Faculty Bibliography

Male Munich-Wistar rats underwent right nephrectomy and were given weekly injections of deoxycorticosterone acetate (DOCA) and 1% saline (salt) to drink. Two studies were performed. In the first, rats given enalapril (ENP) were compared with controls. In the second, rats ingested either standard chow or chow to which the calcium-entry blocker nifedipine (NIF) had been added. Six to eight weeks after nephrectomy, both control DOCA-salt rats and those given ENP had severe hypertension and significant proteinuria. Rats given NIF excreted less protein, and glomerular lesions were not observed in this group. The effects of NIF on several parameters that have been associated with glomerular injury were examined. Micropuncture studies revealed that glomerular capillary pressure was increased in DOCA-salt rats and was not reduced by NIF. Platelet aggregation was also similar in NIF-treated and control rats. Morphometric studies revealed a tendency toward lower glomerular volume of NIF-treated rats; however, kidney weight and glomerular capillary radius were unaffected by therapy. Thus NIF, but not ENP, prevents DOCA-salt rats from developing hypertension and glomerular injury. This effect does not depend on reduction in glomerular pressure or inhibition of platelet aggregation

The observation that aspirin inhibits the increment in tissue plasminogen activator (t-PA) activity induced by venous occlusion of the forearm became controversial with the publication of several nonconfirmatory studies. The current study was performed to confirm the original observation and determine the mechanism by which aspirin suppresses the incremental t-PA activity induced by venous occlusion. Aspirin (650 mg/d X 2) caused no change in resting levels of t-PA antigen (t-PA:Ag) or activity, plasminogen activator inhibitor 1 antigen (PAI-1:Ag), or activity or t-PA-PAI-1 complexes. In contrast, aspirin reduced the increments induced by venous occlusion as follows: t-PA:Ag by 45% (P = .001); t-PA activity (euglobulin lysis time, ELT) by 43% (P = .006); and t-PA activity (alpha 2-plasmin inhibitor-plasmin complexes, PIPC) by 41% (P = .003). The inhibition of incremental t-PA activity measured as ELT or PIPC was linearly correlated with the inhibition of incremental t-PA:Ag (respectively, r = .75, P less than .02; r = .67, P less than .05). Aspirin had no effect on the increment in PAI-1:Ag induced by venous occlusion, but similar to the effect on t-PA:Ag, aspirin induced a 51% inhibition of the increment in t-PA-PAI-1 complex formation. Aspirin did not alter the ability of alpha 2-plasmin inhibitor to bind plasmin, nor the ability of plasma to support the fibrin-catalyzed generation of plasmin by t-PA, nor the subsequent formation of PIPC. Aspirin inhibits the t-PA activity induced by venous occlusion primarily by inhibiting the release of t-PA antigen

The role of prostaglandins in mediating the hemodynamic response to nitroglycerin in vivo is controversial. To determine the effect of inhibiting prostaglandin production on the response to nitroglycerin, either placebo or aspirin (650 mg) was administered 1 hour prior to the administration of nitroglycerin (432 micrograms) sublingually to 40 healthy volunteers in a double-blind, randomized, cross-over study. Prior to nitroglycerin administration, blood pressure and pulse rate were determined noninvasively every 2 minutes until stable conditions were reached, and then after nitroglycerin administration determinations were made every 1 minute for the first 10 minutes, every 2 minutes for the next 10 minutes, and every 5 minutes until 30 minutes had elapsed. At peak response in the placebo study, nitroglycerin lowered systolic pressure from 117 +/- 10 to 111 +/- 10 mm Hg (p less than 0.0001). Unexpectedly, nitroglycerin increased diastolic pressure from 75 +/- 8 to 80 +/- 7 mm Hg (p less than 0.005), thus reducing pulse pressure significantly. Pulse rate after nitroglycerin increased from 72 +/- 11 to 85 +/- 14 (p less than 0.001). Aspirin slightly modified the pattern of response at 1 minute but altered neither the peak hemodynamic responses nor the areas under the time-pressure and time-pulse curves. Thus nitroglycerin-induced prostaglandin production does not play a major role in the systemic hemodynamic response to nitroglycerin in vivo

Transient myocardial ischemia is more frequently silent than accompanied by angina. The frequency of ischemia varies markedly from day to day, so that in order to accurately define the total ischemic burden, it may be necessary to quantitate ischemic episodes for periods longer than 24 hours. Therefore, a programmable, digital device was developed for long-term, interactive, ambulatory monitoring of the electrocardiogram, which uses variations in a time-averaged ST level as an indicator of myocardial ischemia. The electrocardiographic signal is digitized at 256 Hz and analyzed by an algorithm. If ST depression is planar or downsloping and persists for more than 40 seconds, and if the ST depression is equal to or more than a user-programmed threshold, the device marks the onset of an ischemic event and times it. The algorithm has been validated by comparison of its analysis of the ST segment to human and computerized analyses of frequency-modulated Holter recordings and stress tests. To assess the feasibility and utility of long-term monitoring, patients with documented coronary artery disease were monitored continuously for 14-day periods. Of 26 patients enrolled, 8 completed a protocol for individualization of anti-ischemic therapy using transdermal nitroglycerin. Over 90% of ischemic episodes in this group of patients, all of whom had had a previous myocardial infarction, were silent. Treatment with 10 mg of transdermal nitroglycerin reduced the number of ischemic episodes by 59% and the duration of ischemia by 60% (p less than 0.001); there was no diminution in the effectiveness of treatment from week 1 to week 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Current dogma holds that non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibition of the synthesis and release of prostaglandins. However, NSAIDs also inhibit the activation of neutrophils, which provoke inflammation by releasing products other than prostaglandins. We now report that NSAIDs (for example, indomethacin, piroxicam) inhibit activation of neutrophils by inflammatory stimuli such as C5-derived peptides and leukotriene B4 even when cyclooxygenase products generated in suspensions of stimulated neutrophils (prostaglandin E and thromboxanes) are present. Sodium salicylate (3mM) greatly inhibited aggregation of neutrophils but had no effect on aggregation of platelets or production of thromboxane induced by arachidonate. Sodium salicylate and other NSAIDs also inhibit calcium movements (45Ca uptake, changes in fluorescence of chlortetracycline and Quin-2). Aspirin, sodium salicylate, indomethacin, and piroxicam also enhanced the post-stimulation rise in intracellular cyclic AMP. NSAIDs therefore inhibit early steps in neutrophil enhance intracellular levels of cyclic AMP