bluuebunny/crossref_metadata_2025 huggingface dataset:
INCREASES IN THE MYOCARDIAL CONCENTRATION OF VASOACTIVE INTESTINAL PEPTIDE MAY EXPLAIN THE POSITIVE INOTROPIC EFFECT OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS
Authors: Ye VZC , Duggan KA
Published: June 2007

1. In patients with congestive cardiac failure, treatment with angiotensin converting enzyme (ACE) inhibitors results in peripheral vasodilatation and an increase in cardiac output without an increase in heart rate, which suggests a positive inotropic effect. This cannot be explained by changes in angiotensin II and bradykinin concentrations that occur. ACE has been suggested to also metabolise vasoactive intestinal peptide (VIP), which is a positive inotrope. As VIP is synthesized by the heart and acts locally to increase cardiac output, we postulated that ACE inhibition would increase the myocardial concentration of VIP.

2. Male Sprague‐Dawley rats received enalapril (2mg/kg per day) in their drinking water or no therapy for 7 days. On day 7 the rats were anaesthetized and blood was sampled. Hearts and kidneys were then harvested and snap frozen by immersion in liquid nitrogen. Concentrations of VIP in plasma and tissue extracts were measured by radioimmunoassay.

3. Plasma and renal concentrations of VIP did not change in enalapril‐treated rats. However, the myocardial concentration of VIP increased significantly in rats receiving enalapril compared with control animals (P<0.0005).

4. We conclude that treatment with ACE inhibitors results in increased myocardial VIP concentrations and suggest that this may contribute to the improvement in cardiac function that occurs with these agents.
Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: MOLECULAR DETERMINANTS OF PEPTIDE AND NON‐PEPTIDE BINDING TO THE AT1 RECEPTOR
Authors: Karnik Sadashiva S , Husain Ahsan , Graham Robert M
Published: June 2007

Several residues critically involved in AT1 receptor ligand‐binding and activation have now been identified based on mutational and biochemical studies.

Asp281 and Lys199 of the rat AT1 receptor ion‐pair with Arg2 and the Phe3 α‐COOH of angiotensin II (AngII), respectively, and the Asp281/Arg2 interaction is critical for full agonist activity.

Agonist activity of AngII also requires an interaction of the Phe2 side chain with His256, which is achieved by docking of the α‐COOH with Lys199. Non‐peptide agonists interact with Lys199 and His256 in a similar fashion.

The crucial acid pharmacophores of AngII and the non‐peptide antagonist, Iosartan, appear to occupy the same space within the receptor pocket. Binding of the tetrazole anion moiety of losartan involves multiple contacts, such as Lys199 and His256. However, this interaction does not involve a conventional salt bridge, but rather an unusual lysine‐aromatic interaction.

Asp1 of AngII forms an ion‐pair with His183, which stabilizes the receptor‐bound conformation of AngII but is not critical for receptor activation.

These interactions and the involvement of other residues in stabilizing the wild‐type receptor conformation or in receptor/G‐protein coupling are considered here.

Despite these insights, considerable effort is still needed to elucidate how ligand binding induces receptor activation, what determines the specificity of AT1 receptor coupling to multiple G‐proteins and the in vivo role of receptor down‐regulation.
Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: TRANSGENIC RATS: TOOLS TO STUDY THE FUNCTION OF THE RENIN‐ANGIOTENSIN SYSTEM
Authors: Bader Michael , Ganten Detlev
Published: June 2007

The development of the transgenic technology for the rat allowed the evaluation of gene functions in the cardiovascular system in vivo. New insights have been gained particularly in the functions of the renin‐angiotensin system (RAS), as most transgenic rat models established so far carry genes of this system.

TGR(mREN2)27 is a rat harbouring the mouse Ren‐2 gene and exhibiting fulminant hypertension. The plasma RAS in this animal is down‐regulated; however, the tissue‐specific production of angiotensin II is activated (e.g. in the adrenal gland, the brain and the vessel wall). The physiological consequences of this activation, which finally leads to hypertension, can be studied in TGR(mREN2)27, rendering it a valuable tool in the functional analysis of tissue RAS.

TGR(hREN) and TGR(hAOGEN) carry the human genes for renin and angiotensinogen, respectively. In these animals the species‐specific interaction of the two proteins and the expression pattern of the genes can be studied. Furthermore, these animals can be used to test renin‐inhibitory drugs for use in antihypertensive therapy.

Further refinement of transgenic methodology (e.g. by the development of gene targeting in rats), should enhance our understanding of the functions of the RAS in cardiovascular regulation.
EFFECTS OF HYPERINSULINAEMIA ON RENAL FUNCTION AND THE PRESSOR SYSTEM IN INSULIN‐RESISTANT OBESE ADOLESCENTS
Authors: Miyazaki Y. , Shimamoto K. , Ise T. , Shiiki M. , Higashiura K. , Hirata A. , Masuda A. , Nakagawa M. , Iimura O.
Published: June 2007

1. In the present study, using the euglycaemic hyperinsulinaemic glucose clamp technique, we investigated the effects of hyperinsulinaemia on sodium‐water metabolism and the pressor system in obesity, both of which have been reported to be closely associated with insulin resistance and/or hyperinsulinaemia.

2. Sixteen obese young subjects and 24 non‐obese young subjects who were all normotensives, participated in this study. The 2h euglycaemic hyperinsulinaemic glucose clamp was performed in a fasting state. The mean glucose infusion rate needed to maintain a fasting blood sugar level (FBS) during the last 30 min of the clamp was used as an indicator of insulin sensitivity (M‐value). Before and after the clamp, the following parameters were measured: creatinine clearance (Ccr); urinary excretion of sodium (UNaV); fractional excretion of sodium (FENa); plasma renin activity (PRA); plasma aldosterone concentration (PAC) and plasma noradrenaline concentration (PNA).

3. The M‐value was significantly lower in obese subjects compared with non‐obese subjects, although FBS and fasting immunoreactive insulin levels were similar in both groups. UNaV and FENa fell only in obese subjects during the clamp, while Ccr showed no significant change in either group. PNA and PRA increased significantly and PAC tended to increase in both groups.

4. These results suggest that obese subjects have insulin resistance with respect to glucose metabolism, but that urinary sodium excretion and the pressor system remain insulin‐sensitive; the sensitivity of the sodium retaining action to hyperinsulinaemia was actually higher in obese subjects than in non‐obese subjects. Therefore, if compensatory endogenous hyperinsulinaemia was raised by insulin resistance, these two factors may lead to chronic sodium retention and pressor system stimulation and, in turn, to hypertension in obesity.
SYMPOSIUM Experimental Biology 1995 Endothelin Receptors: Role in Renal Function and Dysfunction SIGNALLING PATHWAYS ACTIVATED BY ENDOTHELIN STIMULATION OF RENAL CELLS
Authors: Nord Edward P
Published: June 2007

1. Endothelin mediates its effects in a variety of renal cells via a multiplicity of intracellular signalling pathways.

2. Stimulation of phosphatidylinositol‐specific phospholipase C (PI‐PLC), resulting in the activation of inositol trisphosphate and diacylglycerol, can be detected even at picomolar concentrations of peptide.

3. Endothelin activation of cPLA2 is sensitive to ambient [Ca2+]i, is not contingent upon protein kinase C activation and is independent of PI‐PLC stimulation, being coupled to the endothelin receptor in a yet to be determined manner.

4. Activation by endothelin of phosphatidylcholine‐specific phospholipase D is under the dual regulation of protein kinase C and [Ca2+]i, with protein kinase C being the major regulator and [Ca2+]i playing a secondary, modulatory role.

5. Phosphatidylcholine‐specific phospholipase C (PC‐PLC) is stimulated by endothelin and accounts for the prolonged activation of diacylglycerol by this peptide. PC‐PLC activity is critically dependent upon [Ca2+]i, whereas protein kinase C plays no role in modulating the activity of this enzyme.

6. Endothelin enhances the phosphorylation of protein tyrosine kinases, with evidence that phosphorylation of pp60 Src may be an important early event.
SYMPOSIUM Experimental Biology 1995 Endothelin Receptors: Role in Renal Function and Dysfunction ROLE OF ENDOTHELIN IN RENAL FUNCTION AND DYSFUNCTION
Authors: Brooks David P
Published: June 2007

1. Endothelin has significant effects on renovascular, glomerular and tubular function.

2. Endothelin causes severe renal vasoconstriction, resulting in a decrease in renal blood flow and glomerular filtration rate.

3. Endothelin can inhibit sodium reabsorption and, in the rat, vasopressin‐induced water transport.

4. The endothelin receptor subtypes mediating renovascular and tubular effects of endothelin may differ between species.

5. Renal endothelin production, metabolism and receptor binding is altered in a number of renal diseases, including acute and chronic renal failure and cyclosporine and radiocontrast nephrotoxicity.

6. Endothelin receptor antagonists or antibodies can attenuate the severity or progression of a number of renal diseases.
ANGIOTENSIN II RECEPTORS AND RENIN IN THE PORCINE UTERUS: MYOMETRIAL AT2 AND ENDOMETRIAL AT1 RECEPTORS ARE DOWN‐REGULATED DURING GESTATION
Authors: Nielsen AH , Schauser K. , Winther H. , Dantzer V. , Poulsen K.
Published: June 2007

1. The aim of the present study was to characterize the angiotensin II (AngII) receptor subtypes in the porcine uterus and the variation of receptor densities and renin concentrations during gestation.

2. In myometrium from non‐pregnant sows, the AngII receptors were almost exclusively AT2 receptors. During gestation, the AngII receptor density was decreased and the AT1 receptor became predominant in the last part of gestation as a result of a down‐regulation of the AT2 receptor.

3. In the endometrium, the AT1 receptor was predominant both in non‐pregnant sows and throughout gestation. The AngII receptor density was decreased during gestation as a consequence of down‐regulation of the AT1 receptor.

4. The renin concentrations in the myometrium and endometrium of pregnant sows did not differ from those in non‐pregnant animals.

5. The finding of enzymatically active renin and high densities of AngII receptors in the porcine uterus is in accordance with a functional renin‐angiotensin system (RAS), which may be important for an increased vascular permeability and stimulated angiogenesis in early pregnancy and for contraction of the myo‐metrial smooth muscle cells during parturition. The predominance of ATi receptors in the endometrium of non‐pregnant sows differs from an earlier finding in non‐pregnant women, where AT2 receptors were predominant in the endometrium. This is in accordance with earlier studies, indicating species differences in the expression and possibly also the physiological roles of the RAS in reproductive tissues.
EFFECT OF EXERCISE ON PLASMA ADRENOMEDULLIN AND NATRIURETIC PEPTIDE LEVELS IN MYOCARDIAL INFARCTION
Authors: Morimoto Atsushi , Nishikimi Toshio , Takaki Hiroshi , Okano Yoshiaki , Matsuoka Hiroaki , Takishita Shuichi , Kitamura Kazuo , Miyata Atsuro , Kangawa Kenji , Matsuo Hisayuki
Published: June 2007

1. We investigated the effect of exercise on plasma adreno‐medullin, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations and studied the relationship between these peptides and haemodynamic parameters in nine patients with old myocardial infarction (MI) and in eight normal subjects.

2. The exercise protocol consisted of two fixed work loads (40 and 80 W) for 4 min each and venous blood samples were taken at rest, during each exercise stage and after exercise while monitoring the mean arterial pressure (MAP) and heart rate (HR). In MI, pulmonary arterial pressure (PAP), pulmonary capillary wedge pressure (PCWP), left ventricular end‐diastolic pressure (LVEDP) and cardiac output (CO) were measured throughout exercise.

3. Adrenomedullin levels did not significantly increase with exercise. Adrenomedullin levels correlated with PAP and PCWP at rest (P < 0.05). Atrial natriuretic peptide levels correlated with PAP, PCWP and LVEDP throughout exercise (P < 0.05) but, on multiple regression analysis, PCWP correlated only with ANP (P < 0.01). Brain natriuretic peptide levels correlated with LVEDP throughout exercise (P < 0.01) and its increment correlated closely with basal BNP levels at rest (P < 0.01).

4. These results suggest that adrenomedullin does not respond to the acute haemodynamic changes of exercise, whereas ANP responds to it and PCWP is the major stimulus factor. Brain natriuretic peptide responds to exercise in proportion to the basal synthesis of BNP in patients with left ventricular dysfunction and LVEDP may play a role in increasing BNP during exercise.
NON‐SPECIFIC INHIBITORS OF NITRIC OXIDE SYNTHASE CAUSE MYOCARDIAL NECROSIS IN THE RAT
Authors: Moreno Heitor , Nathan Luciana P. , Metze Konradin , Costa Soraia KP , Antunes Edson , Hyslop Stephen , Zatz Roberto , de Nucci Gilberto
Published: June 2007

1. To study the effect of acute nitric oxide (NO) inhibition on the rat heart both in vitro and in vivo, male Wistar rats received a single bolus injection of saline, Nω‐nitro‐L‐arginine methyl ester (L‐NAME; 0.5,1.5,5.0,15.0 and 45.0 mg/kg) and D‐NAME (45.0mg/kg).

2. Animals were killed 72 h after the bolus injection of L‐NAME and the hearts were removed and studied under light microscopy. In other groups of animals, saline, L‐NAME and D‐NAME were administered as above and the mean arterial blood pressure (MABP/carotid) was recorded. Furthermore, L‐NAME was also administered in the drinking water (20 mg/kg per day) for 72 h and animals were then killed and their hearts evaluated as described above. Hearts of control animals were perfused in vitro and coronary flow was measured following saline, L‐NAME (45 μg/heart) and D‐NAME (45 μ/heart).

3. Areas of necrosis were observed in the left ventricle of animals that had received L‐NAME at 5.0, 15.0 and 45.0 mg/kg. Also, only doses higher than 1.5 mg/kg caused an important increase in MABP. The frequency and extent of the lesions paralleled the dose of L‐NAME administered and no lesions were observed in D‐NAME‐ and saline‐treated animals.

4. The oral administration of L‐NAME also caused myocardial lesions similar to those described above, but the frequency and extent of these lesions were more discrete compared with those observed following 5.0 mg/kg, i.v., L‐NAME.

5. Bolus injection of L‐NAME into control rat hearts in vitro resulted in a small and transient fall in coronary flow (17.2 ± 1.4 and 12.2 ± 1.2 mL/min before and after L‐NAME administration, respectively) within 30 s and this was followed 4.5 min later by a further (11.5 ± 1.6 mL/min) decrease. The administration of D‐NAME to control hearts caused no change in coronary flow.

6. In conclusion, the acute inhibition of NO biosynthesis by L‐NAME causes myocardial necrosis. Both high levels of MABP and a small but significant reduction in coronary flow (associated or not) can be responsible for the lesions we found.
BENEFICIAL EFFECTS OF PENTOXIFYLLINE ON CYCLOSPORINE‐ INDUCED NEPHROTOXICITY
Authors: Kaputlu İrfan , Şadan Gülay , Karayalçin Binnur , Boz Adil
Published: June 2007

1. Hypertension and renal failure are the two most common and severe complications due to cyclosporine A (CsA) therapy after transplantation. To determine whether an in vivo treatment with pentoxifylline (PTX) can prevent the toxic effects of CsA, three groups of rats were studied.

2. The first group of rats (n = 11) received daily injections of CsA (15 mg/kg, i.m.) and PTX (45 mg/kg, i.p., b.i.d.), the second group of rats in= 11) was treated with CsA only and the third group of rats (n = 11) served as the control group (vehicle treatment).

3. Whole blood CsA levels were similar in CsA + PTX and CsA alone groups. Although CsA treatment significantly increased mean arterial blood pressure (110.00 ± 2.48 nunHg; P<0.01), there was no significant increase in the PTX co‐treated group (104.09 ± 2.96 mm Hg) compared with initial values. In both the CsA alone and CsA + PTX groups the heart rate (365.45 ± 6.62 and 357.27 ± 7.23 b.p.m., respectively; P < 0.05) were found to be significantly higher than initial values. Serum creatinine levels increased significantly in the CsA alone group (1.40 ± 0.11 mg/dL; P < 0.01) compared with control values (0.81 ± 0.04 mg/dL). This increase was prevented by co‐treatment with PTX (serum creatinine 1.11 ± 0.10 mg/dL; P < 0.05). Total [99mTcl‐DTPA percentage renal uptake, as an index of glomerular filtration rate (GFR), was markedly and significantly lower in the CsA alone group (10.01 ± 0.79%; P < 0.01) than in the control group (18.19 ± 132%). Pentoxifylline co‐treatment attenuated this decrease compared with GFR in the CsA alone group (13.00 ± 0.75%; P < 0.01).

4. These results suggest that the co‐administration of PTX with CsA may prevent the dose‐limiting toxic effects of CsA therapy.
URODILATIN (INN: ULARITIDE) AS A NEW DRUG FOR THE THERAPY OF ACUTE RENAL FAILURE FOLLOWING CARDIAC SURGERY
Authors: Meyer Markus , Wiebe Karsten , Wahlers Thorsten , Zenker Dieter , Schulze Frank‐Peter , Michels Peter , Forssmann Wolf‐Georg
Published: June 2007

1. Acute renal failure is a severe complication following major cardiac surgery.

2. The effects of urodilatin were evaluated in a randomized, double‐blind trial in patients suffering from incipient acute renal failure following cardiac surgery.

3. In the urodilatin group (n= 7) acute renal failure was reverted, whereas in the placebo group (n= 7) six patients had to be haemofiltered or haemodialysed (P < 0.005).

4. Urodilatin induced a rapid onset of diuresis in contrast to placebo‐treated patients, who remained oliguric.

5. In the placebo group four of seven patients died while still on haemodialysis (mortality rate 57.1 %) during a postoperative follow‐up period of 60 days, while all patients treated with urodilatin survived.

6. On the basis of these results it would appear that urodilatin is an effective drug for the treatment of incipient oliguric acute renal failure following cardiac surgery and for avoiding haemodialysis/haemoflltration.
RESPONSES OF THE DURAL CIRCULATION TO ELECTRICAL STIMULATION OF THE TRIGEMINAL GANGLION IN THE CAT
Authors: Lambert Geoffrey A. , Michalicek Jan , Regaglia Francesca
Published: June 2007

1. In cats anaesthetized with a‐chloralose, electrical stimulation (ES) of the trigeminal ganglion produced a fall in blood pressure, a predominantly ipsilateral dilatation in the common carotid vascular bed and bilateral dilatation of the middle meningeal vascular bed. Section of the trigeminal root abolished these responses.

2. Dilatation in the middle meningeal artery was not affected by section of the cervical sympathetic trunk nor by the section of the seventh cranial nerve trunk. The dilator response was abolished by section of the spinal cord at the C3 level and by intravenous administration of bretylium (10 mg/kg) or phentol‐amine (5 mg/kg). The response was significantly reduced by the prior administration of papaverine (10 mg/kg).

3. Functional adrenalectomy by means of a snare placed around the nerves and blood vessels supplying the adrenal glands significantly reduced the response. Electrical stimulation of the trigeminal ganglion was accompanied by a fall in circulating levels of noradrenaline and serotonin.

4. We conclude that ES of the trigeminal ganglion produces dilatation in the middle meningeal artery partly by autoregu‐lation during the trigeminal depressor response and partly by a reduction in the circulating levels of noradrenaline. It differs from the dilatation seen in the general carotid circulation and the cortical microcirculation, which is mediated by parasympathetic nerves. There is no evidence that antidromic release of neuropeptides from sensory nerve endings in the dura plays a part in the dilatation.
EFFECTS OF DIET ON MEASUREMENT OF NITRIC OXIDE METABOLITES
Authors: Wang Jian , Brown Mark A. , Tarn Sim Horn , Chan Maria C. , Whitworth Judith A.
Published: June 2007

1. The present study investigated whether a low nitrate/nitrite diet could minimize variability in the measurement of endogenous plasma and urine nitric oxide (NO) metabolites, nitrate and nitrite (NOx) in normal subjects.

2. Nitrate and nitrite concentrations were measured in plasma and urine as indicators of NO production in six subjects during a free diet and then during a low nitrate/nitrite diet for 6 days.

3. The plasma concentration and 24 h urine NOx/creatinine ratio were significantly lower on the low nitrate/nitrite diet than on the free diet (P < 0.01). Nitric oxide production appeared to vary greatly within and between subjects, but these variations were substantially decreased by the fourth day of a low nitrate/ nitrite diet.

4. Human plasma and urine NOx measurements should be determined after a low nitrate/nitrite diet for at least 4 days.
GENETIC FACTORS ASSOCIATED WITH ALTERED SODIUM TRANSPORT IN HUMAN HYPERTENSION: A TWIN STUDY
Authors: Nowson Caryl A. , McMurchie Edward J. , Burnard Sharon L. , Head Richard J. , Boehm Joanna , Hoang Hoa N. , Hopper John L. , Wark John D.
Published: June 2007

1. Na+/H+ antiporter/exchange activity (NHE) in human cheek epithelial cells was assessed in 288 female twins and siblings. The genetic contribution of factors to NHE activity was assessed in 128 matched twin pairs (76 monozygotic (MZ); 52 dizygotic (DZ)).

2. There was a small reduction in NHE with age and body mass index. The significant correlations (± their standard error (SE)) within MZ and DZ pairs of twins were 0.54 ± 0.08 and 0.26 ± 0.13, respectively, implying that genetic factors accounted for 54% of the variance in age‐adjusted NHE. There was no cross‐sectional relationship between NHE and measures of blood pressure. Based on within‐pair differences, however, there was a weak negative association (r= 0.22; P < 0.05) between mean arterial pressure and NHE.

3. It remains to be determined whether NHE in cheek cells is associated with blood pressure tracking over time in young females.
PCR‐SSCP ANALYSIS OF THE GLUCOCORTICOID‐RESPONSIVE ELEMENT OF THE ATRIAL NATRIURETIC PEPTIDE GENE IN FAMILIAL PRIMARY OPEN‐ANGLE GLAUCOMA
Authors: Richardson Kimberley A. , Tunny Terry J. , Clark Charles V.
Published: June 2007

1. Familial primary open‐angle glaucoma (POAG) is a heterogeneous disease of unknown aetiology and the elucidation of the underlying genetic mechanisms contributing to phenotypic expression will be essential if earlier diagnosis of at‐risk individuals and more specific medical treatment can be achieved. In a significant percentage of patients with POAG, intraocular pressure increases in response to topical ocular glucocorticoids.

2. Atrial natriuretic peptide (ANP) assists in the regulation of intraocular pressure levels and binding of the glucocorticoid receptor dimer to the glucocorticoid‐responsive element in intron 2 of the ANP gene has been shown to increase ANP mRNA levels in vitro. We amplified and examined this sequence in the ANP gene by PCR‐SSCP analysis in 100 patients with familial POAG and in 60 normal control subjects. No base alterations in the amplified product were found.

3. Thus, the present study found no evidence for an alteration in the sequence of the glucocorticoid‐responsive element of the ANP gene that could alter ANP gene transcription in patients with familial POAG. The mechanism responsible for the increase in intraocular pressure levels in response to glucocorticoids is most likely independent of the glucocorticoid‐responsive element in the ANP gene.
NITRIC OXIDE SYNTHASE INHIBITION IN A SPONTANEOUSLY HYPERTENSIVE RAT MODEL OF DIABETIC NEPHROPATHY
Authors: Wessels J. , Peake P. , Pussell BA , Macdonald GJ
Published: June 2007

1. To investigate the role of nitric oxide (NO) in diabetic nephropathy the effect of nitric oxide synthase (NOS) inhibition by NG‐nitro‐L‐arginine methyl ester (L‐NAME) was observed in a streptozotocin diabetic spontaneously hypertensive rat (SHR) model.

2. Two groups of SHR (n= 8) with streptozotocin‐induced diabetes were studied. One group was given L‐NAME 5mg/kg body weight per day in the drinking water for 8 weeks while both groups received daily subcutaneous injections of Ultratard insulin. Creatinine clearance, urinary protein excretion, urinary nitrate concentration and systolic blood pressure were measured at fortnightly intervals. Rats were killed at 8 weeks and plasma angiotensin II (AngII) was measured by radioimmunoassay.

3. Renal function (endogenous creatinine clearance) remained stable in both groups. In the L‐NAME group, however, there was a progressive increase in proteinuria that was highly significant at 6 weeks (22.1 ± 2.9 compared with 6.5 ± 0.7 mg/ 24 h per 100 g in control SHR diabetic rats P < 0.001).

4. Systolic blood pressure was significantly elevated in the L‐NAME group throughout the study compared with the control group.

5. Plasma AngII was significantly elevated in the L‐NAME group compared with controls (42.8 ± 10.3 vs 15.1 ± 1.9 pmol/L, respectively; P < 0.05).

6. Activation of the renin‐angiotensin system may account, at least in part, for the resulting vasoconstrictor activity with chronic nitric oxide depletion.
ASSOCIATION ANALYSIS OF SIX CANDIDATE GENES IN A SAMPLE OF AUSTRALIAN HYPERTENSIVE PATIENTS
Authors: Huggard PR , Summers KM , West J. , West MJ
Published: June 2007

1. Essential hypertension is characterized by increased vascular resistance due to narrowing of the small arterioles. This may be influenced by vasoactive substances, cell growth and vascular remodelling.

2. A sample of Australian hypertensive and normotensive subjects was investigated for association with genetic markers which are candidates for a role in blood pressure (BP) regulation due to potential effects on vascular diameter.

3. The six markers used were for genes encoding vasoconstrictors, growth factors and a structural protein of the extracellular matrix.

4. No significant association of any of the markers used was found with BP status in this sample of patients.
EFFECTS OF OESTROGEN AND PROGESTERONE ON AGE‐RELATED CHANGES IN ARTERIES OF POSTMENOPAUSAL WOMEN
Authors: Liang Yu‐Lu , Teede Helena , Shiel Louise M. , Thomas Adrian , Craven Robyn , Sachithanandan Nirupa , McNeil John J. , Cameron James D. , Dart Anthony , McGrath Barry P.
Published: June 2007

1. Hormone replacement therapy (HRT) with oestrogen or oestrogen plus progestin may have different effects on arterial structure and function. To examine this question, carotid artery intima‐medial thickness (IMT) and indices of systemic and carotid arterial compliance were measured in groups of older men, postmenopausal women not on HRT (non‐HRT) and those women on long‐term HRT with oestrogen alone (HRT‐E) or oestrogen plus progestin (HRT‐EP).

2. Sixty men, 90 postmenopausal women taking HRT and 91 not taking HRT participated in the study. The groups were similar for age, body mass index, numbers of smokers, physical activity, alcohol intake and blood pressure.

3. Plasma total cholesterol was reduced and high‐density lipo‐protein‐cholesterol was increased in the HRT group compared with the non‐HRT group; low‐density lipoprotein‐cholesterol, triglyceride and lipoprotein (a) values were similar in these two groups. Results for HRT‐E and HRT‐EP subgroups were similar.

4. Carotid IMT was significantly reduced in the HRT group compared with men and non‐HRT groups. Results for HRT‐E and HRT‐EP subgroups were similar.

5. Mean systemic arterial compliance (SAC) was significantly greater in men than in women and was related to age; SAC was higher in both HRT‐E and HRT‐EP groups compared with the non‐HRT group. Indices of carotid stiffness were similar in men and in non‐HRT groups. The HRT‐EP group showed increased carotid stiffness compared with the HRT‐E group.

6. There is an apparent protective effect of long‐term oestrogen therapy on carotid IMT and age‐related changes in arterial stiffness. Progestin does not alter the IMT effects but may adversely influence arterial stiffness.
DRUG‐MEDIATED INACTIVATION OF CYTOCHROME P450
Authors: Murray Michael
Published: June 2007

1. Multiple forms of cytochrome P450 (CYP) catalyse the oxidation of chemicals of endogenous and exogenous origin, including drugs, carcinogens, steroids and eicosanoids. However, this unusual low substrate specificity also makes CYP susceptible to inhibition by a wide range of drugs, leading to pharmacokinetic interactions of potential clinical significance.

2. Some drugs are converted by CYP to reactive metabolites that bind covalently to sites within the active centre of the same CYP. Such mechanism‐based inhibition leads to CYP inactivation or complexation. These processes give rise to long‐term effects on drug pharmacokinetics, as the inactivated or complexed CYP must be replaced by newly synthesized CYP protein.

3. Drugs that inactivate CYP generally possess recognizable functional groups that are oxidized to reactive products. Thus, drugs with side chains containing unsaturated carbon‐carbon bonds and furan ring systems are associated with CYP inactivation. Nitrogen‐containing systems may also inactivate CYP.

4. Metabolites formed from drugs containing alkylamino and methylenedioxy functionalities can trap CYP as inert complexes without eliciting inactivation. However, the functional effects of inactivation and complexation on drug pharmacokinetics are indistinguishable. Drugs that elicit CYP complexation include the first generation macrolide antibiotics, but newer analogues appear much safer. Some antidepressants, antiepileptics and tuberculostatic agents have been associated with CYP complexation.
CELL‐SPECIFIC PROTEIN AND GENE EXPRESSION IN THE JUXTAGLOMERULAR APPARATUS
Authors: Barajas Luciano
Published: June 2007

1. The juxtaglomerular apparatus (JGA) consists of a tubular component, the macula densa (MD), attached to a vascular component consisting of the afferent and efferent arterioles and the extraglomerular mesangium. The JGA is richly innervated by sympathetic fibres.

2. The MD is morphologically, histochemically and functionally different from the ascending thick portion of the loop of Henle where it is located.

3. The vascular component includes the vascular smooth muscle cells of the arteriole, the renin‐producing cells or juxtaglomerular cells, extraglomerular mesangial cells (Goormagh‐tigh cells) and endothelial cells. They are coupled by gap junctions.

4. Physiological evidence indicates that the composition of tubular fluid at the MD regulates renin secretion and glomerular haemodynamics and that the JGA is important in the maintenance of body salt‐water homeostasis. Evidence suggests that the MD exerts its action on the vascular component through a paracrine mechanism.
WATER CHANNELS AND UREA TRANSPORTERS
Authors: Wintour E Marelyn
Published: June 2007

1. It now appears that when water crosses an endothelium which is not fenestrated, or an epithelium with tight junctions, it does so rapidly, and with low energy cost, only if the cell membrane contains an adequate number of specific water channels, encoded by one of at least six different genes.

2. The water channel genes so far cloned encode a series of integral membrane proteins called aquaporins, all of approximately 30kDa (265–282 amino acids), in the unglycosylated state. All but one (AQP3) are specific water channels and all but one (AQP4) are inactivated by mercurial compounds.

3. Aquaporin 0 is the major (60%) intrinsic protein (MIP) of lens fibre cells of the eye. Mutations in this gene are associated with cataract formation in mice.

4. Aquaporin 1, also called CHIP‐28, exists in the membrane as a homotetramer, and is present in red blood cells, the choroid plexus, the proximal tubule and descending limb of the loop of Henle in the kidney as well as in many other sites. Surprisingly, no pathological consequence is known in patients lacking a functional AQP1 gene.

5. Aquaporin 2, also called WCH‐CD, is the water channel of the principal cell of the cortical and medullary collecting duct, and is located in cytoplasmic vesicles unless arginine vasopressin is acting, when it is translocated to the apical membrane by synaptobrevins or vesicle associated membrane protein 2 (VAMP2). Lack of a functional AQP2 gene leads to a rare form of nephrogenic diabetes insipidus.

6. Aquaporins 3, 4, and 5 are located in many tissues—AQP3 and AQP4 being in the basolateral membrane of the renal cortical and medullary principal cell, as well as in the gastrointestinal tract (AQP3) and the brain (AQP4).

7. Four sequences are known for urea transporters HUT11—the urea transporter of the human red cell membrane, and HUT2, rUT2, rbUT2—the arginine vasopressin inducible urea transporters of the human, rat and rabbit kidney. They are specifically permeable to urea, not to water, and are claimed to be inhibited by phloretin.

8. The water channel proteins contain six membrane‐spanning regions, whilst the urea transporters are thought to contain at least 10 membrane spanning segments.

9. Very little work has examined the ontogeny of these proteins, except in the rat, and virtually nothing is known of the expression of these genes in pregnancy or in any disorder of fluid balance in the mother or foetus.
RE‐EVALUATION OF THE SA GENE IN SPONTANEOUSLY HYPERTENSIVE AND WISTAR‐KYOTO RATS
Authors: Ishinaga Yuji , Nabika Toru , Shimada Toshio , Hiraoka Junko , Nara Yasuo , Yamori Yukio
Published: June 2007

1. To investigate whether the difference in the SA gene expression in the kidneys is causally related to the pathogenesis of hypertension, we reassessed the expression of the SA gene in the kidneys of the spontaneously hypertensive rat (SHR), its stroke‐prone substrain (SHRSP) and Wistar‐Kyoto (WKY) rat from different sources (SHR/Izm, SHRSP/Izm and WKY/ Izm from Izumo colony; SHR/Crj and WKY/Crj from Charles River Laboratories).

2. At the age of 5 weeks, high levels of the SA mRNA were expressed in the kidneys of SHRSP/Izm, SHR/Izm, SHR/Crj and WKY/Izm, while very low levels of the SA mRNA were observed in those of WKY/Crj. At the age of 8 weeks, the expression of the SA mRNA in the kidneys of WKY/Izm was at the same level as in those of SHRSP/Izm and two SHR strains.

3. Four genetic markers at the SA locus, an StuI restriction fragment length polymorphism and three microsatellite markers, were not polymorphic among Izumo strains of SHR, SHRSP and WKY rats.

4. In situ hybridization showed strong signals of the SA mRNA in the renal proximal tubules, while no positive signals were detected in the glomeruli.

5. Because WKY/Izm has normal blood pressure, our observations indicate that a simple difference of the SA gene expression in the kidney cannot be an explanation for the difference of blood pressure between SHR(SP)/Izm and WKY/Izm.
AUTONOMIC BLOCKADE AMPLIFIES CORTISOL‐INDUCED HYPERTENSION IN MAN
Authors: Tam Sim Horn , Williamson Paula M. , Kelly John J. , Whitworth Judith A.
Published: June 2007

1. We investigated the role of the autonomic nervous system (ANS) in Cortisol induced hypertension using the technique of total autonomic blockade (AB).

2. Four healthy young males were given 50 mg Cortisol 6 hourly for 6 days. On the day prior to, and the last day of, Cortisol treatment, AB was produced using oral prazosin 1 mg, intravenous clonidine 300 μg, propranolol 0.2 mg/kg and atropine 2 mg. The adequacy of blockade was assessed using the haemodynamic response to Valsalva manoeuvre.

3. Cortisol produced a significant rise in systolic blood pressure (130 ± 2 vs 110 ± 1 mmHg, pre vs post Cortisol; P<0.01). On the final treatment day, AB augmented the increase in diastolic blood pressure (ΔDBP), mean arterial pressure (ΔMAP) and heart rate (ΔHR) compared to the pre‐treatment day, ΔDBP: 43 ± 6 vs 17 ± 4 mmHg, post vs pre Cortisol, P<0.005, ΔMAP: 39 ± 4 vs 14 ± 4 mmHg, P<0.001, ΔHR: 45 ± 5 vs 26 ± 4 b.p.m., P<0.05. The change in systolic blood pressure (ΔSBP) was not statistically significant (32 ± 4 vs7 ± 3 mmHg, P= 0.065).

4. These results suggest that the ANS exerts a modulating influence on the hypertensive effect of Cortisol.
INTERACTION OF EXOGENOUS OUABAIN AND CHRONIC MINERALOCORTICOID TREATMENT IN THE KIDNEY OF THE CONSCIOUS SHEEP
Authors: Yates NA , McDougall JG
Published: June 2007

1. Ouabain is known to have natriuretic effects only at high doses, and therefore if endogenously produced ouabain has a role in the regulation of sodium excretion, the renal response to ouabain must be increased substantially in certain physiological situations. The aim of this study is to determine whether treatment with the mineralocorticoid, aldosterone, potentiates that natriuretic response to ouabain.

2. Six conscious sheep received renal arterial infusion of either vehicle or aldosterone (3 μg/h). Forty hours after commencement of infusion ouabain was infused into the renal artery at 400 μg/h for 60min. A second infusion of ouabain was administered on the 6th day of aldosterone treatment.

3. In the absence of aldosterone, the effects on sodium excretion produced by ouabain infusion at 400 μg/h into the renal artery were variable and not statistically significant. Ouabain infusion after 40 h of aldosterone treatment increased sodium excretion from 40 ± 14 to 676 ± 69 μmol/min in the second hour following cessation of ouabain infusion (P< 0.001). Ouabain infusion after 6 days of aldosterone treatment increased sodium excretion similarly. Ouabain‐stimulated sodium excretion was significantly greater during aldosterone treatment compared to vehicle treatment (P<0.05). In contrast, no enhancement of effect was observed after acute treatment with aldosterone.

4. These results demonstrate potentiation of the natriuretic response to ouabain infusion by chronic mineralocorticoid treatment and suggest a potential role of endogenous digitalislike factor in the physiological control of sodium homeo stasisaldo sterone, endogenous digitalis‐like factor, ouabain, sodium excretion.
LONG‐TERM INCREASES IN RENAL SYMPATHETIC NERVE ACTIVITY AND HYPERTENSION
Authors: Osborn Jeffrey L. , Plato Craig F. , Gordin Erez , He Xiao Rui
Published: June 2007

1. Essential hypertensive patients have been characterized by increased sympathetic nerve activity, increased peripheral vascular tone, decreased plasma volume and normal cardiac output when compared with normotensive subjects. Bilateral renal denervation reduces the magnitude or delays the onset of the blood pressure response in numerous models of experimental hypertension regardless of the aetiology of the elevation in arterial pressure.

2. Using a servocontrolled intrarenal infusion system, we have elevated intrarenal noradrenaline concentration via intermittent renal artery infusion without decreasing renal blood flow as a method of simulating selective elevation of renal sympathetic outflow.

3. Chronic intrarenal adrenergic stimulation increased arterial pressure within 24 h and this hypertension persisted for 28 consecutive days. The elevated arterial pressure was not associated with sustained increases in plasma renin activity, aldosterone, circulating catecholamines, arginine vasopressin or significant renal vasoconstriction. Urinary sodium excretion was chronically elevated and the dogs remained in negative sodium balance for the duration of the intrarenal noradrenaline infusion.

4. After 2 weeks of elevated intrarenal neurotransmitter coupled with hypertension, renal vascular reactivity to further adrenergic stimulation was significantly increased because the hypertension was maintained during continual reductions in the daily dosage of neurotransmitter allowed to be infused by the servocontroller. After only 28 days of noradrenaline infusion, renal vascular hypertrophy developed in vessels from 150–300 μm.

5. We conclude that selective and intermittent increases in intrarenal adrenergic neurotransmitter are sufficient to elicit chronic hypertension in the absence of volume expansion. This intrarenal neuroadrenergic hypertension is closely associated with the haemodynamic parameters which characterize a major subset of human essential hypertensives.
INTERACTIONS BETWEEN ANGIOTENSIN II AND THE SYMPATHETIC NERVOUS SYSTEM IN THE THE LONG‐TERM CONTROL OF ARTERIAL PRESSURE
Authors: Brooks Virginia L.
Published: June 2007

1. The role of the renin‐angiotensin system in long‐term control of sympathetic activity and arterial pressure is reviewed.

2. There is evidence that favours a necessary role for the sympathetic nervous system in long‐term arterial pressure regulation. First, appropriate changes in sympathetic activity appear to be produced in response to chronic changes in blood volume or blood pressure. Second, prevention of the normal homeostatic decrease in sympathetic activity in response to an increase in sodium intake produces hypertension.

3. Long‐term changes in sympathetic activity cannot be mediated by the baroreceptor reflex, because it adapts to sustained changes in pressure. Therefore, an hypothesis is presented that evokes a key role for angiotensin II (AngII) in determining the chronic level of sympathetic activity. The key feature of this model is that the role of AngII is non‐adaptive: chronic changes in extracellular fluid volume produce sustained reciprocal changes in AngII, and long‐term increases in AngII produce sustained increases in sympathetic activity.

4. Evidence is reviewed that suggests that a lack of the normal suppression in AngII and/or sympathetic activity in response to an increase in sodium intake produces salt‐sensitive hypertension.
STEREOCHEMISTRY IN ANAESTHESIA
Authors: Sidebotham David A. , Schug Stephan A.
Published: June 2007

1. Interest in the pharmacokinetic and pharmacodynamic properties of the enantiomers of chiral drugs has greatly increased in recent years. This is particularly so for agents used in anaesthesia.

2. Chiral compounds are those that can exist in two non‐superimposable forms. Each form is termed an enantiomer or stereoisomer. Two naming systems are in use: one uses the terms (+) and (–) to indicate the direction the compound will rotate polarized light, while the other system, based on the absolute three‐dimensional structure of the enantiomers, uses the terms R and S.

3. Investigation of the stereoisomers of the volatile anaesthetic agent isoflurane is increasing our understanding of the mechanism of general anaesthesia. Current evidence suggests a protein, rather than a lipid, receptor site.

4. Investigation of the stereoisomers of local anaesthetics is increasing the safety of these drugs.

5. For bupivacaine, a widely used amide local anaesthetic, important enantiomeric differences can be found for toxicity, clinical effect and pharmacokinetics. In particular S‐(–)‐bupivacaine has an improved central nervous system and cardiac safety profile. This is partly explained by the pharmacokinetic differences.

6. Based on these differences, ropivacaine, a propyl homo‐logue of bupivacaine, has been produced solely as the S‐(–)‐enantiomer. The available evidence suggests significantly improved safety for this agent over racemic bupivacaine.
RELAXANT EFFECTS OF VASODILATOR PEPTIDES ON ISOLATED BASILAR ARTERIES FROM STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Nishimura Yoshitaka , Suzuki Aritomo
Published: June 2007

1. The relaxant effects of vasodilator peptides were examined in ring preparations of basilar arteries from stroke‐prone spontaneously hypertensive rats (SHRSP) and Wistar‐Kyoto (WKY) rats.

2. Vasoactive intestinal peptide and peptide histidine iso‐leucine produced similar endothelium‐independent relaxations in basilar arteries from WKY rats and SHRSP. Calcitonin gene‐related peptide (CGRP) elicited endothelium‐independent relaxations in both groups and the CGRP‐induced relaxation was greater in SHRSP than in WKY rats. Substance P and neurokinin A did not relax basilar arteries from either group.

3. Both WKY rat and SHRSP basilar arteries were relatively insensitive to atrial natriuretic peptide, brain natriuretic peptide and C‐type natriuretic peptide.

4. Bradykinin (BK) potently relaxed basilar arteries with endothelium, but BK produced contractions in endotheliumrubbed arteries in both WKY rats and in SHRSP. There was no significant difference in the relaxant response to BK between WKY rat and SHRSP arteries.

5. Adrenomedullin (AM) produced endothelium‐independent relaxations in both groups and the relaxant response to AM was significantly greater in SHRSP than in WKY rats.

6. Human CGRP(8–37; 1 μmol/L), a CGRP receptor antagonist, significantly inhibited both relaxant responses induced by CGRP and AM in WKY rats and in SHRSP arteries.

7. Among various peptides tested, the responses to CGRP and AM were higher in basilar arteries from SHRSP than in those from WKY rats. The relaxation produced by AM may be via CGRP receptors in WKY rat and SHRSP basilar arteries.
INFLUENCE OF AGEING ON CILIARY BEAT FREQUENCY AND ON CILIARY RESPONSE TO LEUKOTRIENE D4 IN GUINEA‐PIG TRACHEAL EPITHELIUM
Authors: Joki Susanna , Saano Veijo
Published: June 2007

1. In the present study on guinea‐pig tracheal epithelium, the influence of age on ciliary beat frequency (CBF) was investigated.

2. An age‐dependent decrease in CBF was seen: as the age of the guinea‐pig increased from 0.9 to 16.3 months, CBF decreased from 20.2 to 6.9 Hz.

3. The effect of leukotriene D4 (LTD4) on CBF was also examined using tracheal explants from guinea‐pigs of varying ages. The lower CBF of the older animal was increased by LTD4 to a larger extent than was the higher CBF seen in explants taken from younger animals.

4. Ciliary activity and possibly also the sensitivity of the cilia to drugs, seems to be dependent upon the age of the animal, which has to be taken into consideration when comparing the results of different studies on the effects of xenobiotics on mucociliary function.