Bezold-Jarisch Reflex

Duration of action of the compounds is assessed by determining the period of time for which the inhibitory effects remain significantly different from vehicle controls. Statistical analysis of the data is performed by a repeated measure analysis of variance (ANOVA) followed by pairwise comparisons against control at each time period using Fisher s LSD multiple comparison test. 

Harron and Kobinger (1984) used capsaicin to elicit the Bezold-Jarisch reflex in anesthetized artificially respi-rated dogs pretreated with a beta-adrenoceptor antagonist to evaluate the activity of clonidine-like drugs on central alpha2 adrenoceptors after intracistemal administration. 

Jarisch A (1940) Vom Herzen ausgehende Kreislaufreflexe. Arch Kreislaufforsch 7 260-274 

Jarisch A, Richter H (1939a) Die Kreislaufwirkung des Vera-trins. Naunyn Schmiedeberg s Arch exp Path Pharmakol 193 347-354 

Jarisch A, Richter H (1939b) Der Bezold-Effekt - Eine vergessene Kreislaufreaktion. Klin Wochschr 18 185-187 Kalkman HO, Engel G, Hoyer D (1984) Three distinct subtypes of serotonergic receptors mediate the triphasic blood pressure response to serotonin in rats. J Hypertens 2, Suppl 3 143-145 

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HT3 receptor affinity, inhibition of Bezold-Jarisch reflex and antiemetic action 312... 

Inhibition of Bezold-Jarisch reflex in rats. h Antagonism of cisplatin-induced emesis in ferrets and dogs. c L.M. Pinkus, personal communication. 

HT3 RECEPTOR AFFINITY, INHIBITION OF BEZOLD-JARISCH REFLEX AND... 

The most frequently used preparation for assessing the in vivo activity of 5-HT3 receptor agents is the von Bezold Jarisch reflex (the BJ test) in anaesthetized animals [27, 28]. This preparation is relatively simple to perform and can provide rapid comparative data on a series of compounds, although it gives no indication of potential therapeutic uses. 

From a series of 1,7-annelated indole derivatives, cilansetron [(-)-162j was selected for further pharmacologicalprofilingboth in vitro and in vivo (Table 14.14) (454). In the RVN and Gpl, cilansetron [pA, 9.94 (RVN) 7.80 (Gpl)] is about 10-fold more potent than ondansetron [pA, 8.99 (RVN) 6.80 (Gpl)]. In the von Bezold-Jarisch reflex test (BJR) in unrestrained conscious rats, cilansetron (ED = 26 jLLg/kg, p.o.) is orally active at a dose 6 times lower than that of ondansetron (ED =165 ptg/kg, p.o.). Solvay announced Phase III studies for cilansetron for the treatment of diarrhea-predominant irritable bowel syndrome, in July 2001 (455). 

Godlewski G, Gothert M, Malinowska B (2003) Cannabinoid receptor-independent inhibition by cannabinoid agonists of the peripheral 5-HT3 receptor-mediated von Bezold-Jarisch reflex. Br J Pharmacol 138 767-774... 

Collectively, the above-mentioned studies show that the sustained hypotensive effect of anandamide involves a marked cardiodepressor component in addition to a decrease in TPR, and these effects are mediated by CBi but not TRPVl receptors. The role of TRPVl receptors is limited to fhe transient activation of the Bezold-Jarisch reflex by very high plasma concentrations of anandamide. 

Functional CBi receptors are present in vascular tissue as well as the myocardium, and cannabinoid agonists and endocannahinoids exert major hypotensive and cardiodepressor effects in vivo through the stimulation of CB receptors. There is evidence for the existence of an as-yet-undefined endothelial and cardiac receptor or receptors that mediate certain endocannabinoid-induced cardiovascular effects. Vanilloid TRPVl receptors can be activated by anandamide, but the role of these receptor in in vivo hemodynamic effects appears to be limited to the transient activation of the Bezold-Jarisch reflex by very high initial plasma concentrations of anandamide. 

High affinity and selective for 5-HTg receptors is also observed in (R)-N-(quinuclidin-3-yl)-2-(l-methyl-lH-indol-3-yl)-2-oxo-acetamide. This compound behaves as a potent partial agonist when tested on the Von Bezold-Jarisch reflex in rats [215]. The (S)-enantiomer has a 100-fold lower affinity for the 5-HTg receptors and is 14 times less potent in vivo. Both enantiomers have interesting behavioural effects in animal models (to be published). 

The facet of cromolyn s activity profile on which we concentrated was the compound s reported tachyphylactic action in both the rat PCA screen and in producing a Bezold-Jarisch reflex induced fall in blood pressure in the anaesthetised dog flO. 141. In essence, a high dose of the compound administered to a rat 30 - 60 minutes before a second dose, given in the normal manner at the time of antigen challenge, inhibits or abolishes the protective effect of the latter dose on the rat PCA reaction. In the anaesthetised dog, we have found that a fifteen minute infusion of a low dose of cromolyn blocks the normal depressor activity of a subsequent bolus injection of the compound. The blocking action of the infused dose diminishes with time as shown in Figure 1. The loss of activity with time in these experiments probably reflects the rate of elimination of the cromolyn from the sensory receptors in the left ventricle of the heart which have been shown to be involved in the... 

Whereas the occurrence of the Bezold-Jarisch reflex depends on the degree of access of capsaicin to the right side of the circulation, under certain circumstances involving the systemic arterial circulation capsaicin administration may lead to hypertension, tachycardia, and tachypnea. These latter responses prevail after vagotomy (Toh et al., 1955 Coleridge... 

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