Agonist‐independent effects of muscarinic antagonists on Ca2+ and K+ currents in frog and rat cardiac cells.

Abstract

SUMMARY1. The whole-cell patch clamp and intracellular perfusion techniques were used for studying the effects of atropine and other muscarinic acetylcholine receptor (mAChR) antagonists on the L-type calcium currents ('Ca) in frog and rat ventricular myocytes, and on the mAChR-activated K+ current ('K(ACh)) in frog atrial myocytes.2. In frog ventricular myocytes, atropine (01 nm to I /,tM) reversed the inhibitory effect of acetylcholine (ACh, 1 nM) on 'Ca previously stimulated by isoprenaline (Iso, 2 JM), a /l-adrenergic agonist. However, in the concomitant presence of Iso, ACh and atropine, 'Ca was > 50 % larger than in Iso alone.3. The effects of atropine were then examined in the absence of mAChR agonists. 4. Atropine (1 M) had no effect on frog ICa (i) under basal conditions, (ii) upon stimulation of ICa by the dihydropyridine agonist (-)-Bay K 8644 (1 aM), or (iii) when ICa had been previously stimulated by intracellular perfusion with cyclic AMP (3 AM). However, atropine increased Jca after a stimulation by forskolin (0 3 1M).Therefore, an increased adenylyl cyclase activity was required for atropine to produce its stimulatory effect on Jca 5. The order of potency of mAChR antagonists to reverse the inhibitory effect of ACh on Iso elevated ICa in frog ventricle was atropine > AF-DX 116 > pirenzepine.In the absence of ACh, mAChR antagonists produced their stimulatory effect on Iso elevated ICa with the same order of potency.6. Intracellular substitution of Gpp(NH)p (5'-guanylylimidiphosphate) for GTP (420 AtM) induced a strong inhibition of frog Ica in the presence of Iso (2 aM).

Methylene Blue Is a Muscarinic Antagonist in Cardiac Myocytes

“…Mblue did not modify basal I Ca or Iso-stimulated I Ca and had no effect on the specific binding of [ 3 H]CGP 12177, a nonselective ␤-adrenergic ligand. Unlike Mblue, the classic muscarinic antagonist atropine was demonstrated to enhance basal I Ca in rat myocytes (38). Atropine is thought to shift the ratio of active (R*) to inactive (R) receptors toward R, the consequence of which is a reduction of the spontaneous turnover of the G i protein and, subsequently, an increase in adenylyl cyclase activity (38).…”

“…Unlike Mblue, the classic muscarinic antagonist atropine was demonstrated to enhance basal I Ca in rat myocytes (38). Atropine is thought to shift the ratio of active (R*) to inactive (R) receptors toward R, the consequence of which is a reduction of the spontaneous turnover of the G i protein and, subsequently, an increase in adenylyl cyclase activity (38). Thus, in the context of I Ca regulation, only atropine behaves like an inverse agonist, whereas Mblue seems rather a neutral antagonist.…”

Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.

“…Currently, an (41)(42)(43)(44). Yet, inverse agonism has recently also been observed in myometrial cells (53), erythrocytes (54), and cardiomyocytes (55,56), suggesting that inverse agonism might be of physiological relevance.…”

Effet antihypertensif de BpF2, une fraction d\'extrait aqueux de feuilles de <i>Bidens pilosa</i> L. (Asteraceae) chez le lapin

“…Le ralentissement cardiaque s'explique, en partie, par l'hyperpolarisation cellulaire consécutive à l'ouverture des canaux potassiques qui sont directement liés aux protéines G (Zakharov & Harvey, 1997;Kurachi & Ishii, 2003;Fleischmann et al, 2004). La diminution de la force de contraction provient d'une diminution de l'entrée du Ca 2+ dans la cellule, probablement par inhibition de l'adénylcyclase (Hartzell, 1988;Hanf et al, 1993;Jurevièius & Fischmeister, 1996;Han et al, 1998). L'injection d'acétylcholine entraîne une vasodilatation artérielle consécutive à la libération par l'endothélium d'une substance vasodilatatrice, le monoxyde d'azote (NO) ou d'un facteur hyperpolarisant (EDHF).…”