Endogenous Angiotensin II and Bradykinin Delay and Attenuate the Hypotension After N-Type Calcium Channel Blockade in Conscious Rabbits

Abstract

The effects of N-type calcium channel inhibition with omega-conotoxin GVIA (omega-CTX) on cardiovascular parameters and vagally mediated autonomic reflexes and the role of the renin-angiotensin system were assessed in conscious rabbits. Omega-CTX (10 microg/kg, i.v.) resulted in hypotension, tachycardia, and attenuation of the sympathetic and vagal components of the baroreceptor-heart rate reflex (baroreflex). In the control group (no pretreatment), the peak decrease in mean arterial pressure (MAP) of 13 +/- 3 mm Hg from 72 +/- 2 mm Hg occurred after 33 +/- 3 min, with a corresponding tachycardia of 80 +/- 20 beats/min (n = 6). The tachycardia was due to vagal withdrawal, as a similar increase in heart rate (84 +/- 8 beats/min) after omega-CTX was observed after pretreatment with the beta-adrenoceptor antagonist, propranolol (n = 6). Angiotensin-converting enzyme (ACE) inhibition with enalaprilat revealed a larger, more rapid decrease in MAP in response to omega-CTX (-19 +/- 4 mm Hg from 65 +/- 1 mm Hg after 18 +/- 2 min; n = 6) compared with the control group. Similar larger decreases in MAP were also observed in the presence of the AT1-receptor antagonist, losartan, or the bradykinin B2 receptor antagonist, HOE-140 (n = 5-6). Pretreatment with enalaprilat, losartan, or HOE-140 caused a 50% decrease in the reflex tachycardia after omega-CTX compared with that observed in the control group, and omega-CTX caused a greater attenuation of the vagal component of the baroreflex and a decrease in the bradycardia evoked by the Bezold-Jarisch-like reflex. Also, there was a significant decrease in the bradycardia induced by the nasopharyngeal reflex after omega-CTX in the presence of ACE inhibition and HOE-140. Thus in the conscious rabbit, angiotensin II and bradykinin have a role in attenuating and slowing the hypotensive effect of N-type calcium channel inhibition. Vagolytic effects of omega-CTX on the baroreflex are augmented, and on other vagal reflexes are unmasked, via inhibition of the renin-angiotensin system. The complexity and mechanism of the interaction between N-type calcium channels and the renin-angiotensin system remain to be elucidated.

Cardiovascular and autonomic effects of ω‐conotoxins MVIIA and CVID in conscious rabbits and isolated tissue assays

“…Wright et al (Pruneau & Angus, 1990;Whorlow et al, 1998). The hypotension is due to a sympatholytic action which results in peripheral vasodilatation (Pruneau & Angus, 1990;.…”

“…The hypotension is due to a sympatholytic action which results in peripheral vasodilatation (Pruneau & Angus, 1990;. The tachycardia is due to withdrawal of cardiac vagal eerent activity rather than a direct eect on the heart as the tachycardia still occurs in the presence of the b-adrenoceptor antagonist, propranolol (Whorlow et al, 1998). As GVIA and MVIIA both target the N-type calcium channel, it is not surprising that the peptides cause similar changes in cardiovascular parameters.…”

Angiotensin receptor antagonists and vaso-vagal attacks due to sensitisation of the Bezold-Jarisch reflex?

“…Angiotensin II may exert its effect via a central mechanism, which serves to ameliorate the vagallyinduced bradycardia and withdrawal of sympathetic tone consequent upon activation of the afferent pathways of this reflex. 3 The Bezold-Jarisch reflex is initiated by stimulation of chemosensitive and mechanosensitive receptors in the wall of the left ventricle: receptors which respond to a variety of stimuli including reduction in central blood volume, coronary occlusion, hypoxia and certain chemical substances. 3 Afferent pathways consist of unmyelinated or C-fibre afferents which are carried by the vagus nerve to cardiovascular regulatory nuclei in the brain stem (nucleus tractus solitarius, dorsal motor nucleus of the vagus).…”

“…3 The Bezold-Jarisch reflex is initiated by stimulation of chemosensitive and mechanosensitive receptors in the wall of the left ventricle: receptors which respond to a variety of stimuli including reduction in central blood volume, coronary occlusion, hypoxia and certain chemical substances. 3 Afferent pathways consist of unmyelinated or C-fibre afferents which are carried by the vagus nerve to cardiovascular regulatory nuclei in the brain stem (nucleus tractus solitarius, dorsal motor nucleus of the vagus). The efferent pathways involve vagally-induced bradycardia and withdrawal of sympathetic tone.…”

“…By way of contrast, angiotensin II may attenuate the hypotensive and vagal components of the BezoldJarisch reflex. 3 Profound hypo-tension and bradycardia has been reported in man with infusions of renin inhibitors and attributed to an exaggeration of the Bezold-Jarisch reflex. 4 A similar mechanism may contribute to the hypotensive response to the first dose of an angiotensin converting enzyme (ACE) inhibitor when used in the treatment of heart failure.…”