The antihypertensive effect of the angiotensin-converting enzyme inhibitor trandolapril administered in doses of 1, 2, and 4 mg/d was compared in 207 white patients and 91 black patients with mild to moderate hypertension following a double-blind, randomized, placebo-controlled, parallel study design. Trandolapril is a prodrug that is rapidly hydrolyzed to its active diacid metabolite, trandolaprilat. After 6 weeks of double-blind treatment, trandolapril lowered baseline sitting diastolic pressure in both white and black patients. A comparison of the antihypertensive response of the two populations revealed that the black patients required between two and four times the dose of trandolapril to obtain a response similar to that observed in the white patients. A dose of 1 mg/d trandolapril resulted in a 6.1 mm Hg mean decrease in baseline sitting diastolic pressure for white patients; a similar response (-6.5 mm Hg) was observed in the black patients at 4 mg/d. In contrast to the population differences in blood pressure, the decreases in angiotensin-converting enzyme activity were similar for both populations. An evaluation of trandolaprilat levels revealed that there were no racial differences in the trandolaprilat concentrations required to achieve a given degree of angiotensin-converting enzyme inhibition. Therefore, it appears that the antihypertensive response of black patients is not completely explained by a reduction in angiotensin-converting enzyme activity. The lack of response at a lower dose but increasing response at a higher dose could reflect another vasodepressor activity of trandolapril or just be evidence of reduced sensitivity of high blood pressure in blacks to angiotensin-converting enzyme inhibition.

Abstract-Unexplained, persistent cough limits the use of angiotensin-converting enzyme (ACE) inhibitors in a significant number of patients. It has been speculated that occurrence of this adverse effect is genetically predetermined; in particular, variants of the genes encoding ACE, chymase, and B2-bradykinin receptor have been implicated. To investigate this question, we determined genotypes for common polymorphisms for these three genes in subjects with a history of ACE inhibitor-related cough. Specificity of the adverse effect was confirmed by a blinded, double-crossover design protocol in which subjects were rechallenged with either lisinopril or placebo. Key Words: angiotensin-converting enzyme inhibitors Ⅲ cough Ⅲ angiotensin-converting enzyme Ⅲ chymase Ⅲ receptors, bradykinin Ⅲ polymorphism Ⅲ genetics A ngiotensin-converting enzyme inhibitors are widely used for the treatment of hypertension and are presently the uncontested drugs of choice for the treatment of congestive heart failure.1 The major adverse effect encountered with ACEI treatment, and the most frequent reason for withdrawal of the drug, is a persistent, dry (nonproductive) cough.2,3 So far, no specific risk factors or patient characteristics that would predict the occurrence of this cough have been identified, and the underlying mechanism remains unclear; however, it has been speculated that the kininogen-kinin (bradykinin) system may be involved: inhibition of ACE may result in a local accumulation of bradykinin, which in turn may lead to the activation of proinflammatory peptides (eg, substance P, phospholipase C and/or A 2 , prostaglandins, neuropeptide Y) and to local release of histamine in the airways.2,3 Because cough is a class effect of ACEIs, and because its occurrence is not predicted by any external factors, it seems reasonable to suspect that a primary, genetically determined characteristic resulting in alteration of drug action or drug metabolism may be responsible. 4A prime candidate for a protein that might interact differentially with ACEIs on the basis of genetic variation is, of course, ACE itself. Thus, the I/D polymorphism of ACE has recently been proposed as possibly being involved in ACEIinduced cough, 4-6 a speculation fueled by the observation that the incidence of cough among patients under ACEI treatment is roughly similar to the proportion of the population that is homozygous for the ACE insertional allele (about 15% to 20%).More recently, a possible link between ACEI treatmentassociated adverse effects and chymase has also been suggested: as chymase represents an alternative pathway for the activation of angiotensin II, it is possible that ACE inhibition may lead to an increased biological significance of this enzyme. Release of chymase from mast cells results in a range of profound proinflammatory changes; in the dermis, this is associated with skin rashes, whereas in the lungs bronchial and pulmonary infiltration with inflammatory cells and altered regulation of vasoactive peptides 7,8 are observed. A recent re...

Treatment with CAE given twice daily for 5 days is equivalent to treatment for 10 days either with the same regimen of CAE or with AMX/CL given three times daily in pediatric patients with acute otitis media.