Katja Lottermoser

Antihypertensive drug treatment and fibrinolytic function

Thromboembolic complications such as ischemic stroke and myocardial infarction are significantly more frequent in patients with arterial hypertension. From the available intervention studies, it appears that pharmacologic treatment of hypertension-at least with diuretics and beta-blockers-may more effectively protect against cerebrovascular as compared to coronary thromboembolic events. Whether other antihypertensive substances provide a more effective protection with respect to cardiac morbidity and mortality is the subject of numerous studies presently underway. These studies will help to answer the question of whether the extent of protection from coronary events during antihypertensive treatment depends on factors beyond blood pressure control. The fibrinolytic system is crucially involved in the pathogenesis of thromboembolic events. One determinant of this system is the balance between plasminogen activators (tissue-type plasminogen activator [t-PA]) and inhibitors (plasminogen activator inhibitor 1 [PAI-1]). Experimental and clinical evidence suggests that at least some of the drugs used in the treatment of hypertension may alter the activity of the fibrinolytic system. Scarce and controversial data with respect to such an interaction exist with respect to diuretics, beta-blockers, and calcium antagonists. In addition, experimental evidence demonstrates that PAI-1 is stimulated by angiotensin II (A II), whereas t-PA is activated by bradykinin. Thus, antihypertensive drugs acting within the renin angiotensin system should exert effects also within the fibrinolytic system. However, results from clinical studies with angiotensin converting enzyme (ACE) inhibitors and A II receptor antagonists do not unequivocally support such a concept. The discrepancy in the results may, at least in part, be explained by studies performed in healthy volunteer subjects showing that ACE inhibition profoundly affected fibrinolysis only during stimulation of the renin angiotensin system by NaCL restriction.

Fibrinolytic function in diuretic-induced volume depletion

Accumulating evidence suggests that the renin-angiotensin system (RAS) may participate in the regulation of fibrinolytic function. In clinical studies, however, angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor antagonist losartan have failed to consistently affect endogenous fibrinolysis. Because such an effect may depend on the degree of prestimulation of the RAS, we have studied parameters of fibrinolytic function in 15 healthy volunteer subjects during baseline (day 1) and after 10 days of treatment with 25 mg of hydrochlorothiazide (HCT)/day (day 11). On the last day of the study (day 12), a single oral dose of 50 mg of losartan was given to the volunteers in addition to HCT and fibrinolytic function was assessed at the peak effect of losartan (5 h later). Plasma renin activity (PRA) was significantly stimulated during diuretic treatment (1.35 +/- 0.21 v 0.34 +/- 0.06 ng mL(-1) x h(-1) [P < .001]) and further increased after losartan (6.39 +/- 1.16 ng mL(-1) x h(-1) [P < .001]). No effects of either the diuretic or losartan could be observed on tissue-type plasminogen activator (t-PA) antigen concentration and activity. However, 10 days of treatment with HCT significantly increased plasminogen activator inhibitor-1 (PAI-1) antigen (26.8 +/- 5.8 v 21.1 +/- 3.4 ng/mL [p = .037]). In addition, PAI-1 activity was also tentatively raised by HCT treatment (5.48 +/- 1.82 v 3.88 +/- 0.79 IU/mL [P = .067]). In spite of the marked further rise in PRA after losartan, the stimulation of PAI-1 antigen and activity was blunted by losartan (24.4 +/- 3.6 ng/mL and 4.55 +/- 0.99 IU/mL, respectively). Our results demonstrate that volume depletion induced by HCT treatment is associated with a rise in PAI-1. Acute administration of losartan is capable of blunting this effect, suggesting that the angiotensin II type 1 receptor may participate in this effect of angiotensin II.

Short-term effects of exogenous angiotensin II on plasma fibrinolytic balance in normal subjects.

Objective: Numerous studies have provided evidence for a direct functional link between the renin‐angiotensin‐aldosterone system and the fibrinolytic system. Angiotensin II has been suggested to mediate this interrelationship because this peptide was shown to stimulate plasminogen activator inhibitor‐1 (PAI‐1) in experimental settings. However, evidence from studies in man regarding effects of Angiotensin II on fibrinolytic function remains controversial. Methods: In the present study, we have therefore infused Angiotensin II at doses of 1, 3 and 10 ng kg− 1 min− 1, each over 45 min, in 9 healthy volunteer subjects without and with pretreatment with a single dose of the Angiotensin II (type 1) (AT1)‐receptor antagonist valsartan (160 mg). Results: Angiotensin II infusion dose‐dependently increased plasma Angiotensin II concentrations and systolic/diastolic arterial blood pressure from 121 ± 2/70 ± 2 mmHg to 146 ± 2/97 ± 1 mmHg (p < 0.001). The maximum increase in blood pressure was completely abolished (118 ± 3/72 ± 1 mmHg) when Angiotensin II was infused in volunteers pretreated with valsartan. In spite of the marked hemodynamic changes seen with the Angiotensin II infusion, no effect could be demonstrated on the activity and antigen concentration of PAI‐1. Furthermore, pretreatment of the volunteers with valsartan markedly blunted the increase in arterial blood pressure but was not associated with changes in PAI‐1. Conclusion: In conclusion, in healthy volunteer subjects, short‐term infusion of Angiotensin II without and with concomitant administration of an AT1‐receptor antagonist has no effect on PAI‐1 activities and plasma concentrations.

Renin-Angiotensin-Aldosteron-System und Fibrinolyse

ZusammenfassungExperimentelle, genetische und klinische Studien legen einen Zusammenhang zwischen dem Renin-Angiotensin-Aldosteron-System (RAAS) und der Entwicklung thromboembolischer kardiovaskulärer Erkrankungen, wie zum Beispiel der koronaren Herzkrankheit, nahe. Dabei ist die Verknüpfung, zumindest nicht ausschließlich, über Änderungen des arteriellen Blutdruckes vermittelt.Neben vielen anderen möglichen Mechanismen weist eine Reihe neuerer Untersuchungen darauf hin, dass das RAAS an der Regulation der Fibrinolyse beteiligt sein könnte. So zeigen verschiedene Studien, dass eine Aktivierung des RAAS mit einer gesteigerten Freisetzung des Plasminogenaktivator-Inhibitor-1 (PAI-1) einhergeht. Bei unveränderter Aktivität profibrinolytischer Faktoren (insbesondere des Gewebe-Plasminogenaktivators [t-PA]) wäre ein aktiviertes RAAS dementsprechend mit einer Änderung des fibrinolytischen Gleichgewichts und Hemmung der Fibrinolyse assoziiert.Diese Befunde sind von potentieller Bedeutung für eine Reihe von klinischen Fragestellungen, so zum Beispiel der Wertigkeit einer Kochsalzrestriktion für kardiovaskuläre Morbidität und Letalität oder aber der Bedeutung von Pharmaka, die indirekt oder direkt in das RAAS eingreifen, wie zum Beispiel Diuretika, ACE-Hemmstoffe und Angiotensin-II-Typ-1-(AT1–)Rezeptorantagonisten.AbstractExperimental, genetic and clinical evidence suggests that the renin-angiotensin-aldosterone system (RAAS) may participate in the pathogenesis of thromboembolic cardiovascular disorders such as coronary heart disease. This interrelationship may involve mechanisms other than changes in arterial blood pressure. In addition to various possible interactions, accumulating evidence suggests that the RAAS is involved in the regulation of fibrinolytic system.Several recent studies have shown that stimulation of the RAAS may be associated with an activation of plasminogen activator inhibitor 1 (PAI-1). Since profibrinolytic factors (especially tissue plasminogen activator [t-PA]) remain unchanged, increased activity of the RAAS may thus alter the fibrinolytic balance towards a decreased fibrinolytic activity.These findings may be of special importance for a variety of clinical problems such as the long-term effect of a low NaCl-intake on cardiovascular morbidity and mortality and the possible value of drugs indirectly or directly interfering with the RAAS such as diuretics, ACE-inhibitors and angiotensin II Type 1 (AT1) receptor antagonists.

Effects of the mineralocorticoid fludrocortisone on fibrinolytic function in healthy subjects

Recent evidence suggests that the renin-angiotensin-aldosterone system (RAAS) may participate in the regulation of fibrinolytic function. Angiotensin II (Ang II) is the primary candidate to mediate this inter-relationship, since this peptide is capable of stimulating plasminogen activator inhibitor-1 (PAI-1) in vitro and in vivo. It has been suggested that aldosterone may also modulate fibrinolysis, possibly by interacting with Ang II. The present study therefore investigates the effect of short-term treatment with the synthetic mineralocorticoid fludrocortisone (F) on fibrinolytic function. Ten healthy male volunteers, aged 25 to 30 years, on a constant intake of 160—180 mmol Na+ and 60—80 mmol K+, were studied on a control day (C1), after two days of oral administration of F (0.1 mg b.d.), and again three days after cessation of F (C2). F was associated with a marked decrease in plasma renin activity (PRA) from 0.91 ± 0.45 ng ml-1 h -1 to 0.34 ± 0.29 ng ml-1 h-1 (p=0.005), which returned to the baseline range at C2 (0.65 ± 0.45 ng ml-1 h -1; p=0.032). The experimental protocol was not associated with significant changes in the activity or antigen concentration of tissue plasminogen activator (t-PA). PAI-1 exhibited a circadian rhythm with highest values at 0800 hours (41.8 ± 9.1 ng/ml), decreasing by 1230 hours (22.6 ± 5.9 ng/ml), with a further decrease at 1630 hours (12.3 ± 3.1 ng/ml). At all three time points, PAI-1 remained unchanged by the mineralocorticoid. Our results therefore do not support a major mineralocorticoid effect on PAI-1. However, our study does not exclude a modulatory role of F, since unchanged PAI-1 could be observed in spite of a marked suppression of the RAAS.

D96: Effects of captopril on fibrinolytic function in healthy humans

Several lines of evidence point to an interrelation of the renin angiotensin system (RAS) with the endogenous fibrinolytic system. In the present study, we have therefore investigated the effect of the ACE-inhibitor captopril on various parameters of the fibrinolytic system in healthy volunteer subjects. 10 male subjects aged 28-38 years were given captopril 25 mg b.i.d. over 2 weeks. Venous blood was drawn before and at the end of the treatment period at 09.00 AM, after the volunteers had received their last dose of captopril by 07. 30 AM. Blood samples were processed for the determination of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Both parameters were determined with respect to their abundance (as antigen concentrations) and function (activity). In addition, the concentration and activity of the von Willebrand factor were also determined. Two weeks of captopril treatment had no significant effect on any of the above mentioned parameters. Our results thus show that short-term treatment with the ACE-inhibitor captopril, at least in healthy subjects on an unrestricted NaCl intake, does not affect the fibrinolytic balance between t-PA and PAI-1 or the von Willebrand factor.

Differential effect of acute angiotensin II type 1 receptor blockade on the vascular and adrenal response to exogenous angiotensin II in humans

BACKGROUND Aldosterone stimulation by angiotensin II may not exclusively be mediated by the angiotensin II type 1 (AT(1)) receptor. We have, therefore, investigated the vascular and adrenal response to angiotensin II infusion without and with pretreatment with the AT(1) receptor antagonist valsartan (160 mg). METHODS In nine healthy human volunteers, angiotensin II was administered intravenously at doses of 1, 3, and 10 ng/kg/min, each over 45 min. Arterial blood pressure (BP) was measured oscillometrically at 5-min intervals. Blood for the determination of plasma renin activity and aldosterone was taken before the start of the infusion, at the end of each infusion period, and 1 h after the infusion was stopped. RESULTS Angiotensin II increased systolic and diastolic BP from 121 +/- 3/70 +/- 2 mm Hg to a maximum of 146 +/- 2/97 +/- 1 mm Hg (P <.001) and plasma aldosterone from 39.2 +/- 9.8 to 290.7 +/- 48.3 (P <.001). The increase in BP after exogenous angiotensin II was completely abolished in volunteers pretreated with valsartan, averaging 118 +/- 3/72 +/- 1 mm Hg by the end of the maximum angiotensin infusion dose. In contrast, plasma aldosterone stimulation by angiotensin II was only partially blunted by concomitant AT(1) receptor blockade (98.9 +/- 16.3 pg/mL after the maximal dose of angiotensin II). CONCLUSIONS These results indicate that although the vascular response to exogenous angiotensin II is exclusively mediated by the AT(1) receptor, the effects of angiotensin II on adrenal aldosterone release may involve other pathways.