Severe hypotension with bradycardia during renin inhibition with H142 in sodium deplete man.
A healthy sodium depleted subject received, on separate occasions, intravenous infusions of the renin inhibitor H142 at doses of 1.0, 2.5 and 5.0 mg/kg/h. The two lower doses of H142 produced dose-dependent reduction of both systolic and diastolic pressure associated with an increase in heart rate. The highest dose of H142 produced profound hypotension and bradycardia, both during drug infusion in the supine position, and again later, on return to standing, after H142 was stopped. An increase in plasma adrenaline, but not noradrenaline, was associated with this dose of H142. The subject differed from others studied in a randomised controlled trial of H142 at doses of 1.0 and 2.5 mg/kg/h in having the highest basal circulating plasma angiotensin II concentrations during sodium depletion, and in developing a clear reduction in systolic as well as diastolic pressure. The profound hypotensive response at the highest dose of H142 may represent an idiosyncratic response to the drug. Alternatively, and perhaps more likely, it may be a result of a reduction of angiotensin II concentrations in plasma or other tissues, with loss of arteriolar constriction, loss of facilitation of sympathetic activity, withdrawal of vagal inhibition, dilatation of capacitance vessels, or a combination of these events. Subsequent activation of the Bezold-Jarisch reflex is a possibility. The late fall in blood pressure, after H142 was stopped, and when circulating plasma angiotensin II concentrations had returned to normal, suggests that this response may have involved an effect of the inhibitor on renin in a site other than blood.
Webb
D J
DJ
Medical Research Council Blood Pressure Unit, Western Infirmary, Glasgow, UK.
Manhem
P J
PJ
Leckie
B J
BJ
Lever
A J
AJ
Morton
J J
JJ
Robertson
J I
JI
Semple
P F
PF
Szelke
M
M
D000328:Adult; D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000808:Angiotensinogen / Q000009:adverse effects; D001919:Bradycardia / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007022:Hypotension / Q000139:chemically induced*; D007262:Infusions, Intravenous; D008297:Male; D009638:Norepinephrine / Q000097:blood; D016032:Randomized Controlled Trials as Topic; D012083:Renin / Q000097:blood; D012964:Sodium / Q000172:deficiency*; D000092502:Renin Inhibitors
D000803:Angiotensin I; D000804:Angiotensin II; D000808:Angiotensinogen; D004837:Epinephrine; D009638:Norepinephrine; D012083:Renin; D012964:Sodium; D000092502:Renin Inhibitors; C039583:H 142