Pulmonary hypertension, pulmonary blood vessels and vasoactive drugs

There is an urgent need for new drugs to treat pulmonary hypertension. Specific pathophysiological abnormalities, seen in both clinical pulmonary hypertension and experimental pulmonary hypertension in animals, suggest that potassium channel openers, endothelin antagonists and nitric oxide donors may be valuable in the future. Our own studies and those of others have shown that drugs from each of these groups have properties that are consistent with their potential therapeutic use in this disease. Use of the inhalational route of administration may be desirable, or even essential, if any of these drugs are to produce effects that are selective for the pulmonary circulation

The pulmonary vasodilator properties of potassium channel opening drugs

1. This article reviews the effects of potassium channel opening drugs (KCOs) on blood vessels of the pulmonary circulation. KCOs are effective pulmonary vasodilators in vitro (isolated arteries and perfused lungs) and in vivo in a variety of animal species. They prevent or reverse pulmonary vasoconstriction/contraction induced by a range of vasoconstrictor spasmogens or by alveolar hypoxia. 2. The pulmonary vasorelaxant effects of the KCO drugs are blocked by glibenclamide, do not depend on the endothelium, are dependent on the vasoconstrictor spasmogen used to contract the preparations and are enhanced in preparations taken from pulmonary hypertensive rats. 3. Selectivity for pulmonary compared with systemic vessels is seen in vessels from pulmonary hypertensive rats but not in the absence of pulmonary hypertension. 4. The pulmonary vasodilatation that is induced by (a) endothelium derived hyperpolarising factor, (b) endothelin, (c) increased pulmonary blood flow or (d) prolonged, severe hypoxia is probably due to potassium efflux through the same population of potassium channels as chose on which the KCOs act. 5. Acute hypoxic pulmonary vasoconstriction, and also the depolarisation seen in arteries from chronically hypoxic rats, each involve inhibition of potassium efflux through glibenclamide insensitive potassium channels. 6. It is suggested that the KCOs warrant investigation as possible therapeutic agents in the treatment of pulmonary hypertension

In vitro hypoxia attenuates vasorelaxation by potassium channel opening drugs and nitroprusside in isolated pulmonary arteries from rats

The effects of in vitro hypoxia on relaxant responses to various vasodilator drugs were examined on norepinephrine-contracted ring preparations of rat pulmonary artery. The physiological salt solution that bathed the tissues was equilibrated with gas mixtures that contained 95%, 12%, 6%, 4% or 0% oxygen (oxygen tension of solution, > 650, 94, 44, 35 or < or = 11 mm Hg, respectively). Severe in vitro hypoxia (oxygen tension, 4 mm Hg) attenuated responses to pinacidil (negative log EC50 values: control, 5.61; hypoxia, 4.92). This effect of hypoxia was not prevented by endothelium removal or by indomethacin. Less severe hypoxia (oxygen tension < or = 35 mm Hg) attenuated responses to nitroprusside (negative log EC50: control, 8.34; hypoxia, 7.76). This effect of hypoxia was prevented by endothelium removal but not by indomethacin, NG-nitro-L-arginine methyl ester or the endothelin antagonist, cyclo(D-Trp-D-Asp-Pro-D-Val-Leu), and was not mimicked by endothelin. These effects of in vitro hypoxia were rapidly reversible and were distinct from the previously reported effects of chronic in vivo hypoxia on responses of pulmonary arteries to these drugs. It was also found that severe in vitro hypoxia abolished responses to acetylcholine and cromakalim and potentiated responses to sodium nitrite (negative log EC50: control, 3.79; hypoxia, 4.97) but had no effect on responses to colforsin (also known as forskolin).(ABSTRACT TRUNCATED AT 250 WORDS

Evidence that the efficacy (intrinsic activity) of fenoterol is higher than that of salbutamol on β-adrenoceptors in guinea-pig trachea

The functional antagonism of carbachol by fenoterol and salbutamol (β-adrenoceptor agonists) has been used to demonstrate that the efficacy (intrinsic activity) of fenoterol was about twice that of salbutamol on guinea-pig trachea. The mean maximum shifts of the carbachol concentration-response lines by fenoterol and salbutamol were (log units) 1.07 ± 0.07 (n = 5) and 0.64 ± 0.07 (n = 5) respectively. This difference in their efficacies could be demonstrated as differences in maximum relaxation on tracheal preparations contracted with carbachol, although this was dependent on the concentration of carbachol used. β-Adrenoceptor blocking properties of salbutamol (1 mM) but not fenoterol (1 mM) could be demonstrated on trachea in that salbutamol, but not fenoterol, antagonised the shift in the carbachol concentration-response line produced by isoprenaline. The implications of these findings in relation to the use of fenoterol and salbutamol as bronchodilators is discussed

Hexoprenaline: β‐adrenoreceptor selectivity in isolated tissues from the guinea‐pig

1. A catecholamine β‐adrenoreceptor agonist, hexoprenaline, was examined in vitro on five guinea‐pig tissues and its potency relative to isoprenaline (as 100) obtained. 2. Hexoprenaline clearly delineated between those tissues classified as containing β2‐adrenoreceptors (trachea, hind limb blood vessels and uterus; relative potencies 219, 110 and 76 respectively) and those classified as containing β1‐adrenoreceptors (atria and ileum; relative potencies 3·3 and 1·0 respectively). 3. Hexoprenaline differed from some previously studied noncatecholamine β‐adrenoreceptor agonists in being only two‐fold less potent, relative to isoprenaline, as a vasodilator in perfused hind limb than as a tracheal relaxant. Copyrigh

The use of guinea pig K+-depolarized tracheal chain preparations in β-adrenoceptor studies

Guinea pig tracheal chain preparations were K-depolarized using Krebs solution in which all the Na was replaced by an equivalent amount of K. This caused a sustained contraction of the preparations. Reproducible concentration-response (relaxation) curves to isoprenaline could be obtained provided that the preparations were repolarized by washing in normal Krebs solution between curves. pA values for propranolol (8.30) and butoxamine (5.89) were in good agreement with values obtained on other types of tracheal preparation. The maximum relaxation to salbutamol was less than that to isoprenaline and the maxima to both drugs were less than the maximum relaxation of the tissue (to papaverine). It is suggested that K-depolarized tracheal preparations have no β-adrenoceptor reserve and may, therefore, be useful in studies designed to compare the efficacies of β-adrenoceptor agonists

DEMONSTRATION OF BOTH β1‐ AND β2‐ADRENOCEPTORS MEDIATING RELAXATION OF ISOLATED RING PREPARATIONS OF RAT PULMONARY ARTERY

Cumulative concentration‐response (relaxation) curves to three β‐adrenoceptor agonists, fenoterol (β‐selective), isoprenaline (non‐selective) and noradrenaline (β‐selective) were obtained on isolated ring preparations of rat pulmonary artery contracted with 15 mM KCl. α‐Adrenoceptors and neuronal and extraneuronal uptakes were blocked with phenoxybenzamine. The agonist concentration‐response curves were reproducible. Responses to each of the three agonists could be blocked by the β‐adrenoceptor antagonists atenolol (β‐selective) or ICI 118,551 (β‐selective) confirming the presence of β‐adrenoceptors. The relative potencies of the agonists were isoprenaline: fenoterol: noradrenaline = 100: 38: 1.4. This indicated that the predominant β‐adrenoceptor type was β. Schild plots were obtained for atenolol and ICI 118,551 using the three different agonists. For each antagonist the location of the Schild plot varied depending on which agonist was used. This indicated that the β‐adrenoceptor population mediating relaxation responses to β‐adrenoceptor agonists was not homogeneous. Atenolol was most potent when noradrenaline was the agonist and ICI 118,551 was most potent when fenoterol was the agonist. It is concluded that isolated pulmonary artery ring preparations of the rat contain a mixed population of β‐ and β‐adrenoceptors both mediating relaxation. 1981 British Pharmacological Societ