Pinacidil-induced Relaxation in Pulmonary Arteries Isolated From Pulmonary Hypertensive and Normotensive Rats and Pre-contracted With Different Spasmogens

Wanstall, Janet C.; Kay, C.S.; O’Donnell, Stella R.

doi:10.1006/pulp.1994.1047

Cited by 10 publications

(8 citation statements)

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“…First, SIN-1, the NO donor examined in the present study, generates NO without requiring activation by tissue enzymes or sulphydryl groups. 19,21,23,24 In the present study, the reduction in potency of NO donors in arteries from pulmonary hypertensive rats was confirmed with another drug in this group, namely SIN-1. 37 Archer et al 37 have explained the selectivity of NO for large pulmonary arteries in terms of two other findings.…”

Section: Discussionsupporting

confidence: 76%

“…In contrast, responses to KATP channel openers, such as pinacidil, cromakalim and levcromakalim, are not impaired and are sometimes enhanced. 19,21,23,24 In the present study, the reduction in potency of NO donors in arteries from pulmonary hypertensive rats was confirmed with another drug in this group, namely SIN-1. However, there was no decline in the potency of KRN2391 in arteries from pulmonary hypertensive rats, except when glibenclamide was present in the experiments.…”

Section: Discussionsupporting

confidence: 76%

“…Alternatively, in pulmonary hypertensive rats, there may be an increase in the KATP channel opening effect of KRN2391 that offsets any decrease in the potency of the NO donor component. This possibility cannot be excluded because, in a previous study, the potency of another KATP channel opener, pinacidil, was actually increased in pulmonary hypertensive rats 23 (i.e. not merely unchanged as found for levcromakalim in the present study).…”

Section: Discussioncontrasting

confidence: 53%

“…[19][20][21][22][23][24] Hence, the third aim of the present study was to compare the potency of KRN2391 in pulmonary arteries from pulmonary hypertensive and control rats. [19][20][21][22][23][24] Hence, the third aim of the present study was to compare the potency of KRN2391 in pulmonary arteries from pulmonary hypertensive and control rats.…”

Section: Introductionmentioning

confidence: 99%

“…In pulmonary arteries from pulmonary hypertensive rats, the potency of NO donors is reduced when compared with data obtained in arteries from control rats, whereas that of KATP channel openers is not. [19][20][21][22][23][24] Hence, the third aim of the present study was to compare the potency of KRN2391 in pulmonary arteries from pulmonary hypertensive and control rats.…”

Section: Introductionmentioning

confidence: 99%

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Krn2391: Dual Action On Rat Pulmonary Artery And No Loss Of Potency In Pulmonary Hypertension

Wanstall

Gambino

Thomas

2000

Clin Exp Pharma Physio

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1. The pulmonary vasorelaxant properties of KRN2391 (N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide) were examined in isolated ring preparations of main (MPA) and intralobar (IPA) pulmonary artery from control and pulmonary hypertensive rats (exposure to hypoxia, 10% oxygen, for 1 week). 2. On both MPA and IPA, pulmonary vasorelaxant responses were inhibited by methylene blue (10 micromol/L) or glibenclamide (1 or 10 micromol/L). Thus, KRN2391 has the properties of both a nitric oxide (NO) donor and a K(ATP) channel opener on rat pulmonary arteries. 3. KRN2391 was more potent and gave a greater maximum relaxation on MPA (-log EC(50) 6.47; maximum 92% reversal of induced contraction) than on IPA (-log EC(50) 6.09; maximum 58% reversal of induced contraction). Comparable differences between MPA and IPA were seen for SIN-1 (NO donor) and levcromakalim (K(ATP) channel opener). 4. KRN2391 was equipotent in MPA from control and pulmonary hypertensive rats but, when glibenclamide (10 micromol/L) was present, KRN2391 was six-fold less potent in preparations from pulmonary hypertensive than control rats. An eight-fold reduction in potency was seen for SIN-1 (no glibenclamide) in arteries from pulmonary hypertensive rats, confirming previous findings with other NO donors. 5. It is concluded that the dual mechanism of action of KRN2391 accounts for the finding that this drug is equally potent in pulmonary arteries from pulmonary hypertensive and control rats. In the context of pulmonary hypertension, this property of the drug could give it an advantage over drugs that act solely as NO donors because these decline in potency, at least in animal models of this disease.

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