Tissue-Type Plasminogen Activator Release in Healthy Subjects and Hypertensive Patients

Abstract

Abstract-The relationship between adrenergic stimuli and NO in modulating tissue-type plasminogen activator (t-PA) release from endothelial cells was investigated in normotensive subjects and essential hypertensive patients. Sympathetic activation, a well-known stimulus for endogenous fibrinolysis, is also involved in the determination of cardiovascular risk in essential hypertension. However, the existence of cross-talk between adrenergic stimuli and NO availability in modulating t-PA release is not well established yet. We assessed the release of t-PA in the forearm microcirculation of 58 normotensive subjects (mean age: 47Ϯ9 years) and 44 essential hypertensive patients (mean age: 48Ϯ11 years) under specific intra-arterial adrenergic stimuli. Intrabrachial infusion of epinephrine (0.1 to 0.3 g/100 mL per minute) induced greater t-PA release in normotensive subjects as compared with essential hypertensive patients (PϽ0.05). However, inhibition of NO synthase with N G -monomethyl-L-arginine (100 g/100 mL per minute) infusion blunted epinephrine-induced t-PA release in normotensive subjects (PϽ0.05) but not in essential hypertensive patients. In normotensive subjects, t-PA release by epinephrine was not affected by phentolamine (8 g/100 mL per minute) coinfusion and was abolished in the presence of propanolol (10 g/100 mL per minute). Intrabrachial isoproterenol (0.03 g/100 mL per minute) induced a significant increase in t-PA release (PϽ0.01), an effect blunted by N G -monomethyl-L-arginine (PϽ0.05). In essential hypertensive patients, the response to isoproterenol was impaired as compared with normotensive subjects and was unaffected by N G -monomethyl-L-arginine coinfusion. In conclusion, the results of the present study demonstrate that adrenergic-induced t-PA release is mediated by ␤-adrenoreceptors via a mechanism involving the NO pathway. Our results show an impaired adrenergic-stimulated t-PA release among essential hypertensive patients, probably mediated via a reduced NO availability. This impaired fibrinolytic activity might contribute to the increased cardiovascular risk associated with hypertension. (Hypertension. 2008;52:314-321.) Key Words: t-PA Ⅲ receptors Ⅲ adrenergic-␤ Ⅲ NO Ⅲ endothelium Ⅲ hypertension Ⅲ essential T he endogenous fibrinolytic system contributes to the maintenance of vessel patency via the cleavage of insoluble fibrin by plasmin. The activation of plasmin by tissue-type plasminogen activator (t-PA) is a physiological process that, clearing inappropriate intravascular fibrin deposition, prevents vascular atherothrombotic events. 1,2 The coagulation factors thrombin and activated factor X, acting as counterregulatory mechanisms during fibrin deposition, are considered the main stimuli for acute t-PA release from endothelial cells. 2 Thus, the vascular endothelium plays a major regulatory role in endogenous fibrinolysis. 3 One of the main mechanisms by which a healthy endothelium regulates acute release of t-PA involves the NO pathway. 4 In certain pathological conditions charact...

Effect of Sulfaphenazole on Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients

“…In addition, bradykinin-mediated tPA release was found to be sensitive to L-NMMA, which indicates a positive modulatory effect of the NO pathway in physiological conditions, a finding in line with previous reports of application of different endothelial stimuli, such as substance P or epinephrine. 3,26 The positive role of the NO pathway was further confirmed by the finding that acetylcholine-induced tPA release was significantly blunted by NO inhibition in normotensive subjects. 4 In normotensive subjects, sulfaphenazole also significantly reduced bradykinin-induced tPA release, a finding that suggests that a CYP 2C9 -dependent pathway could be physiologically able to participate in fibrinolysis modulation.…”

“…26 It is, however, interesting to observe that in hypertensive patients, the residual but still evident bradykinin-induced tPA release was totally resistant to L-NMMA, whereas it was blocked by sulfaphenazole. Finally, when L-NMMA was coinfused with sulfaphenazole, no further reduction in tPA release was observed.…”

Nebivolol, But Not Metoprolol, Treatment Improves Endothelial Fibrinolytic Capacity in Adults With Elevated Blood Pressure

“…Whereas in humans, impaired capacity of the endothelium to release t‐PA has been linked to atheromatous plaque development and higher rates of myocardial infarction 29. We4 and others30 have previously demonstrated that endothelial t‐PA release is markedly blunted in adults with elevated BP and that the magnitude of impairment is similar between adults with prehypertension and stage 1 hypertension 4. Impaired endothelial fibrinolytic function is considered to be an important factor contributing to the increased risk of atherothrombotic vascular disease associated with elevated BP 31…”

“…Very little is known regarding the effects of BP‐lowering agents on endothelial control of the fibrinolytic system 30, 32. While acutely lowering BP in adults with hypertension does not have beneficial effects on endothelial t‐PA release,33 chronic BP control with angiotensin‐converting enzyme inhibition or calcium channel blockade,8 but not angiotensin receptor blockade,7 improves arterial t‐PA release 31.…”

Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension

“…23 Moreover, the systemic levels of t-PA may not reflect the local profibrinolytic capacity in terms of availability of active t-PA at the organ level, which in turn depends on the magnitude of local t-PA release from the endothelium. 24,25 Data on the effects of Ang II AT1 receptor blockers (ARBs) on fibrinolysis are even more controversial, with some studies showing a reduction in PAI-1 plasma level [26][27][28] and others showing no effect. 19,[29][30][31][32] Reasons for such different findings might be because of differences in experimental models, study population characteristics, duration of treatment and possible methodological bias.…”