Tissue selectivity and spasmogen selectivity of relaxant drugs in airway and pulmonary vascular smooth muscle contracted by PGF_2α or endothelin

Abstract

1 The spasmolytic effects of smooth muscle relaxant drugs with different mechanisms of action have been examined on isolated preparations of guinea-pig trachea and rat pulmonary artery. The preparations were contracted with concentrations of prostaglandin F2. (PGF20) or endothelin selected to give approximately 80% of the agonist maximum response on each tissue. These concentrations also caused similar levels of tone (% of tissue maximum contraction) on each tissue. 2 With endothelin as the spasmogen, the potassium channel opening drug, pinacidil, was more potent on trachea (-log IC50 5.49) than on pulmonary artery (4.39), i.e. was airway-vascular selective, whereas with PGF2. as the spasmogen it was more potent on pulmonary artery (6.01) than on trachea (5.27), i.e. was vascular-airway selective. 3 With endothelin as the spasmogen, fenoterol was also airway-vascular selective (8.35 on trachea; little effect on pulmonary artery), nitroprusside was vascular-airway selective (7.50 on pulmonary artery; 5.99 on trachea) and forskolin was non-selective (6.69 on trachea; 6.70 on pulmonary artery). Thus, the airwayvascular selectivity of the relaxant drugs varied with the drug.4 On pulmonary artery, pinacidil, nitroprusside and forskolin were all more potent against PGF2. than against endothelin, i.e. 42, 4 and 7 fold respectively. On trachea, these drugs were equipotent against PGF2. and endothelin.5 The results suggest that, in pulmonary artery, but not in trachea, the relative contribution of protein kinase C activation and calcium influx to the maintenance of tonic contractions to endothelin and PGF2. may be different. If protein kinase C activation should be the predominant mechanism for endothelin in pulmonary artery, then it may be more difficult to reverse this with relaxant drugs that lower intracellular calcium. 6 The study indicates that the airway-vascular selectivity of relaxant drugs can be spasmogen-dependent as well as dependent on the mechanism of action of the relaxant drug. Thus, relaxant drugs, whether of interest for their airway or vascular effects, should be tested against a full range of spasmogens of likely pathophysiological importance.

Functional effects of 4-aminopyridine (4-AP) on pulmonary and systemic vessels from normoxic control and hypoxic pulmonary hypertensive rats

“…In pulmonary artery the evidence to support a mechanism other than depolarization is indirect; namely, the vasorelaxant responses to the L-type calcium channel blocker, felodipine (J. C. Wanstall and J.A. Kaye, unpublished observations) and the potassium channel opener, pinacidil (O'Donnell et al 1991) are much less pronounced on ET-1-contracted pulmonary arteries than on pulmonary arteries contracted with other spasmogens. If it were assumed that ET-1 causes little or no membrane depolarization, then there would not be any accompanying opening of K V .…”

Role of potassium channels and nitric oxide in the relaxant effects elicited by β‐adrenoceptor agonists on hypoxic vasoconstriction in the isolated perfused lung of the rat

“…In this study, we investigated the effects of a non selective β‐adrenoceptor agonist (isoprenaline), a selective β 2 ‐adrenoceptor agonist (salbutamol) and a selective β 3 ‐adrenoceptor agonist (SR 59104A, Croci et al ., 1995 ) on the pulmonary vascular response to hypoxia, a physiopathological condition that produces vasoconstriction, to study potential dilator agents for the treatment of diseases such as pulmonary hypertension ( Dumas et al ., 1994 ). Isoprenaline, salbutamol and SR 59104A shared the ability to relax the pulmonary circulation during hypoxia ( O'Donnell et al ., 1991 ; Dumas et al ., 1998 ) and in doing so, the relaxant potencies of isoprenaline and salbutamol were similar to or higher than those observed in pulmonary artery and in various other normoxic tissues ( Jones et al ., 1990 ; Oriowo, 1994 ; Sooch & Marshall, 1996 ; Huang & Kwok, 1997 ). Our findings suggest that hypoxia does not influence the relaxant effects of β‐adrenoceptor agonists, thus contrasting with other investigations which reported a negative influence of hypoxia on the relaxant effects of these drugs in pulmonary arteries precontrated with adrenaline or U46619 ( McIntyre et al ., 1994 ; Wagner et al ., 1997 ).…”

The rabbit pulmonary cytochrome P450 arachidonic acid metabolic pathway: characterization and significance.

“…For example, the EETs (a) stimulate glucagon and insulin release from isolated rat pancreatic islets (14) and somatostatin release from the median eminence (15); (b) activate Na+/H+ exchange and are mitogenic in rat renal mesangial cells (12); (c) inhibit cyclooxygenase activity and platelet aggregation ( 16); and (d) cause stereoselective renal artery vasoconstriction (7) and mesenteric (9) and cerebral (73) of synthetic, HPLC-purified P450 arachidonic acid metabolites on airway smooth muscle contractile force using cylindrical segments of guinea pig hilar bronchi. Guinea pigs have been extensively used to study the response of airway smooth muscle to a variety of contractile and relaxant substances, largely because isolated guinea pig airways react in a fashion similar to that of isolated human airways (74,75). Furthermore, the similarities between the guinea pig and the rabbit pulmonary cytochrome P450 arachidonic acid monooxygenase pathways (65) justify the use of guinea pig bronchi for these studies.…”