PMID- 24498166
OWN - NLM
STAT- MEDLINE
DCOM- 20141015
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 1
DP  - 2014
TI  - Milrinone relaxes pulmonary veins in guinea pigs and humans.
PG  - e87685
LID - 10.1371/journal.pone.0087685 [doi]
LID - e87685
AB  - INTRODUCTION: 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. MATERIAL AND METHODS: Precision-cut lung slices (PCLS) were prepared from 
      GPs or from patients undergoing lobectomy. Milrinone-induced relaxation was 
      studied by videomicroscopy in naive 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 microM) lowered the postcapillary 
      resistance of pre-constricted vessels. In PCLS (GP), milrinone relaxed naive 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. DISCUSSION: 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.
FAU - Rieg, Annette D
AU  - Rieg AD
AD  - 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.
FAU - Suleiman, Said
AU  - Suleiman S
AD  - Institute of Pharmacology and Toxicology, Medical Faculty of Rhenish-Westphalian 
      Technical University Aachen, Aachen, Germany.
FAU - Perez-Bouza, Alberto
AU  - Perez-Bouza A
AD  - 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.
FAU - Braunschweig, Till
AU  - Braunschweig T
AD  - Institute of Pathology, Medical Faculty of Rhenish-Westphalian Technical 
      University Aachen, Aachen, Germany.
FAU - Spillner, Jan W
AU  - Spillner JW
AD  - Department of Cardiac and Thorax Surgery, Medical Faculty of Rhenish-Westphalian 
      Technical University Aachen, Aachen, Germany.
FAU - Schroder, Thomas
AU  - Schroder T
AD  - Department of Surgery, Luisenhospital Aachen, Aachen, Germany.
FAU - Verjans, Eva
AU  - Verjans E
AD  - 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.
FAU - Schalte, Gereon
AU  - Schalte G
AD  - Department of Anesthesiology, Medical Faculty of Rhenish-Westphalian Technical 
      University Aachen, Aachen, Germany.
FAU - Rossaint, Rolf
AU  - Rossaint R
AD  - Department of Anesthesiology, Medical Faculty of Rhenish-Westphalian Technical 
      University Aachen, Aachen, Germany.
FAU - Uhlig, Stefan
AU  - Uhlig S
AD  - Institute of Pharmacology and Toxicology, Medical Faculty of Rhenish-Westphalian 
      Technical University Aachen, Aachen, Germany.
FAU - Martin, Christian
AU  - Martin C
AD  - Institute of Pharmacology and Toxicology, Medical Faculty of Rhenish-Westphalian 
      Technical University Aachen, Aachen, Germany.
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140131
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Large-Conductance Calcium-Activated Potassium Channels)
RN  - 0 (Phosphodiesterase 3 Inhibitors)
RN  - JU9YAX04C7 (Milrinone)
SB  - IM
EIN - PLoS One. 2014;9(5):e97207
MH  - Animals
MH  - Female
MH  - Guinea Pigs
MH  - Humans
MH  - Large-Conductance Calcium-Activated Potassium Channels/metabolism
MH  - Male
MH  - Milrinone/*pharmacology
MH  - Organ Culture Techniques
MH  - Phosphodiesterase 3 Inhibitors/*pharmacology
MH  - Pulmonary Edema/drug therapy/metabolism/pathology/physiopathology
MH  - Pulmonary Veins/metabolism/pathology/*physiopathology
MH  - Vascular Resistance/*drug effects
MH  - Vasodilation/*drug effects
PMC - PMC3909212
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/02/06 06:00
MHDA- 2014/10/16 06:00
PMCR- 2014/01/31
CRDT- 2014/02/06 06:00
PHST- 2013/05/08 00:00 [received]
PHST- 2014/01/01 00:00 [accepted]
PHST- 2014/02/06 06:00 [entrez]
PHST- 2014/02/06 06:00 [pubmed]
PHST- 2014/10/16 06:00 [medline]
PHST- 2014/01/31 00:00 [pmc-release]
AID - PONE-D-13-18927 [pii]
AID - 10.1371/journal.pone.0087685 [doi]
PST - epublish
SO  - PLoS One. 2014 Jan 31;9(1):e87685. doi: 10.1371/journal.pone.0087685. eCollection 
      2014.