Blockade by nifedipine of responses to intravenous bolus injection or infusion of α₁‐and α₂‐adrenoceptor agonists in the pithed rat

Abstract

1 Nifedipine was tested against pressor responses in the pithed rat to ten agonists with varying selectivity for a,-and a2-adrenoceptors, injected as a bolus or infused intravenously: i.e. amidephrine, azepexole, cirazoline, indanidine, M7, methoxamine, noradrenaline (NA), oxymetazoline, phenylephrine and xylazine. Nifedipine, administered before the agonists, inhibited responses initiated by all agonists, usually for both the bolus and infusion responses. 2 With a bolus, blockade was significantly greater against the more prolonged, secondary components of the pressor responses. This demonstrates that calcium-entry occurs during the secondary component of the a-adrenoceptor-mediated response and can be initiated by either a,-or 2-adrenoceptor subtypes.3 The time courses of responses to infusion varied. Selective a,-adrenoceptor agonists, with the exception of indanidine, did not produce a stable pressor response during the 20 min infusion time but M2-adrenoceptor agonists did. Nifedipine reduced responses to infusion with no preference for a,-or a2-agonists. Phenylephrine and NA produced pressor responses which reached a peak and then declined during the remainder of the infusion. 4 The levels ofNA in arterial and venous plasma were measured by h.p.l.c. during the infusion ofNA. Arterial NA levels rose throughout the infusion whereas venous levels remained relatively unaffected. The absolute levels of plasma NA suggest that a large proportion of intravenously administered NA is removed in the pulmonary circulation and the remainder is removed in the systemic circulation with negligible recirculation. 5 The consequences of these results, for assessment of the mechanisms of action of adrenoceptor agonists and calcium entry blockers, are discussed.

Pressor effects of the α2‐adrenoceptor agonist B‐HT 933 in anaesthetized and haemorrhagic rats: comparison with the haemodynamic effects of amidephrine

“…It has been suggested previously that 2-rather than a1-adrenoceptor activation is more effective in maintaining the compensatory vasoconstriction to haemorrhage over long periods of time (Bond & Johnson, 1985). This theory is in accord with the observation that, in pithed rats, the pressor responses to infusions of a2-adrenoceptor agonists are maintained for longer than those to infusions of x1-adrenoceptor agonists (McGrath & O'Brien, 1987). It is interesting to note, however, that in the present study, haemorrhage potentiated the pressor response to the amidephrine infusion, whilst it depressed the response to the infusion of B-HT 933.…”

“…The pressor response to amidephrine, as with other ao-adrenoceptor agonists is biphasic (McGrath & O'Brien, 1987), with an initial peak pressor phase followed by a lower, though more sustained, secondary pressor response during which the microspheres were injected. For the normotensive and haemorrhagic, hypotensive saline control groups, an initial bolus of 0.2ml saline was followed by a second 0.2ml bolus and the microsphere injection was given during an 0.1 ml min1 infusion of saline (these are referred to as the saline/saline and haemorrhage/saline groups).…”

Selective blockade by nifedipine of ‘purinergic’ rather than adrenergic nerve‐mediated vasopressor responses in the pithed rat

“…a-Adrenoceptor-mediated pressor responses to circulating agonists are partly affected by Ca2+ antagonists such as nifedipine (Timmermans et al, 1983), but this varies with the agonist and method of administration and is partly attributable to the duration of the response (McGrath & O'Brien, 1987). With sympathetic nerve-mediated responses in different preparations, any variability in blockade is likely to be at least partly attributable both to variations in the contributions from purinergic and adrenergic transmission and to the duration of the stimulus and/or the response.…”

“…pressor responses to exogenous noradrenaline (NA) or other agonists: the initial, early, rapid responses are resistant but the late components or responses to infusion are blocked McGrath & O'Brien, 1987).…”

A comparison of the effects of angiotensin II and Bay K 8644 on responses to noradrenaline mediated via postjunctional α1‐and α2‐adrenoceptors in rabbit isolated blood vessels

“…Since their discovery it has been suggested that a number of factors can differentially modulate responses to a-adrenoceptor agonists, such as blood pH and blood gases (McGrath et al, 1982;Grant et al, 1985), calcium channel blockers (CCBs) or angiotensin converting enzyme (ACE) inhibitors Timmermans et al, 1982). It was initially suggested that x2-adrenoceptor-mediated responses were more susceptible to the action of CCBs and ACE inhibitors than were equivalent sized al-adrenoceptor-mediated responses de Jonge et al, 1982;Timmermans et al, 1982), although there is now evidence that both CCBs and ACE inhibitors preferentially inhibit the late phase of the pressor response to a bolus injection of an agonist, irrespective of subtype specificity McGrath & O'Brien, 1987). The study of modulatory influences on responses mediated via different adrenoceptor subtypes in models such as the pithed rat is limited, however, by a number of factors.…”