Calcium channel blockers as antihypertensive agents.

Because of their unique action on the cardiovascular system, the calcium channel blockers have generated a great deal of excitement among pharmacologists, physiologists, and clinicians. One obvious potential application for these drugs is in antihypertensive therapy and, although experience with these agents for this indication is limited in the United States, it is considerable in Europe and Japan. These agents' ultimate role in antihypertensive therapy, however, has not been established. Since the available calcium channel blockers are structurally diverse, it is uncertain whether they will have comparable effects in hypertension. The rationale for the use of calcium channel blockers in treating hypertension and the relevant pharmacologic actions of these agents is discussed, along with a summary of some of the clinical trials, observations from our own experience with these drugs, and speculation about their future role in antihypertensive therapy.

Antihypertensive therapy with diltiazem and comparison with hydrochlorothiazide.

Fourteen hypertensive patients with a mean sitting systolic and diastolic blood pressure (BP) of 153 +/- 16/100 +/- 4 mm Hg were treated successively with hydrochlorothiazide and diltiazem for 8 weeks each. The BP response and changes in heart rate, left ventricular size and function, and plasma catecholamine concentrations and renin activity were monitored. The 2 drugs had comparable antihypertensive effects, with mean decreases of 14, 9 and 11 mm Hg for the sitting, standing and supine diastolic BP, respectively, during hydrochlorothiazide treatment and mean decreases of 16, 18 and 12 mm Hg during diltiazem treatment. Heart rate was unchanged, although plasma norepinephrine concentrations increased significantly during diltiazem treatment. Plasma renin activity increased slightly, from 0.6 to 0.9 ng/ml/hour during diltiazem treatment, but the change was not significant (p less than 0.10). Left ventricular ejection fraction and end-diastolic volume were not affected by either agent. In conclusion, diltiazem is an effective antihypertensive agent, which because of its benign side effect profile, may be useful as a step 1 agent.

Failure of antihypertensive therapy with diuretic, beta-blocking and calcium channel-blocking drugs to consistently reverse left ventricular diastolic filling abnormalities.

The present protocol was designed to determine whether antihypertensive therapy with hydrochlorothiazide, propranolol or diltiazem, 3 agents with different mechanisms of action and potentially different effects on myocardial function, reverses left ventricular filling abnormalities. Twelve patients with essential hypertension and no evidence of associated cardiovascular disease, either clinically or with noninvasive testing, were evaluated while taking no medication and after 2 months of treatment with these agents. All 3 drugs produced equivalent control of blood pressure (BP), reducing sitting systolic BP by a mean of 20 to 24 mm Hg and diastolic BP by 14 to 16 mm Hg. LV ejection fraction and end-diastolic volume were normal in all but 1 subject (who was excluded from the analyses of LV diastolic filling) and were not altered by drug therapy. The peak LV filling rate and the first-third filling fraction were reduced in the patients with hypertension, but neither of these indexes nor the time to peak filling rate were significantly improved for the group as a whole by any of these medications. Nine of 10 patients whose BP was controlled by diltiazem had increases in their first-third filling fraction, but this change did not reach statistical significance. Our findings suggest that abnormalities of LV diastolic filling are not consistently affected by short-term therapy in patients with chronic, previously treated systemic hypertension.

Monotherapy in mild to moderate hypertension: comparison of hydrochlorothiazide, propranolol and prazosin.

There has been recent interest in using nondiuretic drugs as initial antihypertensive therapy. Therefore, a study was designed to compare the efficacy and the effects on left ventricular function of hydrochlorothiazide, propranolol and prazosin in 13 patients with mild to moderate hypertension. After a 4-week washout period, patients were treated serially with each drug in a randomized order for 2 months each. Dosages were titrated until the patient showed a sitting diastolic blood pressure less than or equal to 90 mm Hg or to a maximum dosage of 100 mg/day of hydrochlorothiazide, 320 mg of propranolol and 20 mg of prazosin. Blood pressure was measured, plasma catecholamine concentrations were assayed and radionuclide determinations of rest and exercise left ventricular function and volume were made at the end of each period as well as after a second 1-month washout period at the end. In the sitting and standing positions, systolic and diastolic blood pressure control was equivalent for all 3 drugs. Goal blood pressure was achieved in 10 of 13 patients receiving hydrochlorothiazide, in 8 of 12 receiving propranolol and in 9 of 13 on prazosin. Importantly, 3 of 4 patients not controlled with prazosin, 5 of 6 uncontrolled with propranolol and 2 of 3 whose blood pressure was not reduced by hydrochlorothiazide were controlled when receiving 1 of the other medications. None of the drugs changed rest or exercise ejection fraction or volume, and side effects were minimal.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal left ventricular filling: an early finding in mild to moderate systemic hypertension.

This study was undertaken to determine the prevalence and significance of diastolic left ventricular (LV) dysfunction in mild to moderate systemic hypertension. Rest and exercise equilibrium blood pool scintigraphy was performed in 39 hypertensive subjects (mean systolic blood pressure [BP] 156 +/- 14 mm Hg [+/- standard deviation]; mean diastolic BP 103 +/- 5 mm Hg) and 11 normal control subjects. These studies were analyzed for ejection fraction (EF), segmental wall motion, peak filling rate (PFR), time to PFR and filling fraction in the first third of diastole normalized for cycle length (first-third filling fraction). EF at rest was similar in the hypertensive patients and control subjects (0.63 +/- 0.09 versus 0.65 +/- 0.07); only 2 patients had a reduced EF. The EF response to exercise was normal in every hypertensive patient (increasing to a mean of 0.74 +/- 0.08); only 1 patient had asynergy. In contrast, even when the 2 patients with abnormal systolic function were excluded, each index of diastolic filling was significantly different from the control group. PFR was lower (2.29 +/- 0.49 vs 2.63 +/- 0.39 end-diastolic volumes per second [EDV/s], p less than 0.05), time to PFR was longer (199 +/- 47 versus 158 +/- 17 ms/s), p less than 0.01) and first-third filling fraction was smaller (0.38 +/- 0.11 vs 0.60 +/- 0.07, p less than 0.001). The latter index fell below the lowest normal value in 84% of the hypertensive patients. The degree of diastolic filling abnormality was not related to the patients' age, heart rate, BP, duration of systemic hypertension or systolic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection and quantification of previous myocardial infarction by exercise-redistribution tomographic thallium-201 scintigraphy.

Although myocardial perfusion scintigraphy at rest accurately diagnoses myocardial infarction (MI), the prevalence and size of previous MI is overestimated by exercise-redistribution thallium-201 studies. A new, quantitative approach to the analysis of tomographic thallium-201 scintigrams was developed in order to determine whether the presence and extent of MI could be determined. Sixty patients undergoing cardiac catheterization for chest pain syndromes, including 28 with previous MI, were studied by exercise and 3-hour delayed thallium-201 scintigraphy, with use of the 7-pinhole tomographic technique. Circumferential profiles of the postexercise and 3-hour radiotracer distribution were generated from apical, midventricular and basal left ventricular slices. The 3-hour profile fell below normal limits in 24 of 28 patients (86%) with remote MI, but was also abnormal in 9 of 22 patients (41%) with coronary disease but no MI. All missed MIs were either inferior or subendocardial and were associated with normal ejection fractions. To distinguish between MI and slowly resolving ischemic defects, a quantitative approach was used. MI area was calculated as the area in which the 3-hour profile fell below the 3-hour normal limits, and a redistribution area in the MI zone was determined as the area between the postexercise and 3-hour profiles in the region where the 3-hour profile was abnormal. The MI area was 1,000 +/- 980 units in patients with MI, vs 79 +/- 120 units in patients without MI (p less than 0.001), whereas the redistribution area was higher in patients without MI (1,240 +/- 810 vs 430 +/- 400 units, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrastructure and 18S rDNA sequence analysis of Wobblia lunata gen. et sp. nov., a new heterotrophic flagellate (Stramenopiles, Incertae sedis).

A new heterotrophic flagellate Wobblia lunata gen. et sp. nov. is described. This organism usually attaches to the substratum showing a wobbling motion, and sometimes glides on the substratum or swims freely in the medium. W. lunata has various features characteristic of the stramenopiles. These include a hairy flagellum with tripartite tubular hairs, a mitochondrion with tubular cristae, arrangement of flagellar apparatus components and a double helix in the flagellar transition zone. W. lunata shares a double helix with heterotrophic stramenopiles, including Developayella elegans, oomycetes, hyphochytrids, opalinids and proteromonads, and could be placed in the phylum Bigyra Cavalier-Smith. However, from 18S rDNA tree analysis, these organisms form two distantly-related clades in the stramenopiles, and Wobblia appears at the base of the stramenopiles. Evaluation of morphological features and comparison of 18S rDNA sequences indicate that W. lunata is a member of the stramenopiles, but it is distinct from any other stramenopiles so far described. Its phylogenetic position within the stramenopiles is uncertain and therefore W. lunata is described as a stramenopile incertae sedis.

The Basal Position of Scaly Green Flagellates among the Green Algae (Chlorophyta) is Revealed by Analyses of Nuclear-Encoded SSU rRNA Sequences.

The prasinophytes comprise a morphologically heterogeneous assembly of mostly marine flagellates and coccoid taxa, which represent an important component of the nano- and picoplankton, and have previously figured prominently in discussions about the origin and phylogeny of the green plants. To evaluate their putative basal position in the Viridiplantae and to resolve the phylogenetic relationships among the prasinophyte taxa, we determined complete nuclear-encoded SSU rRNA sequences from 13 prasinophyte taxa representing the genera Cymbomonas, Halosphaera, Mamiella, Mantoniella, Micromonas, Pterosperma, Pycnococcus, and Pyramimonas. Phylogenetic analyses of SSU rRNA sequences using distance, parsimony and likelihood methods revealed four independent prasi.nophyte lineages (clades) which constitute the earliest divergences among the Chlorophyta. In order of their divergence these clades are represented by the genera Cymbomonas, Halosphaera, Pterosperma, Pyramimonas (clade I), Mamiella, Mantoniella, Micromonas (clade II), Pseudoscourfieldia (strain CCMP 717), Nephroselmis (clade III), and Tetraselmis, Scherffelia (clade IV). The coccoid Pycnococcus provasolii diverged after clade II, but before clade III. Since no other coccoid prasinophyte taxa were analyzed in this study, the phylogenetic status of this taxon is presently unresolved. Our analyses provide further evidence for the basal phylogenetic position of the scaly green flagellates among the Chlorophyta and raise important questions concerning the class-level classification of the Chlorophyta.

The gene for ribosomal protein L27 is located on the plastid rather than the nuclear genome of the chlorophyll c-containing alga Pleurochrysis carterae.

The gene for ribosomal protein L27 (rpl27) has not been found in plastid genomes. We report here that the rpl27 gene is located in the plastid genome of the prymnesiophyte Pleurochrysis carterae. The deduced amino acid sequence showed 59% identity with E. coli L27. 1.0 kb transcript of the gene was detected by Northern blot analysis. Nucleotide sequence analysis of PCR products suggested that rpl27 is widespread in the genomes of Prymesiophyta and Rhodophyta. In all species of Prymnesiophyta examined in this study, the gene is located at the 3' downstream region of Rubisco operon.