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Biomedical subjects

R A Bond

Publications and source records attributed to R A Bond.

At least 37 records · Page 2Linked to original sources
PubMed1995

Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor.

Transgenic mice were created with cardiac-specific overexpression of the beta-adrenergic receptor kinase-1 (beta ARK1) or a beta ARK inhibitor. Animals overexpressing beta ARK1 demonstrated attenuation of isoproterenol-stimulated left ventricular contractility in vivo, dampening of myocardial adenylyl cyclase activity, and reduced functional coupling of beta-adrenergic receptors. Conversely, mice expressing the beta ARK inhibitor displayed enhanced cardiac contractility in vivo with or without isoproterenol. These animals demonstrate the important role of beta ARK in modulating in vivo myocardial function. Because increased amounts of beta ARK1 and diminished cardiac beta-adrenergic responsiveness characterize heart failure, these animals may provide experimental models to study the role of beta ARK in heart disease.

Adenylyl Cyclases↗
PubMed1995

Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the beta 2-adrenoceptor.

G-protein-coupled receptors are thought to have an inactive conformation (R), requiring an agonist-induced conformational change for receptor/G-protein coupling. But new evidence suggests a two-state model in which receptors are in equilibrium between the inactive conformation (R), and a spontaneously active conformation (R*) that can couple to G protein in the absence of ligand (Fig. 1). Classic agonists have a high affinity for R* and increase the concentration of R*, whereas inverse agonists have a high affinity for R and decrease the concentration of R*. Neutral competitive antagonists have equal affinity for R and R* and do not displace the equilibrium, but can competitively antagonize the effects both of agonists and of inverse agonists. The lack of suitable in vivo model systems has restricted the evidence for the existence of inverse agonists to computer simulations and in vitro systems. We have used a transgenic mouse model in which there is such marked myocardial overexpression of beta 2-adrenoceptors that a significant population of spontaneously activated receptor (R*) is present, inducing a maximal response without agonist. We show that the beta 2-adrenoceptor ligand ICI-118,551 functions as an inverse agonist, providing evidence supporting the existence of inverse agonists and validating the two-state model of G-protein-coupled receptor activation.

Adrenergic beta-Agonists↗
PubMed1995

Marked enhancement in myocardial function resulting from overexpression of a human beta-adrenergic receptor gene.

Transgenic mice with intense cardiac expression of a human beta-adrenergic receptor gene were engineered and shown to display marked improvements in baseline myocardial and left ventricular function. Heart/body weight ratios and histologic appearance were not found to be significantly altered, suggesting that receptor gene expression did not induce pathologic changes. Given the substantial reduction in beta-adrenergic receptor density and resultant reduction in inotropic responsiveness observed in chronic heart failure, these findings represent a novel approach for increasing myocardial function with important clinical implications.

Animals↗
PubMed1995

Potentiation of endothelium-dependent hyperpolarization to serotonin by dietary intake of NC 020, a defined fish oil, in the porcine coronary artery.

The membrane potential of vascular smooth muscle cells of the porcine coronary artery was measured to examine whether serotonin evokes endothelium-dependent hyperpolarization, and if it does, whether the electrical responses are modulated by the chronic dietary intake of NC 020, a defined fish oil. Serotonin induced transient, concentration-dependent hyperpolarizations of coronary arterial smooth muscle cells. The hyperpolarization was observed in tissues with, but not in those without endothelium. In coronary arteries obtained from pigs fed chronically with NC 020, serotonin induced significantly larger hyperpolarizations than those observed in control arteries. These results suggest that endothelium-dependent hyperpolarization may contribute to the endothelium-dependent relaxation evoked by serotonin and to its potentiation by the dietary intake of fish oil (NC 020).

Animals↗
PubMed1995

Trends in female sexual behaviour and sexually transmitted diseases in London, 1982-1992.

OBJECTIVE: To measure changes in female sexual behaviour, including condom use, and their relationship with the incidence of sexually transmitted and other genital diseases in women during the decade 1982-92. DESIGN: A prospective series of cross-sectional surveys of sexual behaviour reported by a standardised self-administered questionnaire in new patients who presented for screening and diagnosis. SETTING: A genitourinary medicine clinic in West London. SUBJECTS: 4089 consecutive newly attending patients who completed sexual behaviour questionnaires during 1982, 1987, 1989 and 1992. MAIN OUTCOME MEASURES: Trends in socio-demographic status, sexual behaviour, condom-use, sexually transmitted diseases and other genital infections diagnosed by routine clinical and laboratory methods. RESULTS: Women reported significantly increasing condom use (from 3.6% to 20.7%) and decreasing oral contraception (from 51.2% to 40.1%), but the proportion who used no contraception (23.6% to 24.7%) and the proportion who had never been pregnant (58.3% to 59.9%) remained similar. Numbers of sexual partners in the preceding year decreased (p < 0.001) and an increasing proportion of women practised oral intercourse (p < 0.001). During the same period, there was a progressive decline (p < 0.001) in the incidence of gonorrhoea, chlamydial infection and trichomoniasis by approximately two-thirds. However, the incidence of vaginal candidosis (p < 0.001), bacterial vaginosis (p < 0.001) and genital warts (p < 0.01) increased. CONCLUSIONS: Increasing use of condoms for vaginal intercourse with both regular and non-regular partners has been associated with a decrease in the incidence of gonorrhoea, chlamydial infection and trichomoniasis. There was also an increase in the practice of fellatio and a change in the spectrum of STD and other genital infections with little net reduction in morbidity. HIV infection showed no evidence of heterosexual spread.

Adolescent↗
PubMed1995

Heterosexual relationships and condom-use in the spread of sexually transmitted diseases to women.

OBJECTIVES: To examine the effect of patient-defined non-regular heterosexual relationships on the incidence of sexually transmitted diseases and other genital infections in women and the role of condom use in the prevention of their spread. DESIGN: A cross-sectional study of sexual behaviour reported by a standardised self-administered questionnaire in new patients who presented for screening and diagnosis. SETTING: A genitourinary medicine clinic in West London. SUBJECTS: 938 consecutive newly attending women who completed a sexual behaviour questionnaire in 1992. MAIN OUTCOME MEASURES: Variables relating to socio-demographic status, sexual behaviour, condom use, sexually transmitted diseases and other genital infections stratified by the reporting of non-regular partners. RESULTS: We found that women who reported non-regular sexual partners were more likely to be single (p = 0.0001), white (p < 0.0001), have had coitarche before 17 years of age (p = 0.003) and many more sexual partners both in the last year and in their life-time (p < 0.0001) and were more likely to practise fellatio (p < 0.0001), anal penetration (p = 0.004) and to be smokers (p < 0.0001). Paradoxically, the incidence of sexually transmitted diseases and other genital infections was no higher in this group than in the group of women who did not have non-regular partners. Increasing condom use with regular partners correlated with decreasing incidence of gonorrhoea (p < 0.001), chlamydial infection (p < 0.01) and trichomoniasis (p < 0.02), but increasing condom use with non-regular partners did not show this trend. CONCLUSIONS: Regular heterosexual partners play the major role in transmission of bacterial sexually transmitted diseases to women. This is significantly influenced by use of condoms.

Adolescent↗
PubMed1994

Myocardial expression of a constitutively active alpha 1B-adrenergic receptor in transgenic mice induces cardiac hypertrophy.

Transgenic mice were generated by using the alpha-myosin heavy chain promoter coupled to the coding sequence of a constitutively active mutant alpha 1B-adrenergic receptor (AR). These transgenic animals demonstrated cardiac-specific expression of this alpha 1-AR with resultant activation of phospholipase C as shown by increased myocardial diacylglycerol content. A phenotype consistent with cardiac hypertrophy developed in adult transgenic mice with increased heart/body weight ratios, myocyte cross-sectional areas, and ventricular atrial natriuretic factor mRNA levels relative to nontransgenic controls. These transgenic animals may provide insight into the biochemical triggers that induce hypertrophy in cardiac disease and serve as a convenient experimental model for studies of this condition.

Animals↗
PubMed1994

Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor.

Transgenic mice were created with cardiac-specific overexpression of the beta 2-adrenergic receptor. This resulted in increased basal myocardial adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo; these parameters at baseline in the transgenic animals were equal to those observed in control animals maximally stimulated with isoproterenol. These results illustrate a useful approach for studying the effect of gene expression on cardiac contractility. Because chronic heart failure in humans is accompanied by a reduction in the number of myocardial beta-adrenergic receptors and in inotropic responsiveness, these results suggest a potential gene therapy approach to this disease state.

Adenylyl Cyclases↗
PubMed1993

Effects of S9977 on adrenergic neurotransmission.

1. Experiments were designed to determine whether or not the putative promnesic drug S9977 (1,3,7-trimethyl 8-[3-(4-diethylaminocarbonyl-1-piperazinyl) 1-propyl]-3,7-dihydro (1H)2,6-purinedione hydrochloride) affects peripheral adrenergic neurotransmission. 2. Rings of canine saphenous veins (without endothelium) were suspended for isometric tension recording in conventional organ chambers filled with modified Krebs-Ringer bicarbonate solution. The adrenergic nerve endings were activated with electrical impulses (9 V, 2 msec, 0.25-8 Hz). 3. At 10(-5) M, S9977 significantly reduced the contraction to 0.25, 0.5 and 1 Hz. The compound did not affect the response to higher stimulation frequencies or to exogenous noradrenaline. The inhibitory effect of S9977 was prevented by methiothepin, and not affected by atropine or 8-phenyltheophylline. 4. Helical strips of canine saphenous veins were incubated with [3H]noradrenaline and suspended for superfusion and isometric tension recording. Under basal conditions, S9977 (10(-4) M) augmented, the total 3H-overflow which was due mainly to an augmented overflow of [3H]deoxyphenylglycol (DOPEG); the extraneuronal metabolites 3,4-dihydromandelic acid (DOMA) and 3-methoxy-4-hydroxymandelic acid (VMA) were reduced. 5. During electrical stimulation of the adrenergic nerves, S9977 (10(-4) M) augmented the total 3H-overflow but reduced the contractile response; the evoked overflow of [3H]noradrenaline was not significantly affected. 6. These experiments suggest that S9977 causes the displacement of noradrenaline from the adrenergic varicosities; most of the displaced transmitter is metabolized by intraneuronal monoamine oxidase before reaching the junctional cleft. In addition, S9977 exerts an inhibitory effect on the extraneuronal metabolism of catecholamines. S9977 does not inhibit the exocytotic release of the adrenergic neurotransmitter.

Analgesics↗
PubMed1992

Interaction of tertatolol at the "atypical" or beta 3-adrenoceptor in guinea-pig ileum.

1. Experiments were performed to investigate the possible interaction between tertatolol and the "atypical" beta-adrenoceptor present in guinea-pig ileum. 2. In the electrically field stimulated guinea-pig ileum, both isoprenaline and BRL-37344 produce concentration-dependent inhibition of the "twitch" response. 3. Schild regression analysis of the interaction between isoprenaline and tertatolol indicated two sites of action and yielded an apparent pA2 value for tertatolol of 6.8 at the "atypical" beta-adrenoceptor. 4. BRL-37344 selectively activated the "atypical" beta-adrenoceptor and tertatolol again yielded an apparent pA2 value of 6.7 and 6.8.

Adrenergic beta-Agonists↗
PubMed1992

A colposcopic case-control study of cervical squamous intraepithelial lesions in women with anogenital warts.

OBJECTIVE: To assess whether anogenital warts, present or past, are an indication for women to be referred for colposcopy. DESIGN: A case control study comparing patients with and without a history of anogenital warts. SETTING: A department of genitourinary medicine in West London. PATIENTS: 468 patients examined by colposcopy between January 1985 and December 1987 of whom 147 (31%) had abnormal cytology, 163 (35%) had anogenital warts and 158 (34%) had both. MAIN OUTCOME MEASURES: Colposcopic findings and histology of cervical biopsies compared with behavioural and disease variables. RESULTS: Human papillomavirus infection (HPVI) of the cervix showed no relationship with a life time history of vulval warts, or with the presence of anogenital warts on clinical examination, or with any parameter of sexual behaviour included in the study. Cervical intraepithelial neoplasia (CIN) was strongly associated with current IUCD usage (RR = 7.75) and coitarche under 16 years of age (RR = 3.72), but a history of vulval warts yielded a negative association (RR = 0.34), suggesting a protective effect. This relationship held true when cytological dyskaryosis was made the dependent variable (RR = 0.24). CONCLUSIONS: Anogenital warts are not a risk for subclinical cervical HPVI or for CIN and therefore not an indication for colposcopy.

Adult↗
PubMed1991

Some clinical comparisons between common and classical migraine: a questionnaire-based study.

In a questionnaire-based study we compared the clinical features of migraine with aura (classical migraine) and migraine without aura (common migraine) in 354 and 397 patients, respectively, attending The Princess Margaret Migraine Clinic. Other than those related to the aura, no significant differences were seen in any clinical features of the attack (e.g. frequency or duration of attacks, time of day at onset, location of headache at onset, severity of headache, or nausea and vomiting). Common migraine attacks were significantly more likely to occur at weekends (p = 0.002). Dietary triggers tended to be more troublesome in classical migraineurs while pregnancy and the menstrual cycle affected both migraine types equally. Classical migraine patients were twice as likely to have a history of hypertension (p less than 0.05) and showed a slightly but not significantly greater tendency to depression. Family histories of migraine were similar in each migraine type. We conclude that classical and common migraine are fundamentally similar in their clinical characteristics and that the occurrence of focal neurological symptoms during a migraine attack has little influence on the rest of the attack.

Adolescent↗
PubMed1991

Nebivolol induces endothelium-dependent relaxations of canine coronary arteries.

Nebivolol is a new beta 1-antagonist that acutely reduces arterial blood pressure without depressing cardiac function. The present study was designed to determine the effect of nebivolol on coronary arteries. Rings of canine left anterior descending coronary (LAD) artery with or without endothelium were suspended in organ chambers and the isometric tension was recorded. In some experiments, the transmembrane potential of the smooth muscle cells was recorded by electrophysiological methods. During contractions to prostaglandin F2 alpha, nebivolol induced concentration-dependent relaxations of the coronary arteries. The enantiomer, l-nebivolol, also induced comparable relaxations; however, d-nebivolol induced smaller relaxations. The relaxations induced by nebivolol and its enantiomer were significantly larger in tissues with than in those without endothelium. The differences between tissues with and without endothelium were abolished by nitro-L-arginine (3 x 10(-5) M) or methylene blue (10(-5) M). The nebivolol-induced relaxations were not affected by indomethacin (10(-5) M), phentolamine (5 x 10(-6) M), propranolol (5 x 10(-6) M), or methysergide (3 x 10(-6) M). Nebivolol at a subthreshold concentration for inducing relaxation (3 x 10(-7) M) did not significantly affect endothelium-dependent relaxations to acetylcholine but potentiated ADP-induced endothelium-dependent relaxations. The potentiation is stereoselective for l-nebivolol. Nebivolol induced a small hyperpolarization of the coronary smooth muscle with endothelium (1 mV).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1991

Trends in sexual behaviour and HIV testing among women presenting at a genitourinary medicine clinic during the advent of AIDS.

Changes in female sexual behaviour with the advent of AIDS and safer sex campaigns were studied. Subjects were drawn from a wide social spectrum of women attending an STD clinic in West London where there is a high prevalence of HIV infection among homosexual men. Between 1982 and 1989, 4224 women answered a self-administered questionnaire: women who reported more than one sexual partner in the previous year fell from 56.9% in 1982 to 51.8% in 1989 (p = 0.003). Anal intercourse showed no change and was reported by 8.8% in 1982 and 9.4% in 1989 (p = 0.8). Oral intercourse increased from 36.9% in 1982 to 44.7% in 1989 (p = 0.001). Condom use for contraception increased from 3.6% in 1982 to 16.2% in 1989 (p less than 0.001). Between 1987 and 1989, 35.6% of 3199 women reported having non-regular partners with no significant trend over this period; these women had earlier coitarche (17.0 years cf 17.9 years), many more partners (p less than 0.0001) and more practised anal (p = 0.007) and oral (p less than 0.0001) intercourse. However, frequent use of condoms doubled from 23.6% in 1987 to 47.6% in 1989. During this period, the prevalence of antibody to HIV (anti-HIV) remained unchanged (0.27-0.37%), but more women declined to be tested. Anonymised testing showed that none of those who refused consent for named testing was anti-HIV positive. It is concluded that significant changes in female sexual behaviour have taken place with the advent of AIDS but there has been no evidence of heterosexual spread beyond the confines of well defined risk behaviours. Risks of the magnitude reported in homosexual men were not found in heterosexual women.

AIDS Serodiagnosis↗