Effects of a selective and a nonselective muscarinic cholinergic antagonist on heart rate and intestinal motility in dogs

Abstract

The effects of methoctramine, a cardioselective muscarinic cholinergic antagonist, on heart rate and small intestinal motor activity were compared to those of the nonselective competitive muscarinic antagonist, atropine. Methoctramine or atropine, 6, 10, 30, 60 micrograms/kg, or sterile isotonic saline, was administered intravenously to six conscious dogs in cross-over studies. Methoctramine administration caused dose-dependent tachycardia without affecting intestinal motility, while atropine administration caused dose-dependent tachycardia accompanied by significant reductions in small intestinal motility. Additionally, methoctramine did not inhibit intestinal smooth muscle contractile activity initiated by the muscarinic agonist bethanechol, while atropine inhibited bethanechol-induced contractile activity in a dose-dependent manner. Calculated, dosages of methoctramine and atropine required to produce a 50% increase in heart rate over baseline were 35.1 +/- 5.3 and 39.5 +/- 6.2 micrograms/kg, respectively. This dosage of atropine caused a 93 +/- 13.9% reduction in intestinal motility. These findings suggest that selective muscarinic antagonists may be useful drugs for those veterinary patients in which nonselective muscarinic antagonists have the potential to produce untoward effects on intestinal motility.

Bronchodilator Activity of (3R)-3-[[[(3-fluorophenyl)[(3,4,5-trifluorophenyl)methyl]amino] carbonyl]oxy]-1-[2-oxo-2-(2-thienyl)ethyl]-1-azoniabicyclo[2.2.2]octane bromide (CHF5407), a Potent, Long-Acting, and Selective Muscarinic M3 Receptor Antagonist

“…On this basis, we conclude that CHF5407, much more than tiotropium, possesses a kinetic selectivity for M3 versus M2 receptors. In vivo, both CHF5407 and tiotropium, at high dosage, affected heart rate and blood pressure similarly to the M2 receptor antagonist methoctramine (Howell and Kovalsky, 1995), i.e., they decreased MAP and increased HR, an effect the latter of which is mediated mainly by the cardiac M2 receptor (Hendrix and Robinson, 1997). A modest, although significant, difference between CHF5407 (less effective) versus tiotropium (more effective) in changing cardiovascular parameters became evident only at very high doses (1000 -10,000 nmol/kg).…”

Effects of a muscarinic type-2 antagonist on cardiorespiratory function and intestinal transit in horses anesthetized with halothane and xylazine

“…In the gastrointestinal system, M 3 receptors mediate smooth muscle contraction in response to the release of acetylcholine from the myenteric plexus, 50 and the blockade of this receptor subtype by selective M 3 antagonists (eg, 4-DAMP) or by nonselective muscarinic antagonists (eg, atropine or glycopyrrolate) causes a decrease in intestinal motility. 17,18,20,21 Although an increase in HR and inhibition of gastric motility were detected after administration of similar doses of atropine to conscious rats, 21 inhibition of gastric motility with the M 2 antagonist AFDX-116 was observed only when it was used at doses 5-fold larger than those that significantly increased HR. In conscious dogs, the M 2 antagonist methoctramine reportedly 18 did not have an effect on intestinal motility at doses that caused a 50% increase in HR.…”

“…The dosing range for methoctramine was based on results of a preliminary study a and dose-response studies 18,24 performed in dogs. For each horse, we attempted to control the HR response by administering boluses (10 µg/kg) every 10 minutes until HR was increased by at least 30% above baseline or until a total cumulative dose of 30 µg/kg had been administered.…”

“…14 However, with the characterization of muscarinic receptor subtypes and development of selective muscarinic antagonists, it has become possible to direct antimuscarinic treatment toward a specific organ, thereby avoiding undesirable effects on other organ systems. 14 Based on dose-response and radioligand binding studies [15][16][17][18][19] in other species, it has been determined that parasympathetic modulation of cardiac chronotropism and dromotropism is via muscarinic type-2 (M 2 ) receptors, which are blocked by M 2 antagonists, such as AFDX-116 and methoctramine. On the other hand, stimulation of gastrointestinal motility is mainly via muscarinic type-3 (M 3 ) receptors, which are blocked by M 3 antagonists, such as 4-DAMP and zamifenacine.…”

“…17,20,21 Because of their selective cardiac effects at doses that do not interfere with other parasympathetically mediated functions in vitro and in vivo, the term cardioselective antagonist has been used to designate M 2 receptor antagonists. 18,[22][23][24] Methoctramine, a cardioselective muscarinic antagonist, can prevent fentanyl-induced bradycardia in dogs when administered at a dosage of 14.4 µg/kg. 24 In a preliminary in vitro study, a it was determined that the M 2 antagonist methoctramine had a relatively low potency for antagonizing the effects of acetylcholine on equine longitudinal jejunal smooth muscle, compared with the effects for the M 3 antagonist 4-DAMP.…”