Biomedical subjects

B Jarrott

Publications and source records attributed to B Jarrott.

At least 73 records · Page 4Linked to original sources

PubMed1992

Nature of [3H]rilmenidine binding to membranes of rat cerebral cortex.

The binding of [3H]rilmenidine to membranes of rat cerebral cortex was studied in order to ascertain which receptor populations this novel antihypertensive interacts with in the cortex. A catecholamine-sensitive, alpha 2-adrenoceptor binding site was identified which represented up to 50% of specific, 2 nmol/L [3H]rilmenidine binding and was displaceable by the catecholamines in the rank order epinephrine----norepinephrine----dopamine----isoproterenol. Some imidazolines such as clonidine, naphazoline, and idazoxan and the guanidino compound guanabenz completely and potently inhibited [3H]rilmenidine binding from both catecholamine-sensitive and -insensitive sites. The substituted imidazole and guanidine, cimetidine, and amiloride, respectively, showed no affinity for [3H]rilmenidine binding. The pharmacologic profile of the catecholamine-insensitive [3H]rilmenidine site in rat cerebral cortex suggests it may be novel, as it has the features of an imidazoline-guanidino-oxazoline binding site. However, its identity requires further characterization.

Adrenergic alpha-Agonists↗

PubMed1992

Single-dose and steady-state pharmacokinetics and pharmacodynamics of perindopril in hypertensive subjects.

In a double-blind, placebo-controlled, parallel group study, 24 essential hypertensive subjects were randomised to receive either placebo or 2, 4, or 8 mg perindopril. Perindopril, its deesterified metabolite, perindoprilat, and perindoprilat glucuronide were separated with an ion-exchange resin and determined by a radioimmunoassay (RIA). Pharmacokinetic and pharmacodynamic parameters were estimated for 96 h after the first dose and after 4-week once-daily treatment. Perindopril peak levels were achieved in less than or equal to 2 h after dosing with an elimination t1/2 of 1-2 h. Peak levels of perindoprilat were achieved more slowly, reaching a maximum level 5-8 h after dosing, and had an elimination t1/2 of 40 h. Levels of the perindopril glucuronide peaked approximately 0.5 h later than perindopril, with an elimination t1/2 of approximately 2 h. Perindopril, perindoprilat, and its glucuronide conjugate followed linear kinetics in the dose range of 2-8 mg, and there was no evidence of accumulation with chronic dosing. Perindopril 4 and 8 mg produced significant decreases in predose blood pressure (BP) with chronic dosing, with maximal decreases occurring 5-7 h after dosing. Perindopril also produced a prolonged dose-dependent inhibition of plasma angiotensin-converting enzyme (ACE) activity that was maximum after 4 h and had not fully recovered by 48 h after a single dose.

Aged↗

PubMed1992

Electrophysiological responses of angiotensin peptides on the rat isolated nodose ganglion.

Previous autoradiographic studies have identified angiotensin II (AII) binding sites over the nodose ganglion and along the vagal afferent neurons. In the present study, we examined whether these binding sites are functional receptors by measuring d.c. potential changes by extracellular recording techniques in the rat isolated nodose ganglion preparation in response to superfusion of angiotensin peptides. It was found that AII, as well as AI and AIII elicited concentration-dependent depolarisation of the nodose ganglion. However, the amino terminal angiotensin heptapeptide, A(1-7), failed to evoke any significant response. The AII receptor antagonist, saralasin had no intrinsic activity, but caused a concentration-dependent blockade of AII-induced depolarisation. This study provides evidence for direct neuronal effects of angiotensin peptides on rat vagal afferent neurons. Moreover, this preparation is a relatively convenient one in which to study functional neuronal AII receptor mechanisms on central or peripheral terminals of vagal sensory neurons.

Angiotensin I↗

PubMed1991

[125I]Ifenprodil: a convenient radioligand for binding and autoradiographic studies of the polyamine-sensitive site of the NMDA receptor.

Iodination of ifenprodil, a non-competitive NMDA antagonist, with Na125I/Chloramin-T gave a radioligand which bound rapidly and saturably to a single population of sites (dissociation constant 145 nM) in membranes of rat cerebral cortex. In competition studies, specific binding of [125I]-ifenprodil was inhibited by analogues of ifenprodil, as well as by spermine and spermidine. Binding was sensitive to Ca2+, Mg2+ and Zn2+. [125I]-Ifenprodil labelled a population of binding sites, which was topographically distributed in rat forebrain, as shown by autoradiography. [125I]Ifenprodil is a useful radioligand for the investigation of the polyamine site of the N-methyl-D-aspartate (NMDA) receptor-complex.

Animals↗

PubMed1991

Specific binding of D-Tyr25 (Nle28,31)-CCK(25-33) to cortical membranes from rat brain.

The 125I-labeled sulfonated cholecystokinin (CCK) analogue, D-Tyr25(Nle28,31)-CCK(25-33), bound saturably and reversibly to membranes of rat cerebral cortex. The dissociation constant Kd was estimated to be 0.14 nM by Scatchard analysis and 0.40 nM from analyses of dissociation/association rates. Hill coefficients of 0.99, Scatchard plots and drug competition studies were consistent with a single population of binding sites. Dependence on divalent cations and inhibition by guanylyl-imidodiphosphate suggested binding to a receptor coupled to a G protein. Competition studies with CCK-analogues and non-peptide specific antagonists indicated binding to receptor sites of the B-subtype (CCKB).

Animals↗

PubMed1991

Altered alpha 1-adrenoceptor-mediated responses in atria of rats with chronic left ventricular infarction.

Phosphoinositide (PI) turnover, chronotropic and inotropic responses to alpha 1-adrenoceptor activation, and alpha 1-adrenoceptor density were studied in atria from rats with left ventricular myocardial infarction (LVMI) and noninfarcted rats. LVMI was produced after surgical ligation of the left coronary artery in 8-week-old Wistar rats. Rats were killed 4 weeks after this operation when rats with LVMI had developed significant hypertrophy of both ventricles and atria. Phenylephrine 0.1 mM to 1 mM, with propranolol 0.3 mM, produced a concentration-dependent increase in heart rate (HR) in right atria from noninfarcted rat hearts, and this response was significantly reduced in rats with LVMI. In electrically driven left atria, the concentration-dependent, phenylephrine-induced positive inotropic responses observed with propranolol added were also significantly impaired in rats with LVMI as compared with those of noninfarcted rats. In contrast, neither PI turnover in response to phenylephrine in the presence of propranolol nor alpha 1-adrenoceptor density was reduced in rats with LVMI. These results suggest that the impaired alpha 1-adrenoceptor-induced chronotropic and inotropic responses in atria from rats with LVMI are not due to downregulation of alpha 1-adrenoceptors or to impaired activation of PI turnover after alpha 1-adrenoceptor stimulation, but to impairment of one or more biochemical responses distal to PI hydrolysis or changes in coupling mechanisms other than hydrolysis of PIs.

Animals↗

PubMed1990

[125I][D-Tyr25,Nle28,31]CCK-(25-33): a convenient new aminopeptidase resistant cholecystokinin analogue for radioligand binding and autoradiography.

The 125I-labeled sulfated cholecystokinin (CCK) analogue, [D-Tyr25,Nle28,31]CCK-(25-33), bound saturably to membranes from rat cerebral cortex and to brain tissue sections. Competition studies suggested binding to sites of the CCKB subtypes. The high affinity for brain membranes (Kd = 0.14 nM) and high specific binding to brain sections (80-90% specific binding), as well as its high specific radioactivity, makes it a suitable ligand for autoradiographic studies of cholecystokinin receptors.

Aminopeptidases↗

PubMed1990

Release and spread of immunoreactive neurokinin A in the cat spinal cord in a model of acute arthritis.

Antibody microprobes were used to study the release of immunoreactive neurokinin A into the spinal cord of anaesthetised cats during and following injection of a knee joint with kaolin and carrageenan. A basal level of immunoreactive neurokinin A was detected prior to any noxious stimuli. Innocuous mechanical joint stimuli (flexion or pressure) did not alter this basal level of release. However, on injection of kaolin and carrageenan into a knee joint, evidence of release into the ipsilateral spinal cord was immediately observed. Initially, immunoreactive neurokinin A was detected in 2 regions: one at the dorsal surface of the spinal cord and the other centred on the superficial dorsal horn. Within 1 h of joint injection, however, immunoreactive neurokinin A was detected throughout the dorsal horn and the adjacent white matter. The extensive spread and persistence of immunoreactive neurokinin A in the spinal cord may underlie some of the prolonged excitability changes evoked by brief noxious stimuli and peripheral inflammation reported by other laboratories.

Acute Disease↗

PubMed1990

Release of immunoreactive substance P in the spinal cord during development of acute arthritis in the knee joint of the cat: a study with antibody microprobes.

In anaesthetized spinal cats, the release of immunoreactive substance P in the spinal cord during development of an acute inflammation in one knee joint was studied with antibody microprobes. The microprobes bore antibodies directed to the C- or N-terminus of substance P. With the normal knee joint, innocuous mechanical stimuli (flexion, pressure) did not result in spinal release of immunoreactive substance P. Following injection of kaolin and carrageenan into a knee, evidence for release of substance P following joint stimulation was found in 7 of 10 cats. Such release did not occur for several hours after joint injection and was detected predominantly in the superficial dorsal horn, the dorsal columns and at the dorsal surface of the spinal cord. In some experiments release was detected in the deep dorsal horn and upper ventral horn. Release of immunoreactive substance P required periods of mechanical stimulation such as flexion of, or pressure to, the inflamed joint. The failure to detect central release of substance P from stimulation of normal joints, and the release of substance P, after a delay, from inflamed joints, suggest that the fibres releasing this compound require sensitization by inflammatory mediators before they are excited by joint stimuli.

Animals↗

PubMed1990

The effect of ketanserin on cardiovascular reflexes in conscious normotensive and spontaneously hypertensive rats.

The effect of ketanserin (3 mg/kg i.v.) on the baroreceptor heart rate reflex and the Bezold-Jarisch reflex was examined in conscious Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In the control situation (before ketanserin treatment), reflex bradycardia in response to phenylephrine (baroreflex) and phenyldiguanide (Bezold-Jarisch reflex) were impaired in SHR as compared with WKY, while reflex tachycardia in response to nitroprusside was similar in the two groups. However, after ketanserin administration in SHR, there was a reversal of the baroreflex-mediated tachycardia in response to nitroprusside into a bradycardic response. The nitroprusside-induced bradycardia was not caused by the release of 5-HT stimulating chemosensitive vagal afferents since the 5-HT3 receptor antagonist MDL 72222 did not block this response. In the same SHR, the Bezold-Jarisch reflex evoked by phenyldiguanide and the phenylephrine-induced bradycardia were potentiated by ketanserin. All the above effects of ketanserin were less evident in the WKY. Ketanserin did not alter vagal efferent function in anaesthetized SHR since it did not affect bradycardia induced by electrical stimulation of the vagus nerve. Therefore, it is suggested that ketanserin has sensitised cardiac vagal afferent mechanisms in SHR, which led to a normalization of reflex bradycardic function to a level normally observed in conscious normotensive WKY (i.e. prior to ketanserin treatment).

Animals↗

PubMed1990

Temperature dependence of angiotensin II-mediated depolarisation of the rat isolated nodose ganglion.

The ability of angiotensin II (A II) and 5-hydroxytryptamine (5-HT) to depolarise the rat isolated nodose ganglion preparation was examined. 5-HT depolarised the nodose ganglion, both at room temperature (20-24 degrees C) and at 35-37 degrees C. However, A II depolarised the nodose ganglion only under the latter condition, and these responses were blocked by the A II receptor antagonist saralasin. This study extends previous findings which have demonstrated A II binding sites on the nodose ganglion and axon, and identifies the rat nodose ganglion as a sensitive preparation in which to study the interactions between neuronal A II receptor activation and its blockade by A II receptor antagonists.

Angiotensin II↗

PubMed1990

Intrathecal kynurenate reduces arterial pressure, heart rate and baroreceptor-heart rate reflex in conscious rats.

In the present study, an excitatory amino acid (EAA) pathway in the spinal cord which maintains sympathetic vasomotor tone in conscious rats has been investigated. To this end, the cardiovascular effects of an intrathecally administered EAA antagonist, kynurenate (KYN), were studied in conscious rats. KYN (0.5 mumol in 10 microliters) caused a dramatic reduction in mean arterial pressure (MAP) and heart rate (HR) that persisted for 2-3 h, and also resulted in extensor paralysis of the hindlimbs. The time courses of fall in MAP and HR and hindlimb paralysis were similar. Baroreceptor-HR reflex activity was also markedly impaired after KYN, suggesting functional diminution of sympathetic outflow at the level of the spinal cord after blockade of EAA receptors by KYN. Xanthurenate, a metabolite of KYN without EAA antagonistic properties, produced negligible effects at the same dose of KYN. While these findings do not identify the putative EAA pathway, they do provide the first demonstration that this system is tonically active in conscious rats.

Animals↗

PubMed1990

Release, spread and persistence of immunoreactive neurokinin A in the dorsal horn of the cat following noxious cutaneous stimulation. Studies with antibody microprobes.

In barbiturate anaesthetized spinal cats antibody microprobes were used to examine release of immunoreactive neurokinin A following cutaneous thermal and mechanical stimulation. In the absence of peripheral stimuli, microprobes detected a diffuse basal presence of immunoreactive neurokinin A. Noxious mechanical and to a lesser extent noxious thermal stimuli increased the levels of immunoreactive neurokinin A diffusely throughout the dorsal horn which, in many cases, spread into the adjacent white matter. These diffuse stimulus-evoked increases contrast with previous experiments where the same stimuli produced discrete focal increases in levels of immunoreactive substance P. Evidence was obtained that released immunoreactive neurokinin A persisted in the spinal cord for at least 30 min beyond the period of stimulation. Neurokinin A needs consideration as the agent responsible for the long-lasting increases in excitability of some spinal neurons found by several laboratories to follow a brief input from unmyelinated primary afferents.

Animals↗

PubMed1990

Excitotoxin-induced degeneration of rat vagal afferent neurons.

The inferior vagal or nodose ganglion contains the perikarya of vagal afferent neurons that function as cardiopulmonary and abdominal visceral receptors as well as aortic arch baroreceptors. In this study we have sought to utilize the axon-sparing properties of the excitotoxins kainic acid, N-methyl-D-aspartic acid and alpha-amino-3-hydroxy-4-isoxazolepropionic acid to destroy the perikarya of these sensory neurons and thus selectively de-afferent the vagus in the rat. Kainic acid (0.5 nmol/microliters, 2 X 2 microliters) was applied topically to both nodose ganglia and the rats were allowed to recover for 7-8 days. Baroreceptor heart rate reflex activity was assessed in these conscious rats. Baroreceptor heart rate reflex gain was reduced (-51%) in kainic acid-treated rats, as was the maximal reflex bradycardia induced by the pressor agent, phenylephrine. Kainic acid treatment did not alter resting mean arterial pressure or heart rate. Vagal efferent neurons were spared by kainic acid treatment since bradycardic responses to electrical stimulation of the peripheral end of a cut vagus were not impaired. Histological studies showed marked destruction of perikarya within the nodose ganglia of kainic acid-treated rats: inflammatory and degenerative changes were evident at 2 days, and at 10 days there was considerable loss of neuronal cell bodies, but sparing of axons. Topical application to the nodose ganglion of alpha-methyl-DL-aspartic acid (6.8 nmol/microliters, 2 X 2 microliters), a non-excitotoxic dicarboxylic acid, failed to alter baroreflex sensitivity or produce perikaryal degeneration in nodose ganglia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Regional brain concentrations of calcitonin gene-related peptide in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

The regional brain and spinal cord concentrations of calcitonin gene-related peptide (CGRP) were measured in age-matched (22-23-week-old) spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The highest concentration of CGRP in the WKY rats was in the spinal cord (172 +/- 9 pmol/g), followed by the medulla oblongata/pons (88 +/- 5 pmol/g). The relative order of distribution in the remaining regions was: hypothalamus (12.6 +/- 0.8 pmol/g) = striatum greater than thalamus greater than midbrain = hippocampus greater than cortex (2.1 +/- 0.3 pmol/g). The concentration of CGRP in the cerebellum was at the level of the assay's sensitivity (0.5 pmol/g). The relative order of distribution in the SHR strain was essentially the same. However, in comparison with the WKY rats, the SHR had significantly lower levels of CGRP in the hippocampus (-47%), striatum (-49%) and medulla oblongata/pons (-24%), and in the spinal cord (-24%). In younger age-matched (16-17-week-old) rats, the spinal cord and medulla oblongata/pons concentrations of CGRP were also lower in SHR than in WKY rats. CGRP is a putative neurotransmitter which, when administered centrally or peripherally, has potent cardiovascular effects. The reduced levels of this peptide may be an important factor in the cardiovascular and/or behavioural abnormalities of the SHR strain.

Animals↗

PubMed1990

Impaired arterial baroreceptor reflex and cardiopulmonary vagal reflex in conscious spontaneously hypertensive rats.

The activity of baroreceptor reflexes and cardiopulmonary reflexes was examined in conscious spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats. The baroreceptor heart rate reflex, elicited by phenylephrine- and nitroprusside-induced changes in blood pressure, had a reduced range and lower heart rate plateau in SHR than in WKY rats, which suggests impaired vagal control of the heart rate in SHR. Cardiopulmonary receptor reflex activity was assessed by intravenous injections of phenyldiguanide which evoke the Bezold-Jarisch reflex. Phenyldiguanide elicited dose-dependent bradycardic and hypotensive responses in WKY rats, but these were significantly attenuated in SHR. This is the first demonstration of impaired Bezold-Jarisch responses in conscious SHR and provides evidence of both impaired vagally mediated arterial baroreceptor activity and impaired cardiopulmonary receptor activity in this rat strain.

Animals↗

PubMed1989

Excitotoxin-induced lesions of the central but not basolateral nucleus of the amygdala modulate the baroreceptor heart rate reflex in conscious rats.

The present study has examined the influence of the central nucleus of the amygdala (Ce) and the basolateral nucleus of the amygdala (BL) on the baroreceptor heart rate (HR) reflex in conscious, unrestrained rats. Baroreceptor HR reflex activity was examined in rats with bilateral excitotoxin (N-methyl-D-aspartate; 40 nmol/side)-induced lesions of the Ce or the BL and in control rats (artificial cerebrospinal fluid). After lesioning, the reflex HR responses were recorded following intravenous bolus doses of the pressor agent phenylephrine and the depressor agent sodium nitroprusside. Baroreceptor reflex parameters were determined by sigmoidal computerized curve-fitting. Lesions of either the Ce or the BL failed to affect resting mean arterial pressure (MAP) or HR. However, the Ce lesion reduced the maximum and average gain (sensitivity) of the baroreceptor reflex, and diminished the range of the reflex by altering the minimum, but not the maximum HR plateau. The upper and lower reflex thresholds and the MAP value corresponding to the midpoint of the HR range were not affected. Bilateral lesions of the BL failed to modify any baroreceptor reflex parameters. These results suggest that despite previous evidence for the involvement of the BL in cardiovascular regulation this nucleus does not exert a tonic influence on vasomotor neurons nor does it influence the baroreceptor HR reflex. In contrast, neurons projecting from the Ce appear to provide excitatory input to medullary neurons involved in baroreceptor reflex are regulation.

Amygdala↗

PubMed1989

Pharmacokinetics and antihypertensive effects of low dose clonidine during chronic therapy.

Using a sensitive and specific radioimmunoassay the pharmacokinetic disposition of clonidine was determined in hypertensive patients after a single dose and then after 5, 28 and 56 days of chronic dosing with 75 micrograms bd. Following a single dose of clonidine maximal plasma concentrations of 0.34 +/- 0.06 ng/ml were achieved after 3.6 +/- 1.2 hours. After 5 days of repetitive dosing the maximal concentration was significantly higher, 0.66 +/- 0.06 ng/ml and remained so throughout chronic therapy (P = 0.018). The AUC, Tmax and T1/2 did not differ significantly between the acute dose and the chronic dosing pharmacokinetic studies. Clonidine also produced a significant fall in blood pressure. Supine diastolic blood pressure fell from 106 +/- 5 mmHg predose to 99 +/- 6 mmHg 2 hours after the first dose (P less than 0.05). The corresponding values after cyclopenthiazide alone were 108 +/- 8 and 105 +/- 8 mmHg (P = 0.13). Similar falls in blood pressure were produced during chronic therapy.

Adult↗