β-Adrenoceptor Blocking Agents

Prichard, B. N. C.

doi:10.1007/978-3-642-69524-7_12

Cited by 6 publications

(4 citation statements)

References 457 publications

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“…Although it has been suggested that the most important action of these drugs is blockade of the renin angiotensin system albeit via different mechanisms (Buhler et al, 1972;Case et al, 1978) it is quite clear that P-adrenoceptor blocking agents can exert hypotensive actions independent of this system e.g. direct effects on the heart and central actions (Prichard & Owens, 1986). Thus a drug such as BW A575C with dual activity will not only be a potentially effective antihypertensive agent due to its ability to suppress the renin angiotensin system but will also demonstrate efficacy in hypertensive states where the cardiac response to physiological stimuli such as stress or exercise is controlled by P-adrenoceptor blockade (Ferguson et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

“…Both angiotensin converting enzyme (ACE) inhibitors and P-adrenoceptor blocking agents have become established as effective and well tolerated antihypertensive agents (Case et al, 1978, Prichard & Owens, 1986. Although these agents have been shown to reduce blood pressure in several forms of human hypertension, a number of studies have demonstrated that hypertension cannot be completely controlled by either type of drug alone.…”

Section: Introductionmentioning

confidence: 99%

“…We would like to describe the results of studies with a chemically novel agent, BW A575C (see Figure 1) which combines in a single molecule ACE inhibitor properties with P-adrenoceptor-blocking properties. Whereas both ACE inhibitors and P-adrenoceptorblocking agents can independently reduce blood pressure via different mechanisms, their co-administration may be complementary when considering their actions within the renin-angiotensin system (Prichard & O The Macmillan Press Ltd 1987 Figure 1 The chemical structure of BW A575C Owens, 1986;Johnston, 1986). Inhibition of ACE causes a reduction in the circulating levels of the pressor hormone angiotensin II, however, treatment with such agents results in an increase in renin release.…”

Section: Introductionmentioning

confidence: 99%

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BW A575C, a chemically novel agent with angiotensin converting enzyme inhibitor and β‐adrenoceptor‐blocking properties

Allan

Cambridge

Hardy

et al. 1987

British J Pharmacology

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) is a chemically novel agent which exhibits in a single molecule both angiotensin converting enzyme (ACE) inhibition and P-adrenoceptor-blocking properties.2 BW A575C produced a competitive blockade of heart rate responses to isoprenaline in a guinea-pig right atrial preparation (pKB 7.18 ± 0.05, cf. pindolol 8.9 ± 0.7). BW A575C inhibited a partially purified preparation of ACE obtained from rabbit lung (IC50 10.7 + 2.1 nM, cf. enalaprilat, 4.4 ± 0.8 nM).3 Intravenous administration of BW A575C (1-100 tgkg-' min-')to the pithed rat inhibited in a dose-dependent fashion both angiotensin I-induced pressor responses and isoprenaline-induced tachycardia. Dose-ratios obtained from such studies demonstrated that, in this preparation, BW A575C was approximately 100 times more active as an ACE inhibitor than as a P-adrenoceptor blocking agent. 4 Intravenous administration of BW A575C (I mg kg-') to the conscious rat inhibited angiotensin Iinduced pressor responses, being approximately equipotent to enalapril and 10 times more potent than captopril. At the same dose, BW A575C had a similar duration of action as an ACE inhibitor to enalapril. 5 Intravenous administration of BW A575C (I mg kg-') to either conscious dogs or rats inhibited both angiotensin I-induced pressor responses and isoprenaline-induced heart rate responses. Doseratios obtained from such studies demonstrated that in these species, BW A575C was 2-10 times more active as an ACE inhibitor than as a P-adrenoceptor blocking agent.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BW A575C, a chemically novel agent with angiotensin converting enzyme inhibitor and β‐adrenoceptor‐blocking properties

Allan

Cambridge

Hardy

et al. 1987

British J Pharmacology

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“…These compounds were found to stimulate GTPase activity in HL-60 membranes in a pertussis toxin-sensitive manner [45]. The concentrations of propranolol required to activate G proteins are substantially higher than those used in vivo [105]. Thus, it is most unlikely that G protein activation induced by Padrenergic antagonists contributes to their therapeutic effects in the treatment of cardiac arrhythmias and hypertension [ 1051.…”

Section: G Proteins As Target Of Drugs Already Used In Therapymentioning

confidence: 99%

Drugs interacting with G protein α subunits: selectivity and perspectives

Chahdi

Daeffler

Gies

et al. 1998

Fundamemntal Clinical Pharma

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Extracellular signal molecules as diverse as hormones, neurotransmitters and photons use a signal transduction pathway involving a receptor, a G protein and effectors. Compounds that interact directly with G proteins can mimic the receptor-G protein interaction or can block the activation of G proteins by receptors. Several binding sites exist on the G alpha protein that may be exploited for the design of synthetic stimulatory or inhibitory ligands. The effector binding site is regulated by endogenous proteins and appears to be a target for selective exogenous ligands. The GTP binding site presents a large homology within the G protein families and therefore the nucleotide analogs might not be considered as a tool to discriminate between the G protein subclasses. In contrast, different experimental strategies have substantiated the specificity in the interaction between a receptor and a G protein, the receptor binding site of G proteins should be considered as potential drug targets. Drugs interfering with this site such as mastoparan and related peptides, GPAnt-2 and suramin, are lead compounds in the design of selective G protein antagonists. Benzalkonium chloride and methoctramine have agonist or antagonist properties, depending on G protein subtypes. Such compounds would be very useful to delineate the functions of G proteins and G protein-coupled receptors, to understand some side effects of drugs used in therapy and to develop new therapeutic agents.

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Liquid Chromatographic Assay and Disposition of Carvedilol in Healthy Volunteers

Cubeddu

Powell

1986

Journal of Pharmaceutical Sciences

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β-Adrenoceptor Blocking Agents

Cited by 6 publications

References 457 publications

BW A575C, a chemically novel agent with angiotensin converting enzyme inhibitor and β‐adrenoceptor‐blocking properties

BW A575C, a chemically novel agent with angiotensin converting enzyme inhibitor and β‐adrenoceptor‐blocking properties

Drugs interacting with G protein α subunits: selectivity and perspectives

Liquid Chromatographic Assay and Disposition of Carvedilol in Healthy Volunteers

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