Unlike its tachycardic responses (see above), the vasopressor responses to (
S)-isometheptene: (i) were reproducible as they remained without significant changes after saline (Fig.
3a); and (ii) are mainly mediated by α
1-adrenoceptors as these responses were markedly blocked after prazosin (Fig.
3b), but not (
P > 0.05) after rauwolscine (Fig.
3c) or propranolol (Fig.
3e) in doses high enough to completely block their respective receptors mediating cardiovascular responses [
3]. Consistent with this suggestion, the combination prazosin plus rauwolscine produced a blockade (Fig.
3d) that did not significantly differ (
P > 0.05) from that produced by prazosin alone (Fig.
3b). Furthermore, the fact that reserpine markedly attenuated (but did not abolish) these vasopressor responses (Fig.
4c), and that the subsequent administration of prazosin practically abolished these responses (Fig.
4d) suggests the involvement of a mixed effect of (
S)-isometheptene, namely: (i) a major indirect (tyramine-like) mechanism; and (ii) a minor direct sympathomimetic mechanism mediated by stimulation of α
1-adrenoceptors. In keeping with these findings, and as implied by other studies at the neuro-vascular junction [
3,
22,
23]: (i) neuronally-displaced noradrenaline (i.e. by a tyramine-like action) primarily stimulates intrasynaptic α
1-adrenoceptors; (ii) i.v. bolus of exogenous noradrenaline mainly activates extrasynaptic α
2-adrenoceptors; and (iii) systemic vascular resistance (represented by diastolic blood pressure) is mainly modulated by α
1-adrenoceptors.
Interestingly, the fact that (
R)-isometheptene-induced tachycardic (Fig.
5a) and (weak) vasopressor (Fig.
5b) responses were abolished by reserpine suggests the exclusive role of a tyramine-like action in both responses (with no role of direct sympathomimetic actions). This implies that (
R)-isometheptene would produce stoichiometric displacement of noradrenaline from the sympathetic neurons innervating the heart and resistance blood vessels, resulting in tachycardic and vasopressor responses mediated by stimulation of cardiac β- and vascular α
1-adrenoceptors [
3,
22,
23].