Endogenous angiotensin II and bradykinin delay and attenuate the hypotension after N-type calcium channel blockade in conscious rabbits.
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.
Whorlow
S L
SL
Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
Angus
J A
JA
Wright
C E
CE
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000804:Angiotensin II / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D017704:Baroreflex / Q000187:drug effects / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015773:Enalaprilat / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology; D009305:Nasopharynx / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology*; D011311:Pressoreceptors / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D011817:Rabbits; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D020866:omega-Conotoxin GVIA
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D010455:Peptides; D000804:Angiotensin II; C065679:icatibant; D020866:omega-Conotoxin GVIA; D011433:Propranolol; D015773:Enalaprilat; D019808:Losartan; D001920:Bradykinin