Tissue-type plasminogen activator release in healthy subjects and hypertensive patients: relationship with beta-adrenergic receptors and the nitric oxide pathway.
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: 47+/-9 years) and 44 essential hypertensive patients (mean age: 48+/-11 years) under specific intra-arterial adrenergic stimuli. Intrabrachial infusion of epinephrine (0.1 to 0.3 microg/100 mL per minute) induced greater t-PA release in normotensive subjects as compared with essential hypertensive patients (P<0.05). However, inhibition of NO synthase with N(G)-monomethyl-L-arginine (100 microg/100 mL per minute) infusion blunted epinephrine-induced t-PA release in normotensive subjects (P<0.05) but not in essential hypertensive patients. In normotensive subjects, t-PA release by epinephrine was not affected by phentolamine (8 microg/100 mL per minute) coinfusion and was abolished in the presence of propanolol (10 microg/100 mL per minute). Intrabrachial isoproterenol (0.03 microg/100 mL per minute) induced a significant increase in t-PA release (P<0.01), an effect blunted by N(G)-monomethyl-L-arginine (P<0.05). 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 beta-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.
Giannarelli
Chiara
C
Department of Internal Medicine, University of Pisa, Via Roma, 67, 56100 Pisa, Italy. c.giannarelli@int.med.unipi.it
Virdis
Agostino
A
De Negri
Ferdinando
F
Duranti
Emiliano
E
Magagna
Armando
A
Ghiadoni
Lorenzo
L
Salvetti
Antonio
A
Taddei
Stefano
S
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D016022:Case-Control Studies; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood* / Q000175:diagnosis; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D011336:Probability; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000378:metabolism*; D012016:Reference Values; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000032:analysis / Q000378:metabolism*
D011943:Receptors, Adrenergic, beta; D009569:Nitric Oxide; D010959:Tissue Plasminogen Activator; D004837:Epinephrine