bluuebunny/crossref_metadata_2025 huggingface dataset:
OLEIC ACID‐INDUCED INJURIES IN THE GUINEA‐PIG. EFFECTS OF ALLOPURINOL ON CELL DYNAMICS, ERYTHROCYTE‐CATALASE AND URIC ACID PLASMA LEVELS
Authors: Hultkvist‐Bengtsson U. , Mårtensson L.
Published: June 2007

1. Oleic acid was used to produce adult respiratory distress syndrome‐like pulmonary micro‐vascular injuries. The resulting injuries have previously indicated involvement of accumulating neutrophils (Hultkvist et al. 1988). Activated neutrophils release oxygen free radicals that may be possible to detect in the plasma.

2. The dynamics of neutrophils and platelets were studied in the guinea‐pig after oleic acid‐induced injury (0.03 ml/kg per 10 min).

3. As an indication of oxygen free radical activity, plasma levels of uric acid and red blood cell (RBC)‐catalase, were analysed.

4. Allopurinol (10 mg/kg, i.p.) was given prior to oleic acid infusion to block the production of uric acid.

5. The neutropenia, in contrast to the thrombocytopenia seen at 15 min, was significantly inhibited in the allopurinol pretreated group compared with oleic acid and vehicle alone.

6. The blood plasma concentration of uric acid was significantly elevated after 15 min from start of experiment. Allopurinol pretreatment significantly reduced the uric acid plasma level.

7. The RBC catalase activity did not change with time within or between any groups.

8. The results indicate that sequestration of activated neutrophils in the microvasculature are to some extent oxygen free radical dependent.
THE EFFECT OF VASOACTIVE INTESTINAL PEPTIDE (VIP) ON THE CONTRACTILE ACTIVITY OF HUMAN UTERINE SMOOTH MUSCLE
Authors: Leroy M. J. , Tanguy G. , Vial M. , Rostène W. , Malassiné A. , Ferré F.
Published: June 2007

1. In the present study we examined the in vitro effect of vasoactive intestinal peptide (VIP) on spontaneous contractions in both inner and outer layers of non‐pregnant human myometrium. A dose‐dependent relaxation was observed, but with a marked difference in sensitivity to VIP between the two layers, with an IC50 value of 1 X 10−8 and 1 X 10−5 mol/L in the outer and inner layers, respectively.

2. We also established that VIP did not directly stimulate the adenylate cyclase activity. The only slight stimulations were observed in non‐initial rate conditions. The maximal response of this indirect effect was obtained for VIP concentrations between 1 X 10−9 and 1 X 10−8 mol/L and this occurred to the same extent (an approximately 1.4‐fold increase) in both layers. However this response is specific, since structurally related peptides such as glucagon, gastric inhibitory polypeptide (GIP), secretin, or human growth hormone‐releasing factor (hGRF) had no effect in our preparations.

3. Autoradiographic studies revealed that specific VIP binding sites were located on the vascularization of the intermediate vascular layer and on arterioles and venules distributed in the inner and outer myometrial layers. They were also present in the endometrium, but not on smooth muscle cells of either layer.

4. Such observations could provide evidence for another signal transduction pathway to mediate the biological effect of VIP. An additional intermediate step on the vascularization distributed in all of the muscle cannot be excluded.
USE OF NICOTINE, BRADYKININ AND VERATRIDINE TO ELICIT CARDIOVASCULAR CHEMOREFLEXES IN UNANAESTHETIZED RABBITS
Authors: Evans Roger G. , Ludbrook John , Michalicek Jan
Published: June 2007

1. We have characterized in unanaesthetized rabbits the reflex effects of injecting nicotine into the pericardial sac or left atrium on heart rate, arterial pressure, systemic vascular resistance and the amplitude and frequency of respiration. These effects were compared with those of atrial administration of nicotine and veratridine, and intrapericardial administration of veratridine and bradykinin.

2. Injection of nicotine (6.25–400 μg) into the pericardial sac caused dose‐dependent falls of heart rate and arterial pressure, and a brief period of hypopnoea. The fall in arterial pressure was mainly due to a fall in systemic vascular resistance. The threshold dose was 25 μg. Near maximal falls in heart rate (108 beats/min) and arterial pressure (47 mmHg) occurred at a dose of 200–400 μg. The latency between injection and the onset of bradycardia was 3.0 s.

3. The effects of intrapericardial nicotine on arterial pressure and respiration were antagonized in a dose‐dependent fashion by intrapericardial mecamylamine (1–100 μg/kg) but were unaffected by intrapericardial hyoscine methylbromide (10 μg/kg) or vecuronium (1–10 μg/kg). The haemodynamic and respiratory effects were abolished by intrapericardial procaine. The haemodynamic effects were increased, though not significantly, by sino‐aortic baroreceptor denervation. In decerebrate, artificially ventilated rabbits, bilateral cervical vagotomy converted the hypotensive and bradycardic response into a slowly developing tachycardia without change in arterial pressure.

4. Left atrial injection of nicotine (6.25–100 μg) caused bradycardia, a rise in arterial pressure, and prolonged hyperpnoea preceded by transient hypopnoea. After sino‐aortic barodenervation it caused profound falls in heart rate and arterial pressure and transient hypopnoea, which were abolished by intrapericardial procaine.

5. Intrapericardial injection of veratridine (50–100 μg) had no consistent effect under control conditions. After sino‐aortic barodenervation it caused falls in heart rate and arterial pressure which were abolished by intrapericardial procaine. Left atrial injection of veratridine caused highly variable haemodynamic effects.

6. Intrapericardial bradykinin (2.5–25 μg) caused rises in both arterial pressure and heart rate. These were abolished by intrapericardial procaine.

7. We conclude that when nicotine is injected into the pericardial sac of conscious rabbits the reflex haemodynamic and respiratory effects are due to the selective activation of neuronal‐type nicotinic cholinoceptors on vagal afferents that originate in the epicardium. The reflex effects of left atrial nicotine are probably due to the excitation of a combination of carotid chemoreceptors and cardiac receptors.

8. The effects of nicotine, veratridine and bradykinin that we observed in conscious rabbits were profoundly different from those reported in anaesthetized rabbits.
THE INHIBITORY EFFECT OF BEVANTOLOL ON THE ACCUMULATION OF NON‐ESTERIFIED FATTY ACIDS DURING ISCHAEMIA IN THE DOG HEART IN SITU
Authors: Miura Itaru , Nasa Yoshihisa , Ichihara Kazuo , Abiko Yasushi
Published: June 2007

1. The left anterior descending coronary artery (LAD) was completely ligated for 90 min (i.e. myocardial ischaemia was produced) in the dog anaesthetized with pentobarbital.

2. Bevantolol, a β1‐adrenoceptor antagonist, was injected (1 mg/kg, intravenously) 5 min before LAD occlusion. The bevantolol injection decreased heart rate without affecting blood pressure.

3. The myocardial samples were taken from the LAD area immediately after the end of LAD occlusion, and were subjected to analysis of the myocardial levels of non‐esterified fatty acids (NEFA).

4. In dogs in which saline was injected, ischaemia produced accumulation of NEFA, especially arachidonic and palmitoleic acids, in the myocardium.

5. In dogs in which bevantolol was injected, the accumulation of NEFA induced by ischaemia was almost completely inhibited.

6. It is concluded that bevantolol inhibits ischaemia‐induced accumulation of NEFA in the myocardium, and that stimulation of the β1‐adrenoceptors is probably responsible for NEFA accumulation induced by ischaemia.
CLONIDINE SUPPRESSION TEST RELIABLY DIFFERENTIATES PHAEOCHROMOCYTOMA FROM ESSENTIAL HYPERTENSION
Authors: Bachmann Anthony W. , Gordon Richard D.
Published: June 2007

1. Clonidine resulted in significant suppression of both noradrenaline (NA) and adrenaline (ADR) in essential hypertensives (EHT) without any false positive findings. That is, every patient who failed to suppress had phaeochromocytoma (PH).

2. The clonidine suppression test (CST) produced minimal suppression of NA in NA‐secreting PH (NA‐PH) and correctly identified two NA‐PH with normal basal plasma NA.

3. In ADR‐secreting PH (ADR‐PH) the CST did not result in significant suppression of ADR levels, whether elevated or normal basally.

4. The CST proved to be an accurate discriminator of PH from other forms of hypertension.

noradrenaline
THE SYNDROME OF HYPERTENSION AND HYPERKALAEMIA WITH NORMAL GLOMERULAR FILTRATION RATE: IS THERE A DEFICIENCY IN VASODILATOR PROSTAGLANDINS?
Authors: Klemm Shelley A. , Hornych Antonin , Tunny Terry J. , Gordon Richard D.
Published: June 2007

1. In Gordon's syndrome (GS; a syndrome of hypertension and hyperkalaemia with normal glomerular fitration rate), excessive proximal sodium reabsorption leads to suppression of renin and aldosterone, hyperkalaemia and hyperchloraemic acidosis.

2. Low urinary levels of vasodilator prostaglandins (PG) have been reported in GS, suggesting renal hypoprostaglandinism as a pathophysiological mechanism.

3. In four cases of GS, levels of vasodilator prostaglandins PGE2 and 6‐keto‐PGF1α were low.

4. In one case of GS, low PGE2 levels were normalized by dietary salt restriction or diuretic therapy.
RELEVANCE OF THE WATERFALL PHENOMENON IN CONTINUOUS FINGER CUFF BLOOD PRESSURE MEASUREMENTS
Authors: Kobler H. , Cejnar M. , Hunyor S. N.
Published: June 2007

1. Finger cuff blood pressure monitors that provide continuous presentation of arterial pressure at the finger are available.

2. The operation of such instruments is based on ‘clamping’ arterial volume under a pressurized encircling cuff applied to a digit. Blood volume is detected by measuring infra‐red transmission across the finger.

3. The compressed veins adopt cuff pressure and combine with the resistance of the peripheral vascular bed at the finger tip to control the blood flow. This results in waterfall behaviour in the veins under the cuff.

4. With the cuff set just 5 mmHg below the undisturbed arterial pressure, adequate flow to the distal finger is maintained.

5. Two potential sources of error affect the finger cuff blood pressure method. These are related to the increase in systolic pressure associated with moving peripherally and the variable value of occluding transmural pressure, both of which depend on muscular tone.
REDUCTION IN LEFT VENTRICULAR MASS IN NORMOTENSIVE AND SPONTANEOUSLY HYPERTENSIVE RATS GIVEN ENALAPRIL
Authors: Mooser Vincent , Casley David , Trinder Deborah , Paxton Donna L. , Johnston Colin I.
Published: June 2007

1. To test the hypothesis that the reduction of left ventricular weight (LVW) observed during angiotensin‐converting enzyme (ACE) inhibition in rats is mainly a response to decreased cardiac load, the effect of enalapril on LVW and blood pressure (BP) in normotensive Sprague‐Dawley (SD) and in spontaneously hypertensive rats (SHR) was compared.

2. Enalapril decreased BP by 10% in SD rats and 21% in SHR; and LVW by 6% in SD rats and 12% in SHR. A close linear correlation between BP and LVW was observed in SD (r= 0.65, n= 24, P<0.001) and SHR (r= 0.92, n= 15, P<0.001).

3. The effect of enalapril on LVW, when related to BP, was almost identical in SD and SHR, as the average reduction of LVW (μg/g of bodyweight) per mmHg was 7.7 ± 1.9 versus 7.5 ± 0.9 in SD and SHR respectively.

4. These data constitute additional evidence to support the view that, at least under ACE inhibition, reduction in LVW is mainly due to the fall in BP and the decreased cardiac load.
CHARACTERIZATION OF MONOCLONAL ANTIBODIES TO A RAT LIVER VASOPRESSIN RECEPTOR
Authors: Trinder Deborah , Mooser Vincent , Kelly Janice M. , Phillips Paddy A. , Casley David , Johnston Colin I.
Published: June 2007

1. Balb/c mice were immunized against a vasopressin binding protein purified from rat liver. The hybrids produced from two cell fusions were screened against this receptor. Three hybrids were selected, cloned and expanded in serum‐free media. The monoclonal antibodies (MoAb) secreted by these three hybrids were of the subclass IgM and were able to immunoprecipitate [125I]‐labelled purified receptor.

2. All three MoAb bound to the purified solubilized receptor, crude liver and kidney membranes in a concentration‐dependent manner. However, the binding of MoAb to the membranes did not inhibit the binding of [125I]‐[d(CH2)5, Sar7]AVP, a selective V1 receptor radioligand, to the liver membrane‐bound receptor.

3. These results suggest that the three MoAb recognize epitopes on the V1 receptor which are not denatured by solubilization, but are common to both rat liver and kidney membranes.
ANGIOTENSIN‐CONVERTING ENZYME IN MACRO‐AND MICROVESSELS OF THE RAT
Authors: Jandeleit Karin , Jackson Bruce , Perich Rose , Paxton Donna , Johnston Colin
Published: June 2007

1. Angiotensin‐converting enzyme (ACE) was measured in the aorta, cerebral and mesenteric microvessels of Wistar‐Kyoto rats using a specific radioligand assay.

2. Ligand binding studies revealed a four‐fold increase in concentration of ACE in mesenteric microvessels, compared with aorta or brain microvessels. The dissociation constant (Kd) was similar in all tissues.

3. The effects of oral administration of the ACE inhibitor S9650 on vascular ACE in vivo were measured.

4. S9650 produced a dose‐dependent inhibition of vascular ACE from brain and mesenteric microvessels.
RENIN GENE EXPRESSION IN VARIOUS TISSUES DETERMINED BY SINGLE‐STEP POLYMERASE CHAIN REACTION
Authors: Lou Yi‐kun , Smith D. Lynne , Robinson Bruce G. , Morris Brian J.
Published: June 2007

1. Renin mRNA is present in the kidney and, in lower concentrations, in many extrarenal tissues and serves as an index of renin gene activity, as well as potential renin or prorenin synthesis in cell populations within those tissues. Unfortunately the quantity can be very low.

2. A new, highly sensitive technique is described for detection of renin mRNA that involves the enzyme Taq polymerase for both reverse transcription of renin mRNA into renin cDNA and for amplification of the 769–1099 nucleotide segment by the polymerase chain reaction (PCR), all of which involves a single reaction mixture.

3. In this way renin mRNA was detected in kidney and several extrarenal tissues as a PCR product of ∼330 base pairs on agarose gels by ethidium‐bromide staining or hybridization probing. The region of renin mRNA chosen for amplification spanned several intron sites in the coding sequence so that the presence of amplicants derived from genomic DNA could be readily discriminated, as a band of ∼1.5 kilobases.

4. Thus single‐step PCR offers a powerful new approach to detection of renin mRNA.
HAEMODYNAMIC RESPONSES TO N‐NITRO‐l‐ARGININE IN CONSCIOUS RABBITS
Authors: Du Z. Y. , Dusting G. J. , Woodman O. L.
Published: June 2007

1. The effect of N‐nitro‐l‐arginine (NOLA) on mean arterial pressure (AP), hindlimb vascular resistance (HVR) and heart rate (HR) was examined in conscious rabbits.

2. NOLA (15 mg/kg, i.v.) increased AP (ΔAP = 14 ± 3 mmHg) and HVR (ΔHVR = 0.8 ± 0.3 U) and decreased HR (ΔHR = ‐ 66 ± 8 beats/min). AP remained elevated for at least 2 h following NOLA infusion but had returned to control levels after 24 h. In contrast, the hindlimb vasoconstriction and bradycardia were sustained for at least 48 h but had returned to control levels after 72 h.

3. In the presence of total autonomic blockade (hexamethonium 30 mg/kg; propranolol 1 mg/kg and atropine 0.1 mg/kg) NOLA continued to have a pressor (ΔAP = 33 ± 9 mmHg) and hindlimb vasoconstrictor action (ΔHVR = 0.4 ± 0.1 U) but did not affect HR (ΔHR = ‐ 1 ± 3 beats/min).

4. NOLA has a prolonged pressor and vasoconstrictor action which is independent of any action in the central nervous system and which results in a marked reflex bradycardia. These results suggest that the peripheral biosynthesis of nitric oxide is important in regulation vascular tone and arterial pressure.
ON MAKING MULTIPLE COMPARISONS IN CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
Authors: Ludbrook John
Published: June 2007

1. It is a central thesis of this review that in clinical and experimental pharmacology and physiology the goal of statistical analysis should be to minimize the risk of making any false–positive inferences from the results of an experiment (experimentwise Type I error).

2. It is common in clinical and experimental pharmacology and physiology for the effects of several treatments to be tested within a single experiment. Specific intercomparisons of these several effects, made in a pairwise or more complex fashion, inflates the risk of making false–positive inferences unless special statistical procedures are used.

3. A number of multiple comparison procedures is described and their ability to control experimentwise Type I error is evaluated critically.

4. When only a few (< 5) of all possible pairwise or more complex comparisons are made between treatment groups, the Dunn‐Šdák procedure provides maximum protection against excessive experimentwise Type I error and is very convenient to use.

5. When a control group is compared with all other treatment groups in a pairwise fashion, especially when the number of groups is large, the Dunnett procedure is more powerful than the Dunn‐Šidák.

6. If investigators insist on making all possible pairwise comparisons among treatment groups, the Tukey‐Kramer procedure provides maximum protection against false‐positive inferences but inflates the Type II error rate. If it is especially important to avoid Type II error then the more complicated, stepwise procedures of the Ryan‐Peritz‐Welsch variety should be considered.
CONTRIBUTION OF α2‐ADRENOCEPTORS TO THE CENTRAL CARDIOVASCULAR EFFECTS OF CLONIDINE AND S 8350 IN ANAESTHETIZED RATS
Authors: Deckert Valérie , Lachaud Valérie , Parini Angelo , Elghozi Jean‐Luc
Published: June 2007

1. The α2‐adrenoceptor agonist clonidine elicits centrally mediated effects through an interaction with both α2‐adrenoceptors and imidazoline binding sites.

2. We selected a new oxazoline derivative, S 8350, which competes with [3H]‐yohimbine for binding to cerebral α2‐adrenoceptors (IC50, 67 ± 17 nmol/L) and displays a higher affinity (35‐fold) for α2‐ than for α1‐adrenoceptors.

3. As observed for clonidine, intravenous (i.v.) administration of S 8350 resulted in a brief pressor effect followed by a prolonged hypotension. When S 8350 was administered i.v. to spinally pithed rats, only a rise in blood pressure was observed.

4. In order to discriminate the cardiovascular effects related to the central imidazoline receptor or α2‐adrenoceptor activation, the effects of intracisternal (i.c.) administration of clonidine and S 8350 were investigated in the rat.

5. In the anaesthetized rat, both clonidine and S 8350 displayed a profound central (i.c. route) hypotensive effect associated with a bradycardia.

6. The cardiovascular effects of S 8350 were abolished by the central administration of the selective α2‐adrenoceptor antagonist rauwolscine. Conversely, rauwolscine completely prevented bradycardia but it induced only a partial reversion of the hypotension elicited by clonidine.

7. These results suggest that central α2‐adrenoceptors are responsible for hypotension and bradycardia while imidazoline binding sites do not apparently contribute to heart rate control.
EFFECT OF TOLERANCE TO GLYCERYL TRINITRATE ON VASCULAR RESPONSES IN CONSCIOUS RABBITS
Authors: Du Z. Y. , Dusting G. J. , Woodman O. L.
Published: June 2007

1. The effect of tolerance to glyceryl trinitrate (GTN) on vasodilator and vasoconstrictor responses was examined in conscious rabbits and isolated rabbit aortic rings.

2. In conscious rabbits, depressor responses to 5 min infusions of GTN (10–40 μg/kg per min intravenously (i.v.)), sodium nitroprusside (SNP, 5–20 μg/kg per min i.v.) and acetylcholine (ACh, 3–12 μg/kg per min i.v.) were examined before and after transdermal treatment with GTN (20 mg/48 h). GTN pretreatment significantly attenuated GTN‐induced depressor responses, indicating the development of tolerance, but did not affect the reductions in arterial pressure induced by SNP or ACh.

3. Similarly, aortic rings taken from GTN pretreated rabbits exhibited tolerance to GTN but the relaxant responses to SNP or the calcium ionophore A23187 were not affected. In the aortic rings from GTN‐tolerant rabbits contractile responses to serotonin or the thromboxane‐mimetic U46619 were significantly attenuated, in contrast to the responses to the α1‐adrenoceptor agonist phenylephrine (PE) which were significantly enhanced.

4. Similarly, in conscious rabbits, PE‐induced increases in arterial pressure and hindlimb vascular resistance were significantly enhanced by GTN pretreatment but the responses to the α2‐adrenoceptor agonist BHT 920 were unaffected.

5. In conclusion, tolerance to GTN does not affect endothelium‐dependent vasodilatation but does cause a selective enhancement of α1‐ but not α2‐adrenoceptor‐mediated vasoconstriction.
DISTRIBUTION AND INHIBITION OF NEUTRAL METALLOENDOPEPTIDASE (NEP) (EC 3.4.24.11), THE MAJOR DEGRADATIVE ENZYME FOR ATRIAL NATRIURETIC PEPTIDE, IN THE RAT KIDNEY
Authors: Kanazawa Masayuki , Johnston Colin I.
Published: June 2007

1. Atrial natriuretic peptide (ANP) is degraded by neutral metalloendopeptidase (NEP) (EC 3.4.24.11) and the kidney is a major site of ANP clearance.

2. The regional distribution of NEP in the rat kidney was investigated.

3. The activity of NEP, measured with an enzymatic fluorimetric method employing N‐dansyl‐D‐alanyl‐glycyl‐L‐4‐nitrophenylalanyl‐glycine as a synthetic substrate, was 18 times and eight times higher in the outer stripe of the medulla and inner cortex than in the outer cortex (OC).

4. Low concentrations of NEP were found in the OC, inner stripe and inner medulla.

5. NEP activity in the rat kidney was inhibited by the specific NEP inhibitors (SCH39370, phosphoramidon and thiorphan) at micromolar concentrations.

6. The present result suggests that degradation of ANP by NEP occurs mainly in the proximal tubules of the juxtamedullary nephrons, rather than cortical nephrons, and that the convoluted tubule in the OC is not a major site of location of NEP.

7. The relationship between NEP activities in the kidney in vitro and plasma clearance of ANP in vivo remains to be clarified.
DIGOXIN‐LIKE IMMUNOREACTIVITY INCREASES WITH INTRAVENOUS INFUSION OF SALINE IN RATS
Authors: Takahashi Hakuo , Matsusawa Makoto , Nishimura Masato , Ikegaki Iwao , Nakanishi Tadashi , Yoshimura Manabu
Published: June 2007

1. The effects of sodium‐loading on releases of endogenous digitalis‐like substance were investigated by measuring digoxin‐like immunoreactivity (DLI) during intravenous infusions of isotonic (0.15 mol/L) and hypertonic (1 mol/L) saline in anaesthetized rats. Plasma DLI was measured after death by a digoxin‐radioimmunoassay.

2. The infusion of isotonic saline and hypertonic saline elevated the central venous pressure to similar levels. The plasma DLI concentration in both the infused groups rose significantly compared with that in the control rat not receiving the intravenous infusion.

3. The difference in the hypothalamic concentrations of DLI was not significant among the three groups, however, there was a significant inverse relationship between the plasma and hypothalamic concentrations of DLI.

4. Results indicate that the central venous pressure, but not sodium concentration, is essentially involved in the release of DLI, possibly from the hypothalamus.
LACK OF SYMPATHETIC AUGMENTATION IN RESPONSE TO INTRAVENOUS LOAD OF GLUCOSE IN RABBITS
Authors: Takishita Shuichi , Takata Yutaka , Abe Isao , Tomita Yuji , Kawazoe Nobuyuki , Fujishima Masatoshi , Fukiyama Koshiro
Published: June 2007

1. We investigated a link between sympathetic nervous function and carbohydrate metabolism by measuring renal sympathetic nerve activity in response to intravenous load of glucose in α‐chloralose‐urethane anaesthetized rabbits.

2. Intravenous infusion of a 25% glucose solution (0.5 g/kg) over 3 min caused a transient increase in arterial blood pressure and a decrease in renal sympathetic nerve activity. Thereafter, these parameters were restored and remained around preload levels while plasma glucose and insulin concentrations were still elevated.

3. Equimolar mannitol solution produced similar patterns of change in blood pressure and nerve activity without an elevation of plasma glucose and insulin levels.

4. The transient changes in blood pressure and renal nerve activity could be attributed to acute hypervolaemia indicated by similar changes in plasma osmolality and haematocrits in the two groups of treatment.

5. The present study did not support a close relationship between carbohydrate metabolism and the sympathetic nervous system regulating cardiovascular function.
DIFFERENTIAL EFFECTS ON ACTION POTENTIAL DURATION OF CLASS IA, B AND C ANTIARRHYTHMIC DRUGS: MODULATION BY STIMULATION RATE AND EXTRACELLULAR K+ CONCENTRATION
Authors: Campbell Terence J. , Wyse Kenneth R. , Pallandi Regan
Published: June 2007

1. Standard microelectrode techniques were used to study the effects on the action potential duration (APD) of canine Purkinje fibres of a therapeutic concentration of nine Class I antiarrhythmic drugs. At an extracellular K+ concentration of 5.6 mmol/L all nine agents reduced APD at all drive rates studied (range of interstimulus intervals = 200–1000 ms). At lower levels of K+, quinidine (5 μmol/L) and disopyramide (10 μmol/L) (Class Ia agents) revealed dual effects on APD. At the lowest levels of K+ (2 mmol/L) and the longest interstimulus interval used (2000 ms), both agents significantly prolonged APD. Under all other conditions, APD was either unchanged or reduced. Lignocaine, 15 μmol/L (Class Ib agent) reduced APD at all rates and all K+ concentrations and this effect was greatest at the slowest rates.

2. Flecainide (1 μmol/L) (Class Ic) shortened APD at K+= 5.6 and 4 mmol/L but had no effect at K+= 2 mmol/L.

3. We conclude that these data result from opposing drug actions on inward sodium and outward potassium currents flowing during the plateau of the action potential.

4. Class Ia drugs exhibit significant depression of both currents, with the resultant effect on APD being modulated by external K+ concentration and drive rate.

5. Class Ib agents predominantly depress the sodium current and hence shorten APD, and Ic compounds have intermediate actions.

6. These differential effects on APD must be considered when planning antiarrhythmic therapy, and are directly relevant to the proarrhythmic propensities of these agents.
ACTIVATION OF Na+/H+ EXCHANGE IS UNNECESSARY IN THE INDUCTION OF c‐fos mRNA IN SERUM‐STIMULATED VASCULAR SMOOTH MUSCLE CELLS
Authors: Nabika Toru , Kobayashi Ayame , Nara Yasuo , Endo Jiro , Yamori Yukio
Published: June 2007

1. The effects of extracellular Na+ concentration ([Na+]o) on serum‐stimulated c‐fos mRNA induction in vascular smooth muscle cells (VSMC) were studied to examine whether the activation of Na+/H+ exchange and the following intracellular alkalinization are necessary in the induction of c‐fos in VSMC.

2. When monitored with 2′, 7′‐bis (carboxylethyl)‐5(6)‐carboxyfluorescein, the reduction in [Na+]o in HCO3−‐free buffer caused a dose‐dependent inhibition of Na+‐dependent intracellular pH recovery in acid‐loaded VSMC. In addition, serum‐stimulated intracellular alkalinization in VSMC was completely blocked by the removal of extracellular Na+.

3. By contrast, c‐fos induction, quantified by slit blot hybridization of c‐fos mRNA, was not fully inhibited by the reduction of [Na+]o. Furthermore, amiloride and ethylisopropyl‐amiloride, inhibitors of Na+/H+ exchange, only partially blocked c‐fos induction by serum.

4. We concluded from the observation above, that the intracellular alkalinization caused by the activation of Na+/H+ exchange was unnecessary in serum‐stimulated induction of c‐fos mRNA in VSMC.
URINARY EXCRETION OF PROSTANOIDS DURING SLEEP IN OBSTRUCTIVE SLEEP APNOEA PATIENTS
Authors: Krieger Jean , Benzoni Daniel , Sforza Emilia , Sassard Jean
Published: June 2007

1. Given the unexplained frequent association between systemic hypertension and obstructive sleep apnoea (OSA), the secretion of prostanoids during sleep was investigated (more specifically, the ratio of prostacyclin (PGI2) to thromboxane A2 (TxA2), since they have marked opposite effects on vascular tone). Prostacyclin has vasodilating effects, whereas thromboxane results in vasoconstriction.

2. In 11 OSA drug‐free male patients (age 53 ± 2 years, mean ± s.e.m.; apnoea index 55 ± 15 apnoeas/hour of sleep; body mass index 31 ± 2 kg/m2), we measured the urinary excretion during sleep of 6‐keto‐PGF1‐alpha and of thromboxane TxB2 (the stable metabolites of prostacyclin PGI2 and of thromboxane A2 respectively). This was done on two consecutive nights; one untreated, the other with nasal continuous positive airway pressure (CPAP) treatment. The results were compared with those of nine normal unobese male subjects.

3. The urinary ratio of 6‐keto‐PGF1‐alpha to TxB2 was significantly (P<0.001) lower in the untreated OSA patients (1.7 ± 0.2) than in the controls (3.1 ± 0.3). It significantly increased with CPAP treatment to 2.3 ± 0.2, P<0.02, which was no longer different from the controls.

4. These results suggest that OSA is associated with an abnormal release of prostanoids during sleep resulting in a decrease of the prostacyclin to thromboxane ratio which potentially has a vasoconstricting effect. The relationship between these changes and the systemic hypertension often observed in OSA patients remains to be established.
GENETIC FACTORS REGULATE THE RISE IN BLOOD PRESSURE IN F2 GENERATION CROSSED BETWEEN STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS AND WISTAR‐KYOTO RATS
Authors: Ikeda Katsumi , Nara Yasuo , Nabica Toru , Fujimoto Akihiko , Endo Jiro , Ishino Hiroshi , Yamori Yukio
Published: June 2007

1. There was no significant difference between the systolic blood pressure (SBP) of offspring derived from SHRSP mother and WKY father and the SBP of offspring derived from WKY mother and SHRSP father at the developing stage (5–13 weeks of age).

2. The degree of genetic determinations of SBP in stroke‐prone spontaneously hypertensive rat (SHRSP) at 5, 7, 10 and 13 weeks of age, determined by genetic crosses between SHRSP and WKY, was 73.9, 70.8, 50.2 and 55.3% respectively.

3. Significant correlations between SBP at 5 and 7 weeks, 7 and 10 weeks, 10 and 13 weeks, also at 5 and 13 weeks of age in F2 generation crossed between SHRSP and WKY were observed. SBP falling at or above the 80th percentile group in F2 generation at 5 weeks of age were constantly higher than SBP falling at or below the 20th percentile group from 7 weeks of age onwards.

4. These results indicate that there exists ‘tracking phenomenon of SBP in SHRSP’ and that genetic factors regulate the rise in SBP. Tracking of SBP in F2 generation gives us new methodological insight into hypertensive mechanism in SHR.
AUTACOIDS AFFECTING VASCULAR TONE IN THE HUMAN FETAL EXTRACORPOREAL CIRCULATION
Authors: Walters William A. W.
Published: June 2007

1. The human fetal extracorporeal circulation is normally a vasodilated, low pressure system.

2. As this vasculature lacks innervation, autacoids have been postulated as being of great importance in controlling its tone.

3. This has now been confirmed by pharmacological in vitro techniques, particularly utilizing perfusion of the isolated umbilical cord and placental lobule.

4. The fetal umbilical—placental vessels are sensitive to a wide range of vasoconstrictor autacoids, some of which can cause intense vasospasm.

5. Thromboxane A2 receptors have been identified in both umbilical vein and placental villous vessels.

6. Prostacyclin and endothelial cell‐derived relaxing factor (or nitric oxide) may be largely responsible for the low vascular resistance normally found in the fetal extracorporeal circulation.

7. Immediately after birth it is likely that stimuli such as cooling, stretching and handling of the umbilical cord cause release of eicosanoids and other autacoids from the vessels, leading to their complete closure.
CHEMICAL DESIGN OF PERIPHERALLY ACTING COMPOUNDS
Authors: Jackson W. Roy , Copp Fred C. , Cullen John D. , Guyett Frances J. , Rae Ian D. , Robinson Andrea J. , Pothoulackis Helen , Serelis Algirdas K. , Wong Margaret
Published: June 2007

1. Some guanidines, related in structure to mianserin and to 2‐methyl‐1,2,9,13b‐tetrahydro‐3H‐dibenz[c,f]irnadazo[l,5a]azepin‐3‐imine hydrobromide (WAL 801), have been synthesized and shown to be peripherally acting 5‐HT2antagonists. Structurally related compounds but not bearing a charged ionic group have been shown to have central activity.

2. Computer‐aided molecular modelling has been used to establish a 5‐HT2pharmacophore.

3. The principle of exclusion from the CNS by incorporating a highly polar group to a biologically active molecule has been extended to the design and synthesis of a peripherally acting analgesic.
SENSORY NERVES IN THE AIRWAYS AS A TARGET FOR DRUG DEVELOPMENT
Authors: Rechtman M. P.
Published: June 2007

1. Electrical stimulation (2.5–10 Hz, 80 V, 1 ms for 15 s) within the spinal canal of the pithed guinea‐pig pretreated with atropine, D‐tubocurarine and pentolinium caused a bronchoconstrictor response, indicated by a rise of insufflation pressure.

2. The magnitude of these non‐cholinergic neuronal bronchoconstrictor responses were frequency‐dependent, capsaicin‐sensitive and temperature‐dependent.

3. Responses could be inhibited by the α2‐adrenoceptor agonist B‐HT920 (3 mg/kg, i.v.) and the μ‐opioid agonist H‐Tyr‐D‐Arg‐Phe‐Lys‐NH2 (DALDA; 1 mg/kg, i.v.) and the attenuation observed could be overcome by use of the respective antagonists idazoxan (3 mg/kg, i.v.) and naloxone (3 mg/kg, i.v.).

4. Substance P‐induced bronchoconstriction (0.3 μg/kg, i.v.), but not that due to electrical stimulation, was attenuated by indomethacin (3 mg/kg, i.v.), indicating an indirect action of substance P via a product of arachidonic acid metabolism.

5. The prostanoid product of the substance P response was probably thromboxane A2.

6. Hence, novel drug development could be directed towards tachykinin receptors or to the synthesis, release and degradation of neuropeptides.
AN INDUSTRIAL APPROACH TO DRUG DISCOVERY: A PHARMACOLOGIST'S EYEVIEW
Authors: Armstrong J. M. , Hicks P. E.
Published: June 2007

1. The pressures on the pharmaceutical industry to produce novel, safe and effective therapeutic agents have provoked management to rethink the way in which drug discovery is undertaken.

2. Advances in drug therapy are likely to come from the application of new technologies and leading‐edge science, perhaps in collaboration with academia.

3. Close collaboration between biologists and medicinal chemists is a proven way to discover new products.

4. The complexity of the modern industrial discovery process, due to the interaction of many disciplines, requires matrix‐style management.

5. The early demonstration of efficacy in human subjects is considered essential for providing feedback to the basic scientists about the validity of hypotheses, and the relevance of the methods utilized, as well as whether a decision should be allowed to advance to full development.
ORIGIN OF URINARY EPIDERMAL GROWTH FACTOR IN HUMANS: EXCRETION OF ENDOGENOUS EGF AND INFUSED [131I]‐HUMAN EGF AND KIDNEY HISTOCHEMISTRY
Authors: Lev‐Ran Arye , Hwang David L. , Ben‐Ezra Jonathan , Williams Lawrence E.
Published: June 2007

1. This study examined (i) whether blood‐infused epidermal growth factor (EGF) can pass into urine; (ii) whether infused labelled EGF behaves like endogenous plasma immunoreactive EGF; and (iii) which parts of the human nephron show morphological evidence of EGF synthesis?

2. We infused human [131I]‐EGF into a volunteer. After 6 min, only 66% of the plasma counts represented intact EGF. At the end of infusion, the T 1/2 of EGF was calculated to be 1.6 min. The tail of the curve lasted for at least another 2 h. The total excretion of the labelled EGF was 2.45% of the infused dose and was proportional to the urine volume.

3. After a water load, the excretion of endogenous EGF was, on the contrary, inversely related to urine volume.

4. Immunohistochemically, human kidneys were not stained by monoclonal anti‐EGF antibodies but showed positive in situ hybridization for EGF mRNA in the nuclei of glomerular mesangial cells, distal convoluted tubules and collecting tubules.

5. We conclude that human kidneys synthesize EGF and release it into urine. Plasma‐derived EGF constitutes under normal conditions only a small part of the urinary EGF. Contrasting volume‐dependency of the excretion of endogenous and [131I]‐EGF requires further study and cautions against extrapolating results obtained with labelled EGF to physiological conditions.
EFFECTS OF 4 WEEKS ENDURANCE TRAINING ON CARDIAC LEFT VENTRICULAR STRUCTURE AND FUNCTION
Authors: Dart Anthony M. , Meredith Ian T. , Jennings Garry L.
Published: June 2007

1. The effect of 4 weeks of moderate exercise training on cardiac left ventricular structure and function was examined by repeated echocardiography/ Doppler examination in 10 previously sedentary volunteers participating in a single blind, sedentary phase controlled, cross‐over study.

2. Left ventricular internal diastolic diameter increased after 4 weeks of training from 4.98 to 5.11 cm with a further increase to 5.24 cm after 2 weeks of detraining (s.e.d. 0.05 cm, P < 0.01). These increases were still significant after adjustment for heart rate which fell from a pretraining average of 67.0‐59.9 beats/min after 4 weeks of training.

3. There were no significant changes in systolic diameter or function and left ventricular wall thicknesses were unchanged during training, but were thinned after 2 weeks subsequent detraining.

4. The ratio of early to late transmitral filling velocity (E/A ratio) was significantly increased by training. Although E/A ratio was shown to be heart rate sensitive, training effects were still evident after adjustment for heart rate.

5. These changes in left ventricular volumes and function may contribute to the cardiovascular reflex changes previously shown to be produced by identical training programmes.
POTASSIUM ACCELERATES URINARY SODIUM EXCRETION DURING SALT LOADING WITHOUT STIMULATING ATRIAL NATRIURETIC POLYPEPTIDE SECRETION
Authors: Mano Masayuki , Sugawara Akira , Nara Yasuo , Nakao Kazuwa , Horie Ryoichi , Endo Jiro , Imura Hiroo , Yamori Yukio
Published: June 2007

1. Effects of potassium (K) supplementation (100 mEq/day) on urinary sodium (Na) excretion and on the secretion of atrial natriuretic polypeptide (ANP) during salt loading (350 mEq/day) were studied in 12 healthy salt‐resistant normotensives under strictly controlled metabolic ward conditions.

2. Urinary volume and Na excretion on the first day of the high salt period (HSP) were significantly greater in the K‐supplemented group (KG) than in the control group (CG).

3. There was a significant gain in bodyweight after salt loading in both groups, with a significantly greater gain in CG on the second day of HSP. Haematocrit decreased significantly during salt loading in both groups, the degree of which was significantly greater in CG.

4. Plasma norepinephrine decreased significantly during salt loading in both groups, the degree of which was significantly less in KG than in CG. A significant increase in plasma ANP was observed in CG on and after the second day of HSP, while a significant increase in plasma ANP was observed on the fifth day of HSP in KG.

5. These findings indicate that K supplementation accelerates diuresis and natriuresis, resulting in moderate suppression of volume expansion induced by salt loading and that this accelerated diuresis and natriuresis is not a result of the action of ANP.
ASSESSING VASCULAR REACTIVITY OF ARTERIES IN THE SMALL VESSEL MYOGRAPH
Authors: McPherson Grant A.
Published: June 2007

1. Using a small vessel myograph, experiments were performed on rat small mesenteric arteries (and in some cases dog small coronary arteries) to assess the dependence of vasoconstrictor potency (EC50) and maximum response (Emax) on the initial passive conditions and on the mode of recording (i.e. isometric, isobaric or isotonic).

2. Maximum active isometric tension development to methoxamine occurred at different points on the passive diameter‐tension curve depending on the origin of the vessel. The point of maximum sensitivity of methoxamine did not coincide with the point of maximum tension development on the passive diameter‐tension curve.

3. Vascular reactivity to methoxamine was assessed under isobaric, isotonic and isometric conditions using a new computerized myograph. Methoxamine was significantly more potent, but only by a factor of twofold, when assessed under isometric conditions. In addition, the maximum response to methoxamine, in terms of diameter change, was always greater under isobaric than under isotonic conditions.

4. The results show that, in studies comparing vascular reactivity of vasoactive drugs, the results depend, to some extent, on the initial passive conditions selected. In terms of assessing the pharmacological activity of drugs on isolated blood vessels, the use of common isometric recording procedures are adequate. However, the use of isobaric, isotonic and isometric recording procedures have shown the complexities of vascular reactivity which depend on the passive and active properties of the blood vessel. These factors may need to be taken into account when comparing the reactivity of isolated blood vessels.
CYCLIC ADENOSINE 3′,5′‐MONOPHOSPHATE CONTENT AND BRONCHIAL SMOOTH MUSCLE CONTRACTILITY OF HYPER‐ AND HYPOTHYROID LUNGS
Authors: Nabishah B. M. , Morat P. B. , Alias A. K. , Kadir B. A. , Khalid B. A. K.
Published: June 2007

1. Male Sprague‐Dawley rats were made either hyper‐ or hypothyroid with thyroxine or 4‐methyl‐2‐thiouracil, respectively. Bronchial smooth muscle (BSM) contractility and lung cyclic adenosine 3′,5′‐monophosphate (cAMP) content were measured in both conditions.

2. Bronchial smooth muscle contractility was significantly weaker in hyperthyroid rats, while the BSM contractility of hypothyroid rats was the same as controls.

3. The cAMP content of hyperthyroid rat lungs was similar to controls but was decreased in hypothyroid rats.

4. These studies demonstrated that both the hyper‐ and hypothyroid states affect respiration, although the mechanisms involved with different for each condition.
IMPEDANCE MEASUREMENT DURING AIR AND HELIUM‐OXYGEN BREATHING BEFORE AND AFTER SALBUTAMOL IN COPD PATIENTS
Authors: Wouters E. F. M. , Lándsér F. J. , Polko A. H. , Visser B. F.
Published: June 2007

1. The forced oscillation technique is an effort‐independent method used to characterize the mechanical impedance of the respiratory system. To support the hypothesis that non‐invasive partitioning of total pulmonary resistance is possible by this technique, impedance was measured during air breathing and after equilibration with a mixture of 80% helium (He) and 20% oxygen (O2) in 21 chronic obstructive pulmonary disease (COPD) patients by means of a forced pseudo‐random noise pressure signal over a frequency spectrum from 4 to 52 Hz. Furthermore, during inhalation of both gas mixtures impedance was determined before and after inhalation of 0.400 mg Salbutamol.

2. He + O2 breathing caused less negative frequency dependence of resistance and a significant decrease in reactance over the range 16–52 Hz. Inhalation of Salbutamol caused a marked increase in reactance values over the range 8–40 Hz. However after equilibration with the He + O2 mixture, Salbutamol caused a significant decrease in resistance and a significant increase in reactance at all frequencies.

3. The results during He + O2 breathing are in accordance with a partitioning of airways resistance into central and peripheral components. The decrease in reactance during He + O2 can be explained by a density dependent decrease in inductive reactance. By comparing the impedance data during air and He + O2 breathing, it can be concluded that a distribution of pulmonary resistance with minimal losses in the larger airways is more sensitive for detecting changes in the peripheral airways in COPD patients.
PLASMA PHOSPHOLIPASE A2 ACTIVITY IN CLINICAL ACUTE MYOCARDIAL INFARCTION
Authors: Leong Lillian L. L. , Sturm Marian J. , Ismail Yahya , Stephens Charlene J. , Taylor Roger R.
Published: June 2007

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1. Phospholipase A2 (PLA2) cleaves phospholipids to produce a lyso‐phospholipid and free fatty acid and, in view of the biological activity of the products, PLA2 may play a role in many disease states. Lyso‐phospholipids and free arachidonic acid increase in ischaemic myocardium, indicating that ischaemia activates the enzyme.

2. Plasma PLA2 activity was measured in patients with acute myocardial infarction, based on the release of labelled arachidonic acid from Escherichia coli cell membrane. Fourteen males (peak serum creatine phosphokinase (CK) above twice upper normal) were studied on day 1 (within 6 h of chest pain onset), days 2–4, and days 6–9. Normal age matched males (n= 13) were also studied.

3. Plasma PLA2 in patients with uncomplicated myocardial infarction (n= 12) was, initially, 1.14±0.10 (s.e.m.) nmol/min per mL plasma, similar to that in the normal group (1.52 ± 0.14). On days 2–4, PLA2 activity increased to 1.94±0.18(P<0.001) and this activity was correlated with the earlier peak CK level (P<0.02). On days 6–9, PLA2 activity was 1.49±0.13 while in two patients who developed complications and underwent open‐heart surgery between the last two measurements, there were further increases to 4.22 and 4.04 nmol/min per mL.

4. The increase in plasma PLA2 in uncomplicated myocardial infarction is likely to be due to release from the damaged myocardium; whether it contributes to pathophysiology is uncertain.
SUPEROXIDE DISMUTASE ATTENUATED POST‐ISCHAEMIC CONTRACTILE DYSFUNCTION IN A MYOCARDIAL XANTHINE OXIDASE DEFICIENT SPECIES
Authors: Ooiwa Hitoshi , Miura Tetsuji , Iwamoto Toshihiro , Ogawa Takashi , Ishimoto Row , Adachi Takeo , Iimura Osamu
Published: June 2007

1. We assessed the effect of polyethylene glycol conjugated superoxide dismutase (PEG‐SOD) on myocardial stunning in the rabbit heart in which xanthine oxidase level is extremely low.

2. In open‐chest anaesthetized rabbits, the left marginal branch of the coronary artery was occluded for 10 min and then reperfused for 30 min. A group of rabbits (PEG‐SOD group) received 1000 units/kg of PED‐SOD and another group (control group) was given saline 15 min before the coronary occlusion.

3. Regional systolic thickening fraction (TF) was similarly reduced to approximately ‐ 25% of baseline value during ischaemia in both groups. However recovery of TF after reperfusion was significantly better in the PEG‐SOD group (n= 9) and TF at 30 min after reperfusion was 70.1 ±3.9% of baseline value compared with 44.9 ±3.4% in the control group (n= 9; P < 0.05). Rate‐pressure products, left ventricular pressure, and LV dP/dt max were not significantly different between the PEG‐SOD treated and untreated control rabbits at any time during the experiment. PEG‐SOD did not modify the regional myocardial blood flow (coloured microsphere method) during ischaemia/reperfusion, which was assessed by using separate groups of rabbits.

4. These findings indicate that oxygen free radicals are important in the pathogenesis of myocardial stunning in xanthine oxidase deficient hearts.