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J C Wanstall

Publications and source records attributed to J C Wanstall.

At least 37 records · Page 2Linked to original sources
PubMed1996

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 those 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.

Animals↗
PubMed1995

Evidence that nitric oxide from the endothelium attenuates inherent tone in isolated pulmonary arteries from rats with hypoxic pulmonary hypertension.

1. The inherent contractile tone, and its modulation by the endothelium, have been studied in isolated pulmonary artery preparations taken from rats in which pulmonary hypertension was induced by exposure to a hypoxic environment (10% O2) for 14 days. Control rats were housed in room air. 2. All preparations in which the endothelium was left intact relaxed in response to acetylcholine (43 +/- 4% and 54 +/- 9%, reversal of the noradrenaline-induced contraction in control and hypoxic rats, respectively) indicating that the endothelium was functional in both groups of rats. 3. Exposure of the preparations to Ca(2+)-free physiological salt solution containing 2 mM EGTA for 30-40 min had no effect on preparations from control rats but caused relaxation in preparations from hypoxic rats. The relaxation (taken as a measure of the inherent tone in the preparations) was larger in preparations without endothelium (14.5 +/- 1.9 mN mm-2; n = 5) than in preparations with endothelium (9.1 +/- 1.2 mN mm-2; n = 5). 4. In preparations from hypoxic rats the magnitudes of the contractions to 80 mM K+ and to noradrenaline (0.1 microM) were less than in preparations from control rats. This may have been because the preparations from hypoxic rats were already partially contracted due to the inherent tone. 5.The nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 0.1-1 100 microM)had negligible effect on preparations from control rats or on endothelium-denuded preparations from hypoxic rats, but produced concentration-dependent contractions (maximum contraction 7.4 +/- 0.7 mN mm-2 (n = 4) with 100 micro M) in endothelium-intact preparations from hypoxic rats. This effect of L-NAME was prevented by L-arginine (1 mM) but not by D-arginine (1 mM).6. Contractions to L-NAME were also seen in endothelium-intact arteries from control rats if the preparations were first partially contracted by exposure to K+, endothelin, U46619 (thromboxane mimetic)or noradrenaline.7 It is concluded that isolated pulmonary artery rings from hypoxic rats, but not those from control rats, have substantial inherent tone. This inherent tone is normally attenuated by the generation of an endothelium-derived factor that is probably NO. A stimulus for the release of NO from the endothelium may be the contraction of the underlying smooth muscle, whether the contraction is inherent in the tissue, as in preparations from hypoxic rats, or is induced by a vasoconstrictor spasmogen.

Acetylcholine↗
PubMed1995

Vasorelaxation by pinacidil in isolated perfused lungs is enhanced in rats with hypoxic pulmonary hypertension but is dependent on the constrictor.

The potassium channel opening drug, pinacidil, has been examined in isolated perfused lungs taken from rats with hypoxic pulmonary hypertension (housed in 10% oxygen for 7 days) and control rats. Inhibition by pinacidil (1 to 30 microM) of noradrenaline (NA)-induced vasoconstriction (NA infusions; beta-adrenoceptors blocked) and of hypoxic pulmonary vasoconstriction (HPV; ventilation for 3.5-4.5 min with 0-1% oxygen) were compared. The vasoconstrictor responses in preparations from control and hypoxic rats, respectively, were (mm Hg) NA 6.6 +/- 0.68 (6); 8.2 +/- 1.45 (9); HPV 7.8 +/- 1.03 (12); 8.8 +/- 0.93 (13). These responses were reversibly inhibited by pinacidil. In lungs from control rats pinacidil was 10-fold less potent against NA than against HPV, but in lungs from hypoxic rats it was equipotent against NA and HPV. When tested against NA, but not HPV, pinacidil was significantly more potent in lungs from hypoxic rats than control rats. It is postulated that NA-induced vasoconstriction in lungs from hypoxic rats, and HPV in both groups of rats, involve calcium influx through voltage-operated calcium channels. Consequently, these responses are readily inhibited by drugs such as pinacidil which open potassium channels and hyperpolarise the cell membrane. In contrast in lungs from control rats, NA-induced constriction may involve mainly intracellular calcium release and thus be less readily inhibited by the hyperpolarising effect of pinacidil.

Animals↗
PubMed1994

Pinacidil-induced relaxation in pulmonary arteries isolated from pulmonary hypertensive and normotensive rats and pre-contracted with different spasmogens.

Vasorelaxant responses to the potassium channel opening drug, pinacidil, were obtained on preparations of pulmonary artery and aorta taken from rats with pulmonary hypertension (induced by chronic hypoxia or monocrotaline) and pre-contracted either submaximally with endothelin-1 (ET-1), PGF2 alpha, U46619 (thromboxane-mimetic) or noradrenaline (NA), or with 80 mM K+. In pulmonary artery, but not aorta, from pulmonary hypertensive rats the maximum relaxant response to pinacidil was increased, when compared with data in control rats, irrespective of the spasmogen used to precontract the tissues. The increase in maximum was associated with relaxation to below the tissue resting baseline and probably reflected the presence of inherent contractile tone in arteries from pulmonary hypertensive rats. In addition the potency (-log EC50) of pinacidil was increased in pulmonary arteries from pulmonary hypertensive rats but this was seen only in preparations contracted with ET-1 (30-fold increase) or NA (seven-fold increase) and not in those contracted with PGF2 alpha, U46619 or K+. As a result, in ET-1 contracted preparations from pulmonary hypertensive rats pinacidil was 29-fold more potent on pulmonary artery than on aorta. To explain the increase in potency it is speculated that during the development of pulmonary hypertension the mechanism whereby ET-1 and NA contract pulmonary arteries may change from one in which Ca2+ influx plays only a minor role to one in which Ca2+ influx predominates, although no direct evidence to support this speculation has yet been obtained.

Animals↗
PubMed1994

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)

Animals↗
PubMed1993

Effects of atrial natriuretic peptide and nitroprusside on isolated pulmonary resistance and conduit arteries from rats with pulmonary hypertension.

1. The relaxant effects of atrial natriuretic peptide (ANP) and nitroprusside were studied on prostaglandin F2 alpha (PGF2 alpha)-contracted preparations of pulmonary resistance vessels (internal diameter 200-500 microns) and main pulmonary arteries taken from rats with pulmonary hypertension induced by monocrotaline (105 mg kg-1, s.c., 4 weeks previously). Control rats received saline. 2. In preparations from monocrotaline-treated rats, the potencies (negative log EC50) of ANP on resistance vessels (8.45) and main pulmonary arteries (8.25) were similar to those obtained in vessels from control rats (8.78 and 8.53 respectively), whereas those of nitroprusside were significantly less than in controls in both resistance vessels (7.13 compared with 7.63 in controls; three fold decrease in potency) and main pulmonary arteries (6.92 compared with 8.17 in controls; 18 fold decrease in potency). 3. On pulmonary resistance vessels from monocrotaline-treated rats, the maximum relaxant responses to ANP and nitroprusside, and also to pinacidil, were increased compared with controls, and reversal of the PGF2 alpha-induced contraction by these drugs was greater than 100%. In contrast, on main pulmonary arteries from monocrotaline-treated rats, the maximum relaxations to ANP and nitroprusside were not increased relative to controls, and reversal of PGF2 alpha was not greater than 100%. 4. Since the high potency of ANP on pulmonary resistance and conduit arteries is retained in vessels from rats with pulmonary hypertension, whether induced by monocrotaline (this study) or by chronic hypoxia (previous findings), it is postulated that elevation of plasma levels of ANP by use of drugs that inhibit the breakdown of this endogenous peptide, may be one approach to the pharmacological treatment of pulmonary hypertension.

Animals↗
PubMed1992

Reduced relaxant potency of nitroprusside on pulmonary artery preparations taken from rats during the development of hypoxic pulmonary hypertension.

1. Relaxant responses to nitroprusside were examined on U46619-contracted pulmonary artery ring preparations from rats exposed to hypoxia, in chambers containing 10% oxygen, for 1, 3, or 14 days, or for 14 days followed by 12 days in room air. Control rats were housed in room air. 2. After 3 days of hypoxia (but not 1 day), rats had elevated pulmonary artery pressure, right ventricular hypertrophy and polycythemia. After 14 days of hypoxia there was, in addition, hypertrophy of the pulmonary artery. In rats returned to room air for 12 days after 14 days of hypoxia, there was still some right ventricular and vascular hypertrophy but no increase in pulmonary artery pressure or polycythemia. 3. The potency (neg log EC50) of nitroprusside on pulmonary arteries taken from rats after 3 or 14 days of hypoxia was significantly less than on preparations from control rats (3 and 11 fold, respectively). This was not seen after 1 day of hypoxia or after 14 days of hypoxia followed by 12 days in room air. Removal of the endothelium from the preparations had no effect on the potency of nitroprusside in control or hypoxic rats (14 days). 4. In preparations from hypoxic, but not control, rats (14 days), the maximum response to nitroprusside was > 100% (177% reversal of the U46619 contraction) in the absence, but not in the presence, of the endothelium, indicating that pulmonary arteries from hypoxic rats had inherent tone which could be counteracted by a relaxing factor from the endothelium. 5. Exposure of rats to hypoxia (14 days) did not affect the potency of nitroprusside on aorta or trachea.6. It is concluded that exposure of rats to hypoxia results in reversible desensitization of the vascular smooth muscle of pulmonary artery to nitroprusside. The time course of this desensitization suggests that it is probably associated with the elevated pulmonary artery pressure or maintained hypoxaemia rather than with the vascular hypertrophy.7. It is postulated that the increase in pulmonary artery pressure and/or the maintained hypoxaemia may cause chronic release of nitric oxide from the pulmonary vascular endothelium or smooth muscle resulting in desensitization of soluble guanylate cyclase to the action of nitroprusside.

Animals↗
PubMed1992

Responses to vasodilator drugs on pulmonary artery preparations from pulmonary hypertensive rats.

1. Relaxant responses to six vasodilator drugs, with different mechanisms of action, were examined on noradrenaline (0.1 microM)-contracted ring preparations of pulmonary artery and aorta taken from rats with pulmonary hypertension induced by monocrotaline or chronic hypoxia. 2. On pulmonary artery preparations from monocrotaline-treated rats, compared with controls, (a) the maximum relaxation to pinacidil and cromakalim was significantly increased, but their potency (negative log EC50) was unchanged, (b) the potencies of nitroprusside and sodium nitrite were significantly reduced (10 fold and 3 fold respectively), but there was no change in the maxima, (c) for nicorandil there was an increase in maximum relaxation and a decrease in potency (3 fold), and (d) for atriopeptin II there was no change in potency or maximum. 3. The increase in maximum relaxation for pinacidil and the decrease in potency for nitroprusside were also demonstrated in pulmonary artery preparations from rats with chronic hypoxic pulmonary hypertension. The other four drugs were not examined in preparations from hypoxic rats. 4. In both models of pulmonary hypertension, no change in maximum response or potency was seen on aortic preparations for any of the vasodilator drugs. 5. In control preparations, none of the drugs was more potent on pulmonary artery than on aorta (i.e. they were not pulmonary-selective). In preparations from pulmonary hypertensive rats, pinacidil was selective for pulmonary artery, in contrast to nitroprusside which was selective for aorta.6. It is concluded that the development of pulmonary hypertension in rats is accompanied by changes in the responsiveness of the pulmonary arteries to some vasodilator drugs; whether or not these changes occur depends on the mechanism of action of the vasodilator drug, but they are independent of the method of inducing pulmonary hypertension.7. It is postulated that the reduction in potency seen for nitroprusside, sodium nitrite and nicorandil may be due to desensitization of soluble guanylate cyclase in pulmonary vascular smooth muscle in pulmonary hypertension.

Animals↗
PubMed1991

Increased relaxation by felodipine on pulmonary artery from rats with monocrotaline-induced pulmonary hypertension does not reflect functional impairment of the endothelium.

The effects of the calcium entry blocking drug, felodipine, were examined against the spasmogens, noradrenaline, 5-hydroxytryptamine (5-HT) and endothelin on pulmonary artery preparations taken from rats treated with saline or monocrotaline (endothelium present) and from untreated rats (endothelium removed). In saline-treated rats, the potencies (negative log EC50) of noradrenaline, 5-HT and endothelin were 7.97, 5.25 and 8.39 respectively, and felodipine (10 nM) reduced the maximum responses to noradrenaline (28% reduction) and 5-HT (47% reduction), without reducing their potency. In monocrotaline-treated rats, the potencies of noradrenaline, 5-HT and endothelin were 8.43, 6.42 and 8.44, and felodipine significantly reduced the potencies of noradrenaline (0.60 log units) and 5-HT (0.48 log units) in addition to reducing their maximum responses (60% and 69% reductions, respectively). Felodipine had no effect on endothelin in either group of rats. Removal of the endothelium caused a small increase in the potency of 5-HT, but had no influence on the other spasmogens or on the effects of felodipine. It is concluded that monocrotaline treatment of rats leads to increases in a) the potencies of noradrenaline and 5-HT on pulmonary artery, and b) the effectiveness of felodipine against these two spasmogens. Neither of these increases can be attributed to monocrotaline-induced endothelial cell damage.

Animals↗
PubMed1991

Tissue selectivity and spasmogen selectivity of relaxant drugs in airway and pulmonary vascular smooth muscle contracted by PGF2 alpha or endothelin.

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 alpha (PGF2 alpha) 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 alpha 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 airway-vascular selectivity of the relaxant drugs varied with the drug. 4. On pulmonary artery, pinacidil, nitroprusside and forskolin were all more potent against PGF2 alpha than against endothelin, i.e. 42, 4 and 7 fold respectively. On trachea, these drugs were equipotent against PGF2 alpha 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 alpha 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.

Animals↗
PubMed1991

Endothelin-induced contractions of rat pulmonary artery are not affected by drugs acting on potassium channels.

The effects of the potassium channel opening drug, pinacidil, and the potassium channel closing drug, tetraethylammonium (TEA), on concentration-response (contraction) curves to spasmogens on rat pulmonary artery were examined. Pinacidil (3 microM) decreased, and TEA (2 mM) increased contractions to 5-hydroxytryptamine (5-HT) more than it did to noradrenaline but contractions to endothelin-1 were only minimally affected. It is concluded that the mechanism whereby endothelin-1 contracts rat pulmonary artery differs from that of noradrenaline or 5-HT in that it does not involve membrane depolarization or calcium entry through voltage operated calcium channels.

Animals↗
PubMed1990

Endothelin and 5-hydroxytryptamine on rat pulmonary artery in pulmonary hypertension.

Contractile responses to endothelin, 5-hydroxytryptamine (5-HT), noradrenaline and potassium were obtained on isolated preparations of pulmonary artery from rats made pulmonary hypertensive by an injection of monocrotaline (105 mg/kg s.c.) 4 weeks previously. When compared with data obtained in control rats, the potencies (negative log EC50 values) for 5-HT, noradrenaline and potassium were increased (30, 3- and 3-fold, respectively), and the maximum contractions (mN/mm2) to endothelin, noradrenaline and potassium were reduced (65, 40 and 45% reduction). These changes were not seen 2 weeks after injection of monocrotaline, before pulmonary hypertension developed, or in preparations of aorta. It is concluded that monocrotaline-induced pulmonary hypertension affects pulmonary vascular responsiveness to spasmogens differentially. The comparative importance of endothelin and 5-HT as pulmonary vasoconstrictors may change in monocrotaline-induced pulmonary hypertension, there being an increase in responsiveness to 5-HT and a decrease in responsiveness to endothelin.

Acetylcholine↗
PubMed1990

Pinacidil antagonism of endothelin-induced contractions of smooth muscle in the lungs: differences between tracheal and pulmonary artery preparations.

Contractions to endothelin and their reversal by pinacidil have been examined in isolated preparations of guinea pig and rat trachea and rat pulmonary artery. Indomethacin attenuated endothelin (less than or equal to 10 nM) on guinea pig trachea, but not on the rat tissues. This indicates that part of the effect of endothelin on guinea pig trachea is indirect and mediated by cyclooxygenase products. Endothelin (direct effects) was more potent on pulmonary artery than on guinea pig or rat trachea (negative log EC50 values: 8.42, 7.71 and 7.76, respectively) and was also a more effective spasmogen on pulmonary artery (maximum was the tissue maximum, i.e., greater than or equal to 80 mM K+) than on trachea (maximum was 60-70% of the tissue maximum to 10 microM carbachol). Pinacidil was less effective preventing (anti-spasmogenic) than reversing (spasmolytic) contractions to endothelin on either tissue type. This is compatible with different mechanisms for the initiation and maintenance of smooth muscle contraction in these tissues. As a spasmolytic against endothelin (0.03 microM), pinacidil was less potent on rat pulmonary artery than on guinea pig or rat trachea (negative log IC50 values: 4.45, 5.65 and 5.49, respectively). This may reflect 1) the greater tone induced by endothelin on pulmonary artery, 2) a smaller receptor reserve for endothelin in trachea and/or 3) a different mechanism whereby endothelin contracts pulmonary vascular smooth muscle compared with tracheal smooth muscle.

Animals↗
PubMed1989

Influence of age on calcium entry blocking drugs in rat aorta is spasmogen-dependent.

On rat aorta, diltiazem (0.2 microM) caused parallel shifts in the Ca2+ concentration-response curves (K+-depolarized preparations). In aged (greater than 19 months) rats, this shift (0.57 log units) was smaller than in young (2 months) rats (1.04 log units) indicating an age-related reduction in the potency of diltiazem. Felodipine (10 nM), like diltiazem (1 microM) in a previous study, depressed the maximum response to noradrenaline more in preparations from aged rats (40% reduction) than from young rats (14% reduction). This increase in the effect of felodipine or diltiazem vs. noradrenaline reflected a reduction in the alpha-adrenoceptor reserve for noradrenaline. Accordingly, the depression in the maximum responses to other spasmogens (5-HT or K+) by 1 microM diltiazem was not increased by age (5-HT, young 59%, aged 49% reduction; K+, young 65%, aged 70% reduction). This aging can have two opposing influences on the effects of Ca2+ entry blocking drugs on rat aorta - a decrease in potency, yet an increase in effectiveness against spasmogens with a reduced receptor reserve.

Aging↗
PubMed1989

Vasodilator responses to dopamine in rat perfused mesentery are age-dependent.

1. Dose-dependent vasodilator responses to dopamine, isoprenaline, noradrenaline, 3-isobutyl-1-methylxanthine (IBMX) and sodium nitroprusside were obtained in isolated perfused mesentery preparations, taken from reserpine-treated rats of different ages. The preparations were pretreated with phenoxybenzamine (1 microM) and perfused with physiological salt solution containing cocaine (10 microM), additional KCl (20 mM) and vasopressin (0.1 microM). 2. Vasodilator responses to dopamine were abolished by the dopamine1 (DA1)-selective antagonist SCH 23390 (10 nM) and those to isoprenaline by propranolol (1 microM), but the vasodilator responses to noradrenaline were abolished only when SCH 23390 and propranolol were used together. This indicated that dopamine was acting via DA1-receptors, isoprenaline via beta-adrenoceptors and that noradrenaline could act via DA1-receptors and beta-adrenoceptors in this preparation. 3. Responses to all the vasodilator drugs decreased in magnitude between the ages of 1 and 2 months. Responses to dopamine declined further in 4 month-old rats and were negligible at 6 or 22-24 months of age. Responses to isoprenaline were well maintained up to 6 months of age, but were negligible at 22-24 months. 4. It is concluded that, in the rat mesenteric vasculature, there is a non-specific decline in responses to vasodilator drugs during development (1 to 2 months). Subsequently there is a specific decline in DA1-receptor-mediated and beta-adrenoceptor-mediated responses; the former are lost at an earlier age than the latter. This different time course suggests that age influences receptor numbers, or their coupling to adenylate cyclase, rather than a post-receptor event in the adenylate cyclase/cyclic AMP pathway.

Aging↗
PubMed1989

Age-dependence of the effects of pinacidil on rat aorta.

The effect of the K+ channel opening drug, pinacidil, has been examined on aortic ring preparations from young (2 months) and aged (greater than 24 months) rats. The potency (neg log IC50) values for pinacidil in relaxing K+ (20 mM)-contracted preparations were in the range expected for its K+ channel opening (hyperpolarizing) effects but were not significantly different between young (6.34) and aged (6.31) rats. Thus, ageing does not affect the drug's potency as a K+ channel opening drug. The more marked depression of the maximum response to noradrenaline by pinacidil (10 microM) in aged rats (85% reduction) compared with young rats (43% reduction), reflected a reduced alpha-adrenoceptor reserve for noradrenaline in preparations from aged rats. Pinacidil, in concentrations greater than 10 microM, was able to relax preparations contracted with 80 mM K+ suggesting that it may have a second mechanism which does not involve hyperpolarization. It was more potent in producing this effect on the preparations from aged rats.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Age influences responses of rat isolated aorta and pulmonary artery to the calcium channel agonist, Bay K 8664, and to potassium and calcium.

Responses of isolated ring preparations of aorta and pulmonary artery from young (2 months) and aged (19-21 months) rats have been obtained to five contractile agents with differing mechanisms of action. The potencies (negative log EC50 values), but not the absolute maximum contractions (mN/mm2), for potassium, calcium (in K+-depolarized preparations), and the calcium channel activator, Bay K 8644, were all reduced in preparations from aged, compared with young, rats, and this reduction was more pronounced in aorta than in pulmonary artery. In contrast, the age of the rats had no influence on responses (potency or maximum contractions) to caffeine or the ionophore, A23187, indicating that the contractile ability of the preparations per se was retained in the aged rats. Aortic preparations from young rats contracted to Bay K 8644 without prior depolarization, whereas those from aged rats required partial depolarization (with 6 mM KCl) before consistent contractile responses to Bay K 8644 could be obtained. It is concluded that the influence of age on vascular contractions varies (a) between contractile agents, depending on their mechanisms of action and (b) between blood vessel types. To explain the reduced potencies of Bay K 8644, potassium, and calcium in aorta from aged rats, it is postulated that the resting membrane potential may be more negative in the preparations from the aged rats.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗