enalaprilat-anhydrous and Hypotension

We compared the efficacy of the combination of enalaprilat/labetalol with that of enalaprilat/nicardipine to prevent emergence postcraniotomy hypertension. A prospective, randomized open labeled clinical trial was designed to compare the incidence of breakthrough hypertension (systolic blood pressure [SBP] > 140 mm Hg) and adverse effects (hypotension, tachycardia, and bradycardia) between the two drug combinations. Secondarily, the effects of the drugs on SBP, mean blood pressure, and diastolic blood pressure were evaluated over the course of the study. Forty-two patients received enalaprilat 1.25 mg IV at dural closure followed by either multidose nicardipine 2 mg IV or labetalol 5 mg IV to maintain the SBP below 140 mm Hg. SBP was similarly controlled in both groups. There was a marginally smaller incidence of failures and adverse effects with labetalol. Blood pressure profiles were similar for both groups.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adult; Aged; Analysis of Variance; Anesthesia Recovery Period; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Bradycardia; Brain Neoplasms; Calcium Channel Blockers; Chi-Square Distribution; Craniotomy; Enalaprilat; Female; Humans; Hypertension; Hypotension; Incidence; Labetalol; Male; Middle Aged; Nicardipine; Prospective Studies; Tachycardia; Treatment Outcome

The acute hypotensive response to oral and parenteral enalapril (E) and lisinopril (LI) was assessed in 24 patients with chronic congestive heart failure in two open, randomized, balanced, crossover studies. In the E study, 12 patients received each of three treatments: a single oral dose of 10 mg E, a single intravenous bolus of 5 mg E, and a single intravenous bolus of 5 mg enalaprilat (ET). In the LI study, 12 patients received each of two treatments: a single oral dose of 10 mg LI and a single intravenous bolus of 5 mg LI. Intraarterial blood pressure was measured continuously. Significant decreases from baseline in mean arterial pressure (MAP) were observed in all cases, starting at 15 min. The maximal hypotensive effect (MAP; mean +/- SD) was greatest and the nadir earliest for intravenous ET (-30 +/- 7 mm Hg at 75 min) compared with oral E (-25 +/- 10 mm Hg at 210 min) and intravenous E (-19 +/- 10 mm Hg at 195 min). Oral E and intravenous E had similar onsets of action. The maximal reduction following oral LI (-19 +/- 13 mm Hg at 210 min) was similar to oral E and intravenous E. The effect of intravenous LI (-25 +/- 9 mm Hg at 105 min) was similar to that of intravenous ET. Among the parenteral treatments, E produced the most gradual and least pronounced reduction in blood pressure, and may be best suited for use in the acute situation to minimize the risk of abrupt hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Aged; Blood Pressure; Chronic Disease; Enalapril; Enalaprilat; Female; Heart Failure; Humans; Hypotension; Injections, Intravenous; Lisinopril; Male; Middle Aged

Infusion of the angiotensin-converting enzyme inhibitor enalaprilat into fetal sheep caused a profound arterial hypotension within days. Five fetal lambs were infused with enalaprilat for 8 days starting at day 128 of gestation. Total accumulated dose was 0.30 ± 0.11 mg/kg. Arterial pressure decreased from 43.6 to 25.6 mmHg; venous pressure did not change. Biventricular output was not statistically significantly changed; placental blood flow decreased almost in proportion to the decrease in pressure but the increase in somatic flow was not statistically significant. There were no significant changes in pressure 30 min after the initial 50-μg loading dose of enalaprilat. However, the arterial pressure responses to test doses of ANG I were largely abolished. After 1 day, however, there was a significant decrease in somatic vascular resistance, which became stronger with time, but almost no decrease in the placental resistance. We conclude that the fetal somatic circulation exhibits a slow but strong decrease in resistance but that the response to hypotension is weak or absent in the fetal placenta, possibly because it is already fully relaxed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autopsy; Blood Pressure; Enalaprilat; Female; Fetus; Hypotension; Placenta; Placental Circulation; Pregnancy; Sheep; Vascular Resistance

Individuals with tetraplegia have impaired central control of sympathetic vascular modulation and blood pressure (BP); how this impairment affects cerebral blood flow (CBF) is unclear.. To determine if persons with tetraplegia maintain CBF similarly to able-bodied controls after a hypotensive challenge.. Seven individuals with chronic tetraplegia and seven age-matched, non-SCI control subjects underwent a hypotensive challenge consisting of angiotensin-converting enzyme (ACE) inhibition (1.25 mg enalaprilat) and 45 degrees head-up tilt (HUT). Heart rate (HR), low frequency systolic BP variability (LFsbp), brachial mean arterial pressure (MAP) and middle cerebral artery CBF were measured before and after the challenge. Group differences for the baseline (BL) to post-challenge response were determined by repeated measures ANOVA.. HR did not differ between the groups in response to the hypotensive challenge. LFsbp response was significantly reduced in the tetra compared to the control group (-38 +/- 51 vs. 72 +/- 93%, respectively). MAP did not differ between the groups at BL but was significantly lower in the tetra compared to the control group post-challenge (55 +/- 13 vs. 71 +/- 9 mmHg, respectively); the percent change in MAP was significantly greater in the tetra than in the control group (-29 +/- 14.1 vs. -13 +/- 9%, respectively). However, CBF did not differ between the groups at baseline or post-challenge; the percent change in CBF post-challenge was not different between the tetra and control groups (-29 +/- 13.2 vs. -23 +/- 10.3%, respectively).. Despite impaired sympathetic vasomotor and BP control, CBF in persons with tetraplegia was comparable to that of control subjects during a hypotensive challenge.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Cerebrovascular Circulation; Enalaprilat; Female; Hemodynamics; Humans; Hypotension; Male; Middle Aged; Quadriplegia; Tilt-Table Test

Resuscitative interventions that improve mesenteric perfusion without causing instability in systemic arterial pressures may be helpful for improving trauma patient outcomes. Blocking angiotensin II formation with enalaprilat may be such an intervention. Two questions were addressed in this two-part study investigating resuscitation from hemorrhagic shock in dogs: Can systemic arterial pressures be maintained while administering a constant rate infusion of enalaprilat during resuscitation, and can enalaprilat improve cardiovascular status during resuscitation? Animals were hemorrhaged to a mean arterial pressure (MAP) of 40 to 45 mmHg for 30 min and then 30 to 35 mmHg for 30 min. Group I (n = 5) was resuscitated to a MAP 60 to 65 mmHg with enalaprilat (0.02 mg/kg/h). Group II was resuscitated to a MAP 40 to 45 mmHg with (n = 5) or without (n = 5) enalaprilat. Resuscitation in both groups consisted of intermittent intravenous lactated Ringer's solution (60 mL/kg/h) to reach and maintain the target MAPs. Systemic arterial pressures were unaffected by enalaprilat during resuscitation in Group I, allowing us to proceed to the second study. During severely hypotensive resuscitation (Group II), systemic arterial pressures were also stable and enalaprilat administration was associated with increases (P < or = 0.02) in cardiac index (+1.2 L/min/m2), stroke volume index (SVI) (+14.5 mL/m2), superior mesenteric artery flow (+80 mL/min), stroke work (+561 mmHg/mL/m2), and left ventricular power output (+55.7 mmHg/L/min/m2). Corresponding increases were not observed in controls. We conclude that administration of a constant rate infusion of enalaprilat during resuscitation can be accomplished without causing a hypotensive crisis. Since enalaprilat significantly improved cardiovascular status including mesenteric perfusion even during intentional hypotension, it has potential value for improving the treatment of trauma patients.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular System; Dogs; Enalaprilat; Hypotension; Regional Blood Flow; Resuscitation; Shock, Hemorrhagic; Splanchnic Circulation

Severe hypotensive reactions have been described after the transfusion of platelets or red cells through negatively-charged bedside white cell-reduction filters. The possibility of a role for bradykinin (BK) in the genesis of these reactions has been raised.. To understand if an anomaly of BK metabolism is associated with these reactions, the metabolism of BK and des-Arg9-BK was studied in the sera of four patients who presented with a severe hypotensive transfusion reaction. Tests were performed in the absence and the presence of complete in vitro inhibition of angiotensin-converting enzyme (ACE) activity by enalaprilat.. In the presence of ACE inhibition (enalaprilat), the half-life (t1/2) of BK measured in the sera of patients who presented with a severe hypotensive transfusion reaction (361 +/- 90 sec) was not significantly different from that measured in the sera of normal controls (249 +/- 16 sec). In the presence of ACE inhibition (enalaprilat), the t1/2 of des-Arg9-BK was significantly greater in patients who presented with a severe hypotensive transfusion reaction (1549 +/- 319 sec) than in normal controls (661 +/- 38 sec) (p < 0.001).. A metabolic anomaly mainly affecting the degradation of des-Arg9-BK could be responsible for its accumulation in vivo. Des-Arg9-BK could be responsible, at least in part, for severe hypotensive transfusion reactions.

Topics: Adolescent; Aged; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Enalaprilat; Erythrocyte Transfusion; Female; Half-Life; Humans; Hypotension; Male; Middle Aged; Peptidyl-Dipeptidase A; Platelet Transfusion

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.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Baroreflex; Blood Pressure; Bradykinin; Calcium Channel Blockers; Dose-Response Relationship, Drug; Enalaprilat; Heart Rate; Hypotension; Losartan; Nasopharynx; omega-Conotoxin GVIA; Peptides; Pressoreceptors; Propranolol; Rabbits; Renin-Angiotensin System

The purpose of the study was to evalute the impact of the renin-angiotensin-aldosterone (RAA) system on blood pressure (BP) response in patients with hypertensive emergencies and urgencies treated with intravenous enalaprilat. Thirty-five patients with a systolic BP (SBP) >210 mm Hg and/or diastolic BP (DBP) >110 mm Hg received 5 mg enalaprilat intravenously. The extent of systolic and DBP reduction was correlated with pretreatment concentrations of angiotensin II (ANGII) (SBP: r = -0.47; P = 0.006; DBP: r = -0.55; P = 0.001) and plasma renin activity (PRA) (SBP: r = -0.49; P = 0.003; DBP: r = 0.48; P = 0.007). Non-responders to enalaprilat exhibited significant lower pretreatment levels of PRA, angiotensin-converting enzyme (ACE) and ANG II compared to responders (PRA: 5.5 +/- 3.7 vs 1.1 +/- 2.2 ng/ml/h, P < 0.001; ACE: 12.8 +/- 3.5 vs 8.2 +/- 4.8 U/l, P = 0.003; ANG 11:8.7 +/- 6.2 vs 5.0 +/- 3.8 pg/ml, P = 0.04). In patients with severe hypotension following application of enalaprilat ANG II concentrations were significantly higher compared to patients with mean arterial BP reduction <25% (12.3 +/- 6.7 vs 5.6 +/- 4.0 pg/ml,P = 0.013). These data indicate that PRA and ANG II are the major determinants for BP response to enalaprilat. This relation between BP response and RAA system activity have important clinical implications for the treatment of patients with severe hypertension. Primary therapeutic failure indicates that the RAA system contributes very little to the hypertensive status of the patient. Thus, repetitive application on an ACE inhibitor in primary responders is clinically unhelpful and may result in an unnecessary delay of an effective BP reduction. In contrast, high ANG II concentrations are associated with a considerable risk for severe hypotension after enolanalaprilat application. Therefore, the status of the RAA system determines the efficacy as well as the safety of ACE inhibitor treatment in patients with severe hypertension.

Topics: Adult; Aged; Aged, 80 and over; Aldosterone; Blood Pressure; Emergencies; Enalaprilat; Female; Humans; Hypertension; Hypotension; Injections, Intravenous; Male; Middle Aged; Peptidyl-Dipeptidase A; Prospective Studies; Renin; Renin-Angiotensin System; Treatment Failure

We have previously shown that increasing the renal perfusion pressure by using an extracorporeal circuit in anesthetized rabbits resulted in a progressive fall in systemic arterial pressure. Prior ablation of the renal medulla with 2-bromoethylamine abolished the hypotensive response. In the present study, we investigated whether vasodilator prostanoids or platelet activating factor (PAF), both known to be produced in the renal medulla, were responsible for the hypotensive response to increased renal perfusion pressure. Anesthetized animals were treated with indomethacin (5 mg/kg + 0.5 mg/kg per hour), the PAF antagonist WEB 2086 (0.5 mg/kg + 0.5 mg/kg per hour), enalaprilat (2 mg/kg + 10 micrograms/kg per hour), or all three agents. In response to acute elevation of renal artery pressure to 170 mm Hg, systemic mean arterial pressure fell at 0.76 +/- 0.17, 0.59 +/- 0.08, and 0.76 +/- 0.17 mm Hg/min in the indomethacin, WEB 2086, and enalapril groups, respectively. These responses were not significantly different from the rate of 1.00 +/- 0.21 mm Hg/min in a control group that received vehicle infusion alone. Renal blood flow and the diuretic and natriuretic responses were also similar in all groups. Thus, increased renal perfusion pressure resulted in a progressive fall in systemic arterial pressure that was not mediated by PAF, prostaglandins, or suppression of renin release and angiotensin II production.

Topics: Animals; Azepines; Blood Pressure; Diuresis; Enalaprilat; Hemodynamics; Hypotension; Indomethacin; Natriuresis; Perfusion; Platelet Activating Factor; Pressure; Rabbits; Renal Circulation; Triazoles

Topics: Adult; Enalaprilat; Female; Humans; Hypotension; Injections, Intravenous; Intraoperative Complications; Renal Artery Obstruction; Time Factors

1. To evaluate the effects of angiotensin-converting enzyme (ACE) inhibition on sympathetic nerve activity, renal and total norepinephrine (NE) spillover rates were examined under control conditions and during enalaprilat infusion at rest and in response to sodium nitroprusside (SNP)-induced hypotension. 2. Resting renal and total NE spillover rate during enalaprilat infusion were similar to control values. 3. During SNP infusion at 10 micrograms/kg per min, renal NE spillover rate increased by 26% in enalaprilat-treated group and by 39% in controls, in response to falls in mean arterial pressure (MAP) of 25 and 19% respectively. 4. During sympathetic stimulation induced by SNP, total NE spillover rate was significantly increased in both groups, but the 50% (s.e.m. = 12) increase in the enalaprilat-treated group was less (P less than 0.05) than the 97% (s.e.m. = 16) change observed in controls. 5. Enalaprilat treatment resulted in a higher renal to total NE spillover ratio (P less than 0.05). The ratio fell in parallel in both groups during SNP-induced hypotension. 6. This study indicates that the sympathetic nervous system interacts dynamically with the renin-angiotensin system during hypotensive stimulation but this occurs predominantly at sites other than the kidney.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalaprilat; Heart Rate; Hypotension; Kidney; Nitroprusside; Norepinephrine; Rabbits; Sympathetic Nervous System

The effects of enalaprilat on the renin-angiotensin system and sympathetic nervous system during sodium nitroprusside (SNP)-induced hypotension and halothane anesthesia were studied in three groups of New Zealand white rabbits. Two groups of rabbits (E and EH) were treated with an infusion of enalaprilat at 3.5 micrograms/kg/min i.v. One enalaprilat-treated group (EH) and the third, untreated group (H) received SNP to induce hypotension. In these two groups, the mean arterial blood pressure (MAP) was reduced by 40% for 150 min. Group E did not undergo SNP-induced hypotension and served to document the effects of enalaprilat alone during the 150-min study period. Arterial blood samples for norepinephrine (NE), epinephrine (EPI), and plasma renin activity (PRA) were drawn prior to and during hypotension, and during the recovery period. The SNP dose required to maintain the hypotension was continuously recorded. NE, EPI, and PRA all increased in group H, indicating activation of both the renin-angiotensin system and the sympathetic system during hypotension. The amount of SNP required by group H to maintain a 40% reduction in MAP correlated with circulating NE levels (p less than 0.001) and not PRA. In group EH, PRA levels rose sharply and remained elevated. Plasma NE and EPI levels increased slightly with a decline in the SNP dose requirement. Group E demonstrated a rise in PRA levels, accompanied by unchanged NE and EPI levels and MAP during the study period.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anesthesia; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Enalaprilat; Epinephrine; Heart Rate; Hypotension; Male; Nitroprusside; Norepinephrine; Rabbits; Renin; Renin-Angiotensin System; Sympathetic Nervous System; Vascular Resistance

Intravenous enalaprilic acid (2.5 mg) was given to 11 patients with stable cardiac failure (NYHA functional class II-IV). Reductions in mean right atrial, pulmonary artery and pulmonary capillary wedge pressure of 25%, 18% and 30% respectively (P less than 0.01), were observed. Cardiac output rose by 13% (NS) and mean blood pressure fell by 20% (P less than 0.01) with a decrease in systemic vascular resistance of 24% (P less than 0.01). Heart rate was unaltered. The haemodynamic effects correlated with control plasma renin activity (r = 0.78, P less than 0.01). Marked hypotension occurred in several subjects but no other side-effects were noted. The rapid onset of action and mixed venous and arteriolar dilating activity of intravenous enalaprilic acid may be an advantage in some clinical situations where parenteral vasodilating therapy is required.

Topics: Aged; Enalapril; Enalaprilat; Female; Heart Failure; Heart Ventricles; Hemodynamics; Humans; Hypotension; Injections, Intravenous; Male; Middle Aged; Pilot Projects; Vasodilator Agents