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Biomedical subjects

J R Fozard

Publications and source records attributed to J R Fozard.

At least 19 recordsLinked to original sources
PubMed1992

The role of nitric oxide in the regional vasodilator effects of endothelin-1 in the rat.

1. The role of nitic oxide (NO) derived from L-arginine in the regional vasodilator effects of endothelin-1 has been investigated in anaesthetized, spontaneously hypertensive (SH) rats in which autonomic reflexes were abolished by ganglion blockade. The experimental design incorporated animals infused with phenylephrine to mimic the peripheral vasconstrictor effects of the NO biosynthesis inhibitors and a single dose per animal paradigm to obviate problems of tachyphylaxis to the vasodilator effects of endothelin-1. 2. Infusion of the inhibitor of NO synthase, N-monomethyl-L-arginine (L-NMMA) at a dose (5 mg kg-1 min-1) which maximally raised blood pressure did not influence either the fall in blood pressure or the vasodilator responses induced in the hindquarters and carotid vascular beds by endothelin-1 (1 nmol kg-1, i.v.) The duration (but not the initial magnitude) of the vasodepressor response to endothelin-1 was however significantly attenuated (by 49%) during infusion of the more potent inhibitor of NO synthase, NG-nitro-L-arginine methyl ester (L-NAME), 2 mg kg-1 min-1. 3. Increasing the dose of L-NAME to 10 and 25 mg kg-1min-1 significantly attenuated, but did not abolish, the falls in blood pressure and hindquarters vasodilator responses to acetylcholine, 1 microgram kg-1, and endothelin-1, 1 nmol kg-1 min-1. The effects were selective in that vasodepressor responses to the endothelium-independent vasodilator, sodium nitroprusside, 1-10 micrograms kg-1 min-1, were unaltered. The effects were selective in that vasodepressor responses to the endothelium-independent vasodilator, sodium nitroprusside, 1-l0mg kg min , were unaltered.4. The data indicate that NO generated de novo from L-arginine mediates a significant component of the vasodilator effect of endothelin-1 in the anaesthetized, ganglion-blocked SH rat. However, a major component of the vasodepressor effects of both endothelin-1 and acetylcholine may occur independently of this mechanism.

Animals↗
PubMed1992

5-HT in nervous system disease and migraine.

New developments defining the relationship between 5-hydroxytryptamine (5-HT; serotonin)1B and 5-HT1D receptors are reviewed and a novel pain control system involving spinal 5-HT3 receptors is described. The emerging roles of 5-HT receptor mechanisms in migraine and in the craving for alcohol are discussed.

Alcoholism↗
PubMed1991

Haemodynamic responses to NG-monomethyl-L-arginine in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

1. Nitric oxide (NO) is a major component of endothelium-derived relaxing factor (EDRF) the synthesis of which from L-arginine can be inhibited by NG-monomethyl-L-arginine (L-NMMA). To assess whether basal NO tone is different in experimental hypertension, the haemodynamic effects of L-NMMA have been compared in anaesthetized spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats in which autonomic reflexes were blocked by ganglion blockade. 2. Bolus intravenous injections of L-NMMA, 1-30 mg kg-1, but not D-NMMA, 1-30 mg kg-1, induced dose-related increases in mean arterial pressure and decreases in conductances in the renal, carotid, hindquarters and mesenteric vascular beds in both SH and WKY rats. Although the different vascular beds varied in their maximum responses to L-NMMA, there were neither qualitative nor quantitative differences between the two rat strains in this respect. 3. The effects of L-NMMA, 30 mg kg-1, i.v. on all parameters were rapidly and completely reversed by L-arginine, 30 mg kg-1, i.v., in both SH and WKY rats. 4. The results indicate that NO derived from L-arginine exerts a powerful vasodilator tone in both anaesthetized, ganglion-blocked SH and WKY rats. Although NO appears to contribute differentially to tone in the different vascular beds, there were no major differences between the two rat strains in this respect. Hence a reduced NO tone to the vasculature is unlikely to be a major factor contributing to the elevated blood pressure in the adult SH rat.

Animals↗
PubMed1990

No major role for atrial natriuretic peptide in the vasodilator response to endothelin-1 in the spontaneously hypertensive rat.

Porcine endothelin-1 (endothelin) is a powerful releaser of atrial natriuretic peptide (ANP) from rat atrial myocytes in vitro. The fact that release is greater when atria are taken from spontaneously hypertensive rats (SHR) than normotensive control animals led to the suggestion that ANP release could be the basis of the prominent vasodilator responses seen in SHR in vivo. The present experiments were carried out in the anaesthetized, ganglion-blocked SHR to test this hypothesis. Bolus injections (1-4 nmol/kg) of ANP (atriopeptin III-rat) gave slowly developing (1-5 min), small (less than 10 mm Hg) falls in blood pressure associated with weak but consistent vasoconstrictor responses in the renal, mesenteric, carotid and hindquarters vascular beds. In contrast, i.v. injections of endothelin, 1 nmol/kg, induced rapid (less than 15 s), substantial (greater than 30 mm Hg) falls in blood pressure associated with vasodilation in the carotid and hindquarters vascular beds. In animals rendered essentially unresponsive to ANP following repeated i.v. injections of high doses (4-10 nmol/kg) of the peptide, endothelin still induced prominent vasodilator responses. Injections of endothelin given into the aortic arch in order to minimize contact with the atria, gave vasodepressor/vasodilator responses which were qualitatively similar and quantitatively somewhat greater than those following intra-jugular venous injection. Taken together these data suggest ANP release is not a major factor in the vasodilator effects of endothelin in the rat.

Animals↗
PubMed1990

Differences in regional vascular sensitivity to endothelin-1 between spontaneously hypertensive and normotensive Wistar-Kyoto rats.

1. The systemic and regional haemodynamic effects of porcine endothelin-1 (endothelin) have been measured in anaesthetized spontaneously hypertensive (SH) rats rendered areflexic by ganglion blockade; comparisons were made with age-matched Wistar-Kyoto (WKY) control animals. 2. In both SH and WKY rats endothelin (0.1-1 nmol kg-1 i.v.) elicited an initial, short-lived (less than 2 min), fall in blood pressure which was associated with substantial increases in hindquarter and carotid vascular conductances. Both the blood pressure falls and the peripheral vasodilator responses were greater in SH than in WKY rats. 3. The initial depressor effects of endothelin were followed by marked and sustained increases in blood pressure associated with constriction in carotid, hindquarter, renal and mesenteric vascular beds. Vasoconstrictor responses were quantitatively similar in the two rat strains. 4. Pretreatment with indomethacin (5 mg kg-1 i.p. or i.v.) did not alter the responses to endothelin, 1 nmol kg-1, in SH rats. 5. The regional haemodynamic effects of intravenously administered acetylcholine (0.01-1 microgram kg-1), nitroprusside (0.3-10 micrograms kg-1) and angiotensin II (0.01-0.1 microgram kg-1) were similar in SH and WKY rats. 6. Endothelin (10(-10)-3 x 10(-8) M) contracted aortic rings from both SH rats and WKY control animals. Removal of the endothelium enhanced significantly the sensitivity of tissues from both WKY and SH rats to endothelin; the increase in sensitivity was greater in tissues from SH than WKY rats. 7. The results demonstrate qualitative similarities in the complex haemodynamic effects of endothelin in SH rats and WKY control animals. However, the SH rats display substantially greater vasodilator responses to endothelin than WKY. Eicosanoid generation is not the mechanism of the vasodilator action of endothelin in SH rats under the conditions of our experiments.

Acetylcholine↗
PubMed1990

Characterization of MDL 73005EF as a 5-HT1A selective ligand and its effects in animal models of anxiety: comparison with buspirone, 8-OH-DPAT and diazepam.

1. With radioligand binding techniques, MDL 73005 EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8-az aspiro[4, 5]decane-7,9-dione methyl sulphonate) shows high affinity (pIC50 8.6) and selectivity (greater than 100 fold compared to other monoamine and benzodiazepine receptor sites) for the 5-hydroxytryptamine (5-HT)1A recognition site; it was both more potent and more selective than buspirone in this respect. 2. In rats pretreated with reserpine, 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) induced forepaw treading and flat body posture; in the same model, MDL 73005EF and buspirone showed minimal agonist activity and at high doses MDL 73005EF inhibited responses to 8-OH-DPAT. 3. In rats trained to discriminate 8-OH-DPAT from saline in a drug discrimination paradigm, both MDL 73005EF and buspirone generalized dose-dependently and completely to the 8-OH-DPAT cue. 4. To define the anxiolytic potential of MDL 73005EF, it was examined in the elevated plus-maze test and in the water-lick conflict test in comparison with diazepam and buspirone. In both tests MDL 73005EF induced effects similar to those seen following diazepam. Buspirone had similar effects to both MDL 73005EF and diazepam in the water-lick conflict test but opposite effects in the elevated plus-maze. 8-OH-DPAT also had opposite effects in the elevated plus-maze test to MDL 73005EF and diazepam. 5. The anti-conflict effects of MDL 73005EF were reversed by low doses of the 5-HT1A receptor agonist, 8-OH-DPAT; those of buspirone were neither antagonised nor mimicked by 8-OH-DPAT. 6. These results suggest that an interaction with 5-HTIA receptors is the basis of the anxiolytic-like activity of MDL 73005EF. However, its mechanism of action is clearly different from that of buspirone, possibly reflecting a greater selectivity for the 5-HTlA receptors located presynaptically on central 5- hydroxytryptaminergic neurones.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

5-HT1 receptor agonists attenuate the naloxone-induced jumping behaviour in morphine-dependent mice.

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and RU 24969 have been used to investigate whether 5-HT1A and 5-HT1B receptors are involved in the naloxone-induced jumping behaviour of the chronically morphine-dependent mouse. To control for possible interactions with catecholaminergic systems, the effects of alpha 1- and alpha 2-adrenoceptor antagonists were investigated. 8-OH-DPAT and RU 24969, as well as buspirone, ipsapirone and flesinoxan, were found to suppress jumping. The effects were mimicked by the alpha-adrenoceptor antagonists, idazoxan, WY 26392, yohimbine and rauwolscine. Inhibition of 5-HT synthesis with para-chlorophenylalanine (pCPA) had only minimal effects on withdrawal jumping per se; the attenuating effects of 8-OH-DPAT and RU 24969 were not altered in pCPA-pretreated animals. The effects of RU 24969 were blocked by (-)-pindolol and, stereoselectively, by (-)-SDZ 21-009. (-)-Pindolol neither influenced the action of 8-OH-DPAT nor showed any effect per se. The actions of 8-OH-DPAT and buspirone, but not of RU 24969 and idazoxan, were blocked by the 5-HT1A receptor antagonist, spiroperidol. Similarly, both haloperidol and prazosin prevented the attenuating action of 8-OH-DPAT but did not interfere with the action of RU 24969. We conclude that the actions of 8-OH-DPAT and RU 24969 are mediated by postsynaptic receptors. The 5-HT1B receptor appears to mediate the attenuating action of RU 24969; the exact mechanism of action of 8-OH-DPAT remains open but activation of an alpha 1-adrenoceptor is implicated.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Cardiovascular effects of endothelin 1 in pithed spontaneously hypertensive rats: evaluation of its mechanism(s) of action.

The present experiments were carried out to investigate the cardiovascular effects of endothelin 1 (ET) in pithed spontaneously hypertensive (SH) rats and to evaluate its mechanism of action. The results show that ET (0.1-3 nmol/kg i.v.) is a powerful vasoconstrictor agent in the pithed rat. However, at a dose of 3 nmol/kg i.v. all the pithed animals "died" following a gradual decrease in mean arterial blood pressure and pulse pressure and changes in the form of the electrocardiogram (ECG). The predominant feature of the change in the ECG was a progressive decrease in the amplitude of the T wave resulting in a depression of the curve representing repolarization. Investigations in isolated perfused SH rat hearts showed that ET powerfully reduces coronary flow concentration-dependently (IC50 2.1 +/- 0.3 nM) an effect associated with sinus bradycardia and a decrease in coronary pressure amplitude. No overt ECG changes were seen. Control experiments with mechanical flow restriction suggest that bradycardia is a consequence of reduced coronary flow and that the ECG changes observed in vivo can be explained on the basis of coronary insufficiency and resulting myocardial hypoxia. Vasoconstrictor responses to angiotensin II (0.4 microgram/kg i.v.), phenylephrine (8 micrograms/kg i.v.) and ET (0.5 nmol/kg i.v.) were antagonised by around 70% by isradipine (0.03 mg/kg i.a.). The results suggest that endothelin-induced vasoconstriction may involve receptor operated channel activation and opening of voltage sensitive Ca2+ channels.

Angiotensin II↗
PubMed1989

MDL 72,974: a potent and selective enzyme-activated irreversible inhibitor of monoamine oxidase type B with potential for use in Parkinson's disease.

MDL 72,974, (E)-2-(4-fluorophenethyl)-3-fluoroallylamine, was designed to be a selective inhibitor of monoamine oxidase type B (MAO-B). In vitro, the compound inhibits rat brain mitochondrial MAO in a concentration and time-dependent fashion and shows marked selectivity for the B form (IC50 = 680 and 3.6 nM for MAO-A and MAO-B, respectively). After oral administration to rats, the compound shows preferential inhibition of brain MAO-B with ED50 values of 8 and 0.18 mg/kg p.o. for the A and B forms, respectively. Selectivity is retained on repeat dosing. MDL 72,974 did not significantly potentiate the cardiovascular effects of intraduodenually-administered tyramine in anaesthetized rats and had only minor indirect sympathomimatic effects in the pithed rat. At MAO-B selective doses the neurotoxic effect of MPTP in mice was blocked.

Administration, Oral↗
PubMed1989

8-OH-DPAT, flesinoxan and guanfacine: systemic and regional haemodynamic effects of centrally acting antihypertensive agents in anaesthetized rabbits.

1. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and flesinoxan, agents which show high affinity and selectivity for 5-HT1A receptors, were administered intravenously in doses of 0.003 to 0.1 and 0.01 to 0.3 mg kg-1 respectively to 5 rabbits each. Their effects were compared with those of the centrally acting agent and alpha 2-adrenoceptor agonist, guanfacine, 0.01-0.3 mg kg-1, administered to a group of 5 rabbits. Five further rabbits were used as controls and treated with the vehicle of the active agents. 2. Both flesinoxan and 8-OH-DPAT induced similar systemic and regional haemodynamic changes. Both lowered mean arterial pressure and heart rate. The principal blood pressure lowering mechanism was vasodilatation; cardiac output changed minimally despite the falls in heart rate and myocardial contractile force. 3. With guanfacine the maximal fall of blood pressure was comparable to that obtained with the 5-HT1A receptor ligands; however, in contrast to the latter, the dose-response curve was U-shaped, the highest dose eliciting a pressor effect with reversal of the vasodilatation. 4. Widespread peripheral vasodilatation was found with all the agents in the splanchnic circulation and also in the brain and skeletal muscle. A weak tendency towards vasodilatation was found in the kidneys where the dose-response curve was bell-shaped for guanfacine. 5. This spectrum of activity is different from that of peripheral vasodilators, such as calcium antagonists, potassium channel activating agents or hydralazine; it is, however, consistent with the putative mechanism of action of these compounds to reduce peripheral sympathetic tone by a central mechanism of action.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Cardiovascular response to 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in the rat: site of action and pharmacological analysis.

The cardiovascular response to 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective putative 5-HT1A receptor agonist, has been investigated in the rat. Comparisons were made with clonidine, a centrally acting hypotensive agent with negligible affinity for 5-HT receptors. In conscious, spontaneously hypertensive (SH) rats, 8-OH-DPAT caused dose-related and sustained falls in blood pressure and heart rate that were unaffected by depletion of brain 5-HT by p-chlorophenylalanine. 8-OH-DPAT caused hypotension and bradycardia in anesthetized normotensive rats. In pithed rats, 8-OH-DPAT neither lowered blood pressure nor affected the cardiovascular response to spinal sympathetic stimulation or to phenylephrine. The response to 8-OH-DPAT was blocked selectively by intracisternal injection of 8-methoxy-2-(N-2-chloroethyl-N-n propyl) amino tetralin (8-MeO-CIEPAT), a putative irreversible 5-HT1A receptor antagonist, and was abolished in animals whose central monoamine transmitter stores were depleted selectively by combined treatment with DL-alpha-monofluoromethyl-dopa and dopamine. The cardiovascular response to 8-OH-DPAT was inhibited selectively by metergoline, methiothepin, and 8-MeO-CIEPAT; it was nonselectively inhibited by (+/-)-pindolol, (+/-)-cyanopindolol, buspirone, yohimbine, idazoxan, and WY 26392; and was unaffected by prazosin and cis-flupenthixol. These results establish that the cardiovascular response to 8-OH-DPAT in the rat is centrally mediated and point to the putative 5-HT1A receptor as the key site involved. An indirect link involving a catecholaminergic mechanism is suggested by the fact that alpha 2-adrenoceptor antagonists are also inhibitory despite 8-OH-DPAT having no direct agonist effects at alpha 2-adrenoceptors per se.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1979

Blockade of serotonin receptors on autonomic neurones by (-)-cocaine and some related compounds.

The interaction between (--)-cocaine and responses to 5-HT elicited through serotonin receptors on autonomic neurones has been investigated on the rabbit heart and the guinea-pig ileum. Low concentrations of (--)-cocaine or its stereoisomer, (4)-pseudococaine, produced shifts to the right of the 5-HT dose-response curves on heart and ileum with no depression of the maximum responses to electrical stimulation or dimethylphenylpiperazinium remained unaffected. A Schild analysis of data obtained on heart and ileum indicated competitive antagonism of 5-HT by (--)-cocaine. Antagonism of 5-HT by the cocaine isomers cannot be ascribed to local anaesthesia per se since neither lignocaine, tetracaine, benzocaine nor bu tacaine were selective antagonists of 5-HT. Similarly, inhibition of monoamine uptake seems of minimal relevance since desipramine proved only a weak antagonist of 5-HT on the heart and did not influence the 5-HT antagonist potency of (--)-cocaine. Selective blockade of 5-HT neuronal responses is a property shared by several structural analogues of (--)-cocaine and (+)-pseudococaine; nor-(--)-cocaine proved the most potent of these, being active at a concentration of 2 x 10(-8) M. These data indicate that (--)-cocaine and several of its derivatives inhibit 5-HT stimulation of both adrenergic and cholinergic autonomic neurones through competition with the agonist at serotonin receptor sties. Since morphine, the tool normally used to identify responses mediated through neuronal serotonin receptors, acts only at certain "morphine-sensitive" junctions and then, non-discriminately, the cocaine analogues, and particularly nor-(--)-cocaine would seem to offer real advantages as tools for differentiating such responses.

Animals↗