Controversy about using calcium antagonists for treatment of coronary disease and hypertension

Calcium antagonists are widely used in therapy of hypertension and angina pectoris. Their advantage is good efficacy, relatively few and not dangerous side effects and first of all lack of bad metabolic effects (hypokalemia, hyperuricemia, hyperinsulinemia and hyperlipoproteinemia). In contrast to beta-blockers and diuretics, which decline mortality from myocardial infarctions and strokes there are not similar information concerning calcium antagonists. Two meta-analysis from 1995 unexpectedly suggest, that some preparations of calcium antagonists increase mortality from myocardial infarctions and strokes. In our paper we discuss possible pathogenetic (harmful) mechanisms, pay attention to each class of calcium antagonists and time of action of the particular drugs. Short acting nifedipine formulation should be withdrawn from chronic hypertension and angina pectoris therapy. Ongoing multicenter trials in several European countries and in USA will decide the usefulness of other calcium antagonists preparations.     

Which calcium antagonists for hypertension?

Calcium antagonists have been used for treatment of cardiovascular diseases for more than 25 years. Several recent retrospective studies have suggested that chronic treatment with short-acting dihydropyridines increased the incidence of cardiac events, cancer and gastrointestinal bleedings. Randomized prospective studies have, however, never been able to confirm these observations. In addition, well-conducted studies using verapamil and diltiazem have suggested that these calcium antagonists may even improve cardiovascular mortality and morbidity of the hypertensive patient. There is therefore no reason to believe that the questionable results derived from retrospective studies of the effects of short-acting calcium antagonists on cardiac and noncardiac events may apply to the newer generation of long-acting calcium antagonists.     

L-Arginine normalizes coronary vasomotion in long-term smokers

BACKGROUND: Noninvasive measurements of myocardial blood flow (MBF) with PET revealed an abnormal coronary vasomotor response to cold pressor test in healthy long-term smokers. If coronary endothelial dysfunction accounted for this abnormality, we hypothesized that it could be reversed by L-arginine as the substrate for NO synthase. METHODS AND RESULTS: MBF was quantified with 13N-labeled ammonia and PET in 11 healthy smokers (age, 45+/-10 years; 27+/-10 years of smoking) and in 12 age-matched nonsmokers on 2 separate days. On day 1, MBF was measured at rest and, after intravenous L-arginine, during cold pressor test. On day 2, MBF was measured during cold pressor test and then at rest during L-arginine. Baseline rate-pressure product (RPP) (6559+/-1590 versus 7144+/-1157 bpmxmm Hg) and MBF (0.65+/-0.14 versus 0.73+/-0.13 mL x g-1 x min-1) were similar in nonsmokers and smokers. Cold pressor test increased RPP similarly in both groups (53+/-26% versus 46+/-26%), whereas MBF increased in nonsmokers (to 0.93+/-0.25 mL x g-1 x min-1; P<0.05) but not in smokers (0.80+/-0.16 mL x g-1 x min-1). The percent MBF increase differed between nonsmokers and smokers (44+/-25% versus 11+/-14%; P=0.0017). However, after L-arginine, the magnitude of MBF response to cold pressor test no longer differed between groups (48+/-36% versus 48+/-28%), whereas RPP again increased similarly in the 2 groups (59+/-30% versus 44+/-16%). L-Arginine had no effect on resting MBF in smokers or nonsmokers. CONCLUSIONS: Our findings implicate the coronary endothelium as the major site of the abnormal vasomotor response in long-term smokers. Cold pressor test combined with PET imaging may allow the noninvasive identification of coronary endothelial dysfunction in humans.     

Evidence for abnormal calcium homeostasis in patients with adynamic bone disease

To investigate whether the derangements in calcium kinetics in patients with renal osteodystrophy are similar in the various histologic forms of this metabolic bone disease, 43 patients on chronic maintenance dialysis underwent calcium kinetic studies using the double isotope technique, iliac crest bone biopsies for mineralized bone histology and histomorphometry and determinations of serum indices of calcium and bone metabolism. Intestinal calcium absorption was not different among the three histologic groups. However, women exhibited lower calcium absorption in each histologic form (P < 0.01). Patients with predominant hyperparathyroid bone disease showed plasma calcium efflux, calcium accretion rate and calcium retention markedly above normal values. Patients with low turnover bone disease exhibited a normal or slightly decreased plasma calcium efflux and calcium accretion rate together with a disproportionately low calcium retention. Patients with mixed uremic osteodystrophy presented with a calcium kinetic profile intermediary to the two other forms. Good relationships existed between plasma calcium efflux, calcium accretion rate, calcium retention and histomorphometric parameters of bone turnover as well as serum levels of parathyroid hormone. However, no serum parameter could indicate with certainty the underlying bone disease. These findings demonstrate that adynamic bone disease does not merely represent an academic finding but is characterized by a very low bone capacity to buffer calcium and inability to handle an extra calcium load. This is particularly relevant for the daily care of end-stage renal failure patients presently receiving higher than ever amounts of vitamin D and calcium salts.     

False-positive captopril renography in patients taking calcium antagonists

Captopril-enhanced renography is the noninvasive test of choice for the diagnosis of renovascular hypertension. Previous studies have shown that bilateral symmetrical changes are associated with many renal conditions. However, patients with normal renal angiography occurred in our institutions despite this scintigraphic pattern, and no known conditions could explain these results. The purpose of this study was to evaluate the diagnostic implications of bilateral symmetrical renal function deterioration on captopril renography. METHODS: Eighty-six captopril renal scintigraphies performed at two centers to exclude renovascular hypertension (50 consecutive patients after the observation of a bilateral symmetrical renal function deterioration despite a normal angiogram at one institution and 36 patients with both captopril renography and renal angiography at the other institution) were retrospectively reviewed. Baseline and captopril-enhanced renograms were obtained with 99mTc-mercaptoacetyltriglycine and a 1-day protocol in 50 patients; 36 patients were studied using 99mTc-diethylenetriamine pentaacetic acid and a 2-day protocol. Bilateral symmetrical renal function deterioration was detected. RESULTS: Ten patients presented with bilateral symmetrical renal function deterioration on their captopril renograms; 9 of them were taking calcium antagonists (p=0.015). Control studies performed in 5 patients without these medications demonstrated normal captopril renograms in 4 and persistent renal dysfunction in 1. No explanation was found for the patient who was not taking any medication. Angiograms performed in 5 patients showed normal renal arteries. An 11th patient who was taking a calcium antagonist showed dysfunction of his one kidney on the captopril renogram but no artery stenosis on the renal angiogram. CONCLUSION: Calcium antagonists can cause false-positive captopril renograms. These medications should be stopped before captopril renography, and physicians should be aware of this possible drug interaction if bilateral symmetrical renal function deterioration is seen on a patient's captopril renogram.     

A comparative study of eccentric and concentric coronary stenosis vasomotion in patients with Prinzmental''s variant angina and patients with stable angina pectoris

HPV is the commonest sexually transmitted viral infection in the United Kingdom and as such poses a major public health problem. In addition to the potential physical morbidity associated with genital warts, abnormal cervical cytology, and anogenital dysplasia and neoplasia, the associated psychological morbidity should not be forgotten. Although our knowledge of viral function and disease pathogenesis has advanced appreciably in recent years, we are still some way from developing an in vitro method of viral propagation. Vaccination against HPV infection will hopefully be achieved within the next 10 years, but a prevention and treatment strategy which is appropriate for both developed and developing nations must be our major long term goal.     

Risk of gastrointestinal haemorrhage with calcium antagonists

Klippel-Trenaunay syndrome (KTS) is a congenital vascular abnormality consisting of a cutaneous naevus, varicose veins and bone and soft-tissue hypertrophy affecting one or more limbs. A case is presented here with some unusual associated findings seen on MR that, to the best of the authors' knowledge, has not been reported in the literature. Although colour Doppler in addition to venography is frequently used in demonstration of the KT vein, MRI may well have an important role in complete assessment.     

Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension

BACKGROUND: Patients with essential hypertension have abnormal endothelium-dependent vasodilation. Because the endothelium exerts its action on the vascular smooth muscle through the release of several substances, it is important to identify which of these factors is involved in the abnormal response of hypertensive arteries. METHODS AND RESULTS: To investigate the role of endothelium-derived nitric oxide in this abnormality, we studied the vascular effect of the arginine analogue NG-monomethyl-L-arginine, an inhibitor of the endothelial synthesis of nitric oxide, under baseline conditions and during infusion of acetylcholine, an endothelium-dependent vasodilator, and sodium nitroprusside, a direct smooth muscle dilator. The study included 11 hypertensive patients (seven men; age, 46.5 +/- 9 years) and 10 normal control subjects (seven men; age, 45.7 +/- 7 years). Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by strain-gauge plethysmography. Basal blood flow was similar in normal control subjects and hypertensive patients (2.97 +/- 0.7 versus 2.86 +/- 1.1 mL.min-1.100 mL-1, respectively). NG-monomethyl-L-arginine produced a significantly greater decrease in blood flow in control subjects than in patients (1.08 +/- 0.6 versus 0.32 +/- 0.4 mL.min-1.100 mL-1; p < 0.004). The vasodilator response to acetylcholine was reduced in patients compared with control subjects (maximum flow, 8.2 +/- 4 versus 16.4 +/- 8 mL.min-1.100 mL-1; p < 0.001). NG-monomethyl-L-arginine blunted the vasodilator response to acetylcholine in control subjects (maximum flow decreased from 16.4 +/- 8 to 7.01 +/- 3 mL.min-1.100 mL-1; p < 0.004); however, the arginine analogue did not significantly alter the response to acetylcholine in hypertensive patients (maximum flow, 8.2 +/- 4 versus 8.01 +/- 5 mL.min-1.100 mL-1). NG-monomethyl-L-arginine did not modify the vasodilator response to sodium nitroprusside in either control subjects or patients. CONCLUSIONS: These findings indicate that patients with essential hypertension have a defect in the endothelium-derived nitric oxide system that may at least partly account for both the increased vascular resistance under basal conditions and the impaired response to endothelium-dependent vasodilators.     

Bioequivalence of controlled-release calcium antagonists

In this review, several deficiencies of published bioequivalence studies for controlled-release calcium antagonists have become apparent. As a consequence, some of the published conclusions based on such studies must be viewed with care. A proper statistical analysis of bioequivalence is not frequently reported. A proper statistical analysis of the pharmacokinetic variables involves the calculation of 90% confidence intervals (CI) for the test: reference ratio of the means of the pharmacokinetic variables of the test and reference product. The CI must fall completely within the predetermined bioequivalence range (usually 0.8 to 1.25) for the products to be declared bioequivalent. Serious methodological errors, such as a conclusion of bioequivalence based on a lack of statistically significant difference between products, and conversely, a conclusion of bioequivalence because of a statistically significant difference, or because of a mere failure to show bioequivalence, are still made. With calcium antagonists in particular, an assessment of the rate of absorption and of the maximum concentration is important, as those characteristics may have implications for the safety profile with this class of drugs. As a minimum, in single doses studies the maximum concentration (Cmax), and the time to the maximum concentration (tmax), and in multiple-dose studies the Cmax, and the peak-trough fluctuation (%PTF) must be considered. Some bioequivalence studies of calcium antagonists are deficient in this respect. To show bioequivalence for controlled-release formulations, multiple-dose studies are required but some published bioequivalence studies contain only single-dose assessments. Similarly, bioequivalence studies under fed conditions are rarely published, although food may have a significant effect on the absorption rate of these drugs. Some calcium antagonists, such as verpamil, show stereo-selective pharmacokinetics, so that enantiomers may have to be investigated. Unfortunately, few of the published studies of controlled-release calcium antagonists satisfy all requirements. One would expect that data submitted to regulatory authorities for approval of generic formulations are more complete; published data are in many cases not satisfactory.     

Role of nitric oxide in coronary arterial vasomotion and the influence of coronary atherosclerosis and its risks

Healthy coronary vascular endothelium releases nitric oxide to modulate resting and dynamic coronary arterial tone. We studied the impact of atherosclerosis and/or its risks on endothelial nitric oxide release in response to metabolic stimuli by evaluating coronary vasomotor responses to atrial pacing before and after the inhibition of nitric oxide production by intracoronary NG-monomethyl-L-arginine (L-NMMA) (20 micromol/min) infusion. The study includes 34 patients (15 with coronary disease, 11 with normal coronary arteries and > or =1 risk factor, and 8 with normal coronary arteries and no risks). Coronary blood flow was derived from Doppler flow velocity (0.018-inch Doppler wire) and coronary diameter. L-NMMA infusion reduced coronary blood flow by 18 +/- 16% and coronary diameter by 10 +/- 9%. Responses were identical in all subgroups. Coronary blood flow responses to pacing were similar in all subgroups and were unaffected by L-NMMA (11 +/- 11 vs 13 +/- 9 ml/min; p = 0.26). Epicardial coronary vasodilation to control pacing occurred in patients with normal coronary arteries with (4.0 +/- 5.2%, p = 0.01) or without (8.0 +/- 5.2%, p = 0.03) risks, but not in patients with coronary disease (2.8 +/- 5.9%). L-NMMA abolished pacing-induced epicardial vasodilation in patients without coronary artery disease, producing a 1.8 +/- 5.1% response, which was similar in all subgroups. We conclude that microvascular responses to rapid atrial pacing are not mediated by nitric oxide. Flow-mediated epicardial coronary arterial responses may be nitric oxide dependent.     

Structural and functional alterations of the intramyocardial coronary arterioles in patients with arterial hypertension

BACKGROUND: In hypertensive patients with angina pectoris, the coronary vasodilator reserve is frequently impaired despite a normal coronary angiogram. Experimental data indicate that structural alterations of the intramyocardial coronary vasculature contribute to an increased minimal coronary resistance and a diminished coronary flow reserve. METHODS AND RESULTS: In 14 patients (10 men and 4 women) with arterial hypertension and 8 normotensive subjects, minimal coronary resistance and vasodilator reserve (dipyridamole: 0.5 mg/kg body wt, gas chromatographic argon method) were determined after the angiographic exclusion of relevant coronary artery disease. Coronary reserve was depressed in hypertensive patients (2.7 +/- 2.3 vs 4.6 +/- 1.3, P < or = .05) due to increased minimal coronary resistance (0.64 +/- 30 vs 0.24 +/- 0.055 mm Hg.min.100 g.mL-1, p < or = 0.002). In right septal biopsies, mean external arteriolar diameter (21.6 +/- 2.3 vs 17.2 +/- 2.5 microns, P < or = .001), mean arteriolar wall area (271 +/- 61 vs 172 +/- 62 microns 2, P < or = .01), percent medial wall area (69.9 +/- 4.0 vs 66.0 +/- 3.2%W, P < or = .05), mean periarteriolar fibrosis area (216 +/- 122 vs 104 +/- 68 microns 2, P < or = .05), and volume density of total interstitial fibrosis (3.6 +/- 1.8 vs 1.9 +/- 0.5Vv% fibrosis, P < or = .05) were increased in hypertensive patients compared with normotensive subjects. Minimal coronary resistance correlated with %W (r = .6, P < or = .003) and Vv% fibrosis (r = .62, P < or = .002). Left ventricular mass index (111 +/- 21 vs 97 +/- 17 g/m2, P = NS) and left ventricular end-diastolic pressure (12 +/- 6 vs 8 +/- 3 mm Hg, P = NS) did not correlate significantly with minimal coronary resistance. In multivariate analysis, both %W and Vv% fibrosis explained half of the variability of minimal coronary resistance (r2 = .5, P < or = .002). CONCLUSIONS: Structural remodeling of the intramyocardial coronary arterioles and the accumulation of fibrillar collagen are decisive factors for a reduced coronary dilatory capacity in patients with arterial hypertension and angina pectoris in the absence of relevant coronary artery stenoses.     

Time of occurrence of paroxysmal atrial fibrillation in Holter monitoring in patients with coronary heart disease and in patients with hypertension

Paroxysmal atrial fibrillation (PAF) often accompany coronary heart disease (CHD), and primary hypertension (PH). The aim of the study was to evaluate the time of occurrence and duration of paroxysmal atrial fibrillation (PAF) identified from Holter recordings in 63 patients (27 women and 36 men) with CHD (n = 45) and PH (n = 18). No pharmacological treatment was applied before and during the examination. All patients were in sinus rhythm at the start and the end of the recording which lasted for 24 hours. PAF were defined as the occurrence of at least four beats of supraventricular origin, with no visible P or flutter waves. The time of onset, duration, ventricular rate and symptoms of each PAF were noted. There were 219 paroxysms recorded in 63 patients which occurred more often by day than by night, the time of duration was 0.9-240 s. Of the total, 16.3% of episodes with CHD and 9.5% episodes in patients with PH occurred between the hours 8:00-10:00 and between 16:00 and 18:00; 9.1% and 21% respectively. We concluded that in patients with CHD and with H most of the episodes (95%) are silent, they occurred more often during the day activity (particularly between the hours of 8:00 and 10:00 and 16:00-18:00 in both groups). In patients with CHD we observed the third peak of occurrence of PAF between the hours 22:00-0:00.     

Coronary collateral blood-flow velocity improves with repeated coronary occlusions during angioplasty in patients with coronary artery disease and systemic hypertension

The heterogeneity of schizophrenia has led to a multitude of diagnostic criteria systems. Thus, the best strategy for schizophrenia research might be the use of several diagnostic systems simultaneously. This polydiagnostic approach can be associated with isolating subtypes of symptoms or patients. In this way, the authors present several approaches such as, first, dimensional approaches, second, cluster analyses, and third the selection of a very homogeneous subtype with standardized criteria. One homogeneous subtype can be represented by deficit schizophrenia according to Carpenter as defined by the Schedule of Deficit Syndrome.