bluuebunny/crossref_metadata_2025 huggingface dataset:
RELAXATION FOLLOWING CONTRACTION IN TONICALLY CONTRACTED SMOOTH MUSCLE FROM THE BOVINE TRACHEA
Authors: Clarke Hilary M. , Kirkpatrick C. T.
Published: June 2007

1. Isometric tension was recorded from strips of bovine tracheal smooth muscle in which the tone had been artificially raised by agonist drugs such as histamine and carbachol.

2. Application of exogenous acetylcholine produced a biphasic response consisting of an initial contraction followed by a more prolonged relaxation before tone was restored to normal.

3. Atropine blocked both components of the biphasic response to exogenous acetylcholine.

4. Tetrodotoxin blocked neither phase of the response to exogenous acetylcholine even though a similar biphasic response to electrical stimulation was severely disrupted.

5. Application of exogenous substance P produced a biphasic response of similar magnitude and form to that produced by acetylcholine.

6. Application of exogenous histamine (tone raised by carbachol) also produced a biphasic response although higher concentrations were required to produce a relaxation of equal magnitude to that produced by acetylcholine.

7. It is concluded that the inhibitory component of the biphasic response to exogenous acetylcholine occurs as a non‐specific sequel to contraction.
EFFECTS OF OPIOIDS ON THE ACH‐INDUCED CONTRACTION OF THE TOAD RECTUS
Authors: Sim M. K. , Ramabadran K.
Published: June 2007

1. The inhibitory effect of morphine, nalorphine, oxymorphone, naloxone, naltrexone, N‐methylnaloxone, levorphanol, levallophan, dextrorphan, dextrallophan, levo‐methadone, dextro‐methadone, pethidine, leu‐enkephalin and U‐50 488 on the acetylcholine (ACh)‐induced contraction of the toad rectus was investigated.

2. The dose‐response curves obtained in the absence and presence of increasing concentrations (0.1–3.2 or 10–320 μmol/l) of each opioid were subjected to three types of inhibition model discrimination, namely competitive, noncompetitive and uncompetitive.

3. The results show that the opioids, except morphine, nalorphine and levorphanol, inhibit the ACh‐induced contraction by multiple modes of action. Except for the morphinans, the opioids inhibit competitively indicating that they are able to compete with ACh for cholinergic receptors at the nicotinic site.

4. The opioids also inhibit noncompetitively (except oxymorphone and N‐methylnaloxone) and uncompetitively (except oxymorphone) indicating the possible existence of separate opioid binding sites and the combination of the opioids with the ACh receptor complex, respectively.

5. The effect of morphine and levorphanol on the ACh‐induced contraction varies with the concentration of the two opioids. At concentrations below 80 μmol/l both opioids tend to inhibit the contraction while at concentrations of 80 μmol/l and above there is no apparent effect. Nalorphine has no effect on the contraction at the concentrations (10–320 μmol/l) employed in the study.

6. An apparent structure‐activity relationship between the phenanthrenes and the various binding sites is noticeable; so also is the difference in the activity between the dextro and levo‐isomers of levorphanol and levallorphan indicating that the receptors exhibit stereospecificity.
INVESTIGATIONS INTO THE NATURE OF α2‐ADRENOCEPTORS IN RAT TAIL ARTERIES
Authors: Marwood J. F. , Chapman K. L. , Armsworth S. J. , Stokes G. S.
Published: June 2007

1. In rat isolated perfused tail arteries, dose‐response curves were established for the vasopressor effects of phenylephrine (α1‐adrenoceptor agonist), clonidine (α1‐ and α2‐adrenoceptor agonist), clonidine in the presence of 10‐7 mol/l prazosin (α2‐agonist), and BHT‐920 (α2‐agonist).

2. The ED50 values were: phenylephrine 1.85 × 10‐10 mol; clonidine 6.3 × 10‐10 mol; clonidine + prazosin 3.2 × 10‐6 mol; BHT‐920 6.1 × 10‐6 mol.

3. The arterial reactivity to BHT‐920 was stable only after 4–5 h of perfusion.

4. Responses to BHT‐920 were not antagonized by yohimbine (α2‐adrenoceptor antagonist) but were antagonized by low concentrations of prazosin (α1‐adrenoceptor antagonist).

5. These data constitute conflicting evidence regarding the existence of α2‐adrenoceptors in rat tail arteries.

6. The data are consistent with the proposal that there are two recognition sites on α1‐adrenoceptors; phenylephrine and BHT‐920 may stimulate different sites on α1‐adrenoceptors.
MECHANISM OF ACTION OF NATRIURETIC FRACTION OF URINE
Authors: Chakravarty Bhaskar J. , Gillies Alastair H. B. , Carney Shane L.
Published: June 2007

1. The nature of calcium dependence of natriuretic fraction (NF)‐induced contractions in the rat smooth muscle anococcygeus and a possible correlation between the effect of NF on sodium transport and its natriuretic potency was investigated.

2. NF and noradrenaline‐induced contractions were partially dependent on external calcium concentration. Ouabain and potassium (K) free solution (KoPSS)‐induced contractions were totally dependent on external calcium and were more effectively inhibited by calcium antagonists than those of NF and noradrenaline suggesting pharmacomechanical coupling as the mode of calcium dependence of NF.

3. Like other agonists which contract by pharmacomechanical coupling, NF stimulted sodium transport (86rubidium uptake) in dog saphenous vein. Such stimulation correlated positively (r= 0.495, n= 17, P<0.05) with the natriuretic potency of NF.

4. NF, like noradrenaline, contracts smooth muscle by pharmacomechanical coupling and NF‐induced natriuresis is associated with stimulation of the sodium pump.
ISOLATION OF GENOMIC CLONES CODING FOR THE HEAVY CHAINS OF TWO HUMAN CARDIAC MYOSINS
Authors: Catanzaro Daniel F. , O'Connell Anita M. , Morns Brian J.
Published: June 2007

1. A 14 kilo‐base pair DNA clone (λHCMHC8) was isolated from a human genomic library by hybridization with a complementary DNA coding for a rabbit cardiac myosin heavy chain.

2. λHCMHC8 hybridized to RNA isolated from cardiac but not skeletal muscle and formed heteroduplexes with a genomic clone coding for the fast type of rabbit cardiac myosin heavy chain. λHCMHC8 represented at least the 3′ half of the gene and contained over 11 exons which together spanned 4 kb of the coding region estimated to be 6 kb.

3. Probes made from λHCMHC8 were used to rescreen the library in order to isolate overlapping clones and so extend the sequence (estimated to be approximately 25 kb for the whole gene, including introns). In addition, a clone having a different restriction map was isolated suggesting that man, like rat and rabbit, has two cardiac myosin heavy chain genes. These may code for proteins having different ATPase activity and be expressed in different proportions in different cardiac states, including hypertension.
CHARACTERIZATION OF THROMBOXANE A2 RECEPTORS IN THE HUMAN FETAL PLACENTAL VESSELS AND UMBILICAL VEIN
Authors: Boura A. L. A. , M N. , King R. G. , Mak K. K. ‐W. , Waltere W. A. W.
Published: June 2007

1. An in vitro examination has been made of the thromboxane A2 receptors in human fetal placental villous vessels and umbilical veins utilizing the TxA2 agonist U46619 and its competitive antagonist AH22921.

2. U46619 was a potent constrictor of both preparations. The EC50 were 25.3 nmol/1 (s.e.m. =2.5, n= 8) for causing constriction of perfused villous vessels and 22 nmol/1 (s.e.m. = 5, n= 17) for contraction of the venous longitudinal strip.

3. AH22921 competitively antagonized responses to U46619 in both preparations. The pA2 values were not significantly different and their 95% confidence limits, obtained for its ability to antagonize responses to U46619 in villous vessels and the umbilical vein, were 8.0 (7.3‐8.8) and 7.1 (6.3‐7.9) respectively.

4. It is concluded that TxA2 receptors in both the human fetal placental villous vessels and umbilical vein may be similar. They also may be similar to those in human platelets and pulmonary blood vessels.
MECHANISMS OF CAPTOPRIL‐INDUCED POTENTIATION OF THE DEPRESSOR RESPONSES TO ARACHIDONIC ACID IN RATS
Authors: Hui S‐C. G. , Dai S. , Ogle C. W.
Published: June 2007

1. The mechanisms underlying potentiation by captopril of the depressor responses to arachidonic acid were studied in chloralose‐anaesthetized rats.

2. Captopril, in a dose (0.5 mg/kg, i.v.) which inhibited the pressor responses to angiotensin I (0.03‐1 μg/kg, i.v.), enhanced the depressor responses to bradykinin (3‐300 μg/kg, i.v.) and potentiated the hypotensive action of arachidonic acid (3 mg/kg, intravenously). This phenomenon was observed not only when captopril and arachidonic acid were administered intravenously, but also when these compounds were injected directly into the aortic arch.

3. The enhancement of arachidonic acid‐induced hypotension by captopril was not significantly affected by pretreatment with a low dose of aprotinin (3 mg/kg, i.v.), but was abolished by bilateral nephrectomy or by pretreatment with a higher dose of aprotinin (6 mg/kg, i.v.).

4. It is suggested that captopril augments the depressor responses to arachidonic acid by inhibiting angiotensin converting enzyme. This results in accumulation of bradykinin which in turn increases release of vasodilator prostaglandins, originating most probably, from the kidneys. The possibility that blockade of angiotensin II formation by captopril may leave the vasodilator action of prostaglandin unopposed cannot be excluded.
CHARACTERIZATION OF SUBSTANCE P‐INDUCED BRONCHOCONSTRICTION IN THE GUINEA‐PIG: A COMPARISON WITH ACETYLCHOLINE
Authors: Stewart A. G. , Fennessy M. R.
Published: June 2007

1. Substance P (0.5‐8.0 μg/kg, i.v.) induced bronchoconstriction in anaesthetized, mechanically‐ventilated guinea‐pigs, comprising increases in airways resistance and decreases in dynamic compliance.

2. These bronchoconstrictor responses were unaffected by bilateral vagotomy, pretreatment with pheniramine (2 mg/kg, i.v.) or by pretreatment with atropine (100 μg/kg, i.v.). Acetylcholine‐induced (4‐32 μg/kg, i.v.) bronchoconstriction was prevented by atropine pretreatment, whereas bilateral vagotomy inhibited responses to acetylcholine.

3. Ganglionic blockade using hexamethonium (20 mg/kg, i.v.) potentiated both substance P and acetylcholine on airways resistance and dynamic compliance.

4. Indomethacin (1 or 5 mg/kg, i.v.) did not affect substance P‐induced bronchoconstriction, whereas the higher dose enhanced acetylcholine‐induced increases in airways resistance. In addition, aspirin pretreatment (20 mg/kg, i.v.) did not alter the bronchoconstrictor potency for either substance P or acetylcholine. On the other hand, the combined cyclo‐oxygenase/lipoxygenase inhibitors eicosatetraynoic acid (ETYA, 20 mg/kg, i.v.) and BW755C (20 mg/kg, i.v.) potentiated both acetylcholine and substance P on airways resistance and dynamic compliance.

5. The results suggest that substance P‐induced bronchoconstriction may be modulated by the sympathetic nervous system and does not appear to be influenced by vagal or histaminergic mechanisms. The failure of indomethacin or aspirin to affect substance P‐induced bronchoconstriction, together with the enhancing effects of ETYA and BW755C pretreatments, provide evidence consistent with the existence of a bronchodilator mechanism which may be inhibited by compounds inhibiting lipoxygenase enzymes.
PLASMA AND BILIARY DISPOSITION OF PIRENZEPINE IN MAN
Authors: Lee S. P. , Paxton J. W. , Choong Y. S.
Published: June 2007

1. The binding of pirenzepine, a selective muscarinic receptor antagonist to plasma and bile, was studied in vitro and in vivo. Plasma and hepatic bile were incubated with 14C‐pirenzepine and the bound fraction of 14C‐pirenzepine determined by equilibrium dialysis. The bound fractions were 12.6% (s.e.m. = 1.5) and 12.1% (s.e.m.= 1.6) in plasma and bile samples, respectively. After in vitro incubation, the radioactivity in both plasma and bile was removed by exhaustive dialysis against water for up to 94 h, suggesting that the binding was a noncovalent association.

2. 14C‐Pirenzepine was also given intravenously to five postoperative patients with T‐tube drainage of hepatic bile. In plasma, 12.6% (s.e.m. = 1.8) of 14C‐pirenzepine was reversibly bound to albumin. By contrast, in bile 13.4% (s.e.m. = 3.2) was irreversibly bound, mainly to bilirubin glucuronides (>90%).

3. After an intravenous injection of 14C‐pirenzepine, the radioactivity in plasma decreased bi‐exponentially with an initial distribution half‐life of 0.24 h and an elimination half‐life of 10.2 h. The radioactivity reappeared cyclically in bile, suggesting enterohepatic recirculation of 14C‐pirenzepine.
EFFECTS OF CAPTOPRIL ON THE SLEEP EEG OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Sim M. K. , Hutchinson J. S. , Chua M. E.
Published: June 2007

1. Intracerebroventricular captopril produces significantly different effects on the sleep electroencephalogram (EEG) of normotensive Wistar‐Kyoto (WK) and spontaneously hypertensive rats (SHR).

2. The compound produces a definite pattern of decrease in the percentage and power of the lower frequency EEG of the SHR. Corresponding action on the WK was confined to a general decrease in the power of the EEG.

3. These findings suggest that certain components of the central renin‐angiotensin system in the SHR are abnormal.
HYPERTENSION ALTERS SLOPE AND RANGE BUT NOT SENSITIVITY TO VASOCONSTRICTOR AND VASODILATOR AGENTS IN THE RABBIT HINDQUARTER
Authors: Wright C. E. , Angus J. A. , Korner P. I.
Published: June 2007

1. The vascular reactivity (slope and range) and location parameter (ED50) of dose‐response curves in the hindquarter vascular bed in conscious rabbits previously subjected to renal cellophane wrapping or sham operation were examined.

2. The animals were instrumented with pulsed Doppler flow transducers and chronic indwelling aortic catheters for intra‐arterial drug infusion. The rabbits were ganglion‐blocked with mecamylamine before constructing full dose‐response curves to intra‐arterial infusions of methoxamine, noradrenaline, angiotensin II, acetylcholine, adenosine and serotonin.

3. Curves relating dose to conductance were fitted to the experiments involving constrictors and curves relating dose to vascular resistance fitted to those involving dilator drugs. With both classes of drugs the reactivity was significantly higher in the hypertensive animals than in sham‐operated rabbits.

4. There was no difference in sensitivity (ED50 value) between the hypertensive and control animals for any agonist tested.

5. The increased reactivity, but not sensitivity, could be entirely accounted for by the vascular amplifier action of medial hypertrophy in hypertension.
EFFECT OF REGULAR ALCOHOL USE ON BLOOD PRESSURE CONTROL IN TREATED HYPERTENSIVE SUBJECTS: A CONTROLLED STUDY
Authors: Puddey I. B. , Beilin L. J. , Vandongen R.
Published: June 2007

1. Forty‐four males with treated essential hypertension and a moderate‐to‐heavy alcohol intake participated in a randomized controlled crossover trial of the effects of varying alcohol intake on blood pressure control. Usual antihypertensive therapy was maintained unchanged throughout.

2. Self‐reported alcohol consumption fell from 452 ml ethanol/week (s.e.m. = 29) during normal drinking habits to 64 ml/week (s.e.m. = 8) while drinking low alcohol content beer.

3. Mean systolic and diastolic blood pressures were significantly lower during the last 2 weeks of reduced alcohol (supine 5.0 mmHg, s.e.m. = 1.4, and 3.0 mmHg, s.e.m. = 0.9, respectively; erect 5.9 mmHg, s.e.m. = 1.6, and 2.9 mmHg, s.e.m. = 1.0, respectively).

4. Body weight was also lower (0.94 kg, s.e.m. = 0.25) at the conclusion of the low alcohol intake period.

5. Regression analysis suggested that reduction in alcohol intake contributed independently to the fall in both systolic and diastolic blood pressure, while weight change contributed independently to the fall in systolic blood pressure alone.

6. It was concluded that curtailing moderate to heavy alcohol intake leads to improved blood pressure control in treated essential hypertensive males.
INFLUENCE OF AGE, SEX AND WEIGHT ON MEASUREMENTS OF INTRACELLULAR Na+ AND K+ IN ESSENTIAL HYPERTENSION
Authors: Bramley P. M. , Paulin J. M. , Millar J. A.
Published: June 2007

1. Na+ and K+ concentrations were measured in red cells from 22 patients with untreated essential hypertension and 22 normotensive control subjects who were individually and prospectively matched for age, sex and weight and in a separate population of 31 hypertensive patients and 41 normotensive subjects who were not so matched.

2. Intracellular Na+ and K+ concentrations were similar in the matched subjects. Significant positive correlations were found between intracellular Na+ and body weight (r=0.27, P < 0.041), and between intracellular K+ and age (r= 0.29, P < 0.028).

3. In the unmatched population, intracellular Na+ was significantly increased in patients with hypertension and was correlated significantly with age (r=0.25, P < 0.017). After correction for age, intracellular Na+ was similar in both hypertensive and normotensive subjects. Age‐corrected intracellular K+ was similar in both hypertensive and normotensive groups but was significantly lower in male subjects.

4. These results highlight the importance of matching study groups for age, sex and weight when studying possible abnormalities in cell ionic composition in hypertension. False positive results may arise if study groups are not matched for these characteristics. Red cell Na+ and K+ are not altered in essential hypertension.
SYMPATHETIC DENERVATION OF THE RAT VAS DEFERENS FOLLOWING UNILATERAL VASECTOMY
Authors: DeGaris Richard M. , Pennefather Jocelyn N.
Published: June 2007

1. This paper describes an investigation of the time course of changes in noradrenaline levels in epididymal and prostatic segments of rat vasa deferentia, for up to 91 days following unilateral vasectomy by medial transection, together with an investigation of the responses of isolated preparations of these segments to field stimulation of sympathetic terminals.

2. No atrophy of testes or seminal vesicles, or of the prostatic and epididymal segments of operated vasa deferentia, was evident at 2, 4, 7, 28 and 91 days after unilateral vasectomy.

3. Spectrophotofluorometric assay revealed that noradrenaline levels in epididymal segments of operated vasa deferentia declined rapidly (within 2 days) after unilateral vasectomy and remained below 10% of those in unoperated epididymal segments at days 4, 7, 28 and 91 post‐vasectomy. Noradrenaline levels in prostatic segments of operated vasa deferentia were unaffected by vasectomy.

4. Histochemical studies revealed that catecholamine fluorescence in epididymal segments of operated vasa deferentia declined in parallel with the decline in tissue noradrenaline levels; no comparable changes occurred in prostatic segments.

5. Field stimulation (10 pulses, 60 V, 1 ms, applied at 0.1–50 Hz) evoked frequency‐dependent contractions of unoperated epididymal segments and of operated and unoperated prostatic segments at 2, 4, 7, 28 and 91 days post‐vasectomy. At day 2 and 4 responses of prostatic segments of operated tissues, to frequencies below 5 Hz, exceeded those of corresponding unoperated segments, however, by day 91, there was a small but significant decline in responses. Responses of epididymal segments of operated vasa deferentia to all frequencies of stimulation declined by day 2 post‐vasectomy and were absent thereafter except in three of the 18 preparations studied at day 91.

6. These results, taken together, confirm that there is a rapid decline in catecholamine levels in the epididymal segment of medially transected vasa deferentia following unilateral vasectomy. Minimal, if any, reinnervation of this segment occurs during the 3 month period following unilateral vasectomy.
EFFECT OF SODIUM NITROPRUSSIDE ON THE BIOPHASE CONCENTRATION OF D‐TUBOCURARINE AT THE NEUROMUSCULAR JUNCTION
Authors: Chang P. , Geh S. L.
Published: June 2007

1. d‐Tubocurarine (dTC) at an intravenous dose of 250 μg/kg, or at an intra‐arterial dose of 25 μg/kg, produced about a 50% block on the twitch tension of the indirectly stimulated tibialis anterior muscle of anaesthetized cats.

2. The dTC‐induced neuromuscular block was abolished if it was given intravenously but not intra‐arterially, 30 min after the commencement of sodium nitroprusside (SNP) infusion (5 μg/kg per min) when there was a maximum decrease in blood pressure.

3. The results indicate that the biophase concentration of dTC at the neuromuscular junction may be decreased as a consequence of the vasodilation induced by SNP leading to a reduced transport of the blocker to the site of action.
PREVENTION OF DOCA‐INDUCED HYPERTENSION IN RATS BY CHRONIC TREATMENT WITH TRYPTOPHAN
Authors: Fregly Melvin J. , Fater Dennis C.
Published: June 2007

1. Hypertension developed within 5 weeks in uninephrectomized rats administered deoxycorticosterone acetate (DOCA, 30 mg/kg, s.c., weekly) and given isotonic saline to drink. Chronic dietary administration of tryptophan (50 g/kg food) reduced intake of saline solution and prevented the elevation of systolic blood pressure induced by treatment with DOCA alone.

2. Treatment with tryptophan also protected against the reduction in urinary concentrating ability during a 24 h dehydration that is characteristic of DOCA‐treated rats.

3. Other tests were carried out to assess the responsiveness to the β‐adrenergic agonist, isoproterenol. The tests included measurement of drinking and heart rate following acute administration of isoproterenol. The characteristically depressed drinking response of DOCA‐treated rats to acute administration of isoproterenol was returned to that of untreated controls by chronic treatment with tryptophan. However, the reduced chronotropic response of the heart of DOCA‐treated rats to administration of isoproterenol was unaffected.

4. The cardiac hypertrophy characteristic of DOCA‐treatment was attenuated significantly by chronic treatment with tryptophan.

5. These results suggest that tryptophan provides significant protection against the development of DOCA‐induced hypertension, polydipsia, and cardiac hypertrophy in rats. The mechanism by which tryptophan protects is unknown and requires additional study.
CAPTOPRIL DOES NOT POTENTIATE HYPOTENSION AND ALGESIA BY SUBSTANCE P
Authors: Hui S‐C. G. , Ogle C. W.
Published: June 2007

1. Captopril (1–5 mg/kg, i.v.) did not affect the vasodepressor responses to substance P (1–30 μg/kg, i.v.) in anaesthetized rats.

2. Substance P (100 μg/kg, s.c.) produced significant algesia in mice; this was not potentiated by the smaller doses of captopril (1–2 mg/kg, i.p.), but was instead antagonized by the high dose (5 mg/kg, i.p.).

3. It is concluded that captopril does not have any influence on substance P degradation in vivo since the pharmacological actions of the undecapeptide are not enhanced after captopril treatment.
ATTENUATION OF PRESSOR RESPONSES TO SYMPATHETIC STIMULI IN THE RAT BY ENALAPRIL
Authors: Rechtman M. P. , Ishac E. J. N. , Boura A. L. A. , King R. G. , Walters W. A. W.
Published: June 2007

1. Intravenous administration to pithed Wistar rats of the angiotensin converting enzyme inhibitor enalapril (0.1–1.0 mg/kg) lowered the diastolic blood pressure and reduced pressor responses occurring during electrical stimulation (1–30 Hz) of the spinal sympathetic outflow.

2. These doses of enalapril given intravenously also attenuated pressor responses to intravenous injection of the muscarinic ganglion stimulant McNeil‐A‐343 (50, 100, 150 μg/kg) and noradrenaline (0.1–5.0 μg/kg). Enalapril (1.0 mg/kg, i. v.) reduced pressor responses to the nicotinic ganglion stimulant 1,1‐dimethyl‐4‐phenylpiperazinium (300 μg/kg, i.v.).

3. These results confirmed that the actions of enalapril resemble those of captopril in the pithed rat, by causing reductions in both blood pressure and pressor responses to sympathetic stimuli.
EFFECT OF SODIUM DEPLETION ON PRESSOR RESPONSIVENESS IN ACTH‐INDUCED HYPERTENSION IN MAN
Authors: Connell John M. C. , Fisher B. Miles , Davidson Gillian , Fraser Robert , Whitworth Judith A.
Published: June 2007

1. Pressor responsiveness to angiotensin II (AII) and phenylephrine (PHE) was measured before and after 5 days of ACTH (1 mg i.m. daily) in six normal men maintained on low sodium diet (15 mmol daily).

2. ACTH caused a significant increase in systolic blood pressure of 9 mmHg.

3. There was no change in pressor responsiveness to AII with ACTH.

4. ACTH increased pressor responsiveness to PHE for both systolic and diastolic blood pressure, with a fall in the threshold for response from 0.9 to 0.6 μg/kg per min.

5. Increased pressor sensitivity to catecholamines during ACTH administration in man is not sodium‐dependent.
THE EFFECTS OF SIMULTANEOUS ATROPINE AND LABETALOL ADMINISTRATION ON CARDIOVASCULAR PARAMETERS DURING ANTICHOLINESTERASE POISONING IN ANAESTHETIZED CAT
Authors: Merican Zainuddin , Mahmud Zahari , Morat Paden , Idid Syed Zahir , Bi Khatiza
Published: June 2007

1. The effects of atropine administration during anticholinesterase poisoning on heart rate, blood pressure and electrocardiographic changes (ECG) were studied in the cat.

2. Administration of atropine intravenously during anticholinesterase poisoning caused a significant increase in heart rate and blood pressure; ECG changes were also seen.

3. The simultaneous intravenous administration of atropine and labetalol during anticholinesterase poisoning abolished the increase in blood pressure and heart rate; ECG readings remained normal.

4. It is suggested that labetalol may be a useful adjuvant in the treatment of anticholinesterase poisoning especially in patients with compromised heart function.
HYPOTENSIVE RESPONSE TO ATRIAL NATRIURETIC FACTOR IN CONSCIOUS RENAL HYPERTENSIVE BEAGLES
Authors: Lee K. C. , Rodzinski J. A. , Bex F. J. , Lappe R. W. , Wendt R. L.
Published: June 2007

SUMMARY

1. The hemodynamic responses to i.v. infusion of 0.3 and 0.6 μg/kg per min of human atrial natriuretic factor (hANF [102–126]) in intact, conscious, one‐kidney, perinephritic, hypertensive beagles were examined and compared with the responses in ganglionic‐blocked dogs.

2. Blood pressure and heart rate were not affected but plasma ANF‐like immunoreactivity was increased by as much as 627%.

3. After hexamethonium (20 mg/kg, i.v.) blockade, a dose‐dependent hypotensive response of up to 29 mmHg with no change in heart rate was observed.

4. It is concluded that the compensatory mechanisms of the neurally mediated baroreflex system masked the depressor actions of hANF.
CARDIOVASCULAR RESPONSIVENESS TO ARGININE VASOPRESSIN IN WATER‐LOADED AND SODIUM‐DEPLETED PREGNANT AND NON‐PREGNANT SHEEP
Authors: Wintour E. Marelyn , Coghlan John P. , Congiu Mario , Grim Clarence E. , Laurence Brenda M. , Meehan Peter J. , McDougall John G. , Scoggins Bruce A.
Published: June 2007

1. In conscious ewes pregnancy was associated with a significantly increased heart rate and cardiac output, while mean arterial pressure (MAP) and stroke volume were unchanged.

2. The present study examines the effect of arginine vasopressin (AVP) infused at 0.3, 1, 3.0, and 10 μg/h, into water‐loaded and sodium‐depleted ewes, either non‐pregnant or during the last third of gestation.

3. In the water‐loaded state, MAP rose significantly at the lowest rate of infusion in both pregnant and non‐pregnant ewes. Bradycardia occurred first at 0.3 μg/h in the pregnant ewes but not until 3.0 μg/h in the non‐pregnant animals.

4. In sodium deficiency there was no increase in MAP at any rate of infusion in either group. Bradycardia occurred in both groups at 1 μg/h.

5. This study shows that the pressor effects of AVP are unchanged by pregnancy. However, pregnant ewes are more sensitive to AVP‐induced bradycardia when the ewes are water‐loaded.
MODIFICATION BY DILTIAZEM, A CALCIUM ANTAGONIST, OF THE PULMONARY VAGAL AND CARDIAC SYMPATHETIC CHEMOREFLEXES IN THE DOG
Authors: Staszewska‐Woolley Janina
Published: June 2007

SUMMARY

1. Experiments were performed on anaesthetized, open‐chest dogs to determine the effects of diltiazem on: the pulmonary vagal chemoreflex evoked by intravenous (i.v.) injection of capsaicin; cardiac sympathetic chemoreflexes activated by epicardial application of bradykinin or capsaicin; and baroreflex‐mediated changes in heart rate resulting from both pressor and depressor effects produced by i.v. injections of noradrenaline and bradykinin, respectively.

2. Diltiazem infused i.v. at a rate of 10–30 μg/kg per min (mean cumulative dose 0.53 ± 0.05 mg/kg, n= 9), did not affect basal heart rate, despite significant (P<0.001) reduction of resting blood pressure.

3. Diltiazem treatment did not affect the pressor responses to i.v. noradrenaline (0.3 μg/kg) or the hypotensive effects of i.v. bradykinin (0.3 μg/kg), but reduced significantly both the baroreflex‐mediated bradycardia (P<0.01) and tachycardia (P<0.05) occurring with noradrenaline and bradykinin, respectively.

4. In contrast, diltiazem greatly enhanced reflex bradycardia (P<0.001) and systemic hypotension (P<0.01) resulting from activation of the afferent vagal pulmonary receptors by i.v. capsaicin (3–5 μg/kg).

5. Reflex pressor responses evoked by activation of the afferent cardiac sympathetic neurons by epicardial application of bradykinin (1 μg) or capsaicin (10–20 μg) were not affected by diltiazem, but the corresponding reflex increases in heart rate evoked by both substances were significantly (P<0.01) reduced.

6. The results indicate that diltiazem, while reducing the influence of sinoaortic baroreceptors on heart rate, facilitates the reflex vagal control of the cardiac pacemaker by the afferent cardiopulmonary vagal receptors. These nervous reflex mechanisms, which include attenuation of positive chronotrophic effects that may result from ischaemia‐induced activation of the afferent cardiac sympathetic neurons, may play an important role in the protective action of diltiazem in ischaemic heart disease.
THE EFFECTS OF HIGH Na AND Cl CONCENTRATIONS ON RAT PROXIMAL VOLUME AND Na FLUXES AT ZERO TUBULAR FLOW
Authors: Gyory A. Z. , Ng J. , McNeil D.
Published: June 2007

1. In vivo micropuncture techniques, with and without peritubular capillary perfusion, were used to study the effects of high extracellular Na and Cl concentrations on transepithelial volume (Jv) and sodium (JNa) fluxes in rat proximal tubules.

2. In a double blind manner, the shrinking drop technique of Gertz was used to measure Jv; JNa was calculated from this and the tubular fluid Na concentration.

3. At both 184 and 279 mmol/l pericellular Na concentrations (both inside and outside the tubular epithelium), net Jv decreased significantly by 15 and 64%, respectively. Net JNa remained constant at 184 but decreased by 29% at 279 mmol/l Na concentration.

4. Thus, at both Na concentrations, when translated to free flow conditions, fractional Na reabsorption must have decreased. These findings, also supported by previous results at these Na concentrations, indicate that active Na transport was inhibited by high pericellular Na concentrations.

5. When intratubular Cl concentration was varied between 108 and 138 mmol/l while peritubular Cl was maintained constant (blood perfusing the capillaries), neither Jv nor JNa changed. Thus, at zero tubular flow, differential Cl/HCO3 concentrations do not provide significant driving forces for net Jv or JNa.

6. When only intratubular but not peritubular Na was elevated to 279 mmol/l, Jv and JNa increased markedly by 50 and 187%, providing evidence that a true solvent drag (solute drag) effect does exist in rat proximal tubules.

7. These findings offer a mechanism to explain why Na reabsorption is not increased when the filtered load of Na is increased with an elevation of plasma Na. That is, the high Na, which surrounds the tubular epithelium, inhibits Na and volume flux at the cellular level by mechanisms as yet unknown. The results also showed that differential Cl/HCO3 concentrations made no difference to Na or volume fluxes at zero tubular flow.
FACILITATION OF DRUG ENTRY INTO BRAIN BY OSMOTIC OPENING OF THE BLOOD‐BRAIN BARRIER
Authors: Robinson Peter J.
Published: June 2007

1. After osmotic opening, the blood‐brain barrier (BBB) has been shown to reclose more rapidly to large than to small neutral, water‐soluble molecules. Quantitative analysis of these data supports the creation of interendothelial pores with radii of about 200 Å through which such molecules pass by both restricted diffusion and bulk flow (with solute drag) from blood to brain.

2. The major reduction in BBB permeability from 6 to 35 min following osmotic opening seems to be due to a reduction in bulk flow by a factor of about 10, rather than marked decreases in pore densities or effective pore size. On this basis, quantitative predictions of brain uptake of neutral, water soluble substances are made for various times after osmotic opening of the BBB, as a function of molecular size.

3. Implications of these results are discussed for enhancement of uptake of drugs, including enzymes and certain anti‐cancer agents, by the brain.

4. The idea of a ‘therapeutic window’ as the period of time, following reversible osmotic opening, during which the permeability of the BBB is enhanced significantly for a particular compound, is introduced. Since the BBB is normally highly impermeable to plasma proteins, the effect of BBB opening on the uptake of highly protein‐bound drugs is discussed briefly.

5. The effect of molecular charge on the passage of molecules through interendothelial pores into the brain is also discussed.
THE EFFECT OF CAPTOPRIL OR ENALAPRILIC ACID ON THE Na APPETITE OF Na‐DEPLETE RATS
Authors: Weisinger R. S. , Denton D. A. , Nicolantonio R. Di , McKinley M. J.
Published: June 2007

1. The converting enzyme inhibitors, captopril (SQ14 225, Squibb) or enalaprilic acid (MK 422, Merck Sharp and Dohme), were used to evaluate the role of angiotensin II in sodium (Na) appetite of Na‐deplete rats given a choice of water and 0.5 mol/1 NaCl to drink. Also, the effect of these drugs on taste was evaluated in water‐deprived Na‐replete rats and in Na‐deplete rats given a choice of NaCl, sucrose and water.

2. Intraperitoneal (i.p.) injection of furosemide (20 mg/kg) increased urinary Na loss by 1.3–1.4 mmol and subsequent Na intake by 1.5–1.8 mmol. This increase in Na intake was abolished by a high dose of captopril (50 mg/kg, i.p.) or enalaprilic acid (80 mg/kg, i.p.), but was enhanced by a low dose of captopril (50 μg/kg, i.p.).

3. There was no clear evidence that either captopril or enalapril affected taste for NaCl, sucrose or water in water‐deprived Na‐replete rats. However, the high dose of captopril or enalapril decreased the intake of NaCl and sucrose in Na‐deplete rats.

4. Thus, while the results are consistent with the possibility that angiotensin II is involved in Na appetite induced by Na depletion and that the difference between the high and low doses of converting enzyme inhibitors on Na appetite may be related to their relative effectiveness in blocking angiotensin I conversion at central sites, the observation that sucrose intake is decreased by high dose converting enzyme inhibitor in Na‐deplete rats suggests that other actions of the converting enzyme inhibitors may be involved.
STUDIES ON THE SPECIFICITY OF THE INHIBITORY ACTION OF N,N‐DIISOPROPYL‐N'‐ISOAMYL‐N'‐DIETHYLAMINOETHYLUREA (P‐286) ON ADRENAL CATECHOLAMINE RELEASE IN THE ANAESTHETIZED RAT
Authors: Malta Errol , Angus James A.
Published: June 2007

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1. The ability of P‐286 (N,N‐diisopropyl‐N'‐isoamyl‐N'‐diethylaminoethylurea) to reduce selectively the release of catecholamines from the adrenal medulla has been studied in urethane‐anaesthetized rats.

2. Pressor responses to acetylcholine (Ach) and the nicotinic receptor‐agonist 1,4‐dimethylphenylpiperazine (DMPP) in rats treated with atropine, (±)‐propranolol and guanethidine were used as the index of adrenal catecholamine release.

3. The injection of P‐286 (1–10 mg/kg, i.v.) elicited a dose‐dependent bradycardia which was associated with hypotension. P‐286 reduced pressor responses to Ach and DMPP in a dose‐dependent manner with an IC50 of 2.5 mg/kg and, following near complete blockade, pressor responses to DMPP returned to 50% of control after 90 min.

4. In non‐atropinized rats, P‐286 (30 mg/kg, i.v.) was without effect on the bradycardic responses elicited by stimulation of the right vagus nerve at frequencies of 5–40 Hz while pressor responses to DMPP in bilaterally adrenalectomized, non‐guanethidine treated rats were reduced by approximately 50% after P‐286 (10 mg/kg, i.v.).

5. The latter effect of P‐286 on responses to DMPP in adrenalectomized rats cannot be attributed to ganglionic blockade since in rats with intact adrenals P‐286 (10 mg/kg, i.v.) also reduced pressor responses to i.v. adrenaline and i.v. angiotensin II by approximately 50%. Thus the reduction in response to DMPP in adrenalectomized rats and to the non‐nicotinic agonists may be a reflection of an action on the mechanism of contraction of vascular smooth muscle; that is, at a post‐receptor event.

6. The results of the study show that P‐286 selectively reduces adrenal catecholamine release at doses which do not affect autonomic ganglia. Its usefulness as a tool in cardiovascular research, however, may be limited by an action of vascular smooth muscle.
RESISTANCE OF SYMPATHETIC CARDIAC NERVE FUNCTION IN THE PITHED RAT TO PREJUNCTIONAL EFFECTS OF ANGIOTENSIN II
Authors: Rechtman M. P. , King R. G. , Boura A. L. A.
Published: June 2007

1. The spinal sympathetic outflow (C7‐T2) of pithed male Wistar rats was electrically stimulated (30–50 V, 0.5 ms, 0.1–1.0 Hz) and heart rate and arterial blood pressure were recorded. d‐Tubocurarine (1 mg/kg) and atropine (1 mg/kg) were administered intravenously (i.v.) to reduce voluntary and parasympathetic nerve activity.

2. Angiotensin II (0.39–3.4 μg/kg per min) was infused at a rate which caused a sustained rise in diastolic blood pressure of at least 25 mmHg but which did not alter basal heart rate.

3. Chronotropic responses to sympathetic nerve stimulation were not affected by infusion of angiotensin II, and were also unaltered by pretreatment of rats with indomethacin (5 mg/kg, i.v.) 10 min prior to commencement of stimulation.

4. These results suggest that positive chronotropic responses to cardiac sympathetic nerve stimulation in pithed rats are not affected by increased angiotensin II levels. Indomethacin had no effect, which indicates that cyclo‐oxygenase products were not involved in modulation of chronotropic responses to cardiac sympathetic nerve stimulation.
TRAIN‐OF‐FOUR FADE DURING NEUROMUSCULAR BLOCKADE INDUCED BY TUBOCURARINE, SUCCINYLCHOLINE OR α‐BUNGAROTOXIN IN THE RAT ISOLATED HEMIDIAPHRAGM
Authors: Cheah L. S. , Gwee M. C. E.
Published: June 2007

1. Nerve‐evoked maximal twitches (T1, T2, T3, T4) of the rat isolated hemidiaphragm to train‐of‐four (TOF) stimulation (2 Hz2 s) were recorded continuously in the absence or presence of tubocurarine (1.5 μmol/1), succinylcholine (40 μmol/1) or α‐bungarotoxin (1 μmol/1). The T1 and T4 response‐time profiles for the three drugs were analysed with respect to amplitude depression and the TOF ratio (T4/T1) during the development of and recovery from neuromuscular blockade.

2. Tubocurarine produced T1 block accompanied by intense TOF fade; for the same degree of T1 block, the TOF ratio was lower during the recovery from blockade after washing out tubocurarine from the bath than during the onset of blockade. There was also a correspondingly slower recovery of the TOF ratio from 90% T1 block to control levels when compared with the time for complete T1 recovery. Fade and twitch tension depression were shown clearly to be separate responses, each with its own response‐time profile. Fade is therefore not simply a consequence of postjunctional cholinoceptor blockade.

3. Succinylcholine produced T1 block with only moderate TOF fade; similar recovery rates from 90% T1 block to control levels were obtained for T1 and the TOF ratio.

4. α‐Bungarotoxin produced irreversible and complete neuromuscular blockade during which TOF fade was virtually absent.

5. The results obtained in this study closely resemble those from other similar studies in animals and in humans and clearly demonstrate that the rat isolated hemidiaphragm is a suitable in vitro model for time course studies on TOF fade.
RISK‐BENEFIT OF SPECIFIC ANTIHYPERTENSIVE REGIMENS: RELEVANCE OF METABOLIC AND HAEMODYNAMIC EFFECTS OF α1‐BLOCKERS
Authors: Reid John L. , Curzio Joan , Elliott Henry L.
Published: June 2007

1. Existing strategies for the control of high blood pressure have had a disappointing impact on coronary heart disease—the major cause of death in hypertension.

2. There is a need for more work to identify the relationship between blood pressure, atheroma and other risk factors.

3. A more aggressive approach to treatment may be indicated, especially in high risk groups.

4. In addition to treatment of blood pressure, other major risk factors (lipids and smoking) must be tackled.

5. Alternative treatment regimens with different mechanisms of action and/or effects on lipids should be evaluated in practice.

6. Selective α1‐blockers have potential haemodynamic advantages, improve the lipid profile and are well tolerated as first or second line therapy.
CHANGE IN BLOOD PRESSURE IN RELATION TO CHANGE IN NUTRIENTS EFFECTED BY MANIPULATION OF DIETARY SODIUM AND POTASSIUM
Authors: Nowson C. A. , Morgan T. O.
Published: June 2007

1. As part of a study investigating the effect of dietary alterations of sodium and potassium intake on blood pressure, the changes in nutrients that occurred with dietary intervention were determined.

2. Mild hypertensive subjects were randomized to one of four dietary intervention groups: control; high potassium; low sodium; low sodium, high potassium. The changes in nutrients in each diet group were assessed by dietary history and five repeat 24 h dietary recalls. Assessment was validated by measurement of urinary nitrogen excretion and urinary electrolytes.

3. The three dietary intervention groups experienced a fall in blood pressure (systolic: 4.4 ± 1.0 mmHg, P<0.005; diastolic: 3.3 ± 0.7 mmHg, P<0.001), greater than that observed in the control group.

4. The only significant dietary change across all diet groups was a reduction in the dietary sodium/potassium ratio, which was significantly less than that of the control group. The only other nutrient to differ from the control in all groups was fat intake, which was reduced.

5. In the control group there was a small but significant decrease in energy, fibre, protein, carbohydrate, potassium and magnesium intake. In the high potassium group there was a significant increase in fibre, carbohydrate, potassium, magnesium, and a decrease in calcium intake. In the low sodium group there was a decrease in energy intake with a subsequent reduction in all nutrients except alcohol. In the low sodium, high potassium group there was a significant reduction in dietary sodium and protein and an increase in fibre, carbohydrate, potassium and magnesium.

6. The reduction of the dietary sodium/potassium ratio correlated with a reduction in the urinary sodium/potassium ratio. This was the best predictor for change in diastolic pressure in all groups, suggesting that reduction in the sodium/potassium ratio contributed to the fall in blood pressure.

7. Reduction of sodium intake and increase in potassium intake by dietary means caused a reduction in blood pressure which does not appear to be due to alteration of other measured dietary constituents.
DECREASED RENAL RESPONSES TO ATRIAL NATRIURETIC PEPTIDE IN RENAL WRAP HYPERTENSION
Authors: Takata M. , Denton K. M. , Woods R. L. , Anderson W. P.
Published: June 2007

1. The effects of atrial natriuretic polypeptide (ANP) on renal function were examined in renal wrap hypertensive rabbits and sham operated rabbits.

2. ANP (2μg/min) induced hypotension, but did not produce significant diuresis, natriuresis or change in the glomerular filtration rate (GFR) in renal wrap hypertensive rabbits (n= 8).

3. In sham operated normotensive rabbits (n= 4), ANP induced significant diuresis (230%) and increased GFR by about 40%.

4. Thus, ANP was markedly less effective in the impaired kidneys of renal wrapped rabbits than in normal kidneys.
THE EFFECT OF EPANOLOL ON INTRA‐ARTERIAL AMBULATORY BLOOD PRESSURE AND BARORECEPTOR HEART RATE REFLEX IN ESSENTIAL HYPERTENSION
Authors: Smith Stephen A. , Littler William A.
Published: June 2007

1. The effect of chronic treatment with epanolol, a new cardioselective P‐adrenoceptor antagonist with moderate pi‐selective intrinsic sympathomimetic activity (ISA), on 24 h ambulatory intra‐arterial blood pressure (24 h IABP) and the sino‐aortic baroreceptor heart rate (SAB/HR) reflex was investigated in six hypertensive subjects.

2. All subjects demonstrated a >10% reduction in mean arterial pressure with atenolol therapy (100 mg once daily) before entering a randomized, double‐blind, placebo‐controlled, crossover protocol with epanolol (100 mg twice daily for 4 weeks).

3. Epanolol treatment at this dose was not associated with significant reduction in systolic or diastolic 24 h IABP or heart rate. There was no change in SAB/HR reflex set point, sensitivity or latency with epanolol.

4. β1‐selective ISA may be undesirable in β‐adrenoceptor antagonists used to treat hypertension.
EFFECT OF LABETALOL ON HUMAN PLATELET FUNCTION
Authors: Anfossi Giovanni , Trovati Mariella , Lanzio Mario , Mularoni Elena , Massucco Paola , Emanuelli Giorgio
Published: June 2007

1. The effects of the α‐β‐adrenergic antagonist labetalol on the activation of human platelets by adrenaline and other aggregating stimuli have been investigated.

2. Labetalol inhibited platelet aggregation and secretion induced by collagen and the second phase of aggregation caused by ADP, platelet activating factor, adrenaline and ionophore A23187. Adrenaline‐induced platelet activation was inhibited by the lowest labetalol concentration. The response to Na arachidonate was minimally affected and the arachidonate‐induced thromboxane B2 generation was only partially prevented.

3. The pre‐incubation with low concentration of ionophore A23187 overcame labetalol's inhibition of collagen‐induced platelet aggregation.

4. Labetalol did not influence intraplatelet cyclic AMP levels.

5. The present investigation provided evidences that the modulation of human platelet function by labetalol could be related also to a decreased Ca2+ availability.
BUPIVACAINE ACUTE TOXICITY PROTECTION BY DIAZEPAM IN MICE
Authors: Bruguerolle B. , Emperaire N. , Ottomani A. , Manelli J. C.
Published: June 2007

1. The effects of acute and 8‐day administration of diazepam (DZP) on the acute toxicity of bupivacaine in the mouse were studied.

2. Protection of bupivacaine‐induced acute toxicity by DZP appears to be dose‐dependent after treatment for 8 days but not after acute treatment.
THE INTERRELATIONSHIP OF MORPHINE AND THE PARASYMPATHETIC NERVOUS SYSTEM IN DIGOXIN‐INDUCED ARRHYTHMIAS IN THE GUINEA‐PIG
Authors: Rabkin Simon W.
Published: June 2007

1. The role of the parasympathetic nervous system and the effect of morphine on cardiac arrhythmias induced by digitalis was assessed in guinea‐pigs that had digitalis arrhythmias produced by digoxin 50 μg/kg intravenously plus 500 μg/kg per h.

2. Morphine produced a dose‐dependent rightward shift in the relationship between digoxin dose and arrhythmias. Morphine 5 mg/kg subcutaneously (s.q.) was associated with significantly (P < 0.05) higher digoxin doses both at the onset of ventricular arrhythmias and at development of fatal arrhythmias compared with the control group that received saline s.q.

3. Vagotomy and atropine prevented the effect of morphine so that the dose‐response relationships and the mean digoxin dose at onset of ventricular arrhythmias and the development of fatal arrhythmias were not significantly different from the control group receiving saline.

4. These data indicate that morphine limits the development of digitalis arrhythmias and this effect is, at least in part, mediated through the parasympathetic nervous system.