Milrinone relaxes pulmonary veins in guinea pigs and humans.
BACKGROUND
The phosphodiesterase-III inhibitor milrinone improves ventricular contractility, relaxes pulmonary arteries and reduces right ventricular afterload. Thus, it is used to treat heart failure and pulmonary hypertension (PH). However, its action on pulmonary veins (PVs) is not defined, although particularly PH due to left heart disease primarily affects the pulmonary venous bed. We examined milrinone-induced relaxation in PVs from guinea pigs (GPs) and humans.


METHODS
Precision-cut lung slices (PCLS) were prepared from GPs or from patients undergoing lobectomy. Milrinone-induced relaxation was studied by videomicroscopy in naïve PVs and in PVs pre-constricted with the ETA-receptor agonist BP0104. Baseline luminal area was defined as 100%. Intracellular cAMP was measured by ELISA and milrinone-induced changes of segmental vascular resistances were studied in the GP isolated perfused lung (IPL).


RESULTS
In the IPL (GP), milrinone (10 µM) lowered the postcapillary resistance of pre-constricted vessels. In PCLS (GP), milrinone relaxed naïve and pre-constricted PVs (120%) and this relaxation was attenuated by inhibition of protein kinase G (KT 5823), adenyl cyclase (SQ 22536) and protein kinase A (KT 5720), but not by inhibition of NO-synthesis (L-NAME). In addition, milrinone-induced relaxation was dependent on the activation of K ATP-, BK Ca (2+)- and Kv-channels. Human PVs also relaxed to milrinone (121%), however only if pre-constricted.


CONCLUSIONS
Milrinone relaxes PVs from GPs and humans. In GPs, milrinone-induced relaxation is based on K ATP-, BK Ca (2+)- and Kv-channel-activation and on cAMP/PKA/PKG. The relaxant properties of milrinone on PVs lead to reduced postcapillary resistance and hydrostatic pressures. Hence they alleviate pulmonary edema and suggest beneficial effects of milrinone in PH due to left heart disease.
Institute of Pharmacology and Toxicology, Medical Faculty of Rhenish-Westphalian Technical University Aachen, Aachen, Germany ; Department of Anesthesiology, Medical Faculty of Rhenish-Westphalian Technical University Aachen, Aachen, Germany.
Annette D
AD
Rieg
Institute of Pharmacology and Toxicology, Medical Faculty of Rhenish-Westphalian Technical University Aachen, Aachen, Germany.
Said
S
Suleiman
Institute of Pathology, Medical Faculty of Rhenish-Westphalian Technical University Aachen, Aachen, Germany ; Institute of Pathology, Medical Faculty of Rhenish Friedrich-Wilhelms University Bonn, Bonn, Germany.
Alberto
A
Perez-Bouza
Institute of Pathology, Medical Faculty of Rhenish-Westphalian Technical University Aachen, Aachen, Germany.
Till
T
Braunschweig
Department of Cardiac and Thorax Surgery, Medical Faculty of Rhenish-Westphalian Technical University Aachen, Aachen, Germany.
Jan W
JW
Spillner
Department of Surgery, Luisenhospital Aachen, Aachen, Germany.
Thomas
T
Schröder
Institute of Pharmacology and Toxicology, Medical Faculty of Rhenish-Westphalian Technical University Aachen, Aachen, Germany ; Department of Pediatrics, Medical Faculty of Rhenish-Westphalian Technical University Aachen, Aachen, Germany.
Eva
E
Verjans
Department of Anesthesiology, Medical Faculty of Rhenish-Westphalian Technical University Aachen, Aachen, Germany.
Gereon
G
Schälte
Department of Anesthesiology, Medical Faculty of Rhenish-Westphalian Technical University Aachen, Aachen, Germany.
Rolf
R
Rossaint
Institute of Pharmacology and Toxicology, Medical Faculty of Rhenish-Westphalian Technical University Aachen, Aachen, Germany.
Stefan
S
Uhlig
Institute of Pharmacology and Toxicology, Medical Faculty of Rhenish-Westphalian Technical University Aachen, Aachen, Germany.
Christian
C
Martin
D000818:Animals; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008297:Male; D020105:Milrinone / Q000494:pharmacology*; D009924:Organ Culture Techniques; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D011654:Pulmonary Edema / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011667:Pulmonary Veins / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D014655:Vascular Resistance / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
D051036:Large-Conductance Calcium-Activated Potassium Channels; D058987:Phosphodiesterase 3 Inhibitors; D020105:Milrinone