The effect of enalapril (MK421), an angiotensin converting enzyme inhibitor, on the conscious pregnant ewe and her foetus

Abstract

1 The effects ofenalapril, an angiotensin converting enzyme (ACE) inhibitor, on maternal and foetal blood pressure, heart rate and components ofthe renin-angiotensin-aldosterone system were studied in 9 chronically-cannulated pregnant ewes and their foetuses.2 Six ewes received 1 mg kg-' enalapril i.v. while 3 were given 2mg kg-'.Although the initial fall in blood pressure was slightly greater in the higher dose group, there was substantial overlap of data. The pressor response to angiotensin I, assessing ACE activity, was abolished within 10 min of administration, and did not recover during 3 h of observation. Maternal systolic and diastolic pressures reached a nadir 90min after administration (P<0.001, P<0.002 respectively). The maximum tachycardia was seen at 60 min (P<0.05). 3 The foetuses of the ewes given 1 mg kg-enalapril showed no change in systolic or diastolic blood pressure or heart rate. Those of the ewes given the higher dose showed late-onset hypotension, coincident with the lowest maternal blood pressures. 4 Maternal plasma renin concentration (PRC) had risen significantly by 30 min (P < 0.02), reaching a maximum at approximately 90 min. Maternal plasma angiotensin II and aldosterone concentrations both fell initially (P <0.05) but were almost at basal levels by the end of the experiment. 5 Foetal plasma renin, angiotensin II and aldosterone concentrations were unchanged throughout the experiment. 6 Peak values of enaprilic acid, the active principle, were recorded in maternal plasma 65-90 min after administration of I mg kg-', and 25-30 min after the administration of 2mg kg-'. A trace amount of the active principle was recorded in the foetal plasma of one lamb, whose mother had been given the higher dose. None was recorded in the plasma from three other lambs. 7 Maternal plasma ACE concentrations fell by an average of 84%; in 4 of the 6 ewes in which concentrations were measured they were undetectable after treatment. Foetal plasma ACE concentrations were unchanged throughout. 8 Enalapril at I mg kg-' thus exerts a depressor effect on the pregnant ewe which is probably related to its blockade of the renin-angiotensin system. Both direct measurement of the drug and foetal observation suggest that it does not cross the sheep placenta at this dose. This is consistent with its failure to cross the blood-brain barrier. Foetal effects were noted at 2 mg kg-', and there was an unexpected foetal death in this group.

Distinct effects of intravascular and extravascular angiotensin II on cerebrovascular circulation of newborn pigs

“…The action of enalapril to convert constriction to dilation must be on the endothelium because enalapril does not cross the BBB. 36,37 That the endothelium generates the dilator signals was confirmed by converting the vasodilator response to intravascular Ang II to constriction by selective endothelial injury. Efficient endothelial injury in the pial arterioles under the cranial window was confirmed by total loss of dilation to the endothelial-dependent dilator, bradykinin, 20 but no effect on the dilation to endothelial-independent dilator, isoproterenol, 19 that dilates via activating of vascular smooth muscle β -adrenergic receptors.…”

“…The constriction to topical AngII seen in enalapril pretreated piglets was reversed to dilation with topical losartan, a response identical to that seen in piglets not pretreated with the ACE inhibitor. The action of enalapril to convert constriction to dilation must be on the endothelium because enalapril does not cross the BBB (11,34). That the endothelium generates the dilator signals was confirmed by converting the vasodilator response to intravascular Ang II to constriction by selective endothelial injury.…”