (tetraethylammonium and barium) but not affected by LNNA, indomethacin and calcium-free solution. 4. These results suggest that there may be another endothelial relaxing factor which is not nitric oxide (NO), prostanoids or endothelium-derived hyperpolarizing factor (EDHF) in mesenteric arteries but not in aortae. This unknown factor seems to be extracellular calcium ([Ca2+]o)-independent.

Crossover comparison between the depressor effects of low and high work‐rate exercise in mild hypertension

Abstract: 1. The relationship between work-rate and the antihypertensive effect of exercise in hypertensives, and the mechanism of that effect, were investigated by a crossover clinical trial. 2. Ten mild hypertensives were randomly divided into two groups. One group performed low work-rate exercise (LWE) on a cycle ergometer for 10 weeks (blood lactate threshold; approximately 50% of maximum oxygen consumption [Vo2max]). After a 10 week interval without exercise training, these subjects were then switched to a high work-rate exercise (HWE) regimen (4 mmol/L of blood lactate; approximately 75% of Vo2max) for another 10 weeks. In the other group, the order of exercise training was reversed. Since two patients withdrew from the protocol during HWE periods, statistical analysis was performed on the data from the remaining eight patients. There were no order effects observed in any of the data from the two groups. 3. During both LWE and HWE, resting blood pressure (BP) fell significantly after the initiation of exercise therapy (P < 0.05). Furthermore, the overall effects of 10 weeks of LWE and HWE on BP were not significantly different. 4. The work-rate at the lactate threshold, which reflects physical fitness, had increased significantly by 16 W (P < 0.01) after the LWE period and by 11 W (P < 0.01) after the HWE. 5. During the LWE period, changes in haemodynamic and humoral variables were not significant, except for a reduction in plasma norepinephrine at week 10 (P < 0.05). In the HWE period, changes in haemodynamic and humoral variables were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Novel microscopy using fibre optic confocal imaging and its suitability for subsurface blood vessel imaging in vivo

Abstract: We describe for the first time the use of fibre optic confocal imaging (FOCI) for in vivo microscopy of subsurface blood vessels. In a conventional laser scanning confocal microscope (first described by Minsky 1957), the light source, optical components, a pinhole or equivalent, the scanning mechanism and the light detector must all be accurately aligned. These instruments are therefore bulky, expensive, difficult to miniaturize and inconvenient to use for certain in vivo applications. Indeed, the laser scanning confocal microscope was originally designed primarily for epifluorescence microscopy of fixed and relatively small specimens (Amos et al. 1987; Paddock 1991). We have replaced the pinhole of the conventional laser scanning confocal microscope with an optical fibre (or fibres), thus allowing the imaging end to be more freely mobile and potentially small (King et al. 1992). We now report the use of this microscope (HBH Fibrescan C900) for in vivo imaging of blood vessels. In this FOCI microscope, light from a laser is launched into a single-moded optical fibre. On emerging as concentric wave fronts from the distal end of the fibre, the light is focused to a point (diffraction limited spot) within a translucent object. Only light returning from the focal plane within the object is collected back at the fibre tip, to be transmitted to the proximal end of the fibre. After emerging from this end, it passes via appropriate optics and a beam splitter to a light detector (photomultiplier tube). A scanning mechanism (galvanometer scanning mirrors and optics between the distal end of the fibre and the objective lens) and a computer is used to build up a two-dimensional (2-D) image of structures within the focal plane of the object. Three-dimensional (3-D) images can be obtained by scanning at different depths within the objects. The FOCI microscope can be readily used with almost any objective lens elements, as the imaging end is mobile. This allows it to be assembled easily and reliably in different configurations, some of which can be particularly useful and convenient for in vivo use. Figure l a shows a 3D construct of subsurface blood vessels imaged from the serosal surface of the rat colon in vivo using FOCI. The rat was anaesthetized (60 mg/ kg i.p. pentobarbitone), the colon exposed and FITC dextran injected intravenously prior to imaging. Fluorescent images were obtained (argon laser 488 nm, detection above 515 nm). Nine 2-D scans were performed at 10 pm depth intervals (commencing 20 pm beneath the surface) to construct the 3-D image. Figure lb,c show subsurface blood vessels of the rat ileum imaged by FOCI, before and after administration of noradrenaline. The imaged width of the small vessels (the size of capillaries) remained the same, whereas that of the larger vessel

Effects of hydroxocobalamin and haemoglobin on no-mediated relaxations in the rat anococcygeus muscle.

Abstract: 1. The effects of hydroxocobalamin (Vitamin B12a) on relaxations produced by nitric oxide (NO), some NO-donating compounds and nitrergic nerve stimulation in isolated preparations of the rat anococcygeus muscle were compared with the effects of haemoglobin. 2. Hydroxocobalamin (30 mumol/L) significantly reduced relaxations induced by NO (0.1-3 mumol/L) and sodium nitroprusside (SNP; 0.01-0.3 mumol/L) but did not affect relaxations induced by glyceryl trinitrate (GTN; 0.01-1 mumol/L), S-nitrosocysteine (0.1-0.3 mumol/L) or stimulation of nitrergic nerves. A higher concentration of hydroxocobalamin (100 mumol/L) slightly reduced nitrergic nerve stimulation-induced relaxations. 3. Haemoglobin (10 mumol/L) blocked relaxation induced by NO and reduced relaxations induced by SNP, GTN, S-nitrosocysteine and nitrergic nerve stimulation. 4. When nitrergic nerve stimulation-induced relaxations had been partially reduced by the NO synthase inhibitor L-NAME (5-10 mumol/L), hydroxocobalamin had only a weak and transient inhibitory effect. 5. Noradrenergic contractions induced by field stimulation were not affected by hydroxocobalamin (30 mumol/L), but were enhanced by haemoglobin (10 mumol/L). 6. The results suggest that the transmitter released from nitrergic nerves in anococcygeus muscles resembles NO-releasing compounds such as S-nitrosocysteine and GTN but not SNP or free NO.

Demonstration of defective glucose uptake and storage in erythrocytes from non-insulin dependent diabetic patients and effects of metformin.

Abstract: SUMMARY 1. Red blood cells can store glucose and may thus participate in blood glucose homeostasis. We investigated if a defect in this process exists in non-insulin dependent diabetes (NIDD). 2. Blood was obtained in fasting conditions from 10 normal and 10 newly diagnosed NIDD patients (before and after 4 weeks Metformin therapy). Washed erythrocytes were resuspended in media containing various glucose concentrations (4.4, 6.6, 8.8 and 13.2 mmol/L). Total glucose uptake was calculated as the sum of the measurements of lactate as well as free glucose, the latter being determined before and after addition of amyloglucosidase to the pellet. 3. Cells from diabetics showed a pronounced reduction in glucose uptake, particularly in their capacity to store glucose as glycogen (reactive to amyloglucosidase). Metformin treatment almost normalized glycogen levels, whereas lactate declined concomitantly in the pellet. 4. Our data demonstrate that a defect in glucose uptake exists in erythrocytes from NIDD patients, affecting both free and stored glucose, and that this defect is reversed by Metformin treatment, indicating that this drug can increase glycogen levels even in insulin-insensitive cells. 5. Thus, in view of their total mass, erythrocytes may be important in the impaired glucose homeostasis in NIDD, in particular in marked hyperglycaemia such as after a meal.

Analgesic activity of certain flavone derivatives: a structure‐activity study

Abstract: SUMMARY 1. Flavone, its methoxy derivatives and flavanone were synthesized by standard methods and were tested for analgesic activity in mice by employing acetic acid writhing and tail flick methods. 2. All the tested compounds except flavanone exhibited significant dose-dependent analgesic activity in both the assay models. Some of the compounds were found to involve opioid mechanisms in their analgesic effect. 3. A definite structure-activity relationship was observed in the analgesic activity of flavone derivatives as well as in their mechanism of action.

Mediators of nicotine-induced relaxations of the rat gastric fundus

Abstract: SUMMARY 1. Relaxations of strips of rat gastric fundus were elicited with nicotine (100 μmol/L), nitric oxide (NO; 30 μmol/L), sodium nitroprusside (SNP; 100 nmol/L) and vasoactive intestinal polypeptide (VIP; 1 nmol/L). 2. Methylene blue (30 μmol/L), an inhibitor of soluble guanylate cyclase, reduced relaxations elicited by NO and nicotine, but not those elicited by VIP. 3. Chymotrypsin (1 U/mL) abolished VIP-induced relaxations and reduced nicotine-induced relaxations, but had no effect on SNP-induced relaxations. 4. NG-nitro-l-arginine methyl ester (l-NAME; 100 μmol/L), an inhibitor of NO synthase, reduced relaxations elicited by nicotine, but not those elicited by SNP or VIP. 5. When nicotine-induced relaxations had been reduced by either l-NAME or chymotrypsin, the addition of the other agent produced a greater reduction. However, the relaxations were not abolished. 6. Nicotine-induced relaxations were abolished by tetrodotoxin (1 μmol/L) or hexamethonium (100 μmol/L), indicating that they were due to activation of neuronal nicotinic receptors. Their reduction by methylene blue and l-NAME indicates that an NO-like mediator was involved. Their reduction by chymotrypsin indicates that a VIP-like peptide was involved. However, since they were not abolished by a combination of l-NAME and chymotrypsin, it appears that at least one more as yet unidentified mediator may be involved.

Effect of nicorandil on post-ischaemic contractile dysfunction in the heart: roles of its ATP-sensitive K+ channel opening property and nitrate property.

Abstract: 1. This study aimed to characterize the effect of nicorandil (NC) on myocardial stunning and the role of ATP-sensitive K+ (KATP) channel opening property in its cardioprotective action. 2. In open-chest anaesthetized rabbits, myocardial stunning was induced by 10 min of coronary occlusion followed by 30 min of reperfusion. As an index of regional contractile function, systolic thickening fraction (TF) was measured by an epicardial Doppler sensor. The doses of NC (10 micrograms/kg per min) and nitroglycerin (TNG) (1 micrograms/kg per min) were selected not to lower the systemic blood pressure significantly. 3. In the untreated controls, TF at 30 min after reperfusion was 46.4 +/- 2.9% of the baseline value, indicating myocardial stunning. Both NC and TNG significantly improved post-ischaemic recovery of TF when administered during the pre-ischaemic and post-ischaemic periods (TF = 68.2 +/- 6.4%, 64.7 +/- 2.3%, respectively). However, when their infusion was restricted to a pre-ischaemic 10 min period, TF recovery was improved by NC, but not by TNG (63.4 +/- 7.9%, 40.9 +/- 6.2%, respectively). 4. Pretreatment with glibenclamide (GL; 0.3 mg/kg) did not influence the recovery of TF after the 10 min ischaemia (TF = 52.4 +/- 3.9% at 30 min after reperfusion). However, after the GL injection, a cardioprotective effect from nicorandil pretreatment was not detected (TF = 51.3 +/- 1.7%). 5. These results suggest that nicorandil protects the myocardium against stunning by opening the KATP channel when it is given before ischaemia, and that the nitrate property of nicorandil may also play a role during the reperfusion period in attenuation of post-ischaemic contractile dysfunction.

Identification of adenosine receptors in human spermatozoa

Abstract: 1. The effects of adenosine receptor agonists and antagonists on human sperm motility have been studied. Specific binding sites for adenosine and its analogues on human sperm were also investigated. 2. Agonists stimulated human sperm motility in a dose-dependent manner with a potency order of 5'-N-ethylcarboxamidoadenosine (NECA, EC50 = 0.3 mumol/L) > 2-[p-(carboxyethyl)phenylethylamino]-5'-N- ethylcarboxamidoadenosine (CGS-21680, EC50 = 10 mumol/L) > adenosine (EC50 = 100 mumol/L). 3. NECA-stimulated motility was competitively inhibited by various adenosine receptor antagonists. The potency order was 3,7-dimethyl-1-propargylxanthine > 8-(p-sulfophenyl) theophylline > xanthine amino congener. 4. The radioligand [3H]-NECA bound to sperm membrane in a saturable manner with a Bmax of 21.3 pmol/mg protein and equilibrium Kd of 4 mumol/L. Adenosine agonists and antagonists competed for [3H]-NECA binding with the same rank order of potency as for the stimulation of human sperm motility. 5. GTP gamma s inhibited 63% of specific [3H]-NECA binding with IC50 value of 11 nmol/L. This suggests that the [3H]-NECA binding sites may be coupled to one or more G proteins. 6. These results indicate the presence of adenosine A2 receptors on human sperm which are responsible for adenosine-mediated enhancement of sperm motility.

The inhibition of nitric oxide-mediated relaxations in rat aorta and anococcygeus muscle by diphenylene iodonium

Abstract: 1. The effects of diphenylene iodonium (DPI), an inhibitor of reduced nicotinamide adenine dinucleotide phosphate-dependent oxidases (which generate superoxide anions), were studied on nitric oxide (NO)-mediated responses in isolated preparations of the rat aorta and anococcygeus muscle. 2. In aortic rings, the endothelium-dependent relaxant action of acetylcholine was reduced by DPI (0.3-10 mumol/L) in a concentration-dependent manner and abolished by the NO synthase (NOS) inhibitor L-nitro-NG-arginine methylester (L-NAME; 100 mumol/L). Relaxations induced by sodium nitroprusside (SNP) or NO were not affected by DPI or L-NAME. 3. In anococcygeus muscles, DPI (0.3-10 mumol/L) as well as L-NAME (5-100 mumol/L) produced concentration-dependent reductions of relaxations produced by nitrergic nerve stimulation. Relaxations induced by NO and SNP were not affected by either DPI or L-NAME. L-Arginine (1 mmol/L) prevented the reduction of nitrergic relaxations by L-NAME but not by DPI. 4. Contractions of anococcygeus muscles elicited by exogenous noradrenaline (1 mumol/L) were not affected or were inhibited by DPI (0.3-10 mumol/L), but the contractions elicited by noradrenergic nerve stimulation were significantly enhanced by DPI and L-NAME. When noradrenergic contractions had already been maximally enhanced by L-NAME (100 mumol/L), DPI produced no further enhancement. L-Arginine (1 mmol/L) prevented the enhancement of noradrenergic contractions by L-NAME but not by DPI. 5. The efflux of radioactivity induced by field stimulation from anococcygeus muscles previously incubated with [3H]-noradrenaline was not affected by either DPI or L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal sympathetic baroreflex effects of angiotensin ii infusions into the rostral ventrolateral medulla of the rabbit

Abstract: SUMMARY 1. The effects of local infusion of angiotensin II (AII) into the rostral ventrolateral medulla (RVLM) pressor area on the renal sympathetic baroreflex were compared with the excitatory amino acid glutamate in urethane anaesthetized rabbits with chronically implanted renal nerve electrodes. Baroreflex blood pressure-renal nerve activity curves were obtained by intravenous infusion of phenylephrine and nitroprusside before and after treatments. 2. Infusion of 4 pmol/min of All into the RVLM increased blood pressure by 12 ± 2 mmHg and transiently increased resting sympathetic nerve activity. The renal sympathetic baroreflex curves were shifted to the right. The upper plateau of the sympathetic reflex increased by 29 ± 8% (n= 6, P < 0.025). 3. Infusions of glutamate into the RVLM, at a dose which was equipressor to that of AII, also increased resting renal sympathetic nerve activity. In contrast to AII, this increase was maintained throughout the infusion. Glutamate shifted the reflex curve to the right and increased the upper plateau of the sympathetic reflex by 44 ± 5% without affecting the lower plateau. 4. These results support the suggestion that AII can act at the level of the RVLM pressor area to facilitate baroreflex control of renal sympathetic activity in a similar fashion to that produced by fourth ventricular administration. 5. Thus the RVLM is a likely candidate site for modulation of the renal sympathetic baroreflex. The similarity of the actions of AII to those of glutamate suggest that it may directly excite sympathetic vasomotor cells in this region.

THE EFFECT OF SOME α2‐ADRENOCEPTOR AGONISTS AND ANTAGONISTS ON GASTROINTESTINAL TRANSIT IN MICE: INFLUENCE OF MORPHINE, CASTOR OIL AND GLUCOSE

Abstract: 1. The effects of graded doses of the alpha 2-adrenoceptor agonists clonidine, tizanidine and BHT-920, and the alpha 2-adrenoceptor antagonists yohimbine and idazoxan, on gastrointestinal transit were investigated in mice using the charcoal meal test. 2. The agonists produced significant and dose-dependent decreases in gastrointestinal transit, and the antagonists produced the opposite effect. In affecting the gastrointestinal transit, clonidine (1 mg/kg) was as effective as tizanidine (12 mg/kg) and BHT-920 (40 mg/kg), while yohimbine (2 mg/kg) was as effective as idazoxan (1 mg/kg). 3. Morphine (2, 4 and 8 mg/kg) significantly inhibited gastrointestinal transit. This effect was significantly reversed by the co-administration of yohimbine (2 mg/kg) and idazoxan (1 mg/kg). 4. The acute administration of glucose (5.04 g/kg, i.p.) potentiated the inhibition of gastrointestinal transit produced by clonidine (1 mg/kg) and BHT-920 (40 mg/kg). Glucose treatment, however, had no significant effect on the increase in gastrointestinal transit induced by yohimbine (2 mg/kg) or idazoxan (1 mg/kg). 5. Castor oil (0.25 mL/mouse, orally) induced diarrhoea in saline-treated animals within about 45 min. Clonidine (1 mg/kg), tizanidine (12 mg/kg) and BHT-920 (40 mg/kg) delayed the occurrence of diarrhoea to 2.1, 1.2 and 1.4 h, respectively.

Angiotensin-responsive aldosterone-producing adenomas: postoperative disappearance of aldosterone response to angiotensin.

Abstract: 1. Nineteen out of 47 patients (40%) with confirmed unilateral aldosterone-producing adenoma (APA) were responsive to low-dose angiotensin II infusion (AII-R), as defined by an increase in plasma aldosterone concentration of > 50% over basal at 2 ng/kg per min for 60 min. 2. Seven to ten days after unilateral adrenalectomy, aldosterone was no longer responsive to angiotensin infusion in AII-R APA (100%, n = 17). Therefore, angiotensin responsiveness resides within the adenoma in AII-R APA. 3. The upright posture test for the differentiation of adenoma from hyperplasia was unreliable for the AII-R APA (26%), but generally reliable in the angiotensin-unresponsive subtype, (AII-U APA, 96%). 4. The reported predominance of females in APA was seen in AII-U APA (68%), but was reversed in AII-R APA (37%).

The angiotensin-converting enzyme inhibitor, perindopril, prevents cardiac hypertrophy in low-renin hypertensive rats.

Abstract: SUMMARY 1. To examine whether an angiotensin-converting enzyme (ACE) inhibitor prevents left ventricular (LV) hypertrophy even in low-renin hypertension, we studied the effect of the administration of perindopril on cardiac hypertrophy induced by partial renal ablation in hypertensive rats. 2. Rats that had undergone partial nephrectomy were randomly divided into four groups that received the following as drinking water: Group A, tap water; Group B, 1% sodium chloride (NaCl); Group C, NaCl + perindopril 3 mg/ kg per day; and Group D, NaCl + perindopril 1 mg/ kg per day. Plasma renin activity (PRA), angiotensin-II (AII) concentration and cardiac tissue AII were measured. 3. Supplementation of NaCl following nephrectomy increased the blood pressure and cardiac weight compared with rats that had undergone nephrectomy alone (P<0.05). Treatment with perindopril (3 mg/kg per day) did not affect the blood pressure and plasma AII but inhibited the increase of cardiac weight (P<0.05). Left ventricular AII was decreased in cases of reduced renal mass hypertension, but was not changed by treatment with perindopril. 4. These results demonstrate that perindopril may be able to prevent LV hypertrophy even in low-renin hypertension, which was not mediated by a reduction of blood pressure or suppression of the circulating and cardiac renin-angiotensin systems. Other mechanisms of ACE inhibitors may contribute to the cardioprotective effects.

11β-hydroxysteroid dehydrogenase activity in mesenteric arteries of spontaneously hypertensive rats

Abstract: SUMMARY 1. 11β-Hydroxysteroid dehydrogenase (11-HSD) activity in mesenteric arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was determined and expressed as the percentage conversion of [3H]-corticosterone to [3H]-11-dehydrocorticosterone. 2. 11-HSD activity was significantly decreased in mesenteric arteries of both 4 and 9 week old SHR (8.4 ± 0.8%, 5.0 ± 1.5%, respectively) compared with WKY rats (12.4 ± 0.6%, 15.8 ± 0.7%, respectively; P≤ 0.05). 3. Total RNA from rat vascular smooth muscle cells (VSMC) and endothelial cells (EC) were prepared with selective precipitation in 3 mol/L LiC1/6 mol/L urea. The expression of 11-HSD mRNA was confirmed in the rat VSMC but its mRNA expression was not detected in EC, using northern blot analysis. 4. The results in this study indicate that 11-HSD in the vascular wall may play a role in the pathogenesis of hypertension in SHR.

Release of a substance from the human placenta having digoxin‐like immunoreactivity

Abstract: SUMMARY 1. The human placental lobule, perfused with a constant flow (5 mL/min) of Krebs’ solution after delivery at term, released into the fetal perfusate a digoxin-like substance, as measured by a fluorescence polarization immunoassay. 2. Initially the venous concentration was 360 ± 66.7 pmol/ L digoxin equivalents. This level did not change significantly during fetal vasoconstriction induced by prostaglandin F2α infusion and persisted for the duration of the experiment (1.5–2h). 3. Infusion into the fetal circulation of Fab fragments of sheep antibodies to digoxin caused vasodilatation, indicated by a fall in perfusion pressure. 4. Thus a digoxin-like immunoreactive substance, previously reported to be present in the placenta, is released into the fetal circulation and may play a role in placental control of fetal vascular tone.

Use of a computerized postural sway measurement system for assessing workers exposed to manganese

Abstract: SUMMARY 1. Computerized postural sway measurement systems have been used recently in human physiology and pharmacology for determining postural stability, but their applicability for the assessment of the effects of exposure to neurotoxic agents is lacking. 2. We have examined the feasibility of using a computerized postural sway measurement system to assess the postural sway parameters of manganese exposed workers compared with a control group. 3. Sway parameter data were collected using a kislter multicomponent measuring platform (Type 9281B) connected to vicon motion analysis system for 13 exposed and 16 control subjects. 4. Significant differences in several of the sway parameters (Px, Py—mean distance (mm), from the centre of the platform along the X-axis [anterior-posterior movement] and Y-axis [lateral movement], respectively) between the exposed and control groups were observed even after adjustment for possible confounders. Computerized postural sway measurement system may be a useful method of assessing workers exposed to neurotoxic agents affecting posture.

Effects of bradykinin on [3H]-norepinephrine release in rat hypothalamus.

Abstract: 1. We examined the regulatory actions of bradykinin on norepinephrine release in the hypothalamus of rats. 2. Bradykinin increased the stimulation-evoked [3H]-norepinephrine release from hypothalamic slices of Sprague-Dawley rats in a dose-dependent manner (1 Hz: S2/S1 ratio, mean +/- s.e.m., control 0.868 +/- 0.016, n = 6; bradykinin 1 x 10(-6) mol/L 1.039 +/- 0.018, n = 6, P < 0.05; bradykinin 3.3 x 10(-6) mol/L 1.130 +/- 0.064, n = 6, P < 0.05). The basal release of [3H]-norepinephrine was not affected by the peptide. 3. Bay K 8644, a dihydropyridine-sensitive calcium channel agonist, significantly potentiated the facilitatory effect of bradykinin on norepinephrine release, although Bay K 8644 by itself had no significant effect. By contrast, nicardipine, a dihydropyridine-sensitive calcium channel blocker, reversed the increase in norepinephrine release induced by bradykinin and Bay K 8644. 4. These results indicate that bradykinin may increase norepinephrine release in rat hypothalamus, partially mediated by interactions with dihydropyridine-sensitive calcium channels.

Intralymphocytic free calcium and magnesium in stroke-prone spontaneously hypertensive rats and effects of blood pressure and various antihypertensive agents.

Abstract: SUMMARY 1. Free Ca2+ ([Ca2+]i) and Mg2+ ([Mg2+]i) were measured in peripheral lymphocytes from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY) at the age of 5, 7 and 17 weeks, from various antihypertensive agents-treated SHRSP, and from secondary hypertensive WKY. 2. At the age of 5 weeks, no difference was observed in systolic blood pressure (SBP), or lymphocyte [Ca2+]i and [Mg2+]i between SHRSP and WKY. At the age of 7 or 17 weeks, SBP and [Ca2+]i of SHRSP were significantly higher than in WKY, and at the age of 17 weeks, [Mg2+]i of SHRSP was significantly lower than in WKY. Further, [Ca2+]i or [Mg2+]i was positively or negatively correlated to SBP, and [Mg2+]i was negatively correlated to [Ca2+]i. 3. SBP of SHRSP fell significantly after antihypertensive treatment with calcium antagonist, angiotensin-converting enzyme (ACE) inhibitor or hydralazine for 40 days. [Ca2+]i was significantly lower in calcium antagonist and hydralazine groups, and tended to be low in ACE inhibitor group. These four groups showed no difference in [Mg2+]i. 4. After 40-day administration of NG-nitro-l-arginine (l-NNA), WKY developed severe hypertension, but there were no significant differences in lymphocyte [Ca2+]i and [Mg2+]i between the l-NNA treated and non-treated groups. 5. These results suggested that increased lymphocyte [Ca2+]i and decreased [Mg2+]i observed in SHRSP are not only secondary to hypertension but possibly related to a basic genetic abnormality of divalent cation handling.

Cortisol production by aldosterone-producing adenomas in vitro

Abstract: 1. In vitro short-term production of cortisol by dispersed tumour and non-tumourous adrenal cortical cells was measured with and without added angiotensin II (AII) or adrenocorticotrophin (ACTH) in adrenals removed from five patients with primary aldosteronism. 2. Aldosterone-producing adenomas (APA) were classified as angiotensin responsive (AII-R) or angiotensin unresponsive (AII-U) based on pre-operative behaviour in vivo. 3. Cortisol was produced by both tumour and cortex in vitro without stimulation, and significantly more cortisol was generated by the cortex. 4. Addition of AII significantly increased cortisol production by both tumour and cortex to an equal extent. 5. Addition of ACTH also significantly increased cortisol production by both tumour and cortex, but tumours were more responsive than cortex. The response to ACTH exceeded the response to angiotensin in both tumour and cortex. 6. There was no obvious difference between AII-R and AII-U APA in terms of cortisol production.

Renin and prorenin in reproductive tissues during gestation in pigs and cattle

Abstract: SUMMARY 1. High concentrations of prorenin and active renin were previously found in ovarian follicular fluid from cattle but not from pigs. In the present study female reproductive tissues and fluids from cattle and pigs during gestation were investigated to clarify a possible species difference in active renin and prorenin concentrations. 2. Very high concentrations of active renin but no prorenin were found in corpus luteum from both species. 3. Relatively low concentrations of active renin, in the same order as in maternal blood plasma, were found in myometrium, endometrium, placenta and fetal membranes from both species. Prorenin was undetectable in these tissues except for bovine myometrium and porcine endometrium in some animals. 4. The concentrations of active renin and prorenin in amnionic fluid from both species were below the maternal plasma values. In allantoic fluid the concentrations were higher than in amnionic fluid. 5. The plasma concentrations of active renin and prorenin did not change during gestation in pigs. This finding is in contrast to the observations in humans and does not support a systemic effect of prorenin during gestation. 6. The presence of renin in the reproductive tissues, especially the very high concentrations in the corpus luteum, indicates a local function of the renin-angiotensin system during gestation.

Effects of cortisol on blood pressure and salt preference in normal humans.

Abstract: 1. Adrenocorticotrophic hormone (ACTH) and corticosteroids stimulate salt appetite in laboratory animals. The hypothesis tested was that cortisol administration increases salt preference in humans. 2. Sodium taste studies (detection and recognition thresholds, taste intensity and preference tests) were conducted before, during and after cortisol administration (200 mg/day for 5 days) in normal men on a free diet. 3. Cortisol significantly increased systolic blood pressure (SBP), 113 +/- 3 - 130 +/- 4 mmHg, P < 0.05; diastolic blood pressure (DBP), 65 +/- 3 - 81 +/- 2 mmHg, P < 0.05; mean arterial pressure (MAP), 81 +/- 2 - 97 +/- 3 mmHg, P < 0.05; and bodyweight, 72.9 +/- 3.0 - 75.4 +/- 3.3 kg, P < 0.05. 4. Salt detection and recognition thresholds, taste intensity and preference for sodium chloride were unchanged following cortisol.

Vascular smooth muscle cell proliferation in SHR and WKY rats: evidence for specific differences in growth inhibitory regulatory mechanisms.

Abstract: SUMMARY 1. This study examined and compared the actions of transforming growth factor-β1 (TGF-β1), heparin, dexamethasone and interferon-γ on platelet-derived growth factor-BB (PDGF-BB)-stimulated proliferation of vascular smooth muscle cells (VSMC) from normotensive, Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. Heparin, dexamethasone and interferon-γ all inhibited VSMC proliferation stimulated by PDGF-BB in both SHR and WKY rats. There was no difference (P>0.05) in their inhibitory effects, which varied between 40 and 85% for the different agents. 3. Similarly, TGF-β1 inhibited PDGF-BB-stimulated VSMC proliferation in WKY rats by approximately 50%. In contrast, TGF-β1 potentiated growth factor action on cell proliferation in the SHR by approximately 40%. 4. Specific TGF-β1-stimulated regulatory mechanisms involved in the inhibition of proliferation are absent in SHR and this defect may contribute to the vascular hypertrophy which is apparent in genetic hypertension.

Angiotensin‐converting enzyme and regulation of blood pressure in a large australian family

Abstract: 1. Animal studies have implicated the angiotensin-converting enzyme (ACE) gene as an inherited risk factor contributing towards elevation of blood pressure. 2. A polymorphism of the ACE gene, involving the presence or absence of a 287 base pair (bp) segment within the gene region, was assessed for association with high blood pressure in a large, multigeneration Australian family. The association of these alleles with hypertension in unrelated individuals was also examined. 3. There was no evidence to link the ACE gene and high blood pressure in the large family. Similarly, there was no significant association between this gene and high blood pressure in the population tested. As has been reported previously, plasma levels of the enzyme were associated with genotype. These results suggest that this gene is unlikely to be a major risk factor for hypertension in this group.

Relaxant effects of brain natriuretic peptide on guinea-pig tracheal smooth muscle.

Abstract: SUMMARY 1. The relaxant effects of brain natriuretic peptide (BNP) were investigated on guinea-pig tracheal smooth muscle. 2. Various amounts of BNP (10−9– 10−6 mol/L) showed concentration-dependent relaxant effects on resting tone, leukotriene D4 (LTD4; 10−8 mol/L) and endothelin-1 (ET-1; 10−8 mol/L) induced contraction of tracheal smooth muscle with EC50 values of 3.1± 0.7 ± 10−8, 3.9 ± 1.0 ± 10−8 and 3.5 ± 1.0 ± 10−8 mol/L, respectively. 3. BNP increased tissue cyclic GMP levels in tracheal smooth muscle concentration dependently (187 ± 26 fmol/mg protein in control, 334 ± 77 fmol/mg protein at 10−8 mol/L, 680 ± 54 fmol/mg protein at 10−7 mol/L, 2162 ± 133 fmol/mg protein at 10−6 mol/L). 4. With the addition of BNP, tissue cyclic GMP levels reached a maximum at 1–3 min. The relaxation of tracheal smooth muscle began at 1 min and reached a maximum level at 5 min after the superfusion of BNP (10−6 mol/L). The elevation of cyclic GMP preceded the relaxation of tracheal smooth muscle. 5. These results suggest that BNP may have a potent relaxant effect on tracheal smooth muscle and this effect may be mediated by cyclic GMP level.