bluuebunny/crossref_metadata_2025 huggingface dataset:
EXERCISE‐LOADED BLOOD PRESSURE AND Li‐Na COUNTERTRANSPORT SYSTEM IN THE ERYTHROCYTE MEMBRANE AS PREDICTORS OF MILD ESSENTIAL HYPERTENSION PROGNOSIS
Authors: Saito Toshihiro , Onuma Noriyoshi , Yamamoto Mitsuyuki , Kai Noriyuki , Yamamoto Kazutoshi , Iwata Jiro , Yamada Kenjiro , Deguchi Fujio , Inagaki Yoshiaki
Published: June 2007

1. The blood pressure response to exercise loading, Na concentration in the erythrocyte and Li–Na countertransport (Li–Na CT) system in the erythrocyte membrane in 40 male volunteers and 98 patients with mild essential hypertension were investigated. Subjects were divided into a juvenile group (<36 years) and a middle‐aged (>36 years and <65 years) group. Exercise‐loaded blood pressure in patients with mild essential hypertension was followed up for more than 5 years.

2. Systolic blood pressure (SBP) at 6 min during exercise loading was significantly higher in the mild hypertension group compared with the control group.

3. Patients with high SBP at exercise loading in the mild hypertension group transferred more often to the moderate hypertension group within 5 years.

4. No difference in the haemodynamic parameter at rest was noted in the transferred group for moderate hypertension and the non‐transferred group.

5. A higher blood pressure response to noradrenaline was noted in the transferred group compared with the non‐transferred group of the juvenile group.

6. High Na concentration in the erythrocyte and acceleration of the Li–Na CT system in the erythrocyte membrane were noted in the mild hypertension group compared with the volunteer group.

7. A correlation between SBP at exercise loading and Li‐Na CT system in the erythrocyte membrane was noted. This correlation was strongly noted in subjects less than 50 years old.

8. From these results it was concluded that SBP at exercise loading and Li–Na CT system in the erythrocyte membrane are useful as indicators for the prognosis of mild essential hypertension.
ROLE OF PLATELET CYTOSOLIC CALCIUM IN THE RESPONSE TO SALT INTAKE IN NORMOTENSIVE SUBJECTS
Authors: Yamakawa Hiroshi , Suzuki Hiromichi , Nakamura Makoto , Ohno Yoichi , Saruta Takao
Published: June 2007

1. To investigate the role of cytosolic calcium in salt‐induced hypertension, a high salt diet was given to young normotensive subjects with or without a family history of hypertension.

2. A high salt diet raised blood pressure significantly in normotensive subjects with a family history compared with the age and gender matched subjects without a predisposition to hypertension.

3. Platelet cytosolic calcium was increased in predisposed subjects in a control period before salt intake.

4. A positive correlation was observed between the changes in mean blood pressure and cytosolic calcium before high salt intake, although salt loading did not induce any significant change in cytosolic calcium.

5. These results suggest that cytosolic calcium plays a role in elevation of blood pressure induced by salt loading in subjects with a family history of hypertension.
PHARMACOLOGICAL EVALUATION OF TWO NOVEL ANALOGUES OF MIANSERIN: 2‐N‐CARBOXAMIDINONORMIANSERIN(FCC5) AND 2‐N‐CARBOXAMIDONORMIANSERIN (FCC13)
Authors: Leitch Ian M. , Rawlow Andrew , Rechtman Mary P.
Published: June 2007

1. The pharmacological properties have been examined of FCC5 (2‐N‐carboxamidinonormianserin) and FCC 13 (2‐N‐carboxamidonormianserin), two novel analogues of mianserin.

2. FCC5 or FCC13 (100 μg/kg, i.v.) caused long‐lasting (>1 h) abolition of 5‐hydroxytry‐ptamine (5‐HT) and histamine‐induced bronchoconstriction in the anaesthetized guinea‐pig. Both analogues had no effect (up to 1 mg/kg, i.v.) on bronchoconstriction caused by acetylcholine (25–50 μg/kg, i.v.).

3. The pressor effects of 5‐HT in pithed rats were significantly attenuated by FCC5 (0.1 mg/kg, i.v.) or FCC13 (0.5 mg/kg, i.v.).

4. Oedema in the rat hind paw caused by intraplantar 5‐HT was inhibited by FCC5 (ID500.76 mg/kg, i.p.; 2.7 mg/kg, p.o.) or FCC13 (ID5100.65 mg/kg, i.p.; 5.8 mg/kg, p.o.).

5. In the central nervous system (CNS), FCC 13 caused antagonism of 5‐HT activity. It inhibited: (i) l‐5‐hydroxytryptophan (l‐5‐HTP)‐induced head twitches in mice (ID501.85 mg/kg, i.p.), (ii) fenfluramine‐induced facilitation of flexor reflex activity (FRA) in spinalized decerebrate rats (SDR) (IC500.57 mg/kg, i.p.).

6. FCC5 (≤30 mg/kg, i.p. and ≤3 mg/kg, i.p., respectively) had no effect in either test. In contrast to mianserin, it also had no overt central actions as (≤30 mg/kg, i.p.) had no effect on: (i) morphine‐induced catalepsy (MIC) or (ii) clonidine‐induced facilitation of FRA in SDR. However, high doses of FCC13 inhibited MIC (ID5020 mg/kg, i.p.), but had no effect on (ii) (≤10 mg/kg, i.p.).

7. Thus, FCC5 and FCC13 are potent, orally active H1 and 5‐HT receptor antagonists. However, in contrast to FCC 13 and mianserin, FCC5 did not cause CNS‐mediated effects.
INHIBITORY EFFECT OF NEUROPEPTIDE Y ON STIMULATED RENIN SECRETION OF AWAKE RATS
Authors: Aubert Jean‐Francois , Walker Philippe , Grouzmann Eric , Nussberger Jürg , Brunner Hans R. , Waeber Bernard
Published: June 2007

1. (1‐36)‐NPY is a vasoconstrictor peptide widely distributed in sympathetic nerve terminals. This peptide exerts an inhibitory action on renin release induced by various stimuli. Post‐synaptic neuropeptide Y (NPY) receptors show a high affinity for (1‐36)‐NPY as well as for the agonist (Pro34)‐NPY, while presynaptic receptors bind preferentially (13‐36)‐NPY.

2. This study was undertaken to assess whether the NPY induced renin suppression in awake normotensive rats infused with the β‐adrenoceptor stimulant isoproterenol is mediated by activation of pre‐ or post‐synaptic receptors.

3. Non‐pressor doses of (1‐36)‐NPY and (Pro34)‐NPY markedly attenuated the renin secretion triggered by isoproterenol whereas (13‐36)‐NPY had no effect. This suggests that the effect of NPY on renin release is due to the stimulation of post‐synaptic receptors. However it remains unknown whether NPY acts directly on juxtaglomerular cells or indirectly by modifying intraglomerular haemodynamics.
TIME COURSE OF REGIONAL FLOW DISTRIBUTION FOLLOWING REPERFUSION OF THE ISOLATED ISCHAEMIC RAT HEART
Authors: Sjöquist P‐O. , Abrahamsson T. , Johansson M. H.
Published: June 2007

1. The regional distribution of flow was studied at different times after the onset of reperfusion in isolated rat heart preparations. The hearts were submitted to 30 min of global ischaemia followed by 60 min of reperfusion. Microspheres labelled with various nuclides were added to the perfusate before ischaemia and 1, 5, 20, and 60 min after the onset of reperfusion.

2. One minute after the start of reperfusion, the flow to the left ventricular inner layer was restricted to 0.5 ± 0.2 mL/min per g (2–3% of the pre‐ischaemic flow). In this segment, the perfusion remained at the same low level during the entire reperfusion period studied. At the onset of reperfusion the flow to the outer layer of the left ventricle was 4.8 ± 1.7 mL/min per g (37% of the pre‐ischaemic flow), and 3.0 ± 1.3 mL/min per g (27% of the pre‐ischaemic value) to the free wall of the right ventricle. The flow was progressively reduced in the outer layer of the left ventricle in the course of reperfusion. After 60 min of reperfusion the flow to the left ventricular outer layer was 2.5 ± 0.9 mL/min per g (19% of pre‐ischaemic flow when compared with the onset of reperfusion [P < 0.05]).

3. It is concluded that a ‘no‐reflow’ condition develops very early during reperfusion and becomes more marked during this period.
IS ISOLATED SYSTOLIC HYPERTENSION A WHITE COAT’ PHENOMENON IN THE ELDERLY?
Authors: Silagy C. A. , McNeil J. J. , McGrath B. P. , Farish S.
Published: June 2007

1. Repeated clinic blood pressure measurement was compared with non‐invasive ambulatory blood pressure (ABP) monitoring in 10 elderly subjects with isolated systolic hypertension (ISH) and 11 normotensive controls (NT).

2. Subjects were assessed on four occasions at weekly intervals. None was receiving antihypertensive or vasoactive medication.

3. Mean clinic blood pressure was consistently higher than mean daytime ABP in both clinical groups. This effect was greater for systolic (SBP) than diastolic blood pressure (DBP) and in the ISH group compared with the NT group. The reproducibility of the clinic minus ABP difference was high in both groups; the mean±s.d. of the differences was 26± 15/9 ± 2 mmHg in the ISH group and 7 ± 18/8 ± 9 mmHg in the controls.

4. ABP readings were normally distributed for both SBP and DBP in both groups. In the ISH group, the frequency distribution of SBP readings was shifted to the right whilst the distribution of DBP readings overlapped that of the NT subjects.

5. These results suggest a pressor response may largely account for the elevated SBP seen in elderly subjects with sustained ISH based on casual readings.
NEUROVASCULAR FUNCTION DURING PREGNANCY IN THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Yong E. M. , Mano M. T. , Head R. J.
Published: June 2007

1. Blood pressure (BP) declines dramatically in the final week of gestation in the pregnant spontaneously hypertensive rat (SHR). This study investigated the hypothesis that alterations of vascular neuroeffector function in the pregnant SHR and normotensive Wistar‐Kyoto (WKY) rat are responsible for this decline.

2. Pregnancy in SHR and WKY rats was associated with a significant drop in BP in the last week of gestation.

3. Responses of the perfused mesenteric vasculature to bolus doses of noradrenaline (NA) and potassium chloride (KC1) were decreased in preparations from SHR rats 4 days before delivery. This decreased responsiveness was absent in preparations from SHR rats 1 day before delivery. Responses of the perfused mesenteric vasculature to sympathetic nerve stimulation were not influenced by pregnancy in the SHR.

4. It is concluded that while there are dynamic changes occurring in neurovascular function just prior to delivery, it is unlikely that they are wholly responsible for the dramatic decline in blood pressure in the SHR rat.
Presynaptic α2‐adrenoceptor‐mediated modulation of norepinephrine release from vascular adrenergic neurons in reduced renal mass salt hypertensive rats
Authors: Tsuda Kazushi , Kimura Keizo , Shima Hiroki , Nishio Ichiro , Masuyama Yoshiaki
Published: June 2007

The present study was designed to investigate the presynaptic α2‐adrenoceptor function to inhibit norepinephrine (NE) release in blood vessels of reduced renal mass salt hypertensive rats (Na‐loaded HT). Isolated perfused mesenteric vasculatures were prepared from Na‐loaded HT and normotensive control rats (NT‐control), and the NE release and vascular responsiveness were examined. Periarterial nerve stimulation caused a significantly greater release of NE and pressor responses in Na‐loaded HT than in NT‐control. Yohimbine, a potent α‐adrenoceptor antagonist, demonstrated the facilitatory effects on NE release during nerve stimulation. The effects were significantly attenuated in Na‐loaded HT compared with NT‐control.

These results demonstrate that vascular sympathetic nervous activity might be enhanced in Na‐loaded HT. Furthermore, the increased NE release from vascular adrenergic neurons in Na‐loaded HT could partially depend on impaired presynaptic α2‐adrenoceptor‐mediated modulation, which might contribute to the pathogenesis and maintenance of this form of salt‐dependent hypertension.
CHARACTERIZATION OF THE BARORECEPTOR HEART RATE REFLEX DURING DEVELOPMENT IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Head Geoffrey A. , Adams Michael A.
Published: June 2007

1. We have examined the baroreceptor‐heart rate (HR) reflex in weight‐matched conscious spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto (WKY) rats during development.

2. Graded steady‐state changes in mean arterial pressure (MAP) and the corresponding HR responses before and after vagal blockade with methylatropine were fitted to an S‐shaped logistic function.

3. At 6 weeks of age, SHR had a 17% higher MAP than WKY and an increased baroreflex gain (slope) compared with WKY due to an increased curvature of the MAP‐HR relationship. The HR range (the difference between the upper and lower HR plateaus) was similar in the two strains at this time.

4. From 9–14 weeks of age, the baroreflex gain progressively increased in WKY and decreased in SHR due to corresponding alterations in HR range.

5. By 20 weeks the baroreflex gain was 23% lower in SHR than WKY due to a 37% lower HR range.

6. There were no differences between the two strains in the sympathetic component of the baroreflex at any age, suggesting that the changes to baroreflex properties were confined to the cardiac vagus.

7. Pretreatment with enalapril from 4–9 weeks reduced the hypertension of SHR at 14 and 20 weeks by 38% and abolished all baroreceptor‐HR reflex differences between the two strains.

8. These studies suggest that the major alteration to the baroreceptor‐heart rate reflex in the SHR during development was a reduction in the maximum vagal capacity to respond to changes in blood pressure. This effect developed after the onset of hypertension and was prevented by antihypertensive treatment early in life. The lack of effect on the cardiac sympathetic component suggests that altered arterial baroreceptor afferents are not unlikely to be responsible.
XANTHINES INHIBIT HUMAN PLATELET AGGREGATION INDUCED BY PLATELET‐ACTIVATING FACTOR
Authors: Misso N. L. A. , Thompson P. J.
Published: June 2007

1. Platelet‐activating factor (PAF) may be involved in the pathogenesis of asthma, and therefore the effects of the anti‐asthma drugs theophylline and enprofylline on human platelet aggregation and adenosine triphosphate (ATP) release induced by PAF and adenosine diphosphate (ADP) were studied.

2. Enprofylline (50% inhibitory concentration [IC50] = 94.8±13.2 μmol/L) was more potent than theophylline (IC50= 934.1±40.1 μmol/L) as an inhibitor of PAF‐induced aggregation, and the xanthines were twice as potent as inhibitors of PAF‐induced aggregation when compared with ADP‐induced aggregation. ATP release was 1.4 times more sensitive to inhibition by the xanthines than aggregation.

3. Although high concentrations of xanthines inhibited platelet aggregation and ATP release induced by PAF, therapeutic concentrations are unlikely to inhibit PAF‐induced effects.
A STUDY OF SERUM PROLACTIN LEVELS IN SCHIZOPHRENIA: COMPARISON OF MALES AND FEMALES
Authors: Kuruvilla Alice , Peedicayil Jacob , Srikrishna Geetha , Kuruvilla K. , Kanagasabapathy A. S.
Published: June 2007

1. Serum prolactin levels were measured in large cohorts of schizophrenic patients (67 males and 42 females) and normal subjects (78 males and 42 females).

2. There was no significant differences between the serum prolactin levels of patients and controls, except in the age group 15–29 years. There were no significant differences between the serum prolactin levels of males and females, either among the patients or the control subjects.

3. The rise in serum prolactin levels after the commencement of neuroleptic medication in the patients was greater in females than in males even though the female patients received neuroleptics at lower doses.

4. These data indicate that serum prolactin levels in unmedicated males and females are similar; however, the prolactin response to neuroleptic medication is greater in females than in males.
STUDIES ON THE EFFECT OF DOPAMINE ON THE HUMAN PLATELET RESPONSE
Authors: Anfossi Giovanni , Massucco Paola , Mularoni Elena , Cavalot Franco , Burzacca Serenella , Mattiello Luigi , Trovati Mariella
Published: June 2007

1. The present study investigated the in vitro effect of dopamine on platelet responses in healthy subjects.

2. Dopamine concentrations over 5 μmol/L induced a primary aggregating response and a slight release of α‐granule proteins, β‐thromboglobulin and platelet factor‐4 in all subjects. In 25% of investigated subjects a delayed secondary aggregation was observed with dopamine concentrations over 100 μmol/L.

3. Low dopamine concentrations (5–7.5 nmol/L) increased the platelet sensitivity to other aggregating agents (adenosine diphosphate, collagen and sodium arachidonate). The effect of subaggregating concentrations of serotonin was potentiated by dopamine.

4. The effect of dopamine on platelet responses was prevented by low concentrations of α‐adrenoceptor antagonists (phentolamine and yohimbine); antagonists of dopamine receptors (haloperidol and domperidone) were able to decrease the extent of the dopamine‐induced secondary aggregating wave in the responders, but they failed to prevent the primary aggregation and the effects on platelet response to other aggregating agents.

5. The present data demonstrated that the effects of dopamine on human platelets are mainly mediated by interactions with α‐adrenoceptors.
DOES THE HAEMODYNAMIC RESPONSE TO ACUTE CENTRAL HYPOVOLAEMIA DEPEND ON THE RATE OF FALL OF CARDIAC OUTPUT?
Authors: Evans Roger G. , Hayes Ian P. , Ludbrook John
Published: June 2007

1. In published studies of the effects of acute blood loss in conscious rabbits, the rates of haemorrhage have ranged for 3–9% of blood volume/min. This is potentially a confounding factor when it comes to comparing the results of different studies. We have therefore tested whether the haemodynamic response to acute central hypovolaemia depends on the rate of fall of cardiac output.

2. Cardiac output in six conscious rabbits was reduced by 4, 8 and 12% of baseline levels per min by gradual inflation of a cuff around the thoracic inferior vena cava. These rates correspond approximately to blood loss at rates of 3, 6 and 9% of blood volume/min.

3. The haemodynamic responses were biphasic. In Phase I (compensatory) there was progressive systemic vasoconstriction and tachycardia, and only a small fall in blood pressure. In Phase II (decompensatory), systemic vasoconstriction failed abruptly, arterial pressure plummeted and heart rate declined.

4. We could detect no effect of rate of fall of cardiac output on the pattern of the haemodynamic responses in either Phase I or Phase II.

5. We conclude that the rate of blood loss in different studies of haemorrhage in conscious rabbits, within the range 3 to 9 per cent of blood volume per minute, need not be regarded as a confounding factor when it comes to interpreting the results. It is likely that this conclusion can be generalized to studies of haemorrhage in other mammalian species.
ACUTE AND CHRONIC EFFECTS OF ANGIOTENSIN‐CONVERTING ENZYME INHIBITORS ON TISSUE ANGIOTENSIN‐CONVERTING ENZYME
Authors: Chai Siew Y. , Perich Rose , Jackson Bruce , Mendelsohn Frederick A. O. , Johnston Colin I.
Published: June 2007

1. The effects of angiotensin‐converting enzyme (ACE) inhibitors on the tissue ACE were assessed by quantitative in vitro autoradiography after acute and chronic administrations of the drugs.

2. Following acute administration of lisinopril, perindopril or benazepril, ACE was markedly inhibited in the lung, kidney and blood vessels but not in the testis. In the brain, ACE was inhibited mainly in structures with a deficient blood brain barrier.

3. High doses of perindopril progressively inhibited ACE in other brain structures. Tissue ACE inhibition persisted after serum levels of the enzyme had returned to control levels. In the case of perindopril, the time course of tissue ACE inhibition correlated with the inhibition of the pressor responses to exogenous angiotensin I.

4. After chronic administration of lisinopril or perindopril for 14 days, a similar pattern of ACE inhibition was observed in the kidney, lung and blood vessels. In the lung, however, lisinopril was found to increase total ACE by 30%, while plasma ACE was increased two‐threefold by both lisinopril and perindopril. Testicular ACE remained unaltered by chronic lisinopril treatment.

5. Overall, the changes in tissue ACE after the administration of inhibitors more closely parallel the drugs' biological effects than changes in plasma ACE or drug levels. ACE in the testis and brain is protected by permeability barriers that limit access of the drugs.
EFFECT OF PERINDOPRIL ON THE DEVELOPMENT OF ATHEROSCLEROSIS IN THE CHOLESTEROL‐FED RABBIT
Authors: Campbell Julie H. , Fennessy Paul , Campbell Gordon R.
Published: June 2007

1. The aim of the study was to examine the effect of the angiotensin‐converting enzyme inhibitor perindopril on the development of atheroma in the cholesterol‐fed rabbit.

2. The normal human carotid artery, like most large human arteries, has a preformed diffuse intimal thickening. To model this thickening, the right carotid artery of the 12‐week‐old rabbit had an expanded balloon catheter passed down it to remove the endothelium and partially damage the media.

3. Fourteen weeks after this operation, a myointimal thickening similar in almost all respects to the human intimal thickening had developed. The rabbits were then divided into six groups of six rabbits fed on: (i) a 1% cholesterol diet; (ii) a 1% cholesterol diet plus a hypotensive dose of perindopril (0.3 mg/kg per day); (iii) a 1% cholesterol diet plus a non‐hypotensive dose of perindopril (0.01 mg/kg per day); (iv) a normal diet; (v) a normal diet plus a hypotensive dose of perindopril (0.3 mg/kg per day); and (vi) a normal diet plus a non‐hypotensive dose of perindopril (0.01 mg/kg per day).

4. After 6 weeks of treatment the animals were sacrificed. There were ameliorating effects of both hypotensive and non‐hypotensive doses of perindopril on the development of plaques, as determined by the area of intima covered by Oil Red‐O‐staining plaque and light microscopy.

5. Cell culture studies indicated that perindopril has no effect on smooth muscle proliferation, but increases collagen and non‐collagen synthesis by smooth muscle cells and decreases their binding of the atherogenic lipoprotein beta‐very low density lipoprotein (β‐VLDL).

6. The results suggest that perindopril has a beneficial effect in decreasing the severity of atherosclerotic lesions in the cholesterol‐fed rabbit, possibly by affecting lipoprotein metabolism.
EFFECTS OF AE0047 ON RENAL HAEMODYNAMICS AND FUNCTION IN ANAESTHETIZED DOGS
Authors: Hayashi K. , Uchida T. , Kido H. , Shinyama H. , Watanabe M.
Published: June 2007

1. The effects of AE0047, a newly developed calcium channel blocker, on renal haemodynamics and function were investigated and compared with those of nicardipine in anaesthetized dogs.

2. Intravenous injection of AE0047 (10 and 30 μg/kg) caused a dose‐related fall in blood pressure (BP). The AE0047‐induced fall in BP was of slow onset and long lasting. AE0047 at 10 μg/kg elicited a slight increase in renal blood flow (RBF) and urine formation.

3. When AE0047 was infused intrarenally at non‐hypotensive doses (25 and 50 ng/kg per min), there was no significant increase in RBF. However, the glomerular filtration rate increased significantly after drug infusion. Intrarenal arterial (i.r.a.) infusion of AE0047 led to dose‐related increases in urine flow (UF), urinary excretion of electrolytes (Na+, K+ and Cl‐) and fractional excretion of electrolytes. The AE0047‐induced increase in urine formation was of very slow onset and progressed even after the cessation of the AE0047 infusion.

4. The intrarenal arterial infusion of nicardipine at same doses as AE0047 produced significant increases in urine formation, but these effects were immediately restored to the control values after cessation of the nicardipine infusion.

5. It was shown that AE0047 has a long‐lasting diuretic effect and that AE0047‐induced diuresis may be due to inhibitory effects on sodium and water reabsorption in the renal tubules.
EFFECTS OF HYDROXOCOBALAMIN AND HAEMOGLOBIN ON NO‐MEDIATED RELAXATIONS IN THE RAT ANOCOCCYGEUS MUSCLE
Authors: Li C. G. , Rand M. J.
Published: June 2007

1. The effects of hydroxocobalamin (Vitamin B12a) on relaxations produced by nitric oxide (NO), some NO‐donating compounds and nitrergic nerve stimulation in isolated preparations of the rat anococcygeus muscle were compared with the effects of haemoglobin.

2. Hydroxocobalamin (30 μmol/L) significantly reduced relaxations induced by NO (0.1–3 μmol/L) and sodium nitroprusside (SNP; 0.01–0.3 μmol/L) but did not affect relaxations induced by glyceryl trinitrate (GTN; 0.01–1 μmol/L), S‐nitrosocysteine (0.1–0.3 μmol/L) or stimulation of nitrergic nerves. A higher concentration of hydroxocobalamin (100 μmol/L) slightly reduced nitrergic nerve stimulation‐induced relaxations.

3. Haemoglobin (10 μmol/L) blocked relaxation induced by NO and reduced relaxations induced by SNP, GTN, S‐nitrosocysteine and nitrergic nerve stimulation.

4. When nitrergic nerve stimulation‐induced relaxations had been partially reduced by the NO synthase inhibitor l‐NAME (5–10 μmol/L), hydroxocobalamin had only a weak and transient inhibitory effect.

5. Noradrenergic contractions induced by field stimulation were not affected by hydroxocobalamin (30 μmol/L), but were enhanced by haemoglobin (10 μmol/L).

6. The results suggest that the transmitter released from nitrergic nerves in anococcygeus muscles resembles NO‐releasing compounds such as S‐nitrosocysteine and GTN but not SNP or free NO.
INFLUENCE OF SOMATOSTATIN ANALOGUE (SMS 201–995, OCTREOTIDE) ON BLOOD PRESSURE IN ADRENOCORTICOTROPHIN (ACTH) TREATED RATS: ROLE OF HYPERINSULINAEMIA IN ACTH HYPERTENSION
Authors: Li Ming , Wong Kok‐Seng , Whitworth Judith A.
Published: June 2007

1. The hypothesis that adrenocorticotrophin (ACTH)‐induced hypertension is a consequence of steroid‐induced hyperinsulinaemia was tested using the somatostatin analogue (sandostatin, octreotide) to inhibit insulin release in Sprague‐Dawley (SD) rats (n= 41).

2. Octreotide (20 μg, twice daily) did not modify blood pressure, plasma glucose, bodyweight, water and electrolyte balance, or organ weights but inhibited insulin secretion in the SD rat.

3. Compared with sham injection, ACTH‐treated (0.5 mg/kg per day) SD rats showed an increase in blood pressure (sham 111 ± 4 mmHg; ACTH 140 ± 5 mmHg on treatment day 10 (P≤ 0.01), organ weights, water intake, urine volume, plasma glucose, insulin and sodium concentrations, and decrease of bodyweight and plasma potassium concentration.

4. Systolic blood pressure in rats treated with combined octreotide and ACTH was similar to that in rats on ACTH alone. Plasma insulin concentration was lower in octreotide + ACTH treated rats than with ACTH treatment alone. There were no differences in body or organ weights, plasma glucose, water or electrolyte balance.

5. Octreotide lowered plasma insulin concentration to the normal range but did not modify ACTH‐induced hypertension in SD rats. These data do not support the notion that insulin‐mediated alterations in blood pressure are a major mechanism for ACTH‐induced hypertension in the rat.
SUFENTANIL AND ALFENTANIL CAUSE VASORELAXATION BY MECHANISMS INDEPENDENT OF THE ENDOTHELIUM
Authors: Karasawa F. , Iwanov V. , Moulds R. F. W.
Published: June 2007

1. The aim of these experiments was to determine if the vasorelaxation of the rat isolated aorta induced by sufentanil or alfentanil is mediated by the endothelium, and, if not, by α‐adrenoceptor blockade, or a direct effect on the smooth muscle.

2. Both sufentanil (from 10−7 mol/L to 10−4 mol/ L) and alfentanil (from 10−7 mol/ L to 3 × 10−4 mol/L) relaxed rings, where endothelium was intact and precontracted with 40 mmol/L KC1, in a concentration‐related manner. Similarly, sufentanil and alfentanil relaxed rings, in the presence or absence of endothelium, which had been precontracted with phenylephrine.

3. Naloxone (10−4 mol/L) had no significant effect on the relaxation induced by either sufentanil or alfentanil.

4. In a similar manner as phentolamine, pretreatment with sufentanil protected α‐adrenoceptors from blockade by phenoxybenzamine (PBZ) in both endothelium intact and denuded rings, but the estimated potency of sufentanil was approximately 100‐fold less than that of phentolamine in α‐adrenoceptor protection. Treatment with alfentanil did not produce any receptor protection.

5. We concluded that, in the rat aorta, vascular relaxation induced by sufentanil is mediated by both α‐adrenoceptor blockade and a direct effect on smooth muscle, whilst the relaxant effect of alfentanil is caused by direct effects alone. We also concluded that the endothelium has little role in relaxation produced by either drug.
NALOXONE STIMULATION OF ACTH SECRETION DURING PETROSAL SINUS SAMPLING IN CUSHING'S SYNDROME
Authors: Torpy David J. , Jackson Richard V. , Grice Jeffrey E. , Hockings Gregory I. , Strakosch Christopher R. , Topliss Duncan J.
Published: June 2007

1. Petrosal sinus sampling has been used to establish the source of adrenocorticotropin (ACTH) in ACTH‐dependent Cushing's syndrome. Naloxone, an opioid antagonist, stimulates ACTH secretion, probably via release of endogenous hypothalamic corticotropin releasing hormone (CRH).

2. Three patients with hypercortisolism were studied. Two showed suppressed (>50%) urinary‐free cortisol excretion with high‐dose dexamethasone treatment (2 mg every 6h for 2 days), one did not suppress. The patients were subjected to bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) with simultaneous peripheral venous (forearm) samples. Basal (unstimulated) samples were taken and naloxone (125 pg/kg bodyweight) was given intravenously with subsequent simultaneous sampling. Plasma ACTH was measured by radio‐immunoassay (RIA).

3. All cases exhibited a marked rise in immunoreactive (IR)‐ACTH levels (pmol/L) after naloxone injection, basal to peak: case 1, left 11.5–22.1, right 9.8 with no rise, peripheral 9.1–9.5; case 2, left 456–863, right 125–501, peripheral 59–82; case 3, left 12.7–13.0, right 277–431, peripheral 12.1–11.7. All results indicate pituitary Cushing's syndrome, with a central to peripheral ratio >2.3:1. Pituitary Cushing's syndrome was confirmed on the results of trans‐sphenoidal pituitary surgery in cases 1 and 3.

4. It is suggested that naloxone injection during petrosal sinus sampling in Cushing's syndrome may assist in the diagnosis of ACTH source, by enhancing ACTH release from a pituitary micro‐adenoma.
A LOW AFFINITY, LOW MOLECULAR WEIGHT ENDOTHELIN‐A RECEPTOR PRESENT IN NEONATAL RAT HEART
Authors: Woodcock Elizabeth A. , Land Sarah L. , Andrews Robert K.
Published: June 2007

1. Addition of endothelin‐1 (ET‐1) to [3H]‐inositol‐labelled neonatal rat hearts stimulated the accumulation of [3H]‐labelled inositol phosphates (InsP), but only at high concentrations; concentration at half maximum stimulation (EC50)>0.1 μmol/L). When similar experiments were performed using isolated myocytes, the potency of endothelin‐1 was higher and the EC50 value averaged 3.2 ± 0.5 nmol/L (mean±s.e.m., n = 4).

2. The binding affinity of [125I]‐endothelin‐1 was higher for receptors on isolated cells than for receptors on membranes prepared from intact heart (72 ± 16 pmol/L compared with 3.9 ± 0.7 nmol/L, mean ± s.e.m., n= 4, P < 0.01; Students’t test).

3. Receptors from both sources were cross‐linked to [125I]‐endothelin‐1 and their molecular weights measured using sodium dodecylsulfate gradient polyacrylamide gel electrophoresis (SDS‐PAGE). The receptors present on the isolated cells had a higher molecular weight (48 kD) than the receptor on the heart membranes (38 kD).
SPECTROPHOTOMETRIC STUDY OF α‐ADRENOCEPTORS AFFECTING MICROCIRCULATION OF RAT SKIN
Authors: Kakizoe Eiichi , Kobayashi Yuta , Shimoura Keiko , Hattori Keisuke , Jidoi Joji
Published: June 2007

1. To determine the α‐adrenergic receptor subtypes that affect the microcirculation of skin, the relative absorption (RA) spectra of the skin on the backs of rats were measured using reflectance spectrophotometric methods. We injected α‐adrenergic agonists, noradrenaline (NA), phenylephrine (PE) and clonidine (CL), intravenously and determined changes in the RA value at 569 nm, one of the isosbestic points of the oxyhaemoglobin and deoxyhaemoglobin absorption.

2. NA reduced the RA value and the reduction was inhibited significantly by pretreatment with phenoxybenzamine (PBZ; P<0.01). These findings suggested that the haemoglobin content in the skin tissue decreased as a result of vasoconstriction through α‐adrenoceptors.

3. NA, PE and CL produced dose‐dependent reductions in RA. CL and NA produced virtually equipotent reductions except at the highest dose used. PE produced smaller effects. The potency of these drugs in terms of changes in RA did not correlate with their potency in terms of rises in systemic blood pressure (NA ≤ PE ≥ CL).

4. Yohimbine (YO) inhibited the NA‐induced reduction in RA to a greater degree than bunazosin (BU). Midaglizole, a specific α2‐adrenergic antagonist, significantly and dose dependently inhibited the NA‐induced reduction in RA.

5. Although BU inhibited NA‐induced reduction in RA only slightly, the effect was significant (P<0.05). BU significantly inhibited PE‐induced reduction (P<0.01), but did not inhibit CL‐induced reduction.

6. These observations suggest that the microcirculation of the skin of the rat is affected mainly by α2‐adrenoceptor mediated vasoconstriction. However, α1‐adrenoceptor mediated vasoconstriction also has some effect.
MEDIATORS OF NICOTINE‐INDUCED RELAXATIONS OF THE RAT GASTRIC FUNDUS
Authors: McLaren A. , Li C. G. , Rand M. J.
Published: June 2007

1. Relaxations of strips of rat gastric fundus were elicited with nicotine (100 μmol/L), nitric oxide (NO; 30 μmol/L), sodium nitroprusside (SNP; 100 nmol/L) and vasoactive intestinal polypeptide (VIP; 1 nmol/L).

2. Methylene blue (30 μmol/L), an inhibitor of soluble guanylate cyclase, reduced relaxations elicited by NO and nicotine, but not those elicited by VIP.

3. Chymotrypsin (1 U/mL) abolished VIP‐induced relaxations and reduced nicotine‐induced relaxations, but had no effect on SNP‐induced relaxations.

4. NG‐nitro‐l‐arginine methyl ester (l‐NAME; 100 μmol/L), an inhibitor of NO synthase, reduced relaxations elicited by nicotine, but not those elicited by SNP or VIP.

5. When nicotine‐induced relaxations had been reduced by either l‐NAME or chymotrypsin, the addition of the other agent produced a greater reduction. However, the relaxations were not abolished.

6. Nicotine‐induced relaxations were abolished by tetrodotoxin (1 μmol/L) or hexamethonium (100 μmol/L), indicating that they were due to activation of neuronal nicotinic receptors. Their reduction by methylene blue and l‐NAME indicates that an NO‐like mediator was involved. Their reduction by chymotrypsin indicates that a VIP‐like peptide was involved. However, since they were not abolished by a combination of l‐NAME and chymotrypsin, it appears that at least one more as yet unidentified mediator may be involved.
EVIDENCE THAT IMIDAZOL(ID)INE‐ AND SULPHONYLUREA‐BASED ANTAGONISTS OF CROMAKALIM ACT AT DIFFERENT SITES IN THE RAT THORACIC AORTA
Authors: Challinor Joanne L. , McPherson Grant A.
Published: June 2007

1. Ring segments of rat thoracic aorta were suspended in organ baths to record isometric tension. Tissues were precontracted with K+ (20 mmol/ L), and full concentration—relaxation curves constructed to cromakalim (0,01–30 μmol/L) in the absence and presence of increasing concentrations of glibenclamide, glipizide, tolbutamide (the sulphonylureas), alinidine (an imidazolidine), phentolamine (an imidazoline), and chlorpromazine (the phenothiazine derivative). Whereas the active sulphonylureas, glibenclamide and glipizide, displayed classical competitive antagonism, the remaining compounds (alinidine, phentolamine and chlorpromazine) caused shifts in the cromakalim concentration—effect curves associated with a reduction in the slope and maximum response.

2. A single concentration of each antagonist was selected and the shift in the concentration—effect curve determined. The possibility that sulphonylurea and imidazol(id)ine antagonists act at different sites was tested using the concentration‐ratio method for combined antagonists described by Paton and Rang (1965). The combination of alinidine and phentolamine (collectively called imidazol(id)ines) at a number of different concentrations (10–30 μmol/L) resulted in a concentration‐ratio to cromakalim which was additive, suggesting a common site of action. Similar results were obtained when examining the interaction between two sulphonylurea compounds (glibenclamide and glipizide). However, the interaction between sulphonylurea (glibenclamide) and imidazol(id)ine (alinidine) produced concentration‐ratios which were multiplicative, suggesting a different or additional site of action for compounds from these two groups. Results indicated that chlorpromazine was able to block cromakalim via an action at the same site where alinidine and phentolamine act.

3. The results from this study indicate that sulphonylurea—and imidazol(id)ine‐based K+ channel antagonists interact at different sites to produce their observed antagonism of the vasorelaxation induced by cromakalim. These results indicate the possibility of multiple sites of action underlying the effects of compounds which antagonize the actions of K+ channel opening drugs.
IDENTIFICATION OF ADENOSINE RECEPTORS IN HUMAN SPERMATOZOA
Authors: Shen Meng‐Ru , Linden Joel , Chen Shun‐Sheng , Wu Sheng‐Nan
Published: June 2007

1. The effects of adenosine receptor agonists and antagonists on human sperm motility have been studied. Specific binding sites for adenosine and its analogues on human sperm were also investigated.

2. Agonists stimulated human sperm motility in a dose‐dependent manner with a potency order of 5'‐N‐ethylcarboxamidoadenosine (NECA, EC50= 0.3 μmol/L)>2‐[p‐(carboxyethyl)phenylethylamino]‐5'‐N‐ethylcarboxamidoadenosine(CGS‐21680, EC50= 10 μmol/L)> adenosine (EC50= 100 μmol/L).

3. NECA‐stimulated motility was competitively inhibited by various adenosine receptor antagonists. The potency order was 3,7‐dimethy‐l‐propargylxanthine>8‐(p‐sulfophenyl) theophylline > xanthine amino congener.

4. The radioligand [3H]‐NECA bound to sperm membrane in a saturable manner with a Bmax of 21.3 pmol/mg protein and equilibrium Kd of 4 μmol/L. Adenosine agonists and antagonists competed for [3H]‐NECA binding with the same rank order of potency as for the stimulation of human sperm motility.

5. GTPγs inhibited 63% of specific [3H]‐NECA binding with IC50 value of 11 nmol/L. This suggests that the [3H]‐NECA binding sites may be coupled to one or more G proteins.

6. These results indicate the presence of adenosine A2 receptors on human sperm which are responsible for adenosine‐mediated enhancement of sperm motility.
THE INCREASE OF FEMORAL ARTERIAL FLOW BY STIMULATING THE DORSAL AND VENTRAL MEDULLA IN CATS
Authors: Wang M. R. , Chai C. Y. , J. S. Kuof
Published: June 2007

1. In chloralose‐urethane anaesthetized cats, the dorsal cardiovascular reactive area (DCRA) in the parvocellular reticular nucleus dorsomedial to the facial nucleus, and the ventral cardiovascular reactive area (VCRA) ventromedial to the facial nucleus, were stimulated by microinjections of sodium glutamate (100–200 nmol) or electric current.

2. Stimulation of DCRA, with a long latency of 15–20 s, elicited a marked increase of blood flow in the contralateral femoral artery with little change to moderate increase in systemic arterial blood pressure (ABP). In the relatively dorsal portion of DCRA, however, a smaller increase of blood flow in the ipsilateral femoral artery was elicited.

3. On the other hand, stimulation of VCRA with a short latency (3–5 s) evoked an increase of blood flow in both femoral arteries which was more prominent on the contralateral side. The responses were accompanied with decreases in the blood flow of other vascular beds with only a slight increase or minimal change in ABP.

4. The data suggest that DCRA and VCRA are both viscerotopically organized to alter the resistance of individual vascular beds for redistribution of blood flow.
ENHANCEMENT OF ENDOTHELIUM‐DEPENDENT RELAXATION IN THE AORTA FROM STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS AT DEVELOPMENTAL STAGES OF HYPERTENSION
Authors: Onda Takeshi , Mashiko Satoshi , Hamano Megumi , Tomita Isao , Tomita Takako
Published: June 2007

1. Endothelium‐dependent relaxation (EDR) in aortic rings from young (8 weeks) and adult (16 weeks and 20 weeks) stroke‐prone spontaneously hypertensive rats (SHRSP) was investigated in comparison with age‐matched Wistar‐Kyoto rats (WKY).

2. At 8 weeks, acetylcholine (3×10−‐9‐−10−‐5 mol/L) and ionomycin (4×10−8‐10−6 mol/L)‐induced EDR in SHRSP aortae was significantly enhanced compared to that in WKY aortae. Mechanical denudation of the endothelium completely abolished, and pretreatment of aortae with NG‐monomethyl L‐arginine (1 mmol/L), an inhibitor of nitric oxide formation, greatly reduced the relaxation in both strains. Indomethacin (10−5 mol/L), a cyclo‐oxygenase inhibitor that blocks the production of endothelium‐derived contracting factors, did not significantly alter the relaxation by acetylcholine at this age. There was no difference in endothelium‐independent relaxation of denuded aortae by sodium nitroprusside (10−9‐10−6 mol/L) and 8‐bromoguanosine 3‘, 5‘‐cyclic monophos‐phate (10−6‐10−3 mol/L).

3. In adult SHRSP with established hypertension, however, the acetylcholine (10−8‐−10−5 mol/L)‐induced relaxation markedly diminished at any of the concentrations tested compared to that observed in 8 week old SHRSP and WKY at 8–20 weeks of age. This finding differed from other observations where the relaxation in SHRSP was impaired only at higher concentrations of acetylcholine. Indomethacin pretreatment of aortae from 20 week old SHRSP restored acetylcholine‐induced EDR to a level comparable with that in age‐matched WKY.

4. These results suggest that the aorta from young SHRSP releases more endothelium‐derived relaxing factors in response to acetylcholine and ionomycin, but the relaxation greatly diminishes in adult SHRSP with established hypertension. This may be due to counteraction of endothelium‐derived contracting factors released from the endothelium with functional changes resulting from the long duration of the hypertension.
USE OF RECOMBINANT INBRED STRAINS FOR EVALUATION OF INTERMEDIATE PHENOTYPES IN SPONTANEOUS HYPERTENSION
Authors: Kuneš J. , Křen V. , Pravenec M. , Zicha J.
Published: June 2007

1. The HXB/BXH recombinant inbred (RI) strains, derived from the spontaneously hypertensive rat (SHR) and the normotensive Brown Norway (BN.1x) rat, represent a very useful system for gene mapping and for genetic analysis of certain model diseases, such as spontaneous hypertension.

2. These RI strains were genotyped in multiple genetic polymorphisms and characterized in blood pressure and some intermediate phenotypes.

3. The analysis of RI strains has revealed that (i) a gene in the vicinity of the major histocompatibility complex (RT1) on chromosome 20, a kallikrein‐related gene on chromosome 4 and the renin gene on chromosome 13 were significantly associated with blood pressure, and (ii) Na+ leak in red blood cells correlated with blood pressure whereas relative heart and kidney weights as well as platelet aggregation did not.
RELATIONSHIP BETWEEN THE SUPPRESSIVE ACTIONS ON INTESTINAL ABSORPTION AND ON cGMP PRODUCTION FOR THE NATRIURETIC PEPTIDE FAMILY IN DOGS
Authors: Kagawa Koji , Suzuki Shunji , Matsushita Kohtaroh , Uemura Nobuhisa , Morita Hironobu , Hosomi Hiroshi
Published: June 2007

1. The aim of this study was to investigate whether the suppressive effects of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C‐type natriuretic peptide (CNP) on net intestinal absorption were related to guanosine 3′,5′‐cyclic monophosphate (cGMP) production in the intestine.

2. We measured the plasma cGMP concentration of the arterial, jejunal and ileal venous blood after intravenous infusions of natriuretic peptides (97 pmol/ kg per min for 30 min) in anaesthetized dogs.

3. The infusion of ANP increased cGMP concentration of the aortic blood by 49.9 ± 9.0 (pmol/mL), BNP by 71.8 ± 12.3 and CNP by 5.5 ± 1.3. The increases in cGMP after ANP and BNP were larger than after CNP. The infusion of ANP increased jejunal arteriovenous differences in cGMP concentration by 69.9 ± 3.5 (pmol/mL) and ileal arteriovenous differences by 8.7 ± 3.2. In BNP infusion, the jejunal and ileal arteriovenous differences in cGMP concentration tended to increase by 15.6 ± 5.8 (pmol/mL) and by 14.8 ± 6.6 but neither were significant. CNP infusion did not change the jejunal and ileal arteriovenous differences in cGMP concentration.

4. These results suggest that, while the actions of ANP on intestinal absorption may be mediated by cGMP, those of BNP and CNP are not.
EFFECTS OF GENTAMICIN, NEOMYCIN AND TOBRAMYCIN ON RENAL CALCIUM AND MAGNESIUM HANDLING IN TWO RAT STRAINS
Authors: Garland H. O. , Birdsey T. J. , Davidge C. G. , McLaughlin J. T. , Oakes L. M. , Smith A. J. , Harpur E. S.
Published: June 2007

1. Standard renal clearance techniques were used to compare the acute effects of gentamicin, neomycin and tobramycin on renal calcium and magnesium handling in Sprague‐Dawley and Fischer 344 rats.

2. Significant hypercalciuric and hypermagnesiuric responses to all three drugs (P<0.01) were apparent within 30 min of the onset of drug infusion.

3. The magnitude of the acute hypercalciuric and hypermagnesiuric response to the three aminoglycosides was comparable. This contrasts with their nephrotoxic action where neomycin >> gentamicin > tobramycin. The magnitude of the acute physiological responses to these drugs do not therefore reflect their nephrotoxic potential.

4. Sprague‐Dawley rats were at least as responsive as Fischer rats in their acute renal responses to gentamicin. If Fischer rats are more sensitive to aminoglycoside nephrotoxicity than Sprague‐Dawley rats, this is not reflected in their acute responses to gentamicin.
HUMAN INTERNAL MAMMARY ARTERY RESPONSES TO NON‐PEPTIDE VASOPRESSIN ANTAGONISTS
Authors: Liu James J. , Phillips Paddy A. , Burrell Louise M. , Buxton Brian B. , Johnston Colin I.
Published: June 2007

1. OPC‐21268 and OPC‐31260 are newly developed orally active non‐peptide vasopressin (AVP) V1 and V2 receptor antagonists, respectively. The effects of the two compounds on human vessels have not been studied.

2. The effects of the two compounds on AVP‐induced contraction of human internal mammary arteries (IMA) were investigated. Their effects were compared with the peptide V1 and V2 antagonists d(CH2)sSar7AVP (SAVP) and d(CH2)5D‐Ileu211eu4AVP (Ileu2 Ileu4AVP), respectively.

3. The V1 antagonist OPC‐21268 failed to antagonize AVP‐induced contraction at low concentrations and potentiated the contraction at higher concentration (3 × 10−‐7 mol/L, P<0.05). It also caused a mild direct contractile effect on IMA. In contrast, the peptide V1 antagonist SAVP potently inhibited the AVP‐induced contraction, indicating that functionally constrictor V1 receptors exist in IMA. Both the nonpeptide and peptide V2 antagonists OPC‐31260 (3X10−‐6 mol/L) and Ileu2Ileu4AVP significantly antagonized the AVP‐induced contraction (P<0.01).

4. The AVP‐induced contraction was reversed by high concentrations of OPC‐31260 (10−‐6 mol/L‐3×10−‐5 mol/L) but not by OPC‐21268 (up to 3X 10−‐5 mol/L).

5. These studies indicate that, in human IMA, OPC‐21268 is a partial VI receptor agonist with no V1 receptor antagonist activity, while OPC‐31260 is a V1 receptor antagonist. The results also indicate that Ileu2 Ileu4AVP may be a Vl receptor antagonist in humans.