Different cardiac tissue plasminogen activator release patterns by local stimulation of the endothelium and sympathetic nerves in pigs

Abstract

Myocardial ischemia induces cardiac tissue plasminogen activator (tPA) release, declining by repeated periods of ischemia. However, the mechanisms and cellular sources are unknown. Sympathetic nerve stimulation (SS) and bradykinin (BK), an endogenous inducer of endothelial tPA release, may play roles, potentially involving different sources or mechanisms revealed by different release patterns. Therefore, we compared the cardiac tPA release patterns during repeated coronary BK infusions and SS, both with an ensuing period of local myocardial ischemia/reperfusion (I/R). Nine pigs were subjected to four periods of coronary BK infusion (4 min) and another nine animals to four periods of SS (4 min). Finally, 10 min of I/R was induced in both groups. The single-peaked BK-induced tPA release declined toward baseline by repeated infusions, but tPA release reappeared during I/R. In contrast, total tPA release during repeated SS and subsequent I/R was more stable, and SS-induced total tPA and norepinephrine (NE) releases were strongly correlated. Surprisingly, the instantaneous SS-induced tPA release was biphasic with a stable first peak, and a second peak declining toward baseline by repeated stimulations. The fluctuations in cardiac release of plasminogen activator inhibitor-1 and the endogenous BK inhibitor angiotensin-converting enzyme, could not explain the diverging tPA release patterns. Different tPA release patterns were demonstrated during SS and BK stimulation, as well as diverging responses to repeated stimulations and subsequent I/R. This study demonstrates strong association between tPA and NE during SS and possibly two different sources or mechanisms for SS-induced tPA release.

β-blockade abolishes the augmented cardiac tPA release induced by transactivation of heterodimerised bradykinin receptor-2 and β2-adrenergic receptor in vivo

“…To study the functional consequences of a possible B 2 R-β 2 AR heterodimerisation in vivo, cardiac tPA release in pig was first examined during SS and thereafter again during an ongoing coronary infusion of BK (▶ Figure 1 A). Consistent with previous observations (10,12), tPA release increased during SS 1 and remained high with a biphasic-like pattern throughout a 4-min stimulation period (▶ Figure 2 A). The mt-tPA release was increased by 6.3 ± 2.2-fold compared to baseline (p = 0.028) (▶ Figure 2 B).…”

“…Blood gases were maintained at pO 2 ; 20-25 kPa, and pCO 2 at approximately 5 kPa. The surgical preparations and hemodynamic recordings have been described previously (10,11).…”

“…We further investigated the effects of non-selective β-blockade on this potential receptor interplay. Previously, we have demonstrated different cardiac tPA antigen release patterns in response to repeated BK infusion and electrical stimulation of sympathetic nerves to the heart (SS) in pigs, and that tPA release was desensitised despite continuous BK infusion (10). Based on these findings and the demonstrated cross-talk between heterodimerised B 2 R-β 2 AR in oocytes and PC12 cells (1), we hypothesised the existence of B 2 R-β 2 AR heterodimer in the myocardium and that these receptors' cross-talk would result in enhanced cardiac tPA release in vivo.…”

Histone Deacetylase Inhibition Enhances Tissue Plasminogen Activator Release Capacity in Atherosclerotic Man

“…Prolonged or repeated stimulation of the endothelium is clinically relevant for patients with thrombotic tendencies, though single time-point stimulation also has relevance, since it is recognized that early and immediate local t-PA release has the most effect in preventing local thrombus formation [ 8 , 9 ]. The phenomenon of reduced t-PA release in response to repeated stimulation (exhaustion) has been described in a porcine model previously [ 25 , 26 ], but has not been clearly shown in clinical subjects to date.…”

Histone Deacetylase Inhibitor Treatment Increases Coronary t-PA Release in a Porcine Ischemia Model

“…It has been previously shown that repetitive stress stimulation of t-PA can lead to decline in acute t-PA release capacity of the coronary vascular tree, though recovery is rapid [3], [32]. In our model, the surgical preparation involved a sternotomy and pericardiotomy, followed by a long period of rest before the ischemic provocation.…”