Experimental testing of Mackay's model for functional antagonism in the isolated costo‐uterus of the rat

Henry, Peter J.; Lulich, Karmelo M.; Paterson, J. W.

doi:10.1111/j.1476-5381.1985.tb09443.x

Cited by 4 publications

(2 citation statements)

References 14 publications

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“…It would be expected that individual patient responses to all anti-aggregatory agents would, to some extent, be subject to principles of physiological antagonism [25,26] and therefore tend to vary inversely with extent of ADP-induced aggregation. In the currently examined entire data set, ADP-induced aggregation did not vary significantly (ANOVA) between the control and two patient groups.…”

Section: Anti-aggregatory Responses To Rio Are Not Subject To Signifi...mentioning

confidence: 99%

Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm

Muminovic

Chirkov

Horowitz

2023

IJMS

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Impairment of the nitric oxide/soluble guanylate cyclase (NO)/sGC) signalling cascade is associated with many forms of cardiovascular disease, resulting not only in compromised vasodilatation but also loss of anti-aggregatory homeostasis. Myocardial ischaemia, heart failure, and atrial fibrillation are associated with moderate impairment of NO/sGC signalling, and we have recently demonstrated that coronary artery spasm (CAS) is engendered by severe impairment of platelet NO/sGC activity resulting in combined platelet and vascular endothelial damage. We therefore sought to determine whether sGC stimulators or activators might normalise NO/sGC homeostasis in platelets. ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP), the sGC stimulator riociguat (RIO), and the sCG activator cinaciguat (CINA) alone or in addition to SNP were quantitated. Three groups of individuals were compared: normal subjects (n = 9), patients (Group 1) with myocardial ischaemia, heart failure and/or atrial fibrillation (n = 30), and patients (Group 2) in the chronic stage of CAS (n = 16). As expected, responses to SNP were impaired (p = 0.02) in patients versus normal subjects, with Group 2 patients most severely affected (p = 0.005). RIO alone exerted no anti-aggregatory effects but potentiated responses to SNP to a similar extent irrespective of baseline SNP response. CINA exerted only intrinsic anti-aggregatory effects, but the extent of these varied directly (r = 0.54; p = 0.0009) with individual responses to SNP. Thus, both RIO and CINA tend to normalise anti-aggregatory function in patients in whom NO/sGC signalling is impaired. The anti-aggregatory effects of RIO consist entirely of potentiation of NO, which is not selective of platelet NO resistance. However, the intrinsic anti-aggregatory effects of CINA are most marked in individuals with initially normal NO/sGC signalling, and thus their magnitude is at variance with extent of physiological impairment. These data suggest that RIO and other sGC stimulators should be evaluated for clinical utility in both prophylaxis and treatment of CAS.

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Section: Anti-aggregatory Responses To Rio Are Not Subject To Signifi...mentioning

confidence: 99%

Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm

Muminovic

Chirkov

Horowitz

2023

IJMS

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“…The rat costo-uterine muscle connects the tuba1 end of the uterine horn to the lower ribs (Gabella 1976). Studies with field-stimulated (Hartley & Pennefather 1981 and carbacholcontracted (Henry et al 1984(Henry et al , 1985 preparations have established that this smooth muscle contains adrenoceptors solely of the &subtype which mediate physiological antagonism of contrac-tile stimuli. These P,-receptors are efficiently coupled to the processes mediating inhibitory effects, since the &adrenoceptor selective agonists noradrenaline and R0363 [( +)-1-(3,Cdimethoxyphenethylamino)-3-(3,4-dihydroxyphenoxy)-2-propanol oxalate] (Raper et al 1978;Iakovidis et al 1980), produce full inhibition of electrically evoked contractions, and are blocked selectively by the P2-adrenoceptor antagonist, ICI 118,551 .…”

Section: Introductionmentioning

confidence: 99%

(±)‐pindolol Has Β2‐adrenoceptor Antagonist but Not Agonist Action on the Costo‐uterine Muscle of the Rat

Pennefather

Hartley

Leedham

1987

Clin Exp Pharma Physio

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1. The effects of isoprenaline and (+/-)-pindolol on rat isolated costo-uterine muscle have been compared. 2. Isoprenaline produced reproducible concentration-dependent inhibition of contractions, and maximal doses (less than 0.1 mumol/l) produced mean inhibition of 87, 94 and 97% of field, carbachol and potassium-stimulated preparations, respectively. 3. (+/-)-Pindolol, when effective, produced inhibition only in concentrations greater than its pA2 value (9.87) as an antagonist of isoprenaline; mean maximal effects were less than 60% of those produced by isoprenaline. 4. It is concluded that (+/-)-pindolol is a potent antagonist, but has only variable agonist action, at the beta 2-adrenoceptors of the rat costo-uterine muscle.

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Cholinoreceptors in the isolated costo‐uterine muscle of the rat

Cook

Hartley

Pennefather

et al. 1987

Journal of Autonomic Pharmacology

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1 The aim of this study was to examine the cholinoreceptor population in the rat costo-uterine muscle. 2 The nicotinic cholinoreceptor agonists nicotine and DMPP, and the ganglionic muscarinic cholinoreceptor stimulant McNeil A-343, had no effects upon isolated preparations of this tissue. 3 Acetylcholine was more potent than carbachol and approximately equipotent with methacholine (the mean EC50 values were 7.0, 6.3 and 6.7 respectively) in producing contractions of the preparation; each was a full agonist. The potencies of carbachol and methacholine were similar in preparations taken from animals in oestrus and in dioestrus. 4 Atropine competitively antagonised the effects of carbachol and methacholine, the pA2 values were 9.37 and 9.41 respectively. The pA2 value for pirenzepine with carbachol as the agonist was 6.69. 5 Pilocarpine produced phasic contractions of the tissue (EC50 value = 4.17), and competitively antagonised the effects of carbachol with a pA2 value of 5.26. The anticholinesterase, physostigmine, produced only a small potentiation of the effects of acetylcholine. 6 It is concluded that the cholinoreceptors which mediate contraction of the rat costo-uterine muscle are muscarinic, homogeneous in nature and unaffected by fluctuating levels of ovarian hormones occurring during the oestrous cycle. The consequences of inhibition of cholinesterase activity in isolated preparations of the tissue are minimal.

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Experimental testing of Mackay's model for functional antagonism in the isolated costo‐uterus of the rat

Cited by 4 publications

References 14 publications

Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm

Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm

(±)‐pindolol Has Β2‐adrenoceptor Antagonist but Not Agonist Action on the Costo‐uterine Muscle of the Rat

Cholinoreceptors in the isolated costo‐uterine muscle of the rat

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