Milrinone Relaxes Pulmonary Veins in Guinea Pigs and Humans

Abstract

IntroductionThe 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 MethodsPrecision-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).ResultsIn 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 KATP-, BKCa 2+- and Kv-channels. Human PVs also relaxed to milrinone (121%), however only if pre-constricted.DiscussionMilrinone relaxes PVs from GPs and humans. In GPs, milrinone-induced relaxation is based on KATP-, BKCa 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.

The effects of hydroxyethyl starch and gelatine on pulmonary cytokine production and oedema formation

“…PCLS from BALB/c mice and human PCLS were prepared as described 36 , 43 . Briefly, mice were anaesthetised intraperitoneally (160 mg/kg pentobarbital) and the depth of anaesthesia was monitored by missing reflexes.…”

Novel selective PDE type 1 inhibitors cause vasodilatation and lower blood pressure in rats

“…In man, the PDE3 and PDE5 inhibitors, milrinone and sildenafil, have previously been shown to decrease systemic arterial BP by 5–10 mmHg (Ludmer et al , ; Vardi et al , ) and to induce vasodilatation in pulmonary and systemic arteries from rat and man (Andersen et al , ; Grzesk et al , ; Rieg et al , ). In agreement with these findings, we found that sildenafil and milrinone relaxed rat mesenteric and femoral arteries.…”

Assessment of long-term cultivated human precision-cut lung slices as an ex vivo system for evaluation of chronic cytotoxicity and functionality

“…These improvements have led to the wide application of the PCLS technique [7, 9–11]. Ever since, PCLS from different species have been used for the assessment of pharmacological and toxicological compounds [7, 9, 10], as well as to model airway constriction [6].…”