Biomedical subjects

R A Bond

Publications and source records attributed to R A Bond.

53 records · Page 3Linked to original sources

PubMed1990

Antagonist characterization of atypical beta adrenoceptors in guinea pig ileum: blockade by alprenolol and dihydroalprenolol.

The present study was undertaken to further characterize the atypical beta adrenoceptor in guinea pig ileum. Tension was developed in isolated segments of ileum using transmural electrical stimulation of enteric cholingeric nerves. The ability of isoproterenol to relax the ileum, via beta-1 adrenoceptor and atypical beta adrenoceptor agonism, was measured. Propranolol (5 x 10(-6) M) and bromoacetylaprenololmetane blocked beta-1 adrenoceptors but, at the concentrations tested, were without affinity at atypical beta adrenoceptors. (-)-Alprenolol and (-)-dihydroalprenolol, however, acted as competitive antagonists at both sites (pA2 values of 8.2 and 8.81 at beta-1 adrenoceptors and 6.47 and 6.43 at atypical beta adrenoceptors, respectively). (-)-Alprenolol also exerted agonistic activity at the atypical beta adrenoceptor. [3H](-)-Dihydroproalprenolol failed to identify beta-1 adrenoceptors or atypical beta adrenoceptors but, instead, bound to a putative lipophilic site unrelated to ileal adrenoceptors. Before this study, nadolol (pA2 = 4.7) was the only documented antagonist at the atypical beta adrenoceptor in guinea pig ileum. Thus, the present results detail two additional pharmacological probes which exhibit about a 100-fold greater affinity than nadolol for the atypical site.

Adrenergic beta-Antagonists↗

PubMed1989

Trends in sexual behaviour and risk factors for HIV infection among homosexual men, 1984-7.

To assess whether the spread of infection with HIV can be reduced by changes in behaviour among groups most at risk because of their sexual practices sexual behaviour was monitored among 1050 homosexual men tested for HIV infection at a genitourinary medicine clinic in west London from November 1984 to September 1987. Four cohorts, defined by date of presentation, were studied by questionnaire at their presentation, and blood samples were analysed. Between the first and last cohorts there was a considerable fall in the proportion reporting casual relationships (291/329 (88%) v 107/213 (50%] and high risk activities, such as anoreceptive intercourse with casual partners (262/291 (90%) v 74/106 (70%], with the greatest changes occurring before the government information campaign began in 1986. Nevertheless, half of the men in the last cohort studied reported having casual partners. Multiple logistic regression showed that behavioural risk factors for HIV infection most closely resembled those for hepatitis B and that previous sexually transmitted diseases (syphilis, hepatitis B, and anogenital herpes) were themselves independent risk factors. A history of syphilis ranked above anoreceptive intercourse as the strongest predictor of HIV infection. Actively bisexual men showed a much lower prevalence of HIV infection (3/57, 5%) than exclusively homosexual men (113/375, 30%). Sexual behaviour among homosexual men changed during the period studied, and the incidence of HIV infection fell, although more education programmes directed at homosexual men are needed to re-emphasise the dangers of infection.

AIDS Serodiagnosis↗

PubMed1989

Partial agonistic activity of GR43175 at the inhibitory prejunctional 5-HT1-like receptor in rat kidney.

1. The pharmacological effect of the selective 5-HT receptor agonist GR43175 has been studied in the isolated perfused rat kidney with particular reference to the inhibitory prejunctional 5-HT1-like receptor. 2. GR43175 (1 x 10(-8) to 1 x 10(-5) M) inhibited the electrically evoked release of tritium from renal noradrenergic nerves but did not affect the basal (non-stimulated) release of tritium or perfusion pressure. 3. The inhibitory prejunctional action of GR43175, as well as that of 5-HT, was blocked by methiothepin, suggesting that both agonists act at the inhibitory 5-HT1-like site. 4. GR43175, relative to 5-HT, acted as a weak partial agonist at the inhibitory prejunctional 5-HT1-like receptor and antagonized 5-HT-induced inhibition of tritium release, suggesting again that a common site of action is involved. 5. The results support the conclusion that the 5-HT1-like receptor activated by GR43175 in the rat kidney is very similar to that identified in dog saphenous vein and certain other tissues.

Animals↗

PubMed1989

Unsurmountable antagonism to 5-hydroxytryptamine in rat kidney results from pseudoirreversible inhibition rather than multiple receptors or allosteric receptor modulation.

Experiments were conducted in the isolated perfused rat kidney to determine the mechanism of unsurmountable antagonism by metergoline toward the vasoconstrictor response to 5-hydroxytryptamine (5-HT). Three possible mechanisms were investigated: 1) multiple receptors for 5-HT; 2) pseudoirreversible inhibition; and 3) allosteric modulation of 5-HT receptors. Metergoline and six other 5-HT antagonists acted as potent unsurmountable antagonists, only (-)-propranolol acted competitively (pA2 = 6.5). Multiple receptors for 5-HT were ruled out as the mechanism of unsurmountable antagonism because 5-HT and four 5-HT analogs gave similar pA2 values with (-)-propranolol. In addition, the KA value for 5-HT (185 nM) and the order and relativity of agonist potency suggest the presence of a single 5-HT2 receptor. Pseudoirreversible inhibition, over allosteric modulation of the 5-HT2 receptor, is suggested from experiments in which reversal of metergoline-induced inhibition by (-)-propranolol (studied in the presence of metergoline) was matched, in magnitude, by wash-out of metergoline. (-)-Propranolol is suggested to mimic wash-out by occupying and protecting receptors from which metergoline has dissociated. This is accomplished by virtue of its faster kinetics, on-off the 5-HT receptor, allowing restoration of 5-HT responses via a competitive interaction. Pseudoirreversible antagonism, over allosteric receptor modulation, offers an explanation that does not involve the postulation of allosteric effector sites or changes in the state of the 5-HT2 receptor.

Allosteric Regulation↗

PubMed1988

Human immunodeficiency virus infection, hepatitis B virus infection, and sexual behaviour of women attending a genitourinary medicine clinic.

During the six months immediately after a public information campaign about the acquired immune deficiency syndrome 1115 women who attended a genitourinary medicine clinic in west London were tested for antibodies to the human immunodeficiency virus (HIV). Three women (0.27%) were positive, and all three were regular sexual partners of men with high risk lifestyles--two intravenous drug users and one bisexual. A consecutive series of 647 women from the cohort was tested for antibodies for hepatitis B core antigen: 27 were positive, of whom six had been born in the United Kingdom and were not known to have been at risk. The two women who were seropositive for HIV who completed a questionnaire on their sexual behaviour before they were tested reported both anal and oral receipt of semen and were in the upper fifth percentile for lifetime sexual partners. More than half (53%) of 424 women who reported that they had non-regular sexual partners never used a condom. It is concluded that heterosexual women in London are at a low risk of becoming infected with HIV.

Acquired Immunodeficiency Syndrome↗

PubMed1988

Agonist and antagonist characterization of a putative adrenoceptor with distinct pharmacological properties from the alpha- and beta-subtypes.

1. Experiments were done to characterize a putative adrenoceptor which functions to inhibit longitudinal muscle tension development in the guinea-pig ileum. Several phenylethylamine based agonists were investigated: BRL 37344, (-)-isoprenaline, (+)-isoprenaline, noradrenaline, adrenaline, and fenoterol. Propranolol and nadolol were tested as antagonists. Agonist-induced inhibition of the contractile response to histamine was measured under equilibrium conditions with alpha-adrenoceptors and muscarinic cholinoceptors inhibited. 2. Inhibitory responses were obtained to (-)-isoprenaline and BRL 37344 that were resistant to beta-adrenoceptor blockage with propranolol (5 microM) and nadolol (10 microM). These resistant responses were antagonized by much higher concentrations of nadolol (30 to 1000 microM) yielding apparent pA2 values for nadolol of 4.31 with (-)-isoprenaline as the agonist, and 4.68 with BRL 37344 as the agonist. Similar apparent pA2 values for nadolol at the putative adrenoceptor were obtained with noradrenaline (4.79), adrenaline (4.68), and fenoterol (4.38). 3. The order and relative potency of agonists at the putative adrenoceptor was: BRL 37344 (20) greater than (-)-isoprenaline (8) greater than noradrenaline (1) greater than adrenaline (0.5) greater than fenoterol (0.35) greater than (+)-isoprenaline (0.27). 4. The resistance to blockade by propranolol (5 microM), the low affinity of nadolol, and the order and relative potency of agonists, suggest the presence of an adrenoceptor with distinct pharmacological characteristics from currently defined alpha- and beta-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1988

Sexual behaviour in women attending a genitourinary medicine clinic.

In 1025 women attending a genitourinary medicine (GUM) clinic, sexual experience had started at an increasingly early age during the past 30 years, from a mode of 19 in the early 1950s to 16 in the early 1980s. Up to the age of 40, sexually active older women had as many recent sexual partners as younger women. Oral intercourse (fellatio) was practised by 714 (70%) women, and 378 (37%) experienced ejaculation in the mouth. Anal intercourse was practised by 200 (20%) women and 90 (9%) experienced ejaculation in the anorectum. The prevalence of all these practices increased with age. Women attending a Family Planning Association (FPA) clinic reported a similar prevalence of these practices, and differed from GUM clinic women only in the number of sexual partners in the preceding year. In the GUM group, black women reported significantly fewer recent sexual partners than did white women, and significantly fewer black women practised oral intercourse or permitted anal penetration. Full anal intercourse with ejaculation into the anorectum was practised at least occasionally by 9% (80/873) of white and 8% (10/131) of black women.

Adult↗

PubMed1987

Do migrainous headaches become more consistently lateralized?

Analysis of information collected from 468 patients with common or classical migraine does not suggest that those with a longer history are more likely to have headaches fixed to a single side of the head. This finding does not support the notion that successive unilateral headache attacks on one side cause damage that predisposes the patient to further attacks on the same side.

Chronic Disease↗

PubMed1987

A response to isoprenaline unrelated to alpha- and beta-adrenoceptor agonism.

The hypothesis that beta-adrenoceptor agonism might explain a reported lack of competitive antagonism between alpha 2-adrenoceptor antagonists and agonists of the phenylethylamine class was tested in the electrically field stimulated ileum of the guinea-pig. The beta-adrenoceptor agonist, isoprenaline, was used as the phenylethylamine and inhibition of 'twitch' response evoked by cholinergic stimulation was measured. In the presence of idazoxan (3 microM), to block inhibitory alpha 2-adrenoceptors, propranolol (0.1 to 5.0 microM) failed to act competitively toward isoprenaline. Isoprenaline responses totally resistant to inhibition by propranolol were obtained. As inhibitory alpha 1-adrenoceptors are absent from guinea-pig ileum, a recognition site distinct from the currently defined alpha- and beta-adrenoceptors is postulated. Agonism by phenylethylamine based agonists at this site may explain their inability to act competitively with alpha- and beta-adrenoceptor antagonists.

Adrenergic alpha-Antagonists↗

PubMed1986

Evidence for a receptor mediated action of norepinephrine distinct from alpha- and beta-adrenoceptors.

The mode of action of (-) norepinephrine (NE) and UK-14,304-18 has been investigated using the cholinergically-evoked 'twitch' response of the electrically stimulated guinea-pig ileum. St 587 and benextramine were employed as antagonists. St 587 acted as a competitive antagonist toward UK-14,304-18, yielding an apparent pA2 value of 7.3. In contrast, St 587 failed to act competitively toward NE. Similarly, benextramine (1 X 10(-5) mol/l) blocked the inhibitory responses to UK-14,304-18 but was considerably less active toward NE. Remaining responses to NE after benextramine were not antagonized by St 587, even at a concentration of 3 X 10(-5) mol/l. It is postulated that NE acts to inhibit the 'twitch' response be evoking two different receptor-mediated events: 1. agonism at the alpha 2-adrenoceptor and 2. agonism at a site which is distinct from the alpha- and beta-subtypes. In the concentrations studied, UK-14,304-18, St 587 and benextramine are postulated to lack affinity for the proposed site. The effect of NE and UK-14,304-18 was also investigated on the contractile responses to exogenously applied histamine. These experiments were done in the presence of muscarinic cholinergic and adrenoceptor blockade. NE inhibited responses to histamine but UK-14,304-18 was inactive. Furthermore, the inhibitory action of NE was stereoselective with the (-) form being 25 times more potent than the (+) enantiomer. These findings suggest the presence of a receptor site for NE which is distinct from cholinergic mechanisms and established alpha and beta-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1986

An inhibitory prejunctional 5-HT1-like receptor in the isolated perfused rat kidney. Apparent distinction from the 5-HT1A, 5-HT1B and 5-HT1C subtypes.

The present study has identified a receptor for 5-hydroxytryptamine (5-HT) which functions to inhibit the stimulus-induced release of [3H] noradrenaline following sympathetic periarterial nerve stimulation to the isolated perfused rat kidney. In addition to 5-HT (IC30 = 4.5 X 10(-8) mol/l), both 5-carboxamidotryptamine (IC30 = 8 X 10(-9) mol/l) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl) indole (RU-24969, IC30 = 2.5 X 10(-7) mol/l) acted as agonists whereas 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was inactive. The inhibitory effect of 5-HT on the electrically-evoked release of tritium was antagonized in a concentration-dependent manner by methiothepin (IC50 = 4 X 10(-9) mol/l), metergoline (IC50 = 4 X 10(-8) mol/l) and methysergide (IC50 = 1.3 X 10(-7) mol/l) but not by cyproheptadine, ketanserin, mesulergine, (-)-propranolol, (+/-)-pindolol, (+/-)-cyanopindolol, metoclopramide or phentolamine. It is concluded that the receptor to 5-HT conforms to general criteria defining 5-HT1-like receptors but at the present time the receptor site cannot be fitted to the designated 5-HT1A, 5-HT1B or 5-HT1C subtypes.

Animals↗

PubMed1986

Sexual lifestyle and clinical findings related to HTLV-III/LAV status in homosexual men.

A study of 304 sexually active homosexual men, most of whom had multiple casual partners, showed that receptive anogenital intercourse, independent of anal bleeding, was the only risk factor for HTLV-III/LAV transmission. There was no evidence that HTLV-III/LAV infection, measured by seropositivity, was transmitted by oroanal or orogenital routes, or that insertive penile intercourse constituted a risk. The strongest predictor of seropositivity proved to be homosexual activity for more than five years, which may lead to enhanced susceptibility to infection. Sexual exposure to European men seemed to be even more hazardous than sexual exposure to men from the United States of America, and emphasised the epidemiological importance of the promiscuous homosexual abroad. Skin complaints were the most common presenting symptoms in men with antibody to HTLV-III/LAV. Extrainguinal lymphadenopathy was the commonest sign, which was present in just under half of those who were seropositive. More than one quarter of seropositive patients had had sexual intercourse with a woman in the five years before being tested.

Acquired Immunodeficiency Syndrome↗

PubMed1986

Responses to norepinephrine resistant to inhibition by alpha and beta adrenoceptor antagonists.

The mode of action of clonidine and norepinephrine (NE) has been investigated in the isolated transmurally stimulated guinea-pig ileum preparation using rauwolscine, idazoxan and benextramine as antagonists. Both clonidine and NE produced concentration-dependent inhibition of the cholinergically induced twitch response and were antagonized by rauwolscine and idazoxan, but only clonidine was antagonized in a truly competitive fashion. Benextramine, an irreversible alpha adrenoceptor antagonist, in a concentration of 10(-5) M, inhibited the effect of clonidine completely but only partially antagonized the inhibitory action of NE. The antagonism of NE by rauwolscine and benextramine was most pronounced after reserpine pretreatment and blockade of neuronal and extraneuronal uptake. Under these conditions, the concentration-effect curve to NE remaining after treatment with benextramine showed an IC50 of about 3 X 10(-7) M and an intrinsic activity of 0.6. This curve was resistant to further inhibition by clonidine (10(-5) M), phentolamine (3 X 10(-6) M), rauwolscine (3 X 10(-6) M), prazosin (10(-6) M) and propranolol (1.2 X 10(-5) M). Thus, alpha and beta adrenergic receptors do not appear to be involved. It is postulated that NE-induced inhibition of the guinea-pig ileum twitch response is mediated by two distinct sites: one is the classical alpha-2 adrenoceptor (the site of action of clonidine and the alpha adrenoceptor antagonists) whereas the other is a site seemingly unrelated to the alpha and beta subtypes.

Adrenergic alpha-Antagonists↗

PubMed1974