Similarities in the Mechanism of Action of Two New Vasodilator Drugs: Pinacidil and BRL 34915

Cook, Nigel S.; Quast, Ulrich; Hof, Robert P.; Baumlin, Yves; Pally, Charles

doi:10.1097/00005344-198801000-00014

Cited by 102 publications

(46 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was clearly evident that cromakalim produced a selective inhibition of frequency with little inhibition of amplitude of contractions. This is in accordance with similar observations in isolated uterus (Hollingsworth et al, 1987) and portal vein Quast, 1987;Cook et al, 1988). By contrast, calcium entry blockers, such as nifedipine, produced a selective inhibition of amplitude of uterine contractions relative to frequency .…”

Section: Discussionsupporting

confidence: 92%

“…Vasodepression was seen with cromakalim in accordance with previous findings (Buckingham et al, 1986;Cook et al, 1988). The cardiovascular and uterine effects occurred at the same doses.…”

Section: Discussionsupporting

confidence: 90%

“…By contrast, calcium entry blockers, such as nifedipine, produced a selective inhibition of amplitude of uterine contractions relative to frequency . These findings would support suggestions (Hollingsworth et al, 1987;Quast, 1987;Cook et al, 1988) that the relaxant action of cromakalim is exerted by a selective action on pacemaker cells, while calcium entry blockers selectively affect the cellular mechanism of contraction. It was evident that the effect of cromakalim in the uterus was reversible and that during the decline of its effect contractions returned in an episodic manner.…”

Section: Discussionsupporting

confidence: 80%

See 2 more Smart Citations

Tolerance to cromakalim in the rat uterus in vivo

Downing

Miller

Hollingsworth

1989

British J Pharmacology

View full text Add to dashboard Cite

1 Cromakalim (0.1 and mgkg 1) produced inhibition of uterine contractions and falls in mean blood pressure in ovariectomized, non-pregnant rats, the durations of which were dose-dependent. Frequency of contractions was inhibited selectively compared to amplitude. 2 The durations of the uterine effect of cromakalim (1 mg kg-1), when given at 12 h intervals, were less after the second, third and fourth doses compared to the first dose in non-pregnant rats. In ovariectomized rats treated from day 18 of pregnancy, using the same experimental design, no uterine relaxant effects were seen to the third and fourth doses. The timing of delivery and foetal viability were unaffected by cromakalim. 3 The sensitivity of the uterus to cromakalim was tested using small doses before and after three cromakalim doses (1 mg kg-1) given at 8 h intervals in non-pregnant rats. This regime resulted in a 25 fold decrease in the sensitivity of the uterus to cromakalim. 4 Cromakalim can produce long-lasting inhibition of uterine contractions in the rat after bolus i.v. dose but it exhibits little selectivity relative to its vasodepressor action and there appears to be tolerance to the uterine relaxant action of cromakalim in vivo.

show abstract

Section: Discussionsupporting

confidence: 92%

“…Vasodepression was seen with cromakalim in accordance with previous findings (Buckingham et al, 1986;Cook et al, 1988). The cardiovascular and uterine effects occurred at the same doses.…”

Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 80%

See 1 more Smart Citation

Tolerance to cromakalim in the rat uterus in vivo

Downing

Miller

Hollingsworth

1989

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…It is evident, however, that in isolated arteries such as rat small mesenteric (Mulvany et al, 1982), guinea-pig anterior mesenteric (Bolton et al, 1984) and rabbit pulmonary (Haeusler, 1985), the degree of depolarisation associated with a given contraction is considerably smaller for noradrenaline than for KCL This applies to other receptor agonists such as histamine, 5-HT and angiotensin II (see Johansson & Somlyo, 1980). Nevertheless, cromakalim is an effective inhibitor of contractions to all of these agents (Cain & Nicholson, 1988;Cook et al, 1988;Wilson, 1988). Thus it would appear that this inhibitory activity of cromakalim is not a result of hyperpolarisation opposing agonist-induced opening of VOC.…”

Section: Discussionmentioning

confidence: 99%

“…The efflux of operated Ca2+ channels (VOC). Thus cromakalim K+ ions from the vascular smooth muscle cell hyperinhibits contractions induced by KCl, although high polarises the membrane towards the K+ equilibrium concentrations (>60mM) of KCl, produce contracpotential (Hamilton et al, 1986; tions which are resistant to cromakalim Clapham & Wilson, 1987 Cromakalim also inhibits contractions induced by receptor agonists such as noradrenaline, histamine, 5-hydroxytryptamine (5-HT) and angiotensin II (Clapham & Wilson, 1987;Cain & Nicholson, 1988;Cook et al, 1988;Wilson, 1988), even though contractions to these agents are less dependent on depolarisation than the equivalent contractions to KCI (Mulvany et al, 1982;Bolton et al, 1984;Haeusler, 1985;Neild & Kotecha, 1987). Unlike contractions to KCl, contractions to all concentrations of the receptor agonists are inhibited.…”

Section: Introductionmentioning

confidence: 99%

Effect of cromakalim on contractions in rabbit isolated renal artery in the presence and absence of extracellular Ca²⁺

Wilson

Cooper

1989

British J Pharmacology

View full text Add to dashboard Cite

1 The inhibitory effects of the K+ channel activator, cromakalim, upon contractions to noradrenaline, histamine and caffeine were examined in rabbit isolated renal artery. For comparison, the effects of pinacidil, dazodipine and sodium nitroprusside were also studied in some experiments. 2 In normal Krebs solution, cromakalim (1 M) produced a 39.1% reduction in area under the curve (AUG) of the noradrenaline concentration-response, and a 61.8% reduction in the histamine AUC. Ca2+ removal (with EGTA 0.1 mM) gave an 80.0% reduction in the noradrenaline AUC and a 74.5% reduction in the histamine AUC. The combination of Ca2+ removal and cromakalim (1 pM) had no further effect on the noradrenaline responses (a reduction of 78.4% in AUC), but produced a significantly greater reduction in the histamine AUC (86.2%). 3 LaCl3 (1 mM) reduced the noradrenaline AUC by 74.8% and gave an 81.8% reduction in the response to a single (ECG90) histamine concentration. LaCl3 (1 mM) plus cromakalim (1 pM) produced no further reduction in the noradrenaline AUC (71.9%) but gave a significant further reduction of the histamine response (94.6%). 4 Pinacidil (3pM) reduced the noradrenaline AUC by 35.5%. Pinacidil (3pM) plus LaC13 ( mM) produced the same reduction in the noradrenaline AUC (80.9%) as LaCl3 alone (80.9%).5 In both normal and Ca2"-free Krebs solution, cromakalim (0.1, 1.0 and 10pM) produced concentration-related inhibition of the contraction to caffeine (10mM). This inhibition was antagonised by the K+ channel blocker, glibenclamide (3pM). Similarly, pinacidil (0.3, 3.0 and 30 pM) produced a glibenclamide-sensitive inhibition of the caffeine contraction. At equi-vasorelaxant concentrations, dazodipine (0.01, 0.1 and 1.OpM) and sodium nitroprusside (0.03, 0.3 and 3.0 pM) had no significant effect on caffeine contractions. 6 The data show that the K+ channel activators, cromakalim and pinacidil, unlike the Ca2+ channel blocker, dazodipine, or the guanylate cyclase activator, sodium nitroprusside, can inhibit the contraction which results from caffeine-induced Ca2+ release. Cromakalim and pinacidil, however, inhibit only the component of the noradrenaline response resulting from Ca2+ influx (tonic component) and not that resulting from Ca2 + release (phasic component). Cromakalim may affect both components of the histamine contraction.

show abstract

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

Tinker

Aziz

et al. 2018

Comprehensive Physiology

117

112

View full text Add to dashboard Cite

ATP sensitive potassium channels (K ) are so named because they open as cellular ATP levels fall. This leads to membrane hyperpolarization and thus links cellular metabolism to membrane excitability. They also respond to MgADP and are regulated by a number of cell signaling pathways. They have a rich and diverse pharmacology with a number of agents acting as specific inhibitors and activators. K channels are formed of pore-forming subunits, Kir6.1 and Kir6.2, and a large auxiliary subunit, the sulfonylurea receptor (SUR1, SUR2A, and SUR2B). The Kir6.0 subunits are a member of the inwardly rectifying family of potassium channels and the sulfonylurea receptor is part of the ATP-binding cassette family of proteins. Four SURs and four Kir6.x form an octameric channel complex and the association of a particular SUR with a specific Kir6.x subunit constitutes the K current in a particular tissue. A combination of mutagenesis work combined with structural studies has identified how these channels work as molecular machines. They have a variety of physiological roles including controlling the release of insulin from pancreatic β cells and regulating blood vessel tone and blood pressure. Furthermore, mutations in the genes underlie human diseases such as congenital diabetes and hyperinsulinism. Additionally, opening of these channels is protective in a number of pathological conditions such as myocardial ischemia and stroke. © 2018 American Physiological Society. Compr Physiol 8:1463-1511, 2018.

show abstract

Similarities in the Mechanism of Action of Two New Vasodilator Drugs: Pinacidil and BRL 34915

Cited by 102 publications

References 0 publications

Tolerance to cromakalim in the rat uterus in vivo

Tolerance to cromakalim in the rat uterus in vivo

Effect of cromakalim on contractions in rabbit isolated renal artery in the presence and absence of extracellular Ca²⁺

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

Contact Info

Product

Resources

About

Similarities in the Mechanism of Action of Two New Vasodilator Drugs: Pinacidil and BRL 34915

Cited by 102 publications

References 0 publications

Tolerance to cromakalim in the rat uterus in vivo

Tolerance to cromakalim in the rat uterus in vivo

Effect of cromakalim on contractions in rabbit isolated renal artery in the presence and absence of extracellular Ca2+

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

Contact Info

Product

Resources

About

Effect of cromakalim on contractions in rabbit isolated renal artery in the presence and absence of extracellular Ca²⁺