bluuebunny/crossref_metadata_2025 huggingface dataset:
Responses Of Regional Kidney Perfusion To Vasoconstrictors In Anaesthetized Rabbits: Dependence On Agent And Renal Artery Pressure
Authors: Evans Roger G , Correia Anabela G , Weekes Simon R , Madden Anna C
Published: March 2003

1. We tested the effects of intravenous infusions of angiotensin II (AngII; 300 ng/kg per min) and the vasopressin V1 receptor agonist [Phe
2,Ile
3,Orn
8]‐vasopressin (30 ng/kg per min) on regional kidney perfusion in an extracorporeal circuit model in anaesthetized rabbits in which renal artery pressure (RAP) can be set independently of systemic mean arterial pressure. To test whether the level of RAP can influence the renal vascular response to [Phe
2,Ile
3,Orn
8]‐vasopressin, we compared its effects when RAP was initially set at approximately 65 mmHg with those when RAP was set at approximately 130 mmHg.

2. When RAP was initially set at approximately 65 mmHg, a 20 min infusion of AngII increased RAP (13%) and reduced renal blood flow (RBF; 50%) and cortical perfusion (CBF; 43%). Medullary perfusion (MBF) transiently increased during the first 10 min of infusion, but was not significantly different from control levels during the final 5 min of infusion.

3. When RAP was initially set at approximately 65 mmHg, a 20 min infusion of [Phe 2,Ile
3,Orn
8]‐vasopressin increased RAP (9%) and reduced RBF (21%); MBF was reduced by 57%, but CBF was reduced by only 15%. In contrast, when RAP was initially set at approximately 130 mmHg, infusion of [Phe
2,Ile
3,Orn
8]‐vasopressin reduced RAP (7%) and increased RBF (13%). In these experiments, MBF was reduced by 38%, but CBF increased by 6%.

4. Our experiments show that AngII preferentially reduces CBF, while [Phe 2,Ile
3,Orn
8]‐vasopressin preferentially reduces MBF. The renal vascular responses to [Phe
2,Ile
3,Orn
8]‐ vasopressin appear to be profoundly affected by the level of RAP, because increasing RAP from approximately 65 to approximately 130 mmHg transforms its cortical vasoconstrictor effect into cortical vasodilatation while leaving the response of the medullary microvasculature relatively unchanged. Whether renal vascular responses to other vasoactive agents (e.g. AngII) are similarly affected by the level of RAP remains to be determined.
Effect Of Amlodipine On Cardiopulmonary Performance In Volunteers
Authors: Lay L , Bjorksten Ar , Stainsby Gv , Blake Dw
Published: March 2003

1. In order to exclude a significant effect of the calcium channel antagonist amlodipine on cardiopulmonary performance in normal subjects, we performed a double‐blind cross‐over study of amlodipine (10 mg daily for 2 weeks) on oxygen uptake and catecholamine responses during exercise in eight volunteers.

2. Despite a therapeutic plasma concentration of amlodipine (22.8±9 ng/mL), there was no change in resting heart rate or blood pressure. Amlodipine did not cause significant change in oxygen uptake at the anaerobic threshold or at maximum exercise and there was also no change in heart rate or catecholamine responses.

3. Although there was an awareness of peripheral vasodilation and reports of lethargy during the active treatment period, the volunteers had no objective evidence of a decrease in cardiopulmonary performance. We suggest that use of amlodipine as a vasodilator in the perioperative period would not add to the myocardial depressant effects of general anaesthesia in patients with normal cardiac function.
Proceedings of the Australian Physiological and Pharmacological Society Symposium: The Hypothalamus FETAL HYPOTHALAMUS–PITUITARY–ADRENAL AXIS ON THE ROAD TO PARTURITION
Authors: Schwartz Jeff , McMillen I Caroline
Published: March 2003

1. Activity of the fetal hypothalamus–pituitary–adrenal (HPA) axis waxes and wanes as a function of gestational age.

2. In a number of species, including sheep, at the end of gestation there is an increase in HPA activity, as characterized by an increase in fetal plasma glucocorticoids.

3. To a certain degree, the hypothalamus, pituitary and adrenal all act autonomously and, therefore, may be thought of as contributing to the initiation of the signal that results in the increase in steroidogenesis before birth.

4. Because it integrates sensory information from beyond as well as within the HPA axis and likely triggers developmental changes within the pituitary, the hypothalamus may be a ‘first among equals’ in being the ultimate source of triggering information for the HPA axis.
Type IV Phosphodiesterase Inhibitor Suppresses Insulin‐Dependent Myocardial Glucose Uptake
Authors: Imahashi Kenichi , Yoshioka Jun , Yamakita Tsuyoshi , Yamano Suzuyo , Kusuoka Hideo , Nishimura Tsunehiko
Published: March 2003

1. Phosphodiesterase (PDE) IV has been localized at cardiomyocytes and the coronary vasculature and modulates cAMP, but the effect of PDE IV on myocardial glucose uptake has not been demonstrated.

2. Glucose uptake in rat isolated hearts treated with the PDE IV inhibitor rolipram was measured by [31P] nuclear magnetic resonance spectroscopy.

3. Under non‐stimulating conditions, glucose uptake was not significantly different between control and rolipram (1 μmol/L)‐treated rat hearts, whereas enhanced uptake in insulin‐stimulated conditions was significantly attenuated by rolipram.

4. Phosphodiesterase IV inhibitor negatively affects insulin‐dependent myocardial glucose uptake.
Hyperglycaemia: A Morphine‐Like Effect Produced By Naloxone
Authors: Abouazra Ha , Sharif Si
Published: March 2003

1. Naloxone, which is often regarded as a pure opioid antagonist, produces effects similar to those produced by morphine.

2. In conscious rabbits implanted with an intracerebroventricular (i.c.v.) cannula, naloxone, whether given intravenously (1 mg/kg) or i.c.v. (1–100 μg), produced a significant rise in blood glucose levels.

3. Hyperglycaemia in response to naloxone (1 mg/kg, i.v., or 100 μg, i.c.v.) was not influenced by the selective α1‐adrenoceptor antagonist WB‐4101 given either i.v. (50 μg) or i.c.v. (5 μg).

4. Hyperglycaemia in response to naloxone (1 mg/kg, i.v., or 100 μg, i.c.v.) was completely blocked by pretreatment with the α2‐adrenoceptor antagonist yohimbine (1 mg/kg, i.v., or 100 μg, i.c.v.). However, hyperglycaemia to i.c.v. naloxone (100 μg) was not influenced by i.v. yohimbine (1 mg/kg).

5. Because naloxone behaves like morphine and produces hyperglycaemia in conscious rabbits, the drug may have an appreciable agonist activity and the hyperglycaemic response to naloxone is principally mediated via α2‐ but not α1‐adrenoceptors.
Allosteric Modulation of the GabaA Receptor In Rat Hypothalamus By Somatostatin Is Altered By Stress
Authors: Chigr F , M'Hamed S Ba , Najimi M
Published: March 2003

1. This autoradiographic study was conducted to investigate somatostatin modulation of GABAA receptor binding in hypothalamic structures of immobilization‐stressed rats.

2. GABAA receptor binding was labelled with [35S]‐t‐ butylbicyclophosphorothionate (TBPS), which binds in or near the chloride channel.

3. Several structures of the rat hypothalamus (i.e. the peri‐ and paraventricular nuclei) display an increase in [35S]‐TBPS binding as well as an alteration of the modulatory effect of somatostatin on the GABAA receptor complex under stress. Furthermore, these results demonstrate for the first time that somatostatin is particularly effective in modifying [35S]‐TBPS binding to the GABAA receptor in rat hypothalamus.
Extracellular ATP and cAMP as Paracrine and Interorgan Regulators of Renal Function Renal Microvascular Effects of P2 Receptor Stimulation
Authors: Inscho Edward W
Published: March 2003

1. The field of extracellular nucleotides and purinoceptors has undergone a resurgence of interest and enthusiasm in the past decade. More and more investigators are probing the physiological and pathophysiological roles of P2 receptors in virtually every organ system, including the kidney.

2. With this renewed interest has come a new appreciation for the roles extracellular adenine nucleotides can play in regulating or modulating renal function. In the past 5 years, investigators have provided compelling evidence that extracellular nucleotides, working through activation of P2 purinoceptors, have a significant impact on renal microvascular function, mesangial cell function and on renal epithelial transport.

3. Evidence has been uncovered that implicates P2 receptor activation in mediating renal microvascular autoregulatory behaviour. Locally released ATP has a direct paracrine and/or autocrine effect modulating renal epithelial transporters and tubular epithelial channels to influence tubular fluid composition.

4. While the specific roles of extracellular nucleotides and their receptors in the kidney have not been absolutely identified, it now appears clear that endogenously released ATP may play a significant role in regulating kidney function.

5. The purpose of the present review is to update our current understanding of the effect of P2 receptor activation on renal microvascular function and to detail the signal transduction mechanisms known to be involved.
Significance Of Exaggerated Natriuresis After Angiotensin AT1 Receptor Blockade Or Angiotensin‐ Converting Enzyme Inhibition In Obese Zucker Rats
Authors: Tallam Lakshmi S , Jandhyala Bhagavan S
Published: March 2003

1. Obese Zucker rats (OZR) were shown to be salt‐sensitive in that they develop hypertension when placed on a high‐salt diet. Because angiotensin (Ang) II is a major antinatriuretic factor, the present studies were undertaken to determine whether the characteristic of salt‐sensitivity of OZR is associated with an enhanced antinatriuretic function of endogenous AngII.

2. The extent of AngII‐mediated antinatriuresis was investigated in OZR and lean Zucker rats (LZR) using candesartan (100 μg/kg, i.v.), a selective angiotensin AT1 receptor antagonist, and ramipril (1 mg/kg, i.v.), an angiotensin‐converting enzyme (ACE) inhibitor. The total number of AngII binding sites and their affinity were also assessed in renal cortical tubular membrane preparations of OZR and LZR using a specific radioligand‐binding assay. Plasma renin activity was determined using a standard radioimmunoassay.

3. Both candesartan and ramipril produced substantially greater increases in urinary sodium excretion and urine flow in OZR and these effects were significantly greater than those observed in LZR. These observations suggest that basal antinatriuretic function of endogenous AngII is exaggerated in OZR.

4. The functional overexpression of AngII was not due to any alterations in the affinity or the total number of AngII binding sites in renal cortical tubular membranes. Higher plasma renin values in the OZR could have contributed to the phenomenon.

5. In conclusion, marked diuresis and natriuresis after AT1 receptor blockade and/or ACE inhibition suggest that the extent of endogenous AngII‐mediated sodium transport under basal conditions is greatly augmented in OZR. It is proposed this phenomenon may be a contributing factor for the salt‐ sensitivity in the OZR.
Co‐Release Of Endogenous ATP And Noradrenaline From Guinea‐Pig Mesenteric Veins Exceeds Co‐Release From Mesenteric Arteries
Authors: Bobalova Janette , Mutafova‐Yambolieva Violeta N
Published: March 2003

1. The present study was designed to compare the overflow of sympathetic neurotransmitters of guinea‐pig inferior mesenteric artery and mesenteric vein evoked by electrical field stimulation (EFS) with special emphasis on the simultaneous release of ATP and noradrenaline (NA). The stimulation‐evoked overflow of ADP, AMP and adenosine was also evaluated.

2. Endothelium‐denuded segments of inferior mesenteric arteries or veins were superfused in a small volume (200μL)‐chamber for EFS and subsequent detection of NA (HPLC– electrochemical detection) and adenine nucleotides and adenosine (HPLC–fluorescence detection) in samples of the superfusate.

3. Both arteries and veins responded to EFS (15 V, 4–16 Hz, 0.3 msec for 60 s) with overflow of ATP and NA in a tetrodotoxin (1μmol/L)‐ and guanethidine (10μmol/L)‐sensitive manner. The EFS‐evoked overflow of NA in veins exceeded the overflow of NA in arteries at all frequencies of stimulation, whereas the EFS‐evoked overflow of ATP, ADP and AMP in veins exceeded the overflow of adenine nucleotides in arteries at 4 and 8 Hz but not at 16 Hz stimulation. The EFS–evoked overflow of adenosine was similar in arteries and veins.

4. Activation ofα1‐adrenoceptors with methoxamine (10μmol/L) did not produce overflow of ATP.

5. Blockade ofα1/α2‐adrenoceptors with phentolamine (1μmol/L) did not affect EFS‐evoked overflow of ATP, ADP, AMP and adenosine.

6. It is concluded that overflow of ATP and NA from sympathetic nerves may constitute an effective mechanism in the complex balance between capacitance and resistance in splanchnic circulation.
John Ludbrook APPS Symposium Coronary–Bronchial Blood Flow And Airway Dimensions In Exercise‐Induced Syndromes
Authors: White Sw , Pitsillides Kf , Parsons Gh , Hayes Sg , Gunther Ra , Cottee Db
Published: March 2003

1. We have an incomplete understanding of integrative cardiopulmonary control during exercise and particularly during the postexercise period, when symptoms and signs of myocardial ischaemia and exercise‐induced asthma not present during exercise may appear.

2. The hypothesis is advanced that baroreflex de‐resetting during exercise recovery is normally associated with (i) a dominant sympathetic vasoconstrictor effect in the coronary circulation, which, when associated with obstructive coronary disease, may initiate a potentially positive‐feedback cardio‐ cardiac sympathetic reflex (variable myocardial ischaemia with symptoms and signs); and (ii) a dominant parasympathetic bronchoconstrictor effect in the presence of bronchovascular dilatation, which, when associated with raised mediator release in the bronchial wall, reinforces the tendency for airway obstruction (variable dyspnoea results).

3. There is a need for new techniques to examine hypotheses concerning autonomic control, during and after exercise, of the coronary and bronchial circulations and the dimensions of airways. Accordingly, a new ultrasonic instrument has been designed named an ‘Airways Internal Diameter Assessment (AIDA) Sonomicrometer’. It combines pulsed Doppler flowmetry with transit‐time sonomicrometry of airway circumference and single‐crystal sonomicrometry of airway wall thickness. Initial evaluation suggests it is relatively easy to apply during thoracotomy in recovery animals. The component devices are linear and will measure target variables with excellent accuracy.

4. In anaesthetized sheep, intubated with controlled ventilation, intravenous isoproterenol causes large increases in bronchial blood flow, a fall in arterial pressure and a reduction in airway circumference. This may reflect the dominant action of reflex vagal activity over direct β‐adrenoceptor inhibition of bronchial smooth muscle, the reflex source being baroreflex secondary to the fall in arterial pressure. These findings provide insight into the integrative mechanisms underlying the paradoxical negative effects sometimes observed when β‐adrenoceptor agonists are used in asthma.
Pirfenidone Inhibits Dimethylnitrosamine‐Induced Hepatic Fibrosis In Rats
Authors: Tada Seiya , Nakamuta Makoto , Enjoji Munechika , Sugimoto Rie , Iwamoto Hiroaki , Kato Masaki , Nakashima Yutaka , Nawata Hajime
Published: March 2003

1. In the present study, we investigated the preventive effects of pirfenidone (PFD), an antifibrotic agent, on experimental hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats.

2. Treatment with DMN caused a significant decrease in bodyweight and liver weight. Oral PFD (500 mg/kg daily for 4 weeks) essentially prevented this DMN‐induced loss in bodyweight and tended to suppress the loss in liver weight. There were no significant differences in liver weight and serum L‐alanine aminotransferase levels between PFD‐treated and ‐untreated groups. Pirfenidone has no major side effects in vivo.

3. Pirfenidone suppressed the induction of hepatic fibrosis determined by histological evaluation and reduced hepatic hydroxyproline levels. Expression of mRNA for type I collagen and transforming growth facter‐β in the liver was also suppressed by PFD treatment.

4. Because hepatic stellate cells (HSC) are the major cellular source of extracellular matrix in hepatic fibrosis, we examined the effects of PFD on type I collagen production in vitro using rat primary HSC cultures. Pirfenidone inhibited collagen production in HSC culture in a dose‐dependent manner.

5. These results demonstrate that the inhibitory effects of PFD against hepatic fibrosis may be due, at least in part, to blockade of collagen production by HSC and suggest that PFD may be potentially useful in the prevention of the development of hepatic fibrosis.
Exacerbatory mechanism responsible for water immersion stress‐induced gastric lesions in aged rats compared with young rats
Authors: Goto Hidemi , Tachi Kosuke , Hisanaga Yasuhiro , Kamiya Kenji , Ohmiya Naoki , Niwa Yasumasa , Hayakawa Tetsuo
Published: March 2003

1. The present study was designed to investigate whether or not ageing affects the development of water immersion stress‐induced gastric lesions in rats. Effects of cetraxate, an anti‐ulcer drug, were also examined.

2. Gastric lesions were induced by 6 h water immersion stress in rats. Gastric mucosal blood flow was determined by the hydrogen gas clearance technique and nitric oxide synthase (NOS) activity was measured enzymatically.

3. Early development of gastric lesions was observed in aged rats and exacerbation of gastric lesions was also found. Lowering of gastric mucosal blood flow and reduced NOS activity were observed in aged rats.

4. Cetraxate mitigated the development of gastric lesions in young rats and also increased gastric mucosal blood flow and NOS activity. However, these favourable effects were diminished in aged rats.

5. Decreased NOS activity may be an important exacerbatory factor to the development of gastric lesions in aged rats.

6. Effects of cetraxate differed between young rats and aged rats.

7. These results may explain the refractoriness and drug resistance in gastric ulcers encountered by elderly individuals.
Hypervolaemia improves global and local function and efficiency in postischaemic myocardium
Authors: Du FY , Chen X‐L , Drzewiecki G , Li JK‐J , Kedem J
Published: March 2003

1. In the present study, we investigated the effects of blood volume on postischaemic function and efficiency. In 14 anaesthetized dogs, following recovery from a period of 15 min occlusion of the left anterior descending coronary artery, the effects of hypervolaemia (HYPER; 15% increased volume produced by fast infusion of Hespan; B Braun Medical, Irvine, CA, USA), normovolaemia (NORMO) and hypovolaemia (HYPO) were studied.

2. Although myocardial O2 consumption was not significantly increased by volume (6.37±0.94 vs 6.89±1.1 mL/min per 100 g for HYPO and HYPER, respectively), local work of the stunned myocardium was markedly elevated (8.8±1.7 vs 22.5±3.5 g·mm/ beat, for HYPO and HYPER, respectively; P < 0.05). External work of the heart was also significantly improved (71.8±12.7 vs 139.5±16.2 mmHg·L/min for HYPO and HYPER, respectively). These data indicate markedly improved efficiency produced by volume, because work was increased with no change in myocardial O2 consumption.

3. Local dysfunction was characterized by several parameters, including systolic bulge, end‐diastolic length, delay to onset of shortening, end shortening time delay (EST) and tail work ratio. Hypervolaemia reduced EST compared with hypovolaemia (98.6±18.3 vs 110.7±14.9 msec, respectively; P < 0.05) and improved tail work ratio (28.0±7.0 vs 36.0±7.0%, respectively; P < 0.05), with no effects on systolic bulge, end‐diastolic length and delay to onset of shortening.

4. Thus, even in the postischaemic myocardium, increasing work by volume is energetically efficient and is accompanied by partial improvement of local dysfunction.
Telemetric Monitoring Of Adrenocorticotrophin‐Induced Hypertension In Mice
Authors: Schyvens CG , Mangos GJ , Zhang Y , McKenzie KUS , Whitworth JA
Published: March 2003

1. The mouse is the animal of choice for studies involving genetic manipulation and transgenic and knockout mice are valuable tools for physiological studies. We have studied adrenocorticotrophin (ACTH)‐ and steroid‐induced hypertension in both rat and humans. The aim of the present study was to develop a model of ACTH‐induced hypertension in the mouse and to assess a chronically implanted telemetric device for measurement of blood pressure (BP).

2. Male Swiss Outbred and Quackenbush Swiss (QS) mice (35–45 g) were implanted with TA11PA‐C20 BP devices (Data Sciences International, St Paul, MN, USA) under isoflurane anaesthesia. Seven to 10 days later, mice were monitored telemetrically for baseline BP for 4 days. Mice were then randomly allocated to: (i) sham treatment with normal saline s.c.; or (ii) ACTH at 500 μg/kg per day, s.c. Mice were monitored 24 h/day for 10 days.

3. Sham treatment (n = 7) did not affect BP (114 ± 2/84 ± 1 to 115 ± 2/84 ± 1 mmHg; P = NS). Adrenocorticotrophin treatment (n = 5) raised BP from 112 ± 7/82 ± 4 to 138 ± 3/104 ± 4 mmHg, which was significantly different from sham treatment (P = 0.0021 for systolic BP; P < 0.0001 diastolic BP). The increase in BP with ACTH was comparable with that seen in previous studies in humans, sheep and rat. Sham and ACTH‐treated animals each lost 3% bodyweight.

4. Administration of ACTH (500 μg/kg per day) raises BP in two strains of mice, measured using a telemetry system. This model will allow the selective use of transgenic and/or knockout mice to further elucidate the mechanism of ACTH‐ and steroid–induced hypertension.
Elevated Serum Endogenous Inhibitor Of Nitric Oxide Synthase And Endothelial Dysfunction In Aged Rats
Authors: Xiong Yan , Yuan Li‐Wei , Deng Hang‐Wu , Li Yuan‐Jian , Chen Ben‐Mei
Published: March 2003

1. The purpose of the present study was to determine the relationship between endothelial dysfunction and the endogenous inhibitor of nitric oxide synthase NG,NG′‐asymmetric dimethylarginine (ADMA) in aged rats.

2. Studies were performed in male adult Sprague‐Dawley rats (6 months old; n = 8) and in aged rats (20 months old; n = 8). Serum levels of ADMA and L‐arginine were measured by high‐performance liquid chromatography and responses of endothelium‐intact aortic rings to acetylcholine (ACh) were tested. Nitric oxide synthase activity in kidney tissue and serum concentrations of nitrite, a stable end‐product of nitric oxide, were assayed and serum contents of malondialdehyde, derived from lipid peroxidation and serum lipid and creatinine level were determined.

3. Serum levels of ADMA increased significantly in aged rats compared with adult rats (P < 0.01), whereas serum levels of L‐arginine were similar in both groups (P = NS). Accordingly, the ratio of L‐arginine/ADMA in old rats was lower than that in young rats (P < 0.01). Endothelium‐dependent relaxation responses to ACh in aortic rings from aged rats were impaired and these impaired responses were improved by pre‐incubation of aortic rings with L‐arginine.

4. Nitric oxide synthase activity in the kidney, together with serum concentration of nitrite, was significantly decreased and serum contents of malondialdehyde, cholesterol and triglycerides were increased in old compared with young rats. However, the serum creatinine level was not significantly different between adult and aged rats.

5. Endogenous ADMA may be a contributor to age‐related endothelial dysfunction and increases in endogenous ADMA may be linked to lipid peroxidation in aged rats.
Prenatal Undernutrition, Glucocorticoids And The Programming Of Adult Hypertension
Authors: Edwards Lisa J , Coulter Catherine L , Symonds Michael E , McMillen I Caroline
Published: March 2003

1. A range of epidemiological studies has shown that poor intra‐uterine growth is associated with an increased prevalence of cardiovascular disease, non‐insulin‐dependent diabetes mellitus and the Metabolic syndrome in adult life.

2. Because these associations are independent of adult lifestyle or current size, it has been postulated that a reduced intra‐ uterine nutrient supply perturbs fetal growth and, concomitantly, alters or programmes the structure and function of developing systems.

3. A reduced fetal nutrient supply may be a consequence of poor placental function or inadequate maternal nutrient intake.

4. It has been proposed that one outcome of either a suboptimal placental or maternal nutrient supply is exposure of the fetus to excess glucocorticoids, which act to restrict fetal growth and to programme permanent changes in the cardiovascular, endocrine and metabolic systems.

5. While a range of studies in the rat has investigated the impact of maternal undernutrition on arterial blood pressure in the offspring, there have been relatively few studies in species, such as the sheep, in which the responses of the cardiovascular and neuroendocrine systems to intra‐uterine undernutrition can be measured before birth.

6. The present review summarizes recent evidence that poor placental function or inadequate maternal nutrition each results in an increased exposure of fetal sheep tissues to glucocorticoids and, in specific, changes in the regulation of fetal arterial blood pressure.

7. These studies are important in determining how the timing, type and duration of fetal nutrient restriction are each important in determining the nature of the fetal neuroendocrine and cardiovascular adaptive responses and their pathophysiological sequelae in later life.
Does It Make Sense To Develop New Centrally Acting Cardiovascular Drugs?
Authors: Bousquet P , Monassier L , Feldman J
Published: March 2003

1. The autonomic nervous system plays a pivotal role in modulating all the components of the cardiovascular regulation. Therefore, one can assume that drugs targeting this system may be useful in the management of several cardiovascular diseases.

2. Drugs acting on central nervous system centres seem to be modulators rather than blockers; as such, they are expected to preserve the contraregulatory processes and to generate only a few side effects.

3. Because the sympathetic nervous system is largely involved in the regulation of vasomotor tone, centrally acting antihypertensive drugs were developed first.

4. Recently, new leader compounds selective for non‐ adrenergic imidazoline recepetors have been synthetized. Although such drugs have no capacity to activate α2‐adrenoceptors, they have been proven to be hypotensive. These drugs are expected to be even better tolerated than the currently available centrally active drugs. They may also have additional beneficial effects.

5. Here, the experimental evidence suggesting that such drugs may be useful in the management of some cardiac arrhythmias and/or left ventricular dysfunction will be reviewed.
Analysis Of Agonist‐Evoked Nitric Oxide Release From Human Endothelial Cells: Role Of Superoxide Anion
Authors: David‐Dufilho Monique , Brunet Annie , Privat Christelle , Devynck Marie‐Aude
Published: March 2003

1. Dichlorofluorescein oxidation and electrochemical monitoring of in situ nitric oxide (NO) release from cultured human endothelial cells reveals that agonists such as thrombin and histamine simultaneously stimulate transient superoxide production.

2. The duration of ·NO release was increased only in the simultaneous presence of extracellular L‐arginine and exogenous superoxide dismutase. In contrast, the inhibition of membrane reduced nicotinamide adenine dinucleotide (phosphate) oxidases, the major source of ·O2– in endothelial cells, did not prolong ·NO release, although extracellular L‐arginine was also present. Comparison of these two experimental conditions suggested that H2O2 was involved in the extension of the ·NO signal.

3. The present study demonstrates that, in the absence of external L‐arginine, ·O2– production does not constitute the major pathway controlling the duration of agonist‐induced ·NO signal. These results suggest that L‐arginine and H2O2 act jointly to maintain nitric oxide synthase in an activated form.
Alcohol And Endothelial Function: A Brief Review
Authors: Puddey IB , Zilkens RR , Croft KD , Beilin LJ
Published: March 2003

1. In spite of the dose‐related effects of alcohol consumption to increase blood pressure, regular light to moderate alcohol intake appears to confer protection against both coronary artery disease and ischaemic stroke. In contrast, heavy alcohol consumption increases the risk of coronary artery disease and the risk of both haemorrhagic and ischaemic stroke.

2. Effects of alcohol consumption on endothelial cell function may be relevant to these disparate effects on cardiovascular outcomes. In in vitro animal studies, low doses of alcohol have been demonstrated to increase release of nitric oxide and augment endothelium‐mediated vasodilatation, whereas higher doses impair endothelium‐dependent relaxation responses. In contrast, chronic administration of alcohol to rats has generally been associated with tolerance to the acute inhibitory effects of alcohol on endothelium‐mediated vasodilatation and may even result in augmentation of such responses.

3. The few human studies to date that have examined the effects of alcohol on endothelial function have focused on postischaemic flow‐mediated dilation of the brachial artery (FMD). Although blunted FMD responses have been reported in alcoholic subjects, acute administration of alcohol or short‐term interventions to reduce alcohol intake have had no effect to either improve or impair FMD.

4. Further studies in humans assessing acute and longer term dose‐related effects of alcohol on endothelial function in both conduit and resistance vessels will be necessary if the relevance of the findings from in vitro and in vivo animal studies are to be understood in the context of the complex interrelationships of alcohol with cardiovascular disease.
Phenotypic And Genetic Heterogeneity Of Familial Hyperkalaemic Hypertension (Gordon Syndrome)
Authors: Achard Jean‐Michel , Disse‐Nicodeme Sandra , Fiquet‐Kempf Béatrice , Jeunemaitre Xavier
Published: March 2003

1. Familial hyperkalaemic hypertension (FHH), also called pseudohypoaldosteronism type II (PHA2) or Gordon syndrome, is a rare Mendelian‐form of low‐renin hypertension. The first cases of FHH were reported approximately 30 years ago and they described the peculiar biochemical abnormalities (i.e. hyperkalaemia and hyperchloraemic acidosis despite a normal glomerular filtration rate).

2. Since then, more than 90 single cases and families have been reported in the literature. These various reports show marked differences in phenotype.

3. Our group has now collected 14 unrelated pedigrees originating from different parts of France and Europe. We confirm the large variations in the age of discovery and in the severity of the biochemical abnormalities from one individual to another and from one family to another one.

4. Blood pressure levels have no significant relationship with hyperkalaemia or hyperchloraemia, but there is a positive relationship with age, as in the normal population.

5. Analyses of clinical features and Mendelian segregation in our families demonstrate autosomal‐dominant inheritance, as expected from the literature.

6. Efforts have been made in the past years to unravel the gene responsible for the disease. Until now, a primary responsability of the gene encoding the thiazide‐sensitive Na–Cl cotransporter (SLC12A3) has been excluded in PHA2 families. Three loci have been identified on chromosomes 1 (PHA2A), 17 (PHA2B) and 12 (PHA2C).

7. More recently, analysis of three additional pedigrees, including 10 affected subjects, with over 25 members allowed us to demonstrate further genetic heterogeneity and the existence of at least a fourth locus.

8. The genetic heterogeneity of this syndrome, and thus the variety of molecular defects, suggests the role of either several new components of the same pathway, multiple aldosterone‐ regulated effectors or direct or indirect partners of the Na–Cl cotransporter.
Role Of Nitric Oxide In Mediating Vasodilator Responses To Opioid Peptides In The Rat
Authors: Champion Hunter C , Bivalacqua Trinity J , Zadina James E , Kastin Abba J , Hyman Albert L , Kadowitz Philip J
Published: March 2003

1. Endomorphins 1 and 2, endogenous ligands for the μ‐opioid receptor, and nociceptin (orphanin FQ; OFQ), an endogenous ligand for the ORL1 receptor, have vasodilator activity in the vascular bed of the hindquarters of the rat. In the present study, the role of nitric oxide (NO), vasodilator prostaglandins and the opening of KATP channels in mediating vasodilator responses to these novel agonists was investigated in the rat.

2. Under constant‐flow conditions, injections of endomorphins 1 and 2, PL017 ([N‐MePhe3,D‐Pro4]‐morphiceptin),
nociceptin and Tyr‐D‐Ala‐Gly‐MePhe‐Gly(ol)‐enkephalin (DAMGO) produced
dose‐dependent decreases in hindquarters perfusion pressure. Vasodilator responses
to endomorphin 1 and 2, acetylcholine and adrenomedullin, were attenuated by the
NO synthase inhibitor NG‐nitro‐L‐arginine methyl
ester (L‐NAME) at a time when vasodilator responses to nociceptin, adrenomedullin and the NO donor diethylamine/NO were not altered.

3. Vasodilator responses to endomorphins 1 and 2, nociceptin, PL017 and DAMGO were not altered after administration of sodium meclofenamate at a time when vasodilator responses to arachidonic acid were reduced significantly or after administration of U‐37883A at a time when vasodilator responses to levcromakalim were reduced significantly.

4. The results of these studies indicate that vasodilator responses to endomorphins 1 and 2, PL017 and DAMGO are mediated, in large part, by the release of NO, whereas vasodilator responses to nociceptin are mediated by an L‐NAME‐insensitive
mechanism. Moreover, these results demonstrate that the vasodilator responses to
these peptides are not due to the release of vasodilator prostaglandins or the opening
of KATP channels in the hindquarters vascular bed of the rat.
Functional Roles Of KATP Channels In Vascular Smooth Muscle
Authors: Brayden Joseph E
Published: March 2003

1. ATP‐sensitive potassium channels (KATP) are present in vascular smooth muscle cells and play important roles in the vascular responses to a variety of pharmacological and endogenous vasodilators.

2. The KATP channels are composed of four inwardly rectifying K+
channel subunits and four regulatory sulphonylurea receptors. The KATP channels are inhibited by intracellular ATP and by sulphonylurea agents.

3. Pharmacological vasodilators such as cromakalim, pinacidil and diazoxide directly activate KATP channels. The associated membrane hyperpolarization closes
voltage‐dependent Ca2+ channels, which leads to a reduction in intracellular
Ca2+ and vasodilation.

4. Endogenous vasodilators such as calcitonin gene‐related peptide, vasoactive intestinal polypeptide, prostacylin and adenosine activate KATP by stimulating
the formation of cAMP and increasing the activity of protein kinase A. Part of the
mechanism of contraction of endogenous vasoconstrictors is due to inhibition of KATP channels.

5. The KATP channels appear to be tonically active in some vascular beds and contribute to the physiological regulation of vascular tone and blood flow. These channels also are activated under pathophysiological conditions, such as hypoxia, ischaemia, acidosis and septic shock, and, in these disease states, may play an important role in the regulation of tissue perfusion.
Quinapril Treatment Restores The Vasodilator Action Of Insulin In Fructose‐Hypertensive Rats
Authors: Uchida Takanori , Okumura Kenji , Ito Takayuki , Kamiya Hiroki , Nishimoto Yasuhiro , Yamada Michiharu , Tomida Takahito , Matsui Hideo , Hayakawa Tetsuo
Published: March 2003

1. Angiotensin‐converting enzyme (ACE) inhibitors have been shown to improve insulin‐resistance both experimentally and clinically. We therefore investigated the effects of quinapril, which has high tissue specificity for ACE, regarding the contribution of insulin to vascular contractions, as well as insulin sensitivity in a dietary rat model of insulin resistance.

2. Male Sprague‐Dawley rats were divided into three groups: (i) rats fed normal chow (normal diet group); (ii) rats fed fructose‐rich chow containing 40% fructose and 7% lard (fructose diet group); and (iii) rats fed fructose‐rich chow plus quinapril (10 mg/kg per day; quinapril‐treated group).

3. After 2 weeks, we evaluated systolic blood pressure, insulin sensitivity as assessed by steady state plasma glucose (SSPG) levels, response of aortic rings to phenylephrine (10–9 to 10–6 mol/L) in the presence or absence of insulin and the response of aortic rings to acetylcholine.

4. Feeding rats fructose‐rich chow resulted in an elevation of blood pressure (P < 0.01) and SSPG levels (P < 0.01). Quinapril treatment significantly prevented increases in both blood pressure and SSPG, with a return to the levels seen in the normal diet group.

5. In the absence of insulin, the maximal contractile response to phenylephrine did not differ between the three groups. However, in the presence of insulin (100 mU/mL), the contractile response to phenylephrine (10–6 mol/L) was reduced by 22.8 ± 1.2% in the normal diet group, although no insulin effects were observed in the fructose diet group (P < 0.01). Quinapril restored the inhibitory effect of insulin on phenylephrine‐induced contractions.

6. In addition, the reduction in relaxation induced by acetylcholine in the fructose diet group was significantly reversed by quinapril treatment.

7. It is concluded that the fructose diet impairs the vasodilator effects of insulin as well as acetylcholine‐induced relaxation in rat thoracic aortas. Quinapril prevented deterioration in the responses of the aortic rings, suggesting that ACE inhibitors may be useful for treating vascular insulin resistance.
Antinociceptive Action Of Captopril And Transcutaneous Electric Nerve Stimulation In Mus Musculus Mice
Authors: Motta Mauricy Alves da , Vasconcelos Mallinson da Silva , Catanho Maria Teresa de Almeida Jansen
Published: March 2003

1. In the present study, the antinociceptive action of captopril was investigated, as well as its association with transcutaneous electric nerve stimulation (TENS), in mice under nociceptive stimulation.

2. The modulation of abdominal contortions (writhes) produced by acetic acid was observed in order to evaluate captopril pain stimuli blockade.

3. The administration of captopril produced a significant reduction of nociception, which was further reduced when captopril was associated with TENS.

4. Apparently this increase in the inhibition of nociception was produced by an indirect mechanism, involving opioid liberation by TENS and an enzymatic inhibition induced by captopril and this may lead to clinical applications of captopril and TENS association in pain relief.
Effects Of Molybdenum, Silicon And Nickel On α1‐Adrenoceptor‐Induced Constriction Of Rat Isolated Aorta
Authors: Liu Dong Ling , Yan Ming , Chua Yeow Leng , Chen Chen , Lim Yean Leng
Published: March 2003

1. To determine the effects of trace elements on α1‐adrenoceptor‐mediated vasoconstriction, we studied the effects of molybdenum (Mo), silicon (Si) and nickel (Ni) on vasoconstrictor response to an α1‐adrenoceptor agonist in rat aorta.

2. Cumulative concentration–contraction curves were obtained for phenylephrine (1 nmol/L–10 μmol/L) in the absence and presence of Mo, Si and Ni (0.3, 1 and 3 μmol/L) in rat aorta rings. Increasing the concentration of Mo and Si from 0.3 to 3 μmol/L shifted the cumulative concentration–contraction curve to the right, but did not reduce the maximal contractile response to phenylephrine. In contrast, Ni at 1 and 3 μmol/L shifted the cumulative concentration–contraction curve to the right and, at 3 μmol/L, reduced the maximum contractile response to phenylephrine.

3. We conclude that micromolar concentrations of Mo, Si and Ni affected α1‐adrenoceptor‐induced vasoconstriction and that Ni significantly inhibited the maximal contractile response to phenylephrine in rat isolated aorta.
Effects Of Caffeine On The Uncoupling Protein Family In Obese Yellow Kk Mice
Authors: Kogure Akinori , Sakane Naoki , Takakura Yasuto , Umekawa Tsunekazu , Yoshioka Keiji , Nishino Hoyoku , Yamamoto Takayuki , Kawada Teruo , Yoshikawa Toshikazu , Yoshida Toshihide
Published: March 2003

1. The hypothesis that caffeine upregulates uncoupling protein (UCP)‐1, UCP‐2 and UCP‐3 expression, which contribute to thermogenesis, was investigated in obese mice.

2. The mRNA levels of UCP‐1, ‐2 and ‐3 in brown adipose tissue (BAT), UCP‐2 in white adipose tissue (WAT), and UCP‐2 and ‐3 in skeletal muscle were measured using real‐time quantitative reverse transcription–polymerase chain reaction analysis in obese yellow KK mice 4 h after the subcutaneous administration of either 60 mg/kg caffeine or physiological saline. Plasma free fatty acids, adrenaline, noradrenaline and dopamine levels were also measured.

3. In caffeine‐injected obese mice, UCP‐1 mRNA levels were significantly increased by 1.5‐fold in BAT, UCP‐2 mRNA levels were increased by 1.8‐ and 2.5‐fold in BAT and skeletal muscles, respectively, and UCP‐3 mRNA levels were increased 1.7‐ and 3.4‐fold in BAT and skeletal muscles, respectively, compared with control mice injected with physiological saline. There was no difference in UCP‐2 mRNA levels in WAT between the two groups.

4. Plasma free fatty acids and adrenaline levels were significantly elevated in mice treated with caffeine compared with those injected with physiological saline.

5. It was concluded that caffeine upregulates the expression of UCP‐1, UCP‐2 and UCP‐3 in BAT and UCP‐2 and UCP‐3 in skeletal muscles, which may contribute to thermogenesis in obese mice.
Age‐Related Changes In Dopamine D2 Receptors In Rat Heart And Coronary Vessels
Authors: Cavallotti Carlo , Nuti Federica , Bruzzone Paolo , Mancone Massimo
Published: March 2003

1. The distribution of dopamine D2 receptors in rat heart and coronary vessels and the possible age‐related changes in D2 receptor density were studied. The pharmacological characteristics and the anatomical location of dopamine D2‐like receptor sites in rat heart and coronary vessels were investigated using combined binding techniques and light microscopy autoradiography.

2. Samples of heart and coronary vessels were harvested from young and old rats. On frozen slices, dopaminergic D2 receptors were labelled by means of a selective D2 ligand, namely [3H]‐spiroperidol (spiperone). Inhibition studies were performed using unlabelled agonists and/or labelled and unlabelled antagonists to define pharmacological specificity of the binding. Physiological experiments were performed to demonstrate the selective antagonism between D2 receptors and many dopaminergic drugs.

3. [3H]‐Spiroperidol was bound to sections of rat heart and coronary artery (in a manner consistent with the labelling of dopamine D2‐like receptors) with an equilibrium dissociation constant of approximately 2.4 ± 0.7 nmol/L and a maximum capacity of binding sites of 65.8 ± 4.5 fmol/mg protein. Experiments performed on sections of coronary veins did not allow the evaluation of specific binding. Autoradiography, observed with light microscopy, showed the development of specific silver grains within the whole wall of rat heart and coronary artery. The greater sensitivity to displacement by amisulpride, bromocriptine, domperidone, haloperidol, raclopride and L‐sulpiride than to displacement by N‐propyl‐norapomorphine, quinpirole and clozapine suggests that the binding sites observed in these experiments are likely to belong to the dopamine D2 receptor subtype.

4. Comparing results in young and old rats, we observed numerous significant age‐related changes, including a decrease in D2 receptors localized in rat heart and coronary artery wall. These D2 receptors show a specific location, in close relationship with dopaminergic nerve fibres. They decrease with age and their role remains unknown.
Effects Of Birth On Baroreceptor‐Mediated Changes In Heart Rate Variability In Lambs And Fetal Sheep
Authors: Yu Ze‐Yan , Lumbers Eugenie R
Published: March 2003

1. In adult unanaesthetized sheep, there is a V‐shaped relationship between mean arterial pressure (MAP) and heart rate variability (HRV), measured in both time and frequency domains. In contrast, in fetal sheep, there is only a positive direct relationship between MAP and HRV, which is determined by the cardiac vagus. We postulated that by the time lambs were 8–10 days old, the ‘adult like’ V‐shaped relationship between MAP and HRV would be present and it may appear at or after birth. To test these hypotheses, experiments were performed in six chronically catheterized fetal sheep (aged 132–138 days gestation), 10 newborn sheep (within 10 h of birth) and 10 lambs (aged 8–10 days). The relationships between MAP and HRV (in both time and frequency domains) were studied before and during β‐adrenoreceptor blockade with propranolol and before and during cardiac vagal blockade with atropine.

2. In 8–10‐day‐old lambs, V‐shaped relationships between MAP and HRV (measured in both time and frequency domain) were obtained. The negative limb of this V‐shaped relationship between MAP and HRV was present after cardiac vagal blockade. The positive slope of the V was present after β‐adrenoreceptor blockade.

3. In 4‐h‐old newborn sheep, there was no relationship between MAP and HRV (measured in the time domain), but between 7 and 10 h of age a negative relationship was found during treatment with atropine and a positive relationship was found during β‐adrenoreceptor blockade, when HRV was measured in both time and frequency domains.

4. As described previously, there was only a positive relationship between MAP and HRV in fetal sheep, which was abolished by atropine but not affected by β‐adrenoreceptor blockade.

5. Thus, until relatively late in fetal life, baroreceptor‐ modulated changes in efferent cardiac sympathetic tone, determined by measuring the effects of autonomic blockade on HRV, could not be elicited, although reflex vagal pathways were active. By 7–10 h after birth, baroreceptor‐modulated changes in efferent cardiac sympathetic tone were present. It was possible using measurements of HRV made in the time domain to show that these baroreceptor‐modulated cardiac sympathetic effects became stronger over the first 10 days of life (P < 0.01). These studies are the first to show that the influence of baroreceptor‐mediated changes in cardiac sympathetic tone on HRV increases in early life. This is probably because maturation of sympathetic innervation of the fetal sheep heart is occurring at this age.
Highly Protective Effects Of Chronic Oral Administration Of Nicorandil On The Heart Of Ageing Rats
Authors: Garnier‐Raveaud Stéphanie , Faury Gilles , Mazenot Catherine , Cand Francine , Godin‐Ribuot Diane , Verdetti Jean
Published: March 2003

1. We have tested the effects of 2 month oral treatment with the KATP opener, nitric oxide (NO) donor and anti‐oxidant molecule nicorandil (0.1 mg/kg per day) on major physiological parameters and heart function of 4‐, 12‐ and 24‐month‐old rats.

2. Several methods were used: (i) measurement of blood pressure using a non‐invasive tail‐cuff method; (ii) perfusion of isolated heart; (iii) lactate dehydrogenase (LDH) dosage; and (iv) measurement of monophasic action potential of rat isolated hearts.

3. Blood pressure and ventricular action potential duration regularly increase with age in control animals, whereas nicorandil restores these parameters in aged animals to levels present in young adult animals. Moreover, following ischaemia, nicorandil treatment improved isolated heart survival rate (100 vs 50% for nicorandil‐treated rats and controls, respectively), heart work and left ventricular developed pressure, whereas it decreased cardiac cell damage (LDH release) and perfusion pressure.

4. This condition of chronic oral nicorandil treatment presents a strong potential in the improvement of cardiac function in normal and pathological ageing.