Effects of capsaicin desensitization on the stimulatory effect of kinins, prostaglandins, biogenic amines and various drugs in guinea‐pig isolated atria

Abstract

1 A simple desensitization protocol was set up using capsaicin and isolated, spontaneously beating atria of guinea-pigs to assess the possible participation of cardiac, capsaicin-sensitive, substance P (SP)-and calcitonin gene-related peptide (CGRP)-containing sensory nerve fibres, in the cardiac stimulatory effects of bradykinin (Bk), kallidin (Kd), 5-hydroxytryptamine (5-HT), histamine, prostaglandin E2 (PGE2), prostaglandin El (PGE1), prostaglandin F2., (PGF2Z), adrenaline (Ad), glucagon, nicotine and angiotensin II (All). 2 The positive chronotropic and inotropic effects of Bk, Kd and 5-HT were markedly reduced in capsaicin-desensitized atria compared to control. The percentage inhibition of the chronotropic and inotropic responses to the three agonists seemed to be inversely related to the concentration of agonist used and to vary also with the type of cardiac effect produced by the drug (for Bk the percentage inhibition was: 36-81% (chronotropic effect) and 62-86% (inotropic effect); for Kd: 61-78% (chronotropic effect) and 53-77% (inotropic effect); for 5-HT: 25-66% (chronotropic effect) and 40-64% (inotropic effect)).3 The positive chronotropic and inotropic effects of histamine, PGEl, PGE2, PGF2., glucagon and AII had similar amplitudes in capsaicin-desensitized and control atria. 4 The positive chronotropic and inotropic effects of Ad and nicotine were differentially affected by capsaicin desensitization. The inotropic effects of 7.5 x 1O-' and 7.5 x 10-6M Ad were reduced by 41 and 27% respectively, in capsaicin-desensitized atria compared to control. The chronotropic effects of 1.54 x 10'-and 6.17 x 10-M nicotine were inhibited by 57 and 26% respectively, by capsaicin desensitization. On the other hand, the chronotropic effect of Ad and the inotropic action of nicotine were of similar amplitude in capsaicin-desensitized and control atria. 5 These results were taken as an indication that a substantial part of the chronotropic and inotropic effects of Bk, Kd or 5-HT in guinea-pig atria, unlike those of histamine, PGE1, PGE2 PGF2., glucagon and All, might be the result of stimulation of capsaicin-sensitive, SP-and CGRP-containing sensory nerve fibres. The slight, differential inhibition of the chronotropic and inotropic effects of Ad and nicotine by capsaicin desensitization suggests a minor contribution by cardiac, capsaicin-sensitive sensory nerve fibres to the effects of nicotine and Ad in guinea-pig atria.

Effects of capsaicin and 5‐HT3 antagonists on 5‐hydroxytryptamine‐evoked release of calcitonin gene‐related peptide in the guinea‐pig heart

“…Previous work has indicated that 5-HT activates the 'efferent' function of capsaicin-sensitive sensory neurones. Evidence for this has been obtained indirectly by showing that at least part of the inotropic response produced by 5-HT in the guinea-pig isolated atrium is abolished by capsaicin pretreatment in vitro (Bernoussi & Rioux, 1989). Our present data confirm these previous findings.…”

“…CGRP increases the force and rate of contraction in the guinea-pig isolated atrium and is considered the mediator of the inotropic response produced in this preparation by the activation of sensory nerves (Franco-Cereceda & Lundberg, 1985;Saito et al, 1986;Sigrist et al, 1986;Giuliani et al, 1989). Indirect evidence suggests that in the guinea-pig isolated atria, 5-HT can release CGRP from capsaicin-sensitive sensory nerves, since the inotropic response evoked by 5-HT is reduced by in vitro capsaicin desensitization (Bernoussi & Rioux, 1989). Recently, release of substance P by 5-HT has been shown from dorsal root ganglion neurones in culture (Vedder & Otten, 1991).…”

Characterization of the 5‐hydroxytryptamine receptor mediating the positive inotropic response in guinea‐pig isolated left atria

“…Studies of the positive chronotropic effect of 5-HT in the guinea-pig have suggested that the response is not mediated by P-adrenoceptors, 5-HTI-like, 5-HT2 or 5-HT3 receptors (Walter et al, 1984;Dhasmana et al, 1988;Eglen & Whiting, 1989) but have failed to identify clearly the receptor involved. There is evidence to suggest that the 5-HT-induced positive inotropic response in guinea-pig atria is due to the release of calcitonin gene-related peptide (Bernoussi & Rioux, 1989;Tramontana et al, 1993) and that this effect is due to the stimulation of 5-HT3 receptors (Tramontana et al, 1993 …”

Inhibition of excitatory non‐adrenergic non‐cholinergic bronchoconstriction in guinea‐pig airways in vitro by activation of an atypical 5‐HT receptor

“…Functionally, 5-HT has been shown both to stimulate and inhibit C-fibres to modulate efferent release of neuropeptides. In guinea-pig isolated atria (Bernoussi & Rioux, 1989) 5-HT3 receptors stimulate efferent neuropeptide release (Tramontana et al, 1993); however, in the rat and guinea-pig dura mater 5-HT receptor activation inhibits plasma extravasation indicating an inhibition of extracranial perivascular sensory fibres via 5-HTIB and 5-HTID receptors, respectively (Buzzi & Moskowitz, 1990;Matsubara et al, 1991).…”