Pathophysiology of experimental renovascular hypertension

The genesis of renovascular hypertension follows a continuum from an acute to a chronic phase. Reduction in renal perfusion initiates renin release and angiotensin-mediated systemic vasoconstriction. Aldosterone secretion, sodium and water retention, and expansion of the extracellular volume ensue. Sustained hypertension is further maintained by interacting physiologic mechanisms including increased angiotensin II sensitivity, vasopressin, ouabain-like substance, the sympathetic nervous system, CNS mechanisms, autoregulation, and structural changes.     

Spontaneous pneumothorax in primary cavitating lung carcinoma

Primary cavitating lung carcinomas have not previously been described with spontaneous pneumothorax as the presenting manifestation. Two patients whose pneumothoraces resulted in the initial diagnosis of a primary cavitary lung carcinoma are described. Pathologic evidence of vascular invasion suggests tumor necrosis with secondary rupture into the pleural space as a likely mechanism for pneumothorax.     

Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson-Gilford progeria syndrome

Children with Hutchinson-Gilford progeria syndrome (HGPS) suffer from dramatic acceleration of some symptoms associated with normal aging, most notably cardiovascular disease that eventually leads to death from myocardial infarction and/or stroke usually in their second decade of life. For the vast majority of cases, a de novo point mutation in the lamin A (LMNA) gene is the cause of HGPS. This missense mutation creates a cryptic splice donor site that produces a mutant lamin A protein, termed "progerin," which carries a 50-aa deletion near its C terminus. We have created a mouse model for progeria by generating transgenics carrying a human bacterial artificial chromosome that harbors the common HGPS mutation. These mice develop progressive loss of vascular smooth muscle cells in the medial layer of large arteries, in a pattern very similar to that seen in children with HGPS. This mouse model should prove valuable for testing experimental therapies for this devastating disorder and for exploring cardiovascular disease in general.     

A randomized placebo-controlled trial of combined early intravenous captopril and recombinant tissue-type plasminogen activator therapy in acute myocardial infarction.

The adjunctive use of intravenous captopril with tissue plasminogen activator early during acute myocardial infarction offers theoretic advantages of diminishing left ventricular volume, preventing ventricular dilation and improving patient survival. To test the safety and efficacy of combined early administration of intravenous captopril and recombinant tissue-type plasminogen activator (rt-PA), 38 patients treated with rt-PA 3 +/- 0.3 h (mean +/- SE) after the onset of myocardial infarction were randomized to intravenous followed by oral captopril or placebo therapy. They underwent cardiac catheterization with measurement of hemodynamic variables and left ventricular function and determination of serum renin, angiotensin and aldosterone levels on days 1 and 7. Oral administration of the selected agent was continued for 3 months along with other antianginal medications, including nonangiotensin-converting enzyme inhibitor vasodilators. Repeat measurements of left ventricular function were obtained before hospital discharge and at 3 months. There were no significant differences in baseline clinical characteristics between groups. One patient in the captopril-treated group became hypotensive during intravenous therapy, requiring discontinuation of treatment. Compared with the placebo-treated group, the captopril-treated group had significant reductions at day 7 in left ventricular end-diastolic pressure (22.5 +/- 1.5 versus 16.3 +/- 1.6 mm Hg, p less than 0.01) and mean systemic arterial pressure (93.6 +/- 3.3 versus 86.2 +/- 2.7 mm Hg, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Biology of the impaired endothelium

The endothelium is a regulatory organ that mediates hemostasis, contractility, cellular proliferation, and inflammatory mechanisms in the vessel wall. Injury to the endothelium from hypertension, smoking, hyperlipidemia, and diabetes mellitus disrupts normal regulatory properties and results in abnormal endothelial cell function. Clinically, endothelial cell dysfunction can be manifested as vasospasm, thrombus formation, atherosclerosis, or restenosis. The normal hemostatic properties of the endothelium include the maintenance of a nonadhesive luminal surface, antithrombotic properties, anticoagulant properties, and fibrinolytic properties. The endothelial cell regulates smooth muscle cell contractility by the production of relaxing and constricting factors in response to physiologic stimuli. Endothelial cell injury is also an initial event in the development of atherosclerosis and restenosis by facilitating platelet adhesion and aggregation and by signaling the release of mitogens from platelets, macrophages, and endothelial cells, which stimulate smooth muscle cell proliferation. In addition, endothelial cells undergo morphologic and functional alterations in response to cytokine signals, which may contribute to the pathogenesis of vasculitis and atherosclerosis. In sum, the normal endothelium performs many regulatory functions which become altered when the endothelium is injured.     

Effects of dosing intervals on the development of tolerance to high dose transdermal nitroglycerin

To investigate the antiischemic efficacy and development of tolerance to transdermal nitroglycerin, 14 patients with chronic, stable angina pectoris were studied using continuous ambulatory electrocardiographic monitoring. Patients demonstrated initial hemodynamic responsiveness to sublingual nitroglycerin and were titrated to a maximally tolerated dose of 30 to 60 mg/24 hours (52 +/- 5 mg). Two crossover phases were use in a randomized, double-blind, placebo-controlled manner: continuous nitroglycerin therapy (patches containing active drug worn for 24 hours) and intermittent nitroglycerin therapy (12-hour active drug followed by a 12-hour nitrate-free period). There were no differences in frequency or duration of ischemic episodes between the placebo days of each phase. A significant effect in frequency of episodes was observed between placebo and treatment days of continuous therapy (p less than 0.05). Nonsignificant reductions in frequency and duration of ischemic episodes also occurred during intermittent therapy. The major antiischemic effect of transdermal nitroglycerin therapy occurred during the first day of treatment but was lost by 48 hours. Reductions in frequency and duration of ischemic episodes (p less than 0.05) were present on day 1 of continuous therapy but ischemic episodes returned to placebo levels by day 2, suggesting the development of tolerance. Intermittent therapy did not prevent the development of tolerance on day 2 of treatment. The results demonstrate that the use of high doses of transdermal nitroglycerin in patients with chronic, stable coronary artery disease produced a beneficial reduction in the frequency and duration of ischemia. However, the antiischemic benefit was lost between 24 nd 48 hours after the onset of continuous and intermittent therapy, presumably due to tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)