ACE Inhibitors

Summary

drug class: Angiotensin-Converting Enzyme (ACE) Inhibitors

type of drug: Antihypertensive

Note: See also: Captopril, Analapril.

trade names: Accupril®, Altace®, Capoten®, Lotensin®, Monoril®, Prinvil®, Vasotec®, Zestril®, etc.

used to treat: High blood pressure, some forms of heart failure, and, occasionally, early diabetic kidney disease to help prevent progression to frank nephropathy; often in conjunction with a diuretic and/or digoxin.

mechanism: Angiotensin-Converting Enzyme (ACE) is an enzyme in the body which is important for the formation of angiotensin II. The function of angiotensin II is to cause constriction of arteries, thereby elevating blood pressure. ACE inhibitors lower blood pressure by inhibiting the formation of angiotensin II, thus relaxing the arteries. Relaxing the arteries not only lowers blood pressure, but also improves the pumping efficiency of a failing heart and improves cardiac output in patients with heart failure.

overview of interactions:
• nutrient affecting drug performance: Dietary Fat

• nutrient affected by drug: Potassium

• herb affecting drug performance and toxicity: Capsicum (Cayenne)

• herb affecting drug performance and toxicity: Salix nigra, Salix alba (Willow)

• herbal concerns: Hypertensive and Tachycardic Herbs

• herbal concerns: Hypotensive and Bradycardic Herbs

• herbal concerns: Vasoconstrictor Herbs

related herbal research: Research into herbs with actions similar to pharmaceutical ACE inhibitors has found that several traditional medicines yielded promising results. While these ethnopharmacological studies do not deal with herbs commonly used in typical herbal prescribing in the U.S. or Europe they do indicate that plant-based medicines have a significant past and a potentially strong future in treating conditions such as currently treated by drugs such as ACE inhibitors.
(Adsersen A, Adsersen H. J Ethnopharmacol 1997 Nov;58(3):189-206 ; Nyman, U, Joshi, P, et al. J Ethnopharmacol 1998 Apr;60(3):247-263.)

Interactions

nutrient affecting drug performance: Dietary Fat

• mechanism: A high fat meal can lessen the absorption of Accupril.

nutrient affected by drug: Potassium

• mechanism: ACE inhibitors enhance potassium levels in the blood.

• nutritional concerns: Potassium supplements and even high-potassium foods, such as fruit, can lead to problematic interactions and should be avoided. A patient using ACE Inhibitors is advised to discuss these issues with their prescribing doctor, a pharmacist, or both.

herb affecting drug performance and toxicity: Capsicum
(Cayenne)

• mechanism: Capsicum has the ability to normalize both low and high blood pressure and is often used to equalize blood pressure, hence capsaicin may interfere with the blood-pressure regulating functions of ACE inhibitors. The production of 'substance P' by Cayenne has the known effect of dilating the arteries, thereby lowering blood pressure. Capsaicin may also aggravate cough due to ACE-inhibitor drugs according to studies using rats and humans.
(Yeo WW, et al. Br J Clin Pharmacol. 1995 Nov;40(5):423-429; Takahama K, et al. J Pharm Pharmacol. 1996 Oct;48(10):1027-1033; Damas J, et al. Naunyn Schmiedebergs Arch Pharmacol. 1996 Nov;354(5):662-669; Baluk P, et al. Br J Pharmacol. 1999 Jan;126(2):522-528.)

herb affecting drug performance and toxicity: Salix nigra, Salix alba (Willow)

• mechanism: Phenolic glycosides could theoretically potentiate the drug's action. However, no substantive research has confirmed this speculation.

See also: Hypertensive and Tachycardic Herbs

See also: Hypotensive and Bradycardic Herbs....

See also: Vasoconstrictor Herbs.


Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.



References

Adsersen, A, Adsersen, H. Plants from Reunion Island with alleged antihypertensive and diuretic effects--an experimental and ethnobotanical evaluation. J Ethnopharmacol 1997 Nov;58(3):189-206.
Abstract: Eighty species of vascular plants were collected on Reunion Island and tested for their ability to inhibit the angiotensin converting enzyme (ACE), which plays an important role in the regulation of blood pressure and diuresis. Of these species, 26 serve as antihypertensive remedies in traditional medicine, and 38 as diuretics-10 of the 64 species have both alleged antihypertensive and diuretic effects. Of the species with alleged antihypertensive or diuretic effect, 44% proved active. Of the species with no report of such effects, 31% proved active. 

Baluk P, Thurston G, Murphy TJ, Bunnett NW, McDonald DM. Neurogenic plasma leakage in mouse airways. Br J Pharmacol 1999 Jan;126(2):522-528.
Abstract: 1. This study sought to determine whether neurogenic inflammation occurs in the airways by examining the effects of capsaicin or substance P on microvascular plasma leakage in the trachea and lungs of male pathogen-free C57BL/6 mice. 2. Single bolus intravenous injections of capsaicin (0.5 and 1 micromol kg(-1), i.v.) or substance P (1, 10 and 37 nmol kg(-10, i.v.) failed to induce significant leakage in the trachea, assessed as extravasation of Evans blue dye, but did induce leakage in the urinary bladder and skin. 3. Pretreatment with captopril (2.5 mg kg(-1), i.v.), a selective inhibitor of angiotensin converting enzyme (ACE), either alone or in combination with phosphoramidon (2.5 mg kg(-1), i.v.), a selective inhibitor of neutral endopeptidase (NEP), increased baseline leakage of Evans blue in the absence of any exogenous inflammatory mediator. The increase was reversed by the bradykinin B2 receptor antagonist Hoe 140 (0.1 mg kg(-1), i.v.). 4. After pretreatment with phosphoramidon and captopril, capsaicin increased the Evans blue leakage above the baseline in the trachea, but not in the lung. This increase was reversed by the tachykinin (NK1) receptor antagonist SR 140333 (0.7 mg kg(-1), i.v.), but not by the NK2 receptor antagonist SR 48968 (1 mg kg(-1), i.v.). 5. Experiments using Monastral blue pigment as a tracer localized the leakage to postcapillary venules in the trachea and intrapulmonary bronchi, although the labelled vessels were less numerous in mice than in comparably treated rats. Blood vessels of the pulmonary circulation were not labelled. 6. We conclude that neurogenic inflammation can occur in airways of pathogen-free mice, but only after the inhibition of enzymes that normally degrade inflammatory peptides. Neurogenic inflammation does not involve the pulmonary microvasculature.

Damas J, Bourdon V, Liegeois JF, Simmons WH. Influence of several peptidase inhibitors on the pro-inflammatory effects of substance P, capsaicin and collagenase. Naunyn Schmiedebergs Arch Pharmacol. 1996 Nov;354(5):662-669.
Abstract: Injection of substance P (SP) in a rat hindpaw induced extravasation of 125I-labelled albumin in both hindpaws and salivation. Intravenous injection of SP dose-dependently increased vascular permeability. This latter effect was increased in rat paws by captopril, an inhibitor of angiotensin-converting enzyme (ACE), administered locally in combination with diprotin A, an inhibitor of an dipeptidyl(amino)peptidase IV (DAP IV) or phosphoramidon, an inhibitor of neutral endopeptidase (NEP). The increase in permeability induced by SP was inhibited by RP 67580, a NK-1-receptor antagonist. Intravenous injection of capsaicin induced labelled albumin extravasation in rat paws. This effect was increased by combination of captopril with diprotin A or phosphoramidon, but not by captopril associated with amastatin, an inhibitor of aminopeptidase M (AmM). It was suppressed by RP 67580. Injection of collagenase in rat paws triggered a swelling and a local plasma exudation. These responses were reduced by RP 67580 but not by RP 68651, its inactive enantiomer. They were increased by combination of captopril with diprotin A or phosphoramidon in normal rats. The potentiating effects of captopril and diprotin A were suppressed by RP 67580 in normal rats but did not develop in kininogen-deficient rats. The oedema induced by collagenase was also increased by lisinopril, another ACE inhibitor, administered locally in combination with apstatin, an inhibitor of aminopeptidase P (AmP). In rats pretreated by methysergide, collagenase-induced oedema was reduced and can be increased by captopril, by lisinopril, administered alone or by lisinopril associated with apstatin. It is concluded that SP is mainly inactivated in rat paws by ACE, DAP IV and NEP. In collagenase-induced oedema, a low amount of SP would be released from afferent nerve terminals by bradykinin formed in low amounts. Bradykinin is inactivated in rat paws by ACE and AmP. In collagenase-oedema, the pro-inflammatory effects of bradykinin are concealed by the effects of the other mediators.

Fox AJ, Lalloo UG, Belvisi MG, Bernareggi M, Chung KF, Barnes PJ. Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough. Nat Med 1996 Jul;2(7):814-817.
Abstract: Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease. This symptom is also frequently reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension, although the underlying mechanism is unknown. We have investigated the possibility that the inflammatory peptide bradykinin, normally degraded by ACE, causes sensitization of airway sensory nerves and an enhancement of the cough reflex in conscious guinea pigs. Treatment of guinea pigs for two weeks with captopril led to an increased cough response to inhaled citric acid, which was prevented by concomitant treatment with the bradykinin receptor antagonist icatibant. A similar icatibant-sensitive enhancement of citric acid-evoked cough was seen in untreated animals after prior inhalation of bradykinin, although cough evoked by hypertonic saline was unaffected. In electrophysiological studies performed in vitro, responses of single vagal C fibers to capsaicin, applied to receptive fields of single-fiber units in the trachea, were also markedly increased after perfusion with bradykinin, whereas A delta fiber responses to hypertonic saline were unaffected. These results indicate that bradykinin-evoked sensitization of airway sensory nerves may underlie the pathogenesis of ACE-inhibitor cough. Bradykinin receptor antagonists may be of benefit in treating chronic cough seen with this and other inflammatory conditions.

Good CB, McDermott L, McCloskey B. Diet and serum potassium in patients on ACE inhibitors. JAMA 1995 Aug 16;274(7):538. (Letter)

Mutoh T, Tsubone H, Nishimura R, Sasaki N. Responses of laryngeal capsaicin-sensitive receptors to volatile anesthetics in anesthetized dogs. Respir Physiol 1998 Feb;111(2):113-125 Abstract: The responses of laryngeal capsaicin (CAPS)-sensitive receptors to halothane, enflurane, isoflurane and sevoflurane were evaluated in anesthetized spontaneously breathing dogs from the afferent activity of the internal branch of the superior laryngeal nerve. The CAPS-sensitive receptors were clearly distinguished from irritant receptors by their responsiveness to CAPS and their lack of responsiveness to water. All the CAPS-sensitive receptors were significantly stimulated by all volatile anesthetics in a concentration-related manner, and the activation by halothane, enflurane, and isoflurane was significantly greater than by sevoflurane. In contrast, responses of irritant receptors to the volatile anesthetics were divided into three types (stimulation, inhibition or non-response), and did not differ among anesthetics. In conclusion, the present study demonstrated that the CAPS-sensitive receptors were consistently stimulated by halogenated volatile anesthetics and especially by halothane, enflurane, and isoflurane, and that these responses were dissimilar to the variable responses of irritant receptors.

Nyman, U, Joshi, P, Madsen, LB, Pedersen, TB, Pinstrup, M, Rajasekharan, S, George, V, Pushpangadan, P. Ethnomedical information and in vitro screening for angiotensin-converting enzyme inhibition of plants utilized as traditional medicines in Gujarat, Rajasthan and Kerala. J Ethnopharmacol 1998 Apr;60(3):247-263
Abstract: Plants utilized as traditional medicines in India have been investigated for their ability to inhibit the angiotensin converting enzyme (ACE). In total, 75 species belonging to 42 families have been investigated and new ethnomedical information has been obtained for 41 species. Four species were found to possess a high ACE inhibiting ability and were low in their tannin content.

Ogihara T, Mikami H, Katahira K, Otsuka A. Comparative study of the effects of three angiotensin converting enzyme inhibitors on the cough reflex. Am J Hypertens 1991 Jan;4(1 Pt 2):46S-51S.
Abstract: To compare the effects of three different angiotensin converting enzyme (ACE) inhibitors on the cough reflex, capsaicin and citric acid challenge tests were done in normal subjects and hypertensive patients before and after administration of delapril, captopril, or enalapril. Two groups of 7 normal subjects (single dose study: 15 mg delapril v 18.75 mg captopril or 2.5 mg enalapril) and a group of 6 mildly hypertensive patients (1 week study: cross-over administration of 30 mg/day delapril, 37.5 mg/day captopril, or 5 mg/day enalapril) were studied. Another group of 6 patients with essential hypertension was treated with three ACE inhibitors for 4 weeks in a randomized order, with a 2 week washout period between active therapies. Aerosols of 1 mumol/L and 3 mumol/L capsaicin and 0.68% citric acid in 0.9% NaCl were generated by an ultrasonic nebulizer, and the frequency of cough was counted during inhalation. Delapril treatment resulted in substantially fewer patients with a significant increase (greater than or equal to 4 coughs during treatment than during the control period) in the frequency of cough than did captopril treatment. In the 1 and 4 week studies, enalapril and captopril had substantially more occurrences of significantly increased capsaicin-induced cough than did delapril. These results indicate that delapril has the least cough stimulatory effect among these ACE inhibitors, which may be clinically beneficial.

Takahama K, Araki T, Fuchikami J, Kohjimoto Y, Miyata T. Studies on the magnitude and the mechanism of cough potentiation by angiotensin-converting enzyme inhibitors in guinea-pigs: involvement of bradykinin in the potentiation. J Pharm Pharmacol. 1996 Oct;48(10):1027-1033.

Tjen-A-Looi S, Kraiczi H, Ekman R, Keith IM. Sensory CGRP depletion by capsaicin exacerbates hypoxia-induced pulmonary hypertension in rats. Regul Pept 1998 Apr 24;74(1):1-10.

Yeo WW, Chadwick IG, Kraskiewicz M, Jackson PR, Ramsay LE. Resolution of ACE inhibitor cough: changes in subjective cough and responses to inhaled capsaicin, intradermal bradykinin and substance-P. Br J Clin Pharmacol 1995 Nov;40(5):423-429.
Abstract: 1. In eight hypertensive patients with ACE inhibitor-induced cough the resolution of the cough was examined in a prospective observational study over 4 weeks duration. Resolution of cough was measured by visual analogue scales and questionnaire at baseline and days 3, 7, 14 and 28. In addition changes in cough sensitivity to inhaled capsaicin, and skin responses to bradykinin and substance-P were measured at the same time points. 2. All patients recorded significant subjective improvement in cough questionnaire scores for severity and night time waking, and by visual analogue scales for severity and frequency of cough (all P < 0.0005 for trend from day 0-28). Significant changes in subjective measures were recorded by 3 to 7 days for most measures, but further reductions were observed up to day 28 (all P < 0.01 day 28 vs day 0). 3. The sensitivity to inhaled capsaicin fell over the 28 days of study after stopping enalapril. The potency of capsaicin relative to day 0 was reduced to 0.25 (95% CI 0.07-0.87) by day 14, and to 0.20 (95% CI 0.06-0.67) by 28 days. 4. After stopping enalapril there was a highly significant reduction in wheal area produced by intradermal bradykinin, with the majority of the effect seen by day 3 (P < 0.0005). The wheal area to intradermal substance-P also declined with time after stopping enalapril, but significant changes were not observed until 14 days (P < 0.01). 5. Multiple regression analysis of the rates of decline for the subjective and objective measures of cough showed significant associations between the response to inhaled capsaicin and the VAS scores for severity of cough (P = 0.005) and frequency of cough (P = 0.011). Capsaicin response was not related significantly to the severity of cough measured by self-administered questionnaire. 6. There was a significant association between bradykinin response and VAS scores for frequency of cough (P < 0.04) and severity of cough (P < 0.05), but not with cough by questionnaire or the capsaicin response. The response to substance-P did not relate significantly to any of the measures of cough. 7. Cough caused by enalapril improved markedly by 14 days but took up to 28 days to resolve. It was associated with increased sensitivity to inhaled capsaicin which decreased over 28 days, and which paralleled changes in subjective cough scores.

Wang DH, Li J. Antihypertensive mechanisms underlying a novel salt-sensitive hypertensive model induced by sensory denervation. Hypertension 1999 Jan;33(1 Pt 2):499-503.
Abstract: A novel model of hypertension recently developed in our laboratory shows that neonatal degeneration of capsaicin-sensitive sensory nerves renders a rat responsive to a salt load with a significant rise in blood pressure. To determine the role of the renin-angiotensin system and the sympathetic nervous system in the development of hypertension in this model, newborn Wistar rats were given capsaicin 50 mg/kg SC on the first and second days of life. Control rats were treated with vehicle. After they were weaned, male rats were divided into 6 groups and subjected to the following treatments for 2 weeks: control+high sodium diet (4%) (CON-HS), capsaicin+normal sodium diet (0.5%) (CAP-NS), capsaicin+high sodium diet (CAP-HS), capsaicin+high sodium diet+losartan (10 mg/kg per day) (CAP-HS-LO), capsaicin+high sodium diet+prazosin (3 mg/kg per day) (CAP-HS-PR), and capsaicin+high sodium diet+hydralazine (10 mg/kg per day) (CAP-HS-HY). Levels of calcitonin gene-related peptide in dorsal root ganglia were decreased by capsaicin treatment (P<0.05). Both tail-cuff systolic blood pressure and mean arterial pressure were higher in CAP-HS and CAP-HS-PR than in CON-HS, CAP-NS, CAP-HS-LO, and CAP-HS-HY (P<0.05). The 24-hour urinary volume and sodium excretion were increased when a high sodium diet was given (P<0.05), but they were lower in CAP-HS, CAP-HS-LO, CAP-HS-PR, and CAP-HS-HY than in CON-HS (P<0.05). Urinary potassium excretion was not different among all 6 groups. We conclude that blockade of the angiotensin type 1 receptor with losartan but not antagonism of the alpha1-adrenoreceptor with prazosin prevents the development of salt-sensitive hypertension induced by sensory denervation. Sensory denervation impairs urinary sodium and water excretion in response to a high sodium intake, regardless of blood pressure, suggesting that sensory innervation plays a direct role in regulating the natriuretic response to sodium loading.

Yeo WW, Chadwick IG, Kraskiewicz M, Jackson PR, Ramsay LE. Resolution of ACE inhibitor cough: changes in subjective cough and responses to inhaled capsaicin, intradermal bradykinin and substance-P. Br J Clin Pharmacol. 1995 Nov;40(5):423-429.
Abstract: 1. In eight hypertensive patients with ACE inhibitor-induced cough the resolution of the cough was examined in a prospective observational study over 4 weeks duration. Resolution of cough was measured by visual analogue scales and questionnaire at baseline and days 3, 7, 14 and 28. In addition changes in cough sensitivity to inhaled capsaicin, and skin responses to bradykinin and substance-P were measured at the same time points. 2. All patients recorded significant subjective improvement in cough questionnaire scores for severity and night time waking, and by visual analogue scales for severity and frequency of cough (all P < 0.0005 for trend from day 0-28). Significant changes in subjective measures were recorded by 3 to 7 days for most measures, but further reductions were observed up to day 28 (all P < 0.01 day 28 vs day 0). 3. The sensitivity to inhaled capsaicin fell over the 28 days of study after stopping enalapril. The potency of capsaicin relative to day 0 was reduced to 0.25 (95% CI 0.07-0.87) by day 14, and to 0.20 (95% CI 0.06-0.67) by 28 days. 4. After stopping enalapril there was a highly significant reduction in wheal area produced by intradermal bradykinin, with the majority of the effect seen by day 3 (P < 0.0005). The wheal area to intradermal substance-P also declined with time after stopping enalapril, but significant changes were not observed until 14 days (P < 0.01). 5. Multiple regression analysis of the rates of decline for the subjective and objective measures of cough showed significant associations between the response to inhaled capsaicin and the VAS scores for severity of cough (P = 0.005) and frequency of cough (P = 0.011). Capsaicin response was not related significantly to the severity of cough measured by self-administered questionnaire. 6. There was a significant association between bradykinin response and VAS scores for frequency of cough (P < 0.04) and severity of cough (P < 0.05), but not with cough by questionnaire or the capsaicin response. The response to substance-P did not relate significantly to any of the measures of cough. 7. Cough caused by enalapril improved markedly by 14 days but took up to 28 days to resolve. It was associated with increased sensitivity to inhaled capsaicin which decreased over 28 days, and which paralleled changes in subjective cough scores.