Biomedical subjects

A Hoey

Publications and source records attributed to A Hoey.

12 recordsLinked to original sources

PubMed2000

Changes in function of cardiac receptors mediating the effects of the autonomic nervous system in the muscular dystrophy (MDX) mouse.

Adrenergic and muscarinic receptor mediated effects on the force of contraction and heart rate were studied in the isolated left atria and right atria from dystrophin-deficient mdx mice and age matched C57BL/10ScSn (C57) mice, respectively. The pD(2) and pA(2) values of (-)-isoprenaline and CGP 20712A, respectively, were not different in left atria and right atria from mdx and C57 mice. (-)-Phenylephrine produced a small positive inotropic effect on mdx left atria that could be antagonized by prazosin, whereas in C57 left atria no positive inotropic response was seen. In contrast, the positive chronotropic effect of (-)-phenylephrine was reduced in right atria from mdx compared to C57 right atria (P<0.05). The potency and efficacy to carbachol in the presence of (-)-isoprenaline were higher in right atria from mdx compared to C57 mice (P<0.05), although in left atria only a greater efficacy was evident in mdx mice. In left atria, basal force of contraction and maximum Ca(2+)-induced increases in force of contraction were lower from mdx compared to C57 mice (P<0. 001 and P<0.05, respectively). In conclusion, marked changes were demonstrated in the function of alpha1-adrenoceptors and muscarinic receptors, but not in beta1-adrenoceptors in left and right atria from mdx mice.

Animals↗

PubMed2000

Age- and sex-associated changes in cardiac beta(1)-adrenoceptors from the muscular dystrophy (mdx) mouse.

Variations in beta(1)-adrenoceptor function due to age or sex were examined in the mouse model of Duchenne muscular dystrophy. Positive chronotropic and inotropic responses to (-)-isoprenaline and antagonist effects of CGP20712A were determined in isolated right and left atria from young (12 week) and old (12 month) male and old (12 month) female mdx mice and their age- and sex-matched C57BL/10ScSn (C57) mice. There was no difference in efficacy to (-)-isoprenaline when expressed as an increase in the rate of contraction or force of contraction as a percentage of Ca(2+)-induced increase respectively in right or left atria from age- and sex-matched mdx and C57. Old mdx males showed a decreased sensitivity to (-)-isoprenaline (P<0.05) and a reduced affinity to CGP 20712A (P<0.05) in both right and left atria compared with old C57 males. These same changes were also observed in left atria between old and young mdx males. A reduced efficacy to (-)-isoprenaline was also evident when young and old mdx males were compared. In contrast, in old females, mdx showed an increased affinity to CGP20712A in left and right atria (P<0.05), and an enhanced sensitivity to (-)-isoprenaline in right atria. Finally, in left atria, the maximum Ca(2+)-induced increase in force of contraction was lower in all mdx compared to their age- and sex-matched C57 (P<0.05). In conclusion, age- and sex-associated changes in beta(1)-adrenoceptor function and responses to calcium were demonstrated in cardiac muscle from mdx mice, with a marked deterioration in beta(1)-adrenoceptor function occurring with aging in male mdx being particularly evident.

Aging↗

PubMed1996

Atypical responses of rat ileum to pindolol, cyanopindolol and iodocyanopindolol.

1. Pindolol, cyanopindolol (CYP) and iodocyanopindolol (IodoCYP) have been reported to act either as antagonists, agonists or partial agonists at the beta 3-adrenoceptor in different preparations. A comprehensive investigation has not yet been described with these compounds tested in one tissue from one species. This study was conducted to delineate the pharmacological effects of pindolol, CYP and IodoCYP and to provide data on their affinities at the predominant beta-adrenoceptor in rat ileum. 2. The beta-adrenoceptors present in rat ileum were characterized in the presence of CGP 20712A and ICI 118 551, atropine and corticosterone, with (-)-isoprenaline used as an agonist. The role of the beta 1 and beta 2-adrenoceptors was determined by the omission of either CGP 20712A, ICI 118 551, or both, from the buffers. Conversely, the effectiveness of the beta 1- and beta 2-adrenoceptor blockade was examined by use of the beta 1-adrenoceptor-selective agonist, RO 363 and the beta 2-adrenoceptor-selective agonist, salbutamol. 3. There was no evidence for the presence of functional beta 1-adrenoceptors, and no strong evidence that beta 2-adrenoceptor stimulation contributed to the relaxant effects of (-)-isoprenaline. (-)-Phenylephrine did not produce relaxation of the tissue and 5-hydroxytryptamine produced contraction. 4. The beta 3-adrenoceptor-selective agonist, BRL 37344 and (-)-isoprenaline were potent full agonists (pD2 8.35 +/- 0.04 and 7.76 +/- 0.14 respectively), whereas ICI D7114 was less potent (pseudo pD2 6.92 +/- 0.15). These results indicate that the predominant functional beta-adrenoceptors in rat ileum are beta 3-adrenoceptors. 5. Partial agonist effects were produced by CYP (pD2 5.28 +/- 0.26) and IodoCYP (pD2 7.0 +/- 0.26), but not pindolol. All three compounds antagonized the effects of (-)-isoprenaline with pKb values of 6.68 +/- 0.10, 7.59 +/- 0.07 and 7.59 +/- 0.11 for pindolol, CYP and IodoCYP respectively. Likewise, CYP and IodoCYP antagonized the effects of BRL 37344 with pKb values of 7.20 +/- 0.22 and 7.21 +/- 0.14 respectively. This study provides the first functional data on the effects of IodoCYP, the ligand with the highest known affinity for the beta 3-adrenoceptor, at the characterized rat ileum beta 3-adrenoceptor. 6. In conclusion, whereas pKb values suggest that CYP and IodoCYP have a similar affinity for the beta 3-adrenoceptor in rat ileum, the higher potency of IodoCYP suggests that it promotes a greater coupling efficiency, or that its partial agonist effects are produced through a site other than the beta 3-adrenoceptor. The similar pKb values for CYP and IodoCYP at the beta 3-adrenoceptor contrast with their order of known affinities at the beta 1- and beta 2-adrenoceptors, where IodoCYP is far more potent than CYP. This provides evidence of further differences in the characteristics of the beta 3-adrenoceptors compared to the beta 1- and beta 2-adrenoceptors. Finally, the utility of IodoCYP as a beta 3-adrenoceptor antagonist would appear to be limited because of the greater magnitude of partial agonist effects that it produces.

Adrenergic beta-Agonists↗

PubMed1994

Comparison of the action potential prolonging and positive inotropic activity of DPI 201-106 and BDF 9148 in human ventricular myocardium.

The aim of our study was to compare the effects on contractile function and action potential duration of the new Na+ channel modulator BDF 9148 with the parent compound DPI 201-106 in human ventricular myocardium. Right ventricular papillary muscles were obtained from explanted hearts of heart transplant recipients or from non-failing hearts not suitable for transplantation. BDF 9148 induced an increase in force of contraction that was accompanied by prolongation of action potential duration. The action potential duration prolonging effect of BDF 9148 was not significantly different to that of DPI 201-106. The effects of BDF 9148 were similar in muscles obtained from non-failing and failing hearts. Using Na(+)-sensitive electrodes, we have demonstrated that the positive inotropic effect of BDF 9148 is accompanied by an increase in intracellular Na+ activity. Our results indicate: (i) that BDF 9148 is as effective as DPI 201-106 in increasing force of contraction and prolonging action potential duration in human ventricular myocardium: (ii) that BDF 9148 is effective in enhancing force of contraction, in spite of heart failure; (iii) that the positive inotropic effect is related to an increased Na+ load; and (iv) due to action potential duration prolongation, changes in Q-T interval of the electrocardiogram could be possible during in vivo use of BDF 9148.

Action Potentials↗

PubMed1994

Differential effects of BDF 9148 and DPI 201-106 on action potential and contractility in rat and guinea pig myocardium.

The effects of BDF 9148 and its parent compound DPI 201-106 were compared in guinea pigs and rat cardiac tissue because these tissues possess long and short action potentials (AP), respectively, and have different excitation-contraction coupling mechanisms. Conventional electrophysiologic techniques were used to study drug effects on AP, sodium current, and force of contraction (Fc). In guinea pig and rat papillary muscle, BDF 9148 and DPI 201-106 increased Fc; BDF 9148 was more potent than DPI 201-106. In guinea pig, but not in rat muscle, DPI 201-106 significantly prolonged AP duration (APD) to a greater degree than did BDF 9148. In rat cardiac muscle, both agents were more potent but increased Fc to a lesser degree than in guinea pig cardiac muscle and led to Ca2+ overload, as evidenced by after-contractions and contracture. BDF 9148 failed to increase Fc at low frequencies in guinea pig but was effective at all frequencies in rat muscle. In isolated myocytes, substance effects on sodium current were similar in both species. In guinea pigs, but not in rats, DPI 201-106 prolongs APD to a greater degree than does BDF 9148. Both agents produce a greater positive inotropic effect in guinea pigs than in rats, which may be due to species differences in excitation-contraction coupling.

Action Potentials↗

PubMed1994

Ion channel modulators as potential positive inotropic compound for treatment of heart failure.

1. Current positive inotropy therapy of heart failure is associated with major problems: digoxin and the phosphodiesterase inhibitors can cause life-threatening toxicity while beta-adrenoceptor agonists become less effective inotropic compounds as heart failure progresses. A new approach to positive inotropy is ion channel modulation. 2. An increased influx of Na+ during the cardiac action potential, as measured with DPI 201-106 and BDF 9148 which increase the probability of the open state of the Na+ channel, will increase force of contraction. 3. Activation of L-type Ca2+ channels with Bay K 8644 will increase influx of Ca2+ and increase the force of contraction. However the Ca2+ channel activators developed to date have little potential for the treatment of heart failure as they are vasoconstrictors. 4. Blocking cardiac K+ channels is a possible mechanism of positive inotropy. Terikalant inhibits the inward rectifying K+ channel, tedisamil inhibits the transient outward K+ channel and dofetilide is one of the newly developed inhibitors of the slow delayed outward rectifying K+ channel. All these drugs prolong the cardiac action potential to increase Ca2+ entry and force of contraction. 5. Thus drugs which increase Na+ influx or block K+ channels represent exciting possibilities for positive inotropy and the potential of these compounds for the treatment of heart failure needs to be fully evaluated.

Animals↗

PubMed1994

Effects of the Anemonia sulcata toxin (ATX II) on intracellular sodium and contractility in rat and guinea-pig myocardium.

The effects of the Anemonia sulcata toxin ATX II on action potentials and contractility of isolated papillary muscles and single myocytes from rat and guinea-pig hearts have been studied. ATX II prolonged the action potential in both rat and guinea-pig papillary muscle. Although it produced a positive inotropic effect in guinea-pig papillary muscle, it failed to do so in rat papillary muscle. However, in single rat and guinea-pig ventricular cells, it both prolonged the action potential and had a positive inotropic effect. We suggest that ATX II does not cause a positive inotropic effect in rat papillary muscle, because it induces Ca2+ overload. In single cells the positive inotropic effect was reduced by approximately 50% when the contractions were triggered by voltage clamp pulses of constant duration rather than by action potentials. This suggests that the inotropic effect of ATX II is in part the result of the prolongation of the action potential. The intracellular Na+ activity (a(i)Na) in single ventricular cells was measured with the Na(+)-sensitive fluorescent dye SBFI. After exposure of the cells to ATX II, a(i)Na was increased by a maximum of 1.9 +/- 0.3 and 2.2 +/- 0.3 mM in rat and guinea-pig cells, respectively. It is suggested that the positive inotropic effect of ATX II is also in part the result of the rise in a(i)Na.

Action Potentials↗

PubMed1993

Inotropic actions of BDF 9148 and DPI 201-106 and their enantiomers in guinea-pig, rat and human atria.

The positive inotropic effects of the sodium channel modulators, DPI 201-106 and BDF 9148, were tested in atrial preparations from guinea-pig, rat and man. In rat, the racemate and S enantiomer of both DPI 201-106 and BDF 9148 displayed the same efficacy as did increased extracellular Ca2+, but in guinea-pig and man, the efficacy varied between 60 and 90% of the maximum Ca2+ response. In all three species, BDF 9148 was significantly more potent than DPI 201-106 by approximately one order of magnitude. The same was evident for the S enantiomers. The R enantiomers did not inhibit the effects of the S enantiomers. We have shown pronounced differences in the efficacy and potency of the enantiomers of DPI 201-206 and BDF 9148, which may be useful for future radioligand binding studies.

Animals↗

PubMed1993

Cardiac angiotensin receptors in experimental hyperthyroidism in dogs.

OBJECTIVE: The aim was to define the changes in angiotensin II receptors and the plasma renin-angiotensin system in experimental hyperthyroidism in dogs. METHODS: Hyperthyroidism was induced in dogs by subcutaneous injection of triiodothyronine (T3; 1 mg.kg-1 x d-1 for 14 d; group T); control dogs received saline (group C). Plasma angiotensin II (AII), angiotensinogen, renin activity and concentration, and angiotensin II receptors in left ventricle, right atrium, thoracic aorta, adrenal gland, and liver were measured. RESULTS: T3 treatment caused tachycardia, increased heart weight, hypertrophy of the circumflex and septal coronary arteries, increased plasma renin activity [C = 1.6(SEM 0.2), T = 9.8(2.8) ng angiotensin I.ml-1 x h-1], plasma renin concentration [C = 13.0(3.7), T = 34.5(5.6) ng angiotensin I.ml-1 x h-1], and plasma AII [C = 23(3), T = 104(5) pg.ml-1], while plasma angiotensinogen did not change. There were no significant changes in adrenal gland and right atrial angiotensin II receptor densities; increases were measured in the left ventricle [C = 0.33(0.06), T = 0.75(0.12) pmol.g-1 tissue], thoracic aorta [C = 0.19(0.02), T = 0.28(0.03) pmol.g-1 tissue], and liver [C = 8.4(1.2), T = 12.9(1.7) pmol.g-1 tissue]. The relative affinities of the left ventricular angiotensin II receptor for angiotensin peptides (obtained from displacement assays) were: Sar1, Ile8-AII > AII > angiotensin III > angiotensin I > hexapeptide > pentapeptide. CONCLUSIONS: Experimental hyperthyroidism in dogs results in activation of the plasma renin-angiotensin system and up regulation of left ventricular, aortic, and liver angiotensin II receptors.

Animals↗

PubMed1992

Cardiac beta-adrenoceptor changes in experimental hyperthyroidism in dogs.

1. Triiodothyronine (T3; 1.0 mg/kg per day subcutaneously) was administered to 10 dogs for 14 days; 10 saline-treated dogs served as controls. T3-treated dogs showed the expected physiological responses of hyperthyroidism; further, chronotropic responses to isoprenaline in vivo were significantly increased in T3-treated dogs. 2. Beta-adrenoceptor subtype density was measured in membrane preparations by displacement of 125I-iodocyanopindolol binding by the selective beta 2-adrenoceptor antagonist, ICI 118, 551. T3 treatment led to a 93% increase in right atrial beta 1-adrenoceptor density and a 141% increase in left ventricular beta 1-adrenoceptor density; beta 2-adrenoceptor densities in right atrial, left ventricular and lung membranes were unchanged. 3. T3-treatment did not change basal or maximally stimulated adenylate cyclase activities in left ventricular membranes. 4. Thus, the cardiovascular changes in experimental hyperthyroidism in dogs were accompanied by an increased chronotropic response in vivo to isoprenaline and an increased beta 1-adrenoceptor density in atrial and ventricular membranes. However, there was no corresponding change in basal or maximal responsiveness of adenylate cyclase in ventricular membranes.

Adenylyl Cyclases↗

PubMed1991

Cardiac changes in experimental hyperthyroidism in dogs.

Injection of triiodothyronine (T3) (1 mg/kg per day subcutaneously for 14 days) to 10 healthy dogs produced a hyperthyroid state characterised by high serum T3 concentrations, hypokalaemia, hyperactivity, loss of weight, diarrhoea and thirst. Electrocardiographic measurements showed that these dogs had an increase in heart rate of 63 +/- 11 beats/min with a significantly increased T wave amplitude without changes in R wave amplitude. Echocardiographic measurements showed no changes in fractional shortening and no evidence of ventricular hypertrophy, in contrast to reports in humans, cats and rats. However, the smooth muscle of the coronary arteries was markedly hypertrophied, which may cause a decrease in myocardial perfusion.

Animals↗

PubMedDate not supplied

Positive inotropic responses of the sodium channel modulator BDF 9148 in diseased rat myocardium.

1. This study has defined the positive inotropic responses to the sodium channel modulator BDF 9148 in rats with hypertension, thyroid dysfunction, diabetes or dwarfism. Concentration-response curves to BDF 9148 and calcium chloride were determined in isolated left atria and left ventricular papillary muscles. 2. BDF 9148 increased force of contraction in left ventricular papillary muscles in all disease states with maximal responses comparable to calcium chloride. BDF 9148 potency was significantly decreased in muscles from diabetic rats only. 3. BDF 9148 produced similar responses in left atria except from hyperthyroid rats where negative inotropic responses only were measured. This exception confirms that the left atria is an imperfect model for ventricular responsiveness. 4. Thus, the increase in force of contraction in the ventricles as a consequence of sodium channel modulation by BDF 9148 is maintained in these disease states unlike responses to alpha-or beta-adrenoceptor agonists.

Animals↗