Nitrovasodilator‐induced relaxation and tolerance development in porcine vena cordis magna: dependence on intact endothelium

1 We investigated whether acute (5 h) and chronic (3 days) transdermal glyceryl trinitrate (GTN) patches could cause the development of tolerance in terms of haemodynamics and vascular reactivity in the conscious rabbit. The effects of haemodynamic tolerance were assessed on arterial pressure, heart rate and the baroreflex control of heart rate, while hindquarter vascular reactivity in response to dilator and constrictor drugs and reactive hyperaemia were used to assess vascular tolerance. 2 Seven days prior to experiments, an inflatable cuff, a pulsed Doppler flow probe and an indwelling intra-aortic catheter (for i.a. agonist infusions) were implanted around the lower abdominal aorta. 3 In acute experiments, the effects of 0-5 h treatment with transdermal GTN (0 Sham), 10 or 20 mg 24 h-') on MAP, HR and the baroreflex were examined. Chronic experiments were performed on three separate days (days 0 -before, 4 -with GTN patch and 8 -recovery). On each day, the baroreflex, reactive hyperaemic responses and hindquarter vascular dose-response curves to i.a. GTN, adenosine, acetylcholine, S-nitroso-N-acetylpenicillamine (SNAP) and methoxamine were assessed. On days 1-4, GTN was administered transdermally via a patch(es) (10 mg 24 h-' (low dose) or 20 mg 24 h-' (high dose); renewed every 24 h). 4 Acute treatment with 20 mg GTN 24 h', but not with 0 (n=4) or 10 mg GTN 24 h-' (n=4), caused a significant fall in MAP (-8+1 mmHg; n = 4) and resetting of the baroreflex by 5 h. Chronic GTN caused a significant fall in MAP of 8 + 2 and 8 + 2 mmHg on day 4 with low (n = 8) and high dose (n = 8), respectively, with no change in HR. There was no significant change to hindquarter vascular reactivity to i.a. infusion of GTN, nor were there any significant differences in the reactivity to i.a. adenosine, acetylcholine, SNAP or methoxamine with either low or high doses of GTN. 5 Chronic GTN treatment with low and high dose patches caused a parallel leftward shift ('resetting') of the baroreflex on day 4. By day 8, the baroreflex had still not recovered from this leftward shift. 6 In the rabbit, chronic exposure to clinical nitrate patches caused haemodynamic compensation and baroreflex resetting but no evidence of vascular reactivity tolerance. Novel NO donor drugs and delivery regimens which provide intermittent dosing may prevent the development of haemodynamic resetting rather than preventing vascular tolerance, a commonly perceived difficulty in chronic nitrate therapy.

Section: Vascular Tolerancesupporting

confidence: 83%

Section: Vascular Tolerancementioning

confidence: 99%

Baroreflex resetting but no vascular tolerance in response to transdermal glyceryl trinitrate in conscious rabbits

Serone

Angus

Wright

1996

“…SNAP was synthesized according to Field et al (1978) as described previously (Kojda et al , 1994). NO‐release from SNAP was measured in KH‐buffer by use of a polarographic method (ISO‐NO‐electrode, WPI, Berlin, Germany).…”

Section: Methodsmentioning

confidence: 99%

Positive inotropic effect of exogenous and endogenous NO in hypertrophic rat hearts

Kojda

Kottenberg

Stasch

et al. 1997

Self Cite

1 Recent evidence suggests that nitric oxide (NO) modulates the contractile force of isolated cardiomyocytes in a biphasic manner. We sought to examine whether myocardial hypertrophy induced by long-term hypertension changes the eects of NO on myocardial contractility. 2 We used constant¯ow perfused non-paced Langendor preparations of hearts of 3 months old Wistar rats (WIS, n=23) and of stroke-prone spontaneously hypertensive rats (SHR) at the age of 10 months (SHR10, n=16) and 15 months (SHR15, n=8). Changes of left ventricular peak pressure (LVP), +dP/dt max , 7dP/dt max , coronary perfusion pressure (CPP) and heart rate (HR) were recorded after infusion of noradrenaline (NA, 0.1 mmol l 71 ), glyceryl trinitrate (GTN, 1 ± 100 mmol 13 Long-term hypertension induced myocardial hypertrophy and an abnormal response to NA. The relative heart weight (in mg kg 71 ) increased from 2.95+0.04 (WIS) to 6.67+0.34 (SHR15), while the increase in +dP/dt max induced by NA was absent in SHR15. Hearts of SHR10 showed an intermediate response.4 Both SNAP and GTN signi®cantly increased LVP, +dP/dt max and 7dP/dt max in hearts of WIS and of SHR. In WIS but not in SHR10, SNAP also increased HR. In SHR10 the lowest concentration of SNAP (1 mmol 1 71) showed no eect on contractility but a signi®cantly diminished reduction of CPP suggesting inactivation of extracellularly released NO in the coronary circulation of SHR. 5 L-NOARG signi®cantly reduced contractility in hearts of WIS and of SHR to a similar extent. At a concentration of 1 mmol 1 71 L-NOARG also reduced HR. 6 These results suggests that positive inotropic eects of exogenous and endogenous NO are not changed in hypertension induced myocardial hypertrophy.

“…Despite the suggestion that NO may impair nitrate biotransformation (Kojda et al , 1994), evidence that NO per se is a major mediator of cellular nitrate tolerance in vitro is lacking, since exogenous NO is unable to mimic fully nitrate self‐tolerance (Yeates & Schmid, 1992). Recently, several studies have described the ability of antioxidants to attenuate or even abrogate, tolerance to organic nitrates assessed both in vitro (Yeates & Schmid, 1992; Münzel et al , 1995; Laight & Anggard, 1995; Marfella et al , 1995) and in vivo (Bassenge et al , 1995; Bassenge & Fink, 1995; Skatchkov et al , 1995; Utep‐bergenov et al , 1996).…”

Section: Introductionmentioning

confidence: 99%

Investigation of role for oxidant stress in vascular tolerance development to glyceryl trinitrate in vitro

Laight

Carrier

Änggård

1997

The role of reactive oxygen species (ROS) during the development of vascular cellular tolerance to glyceryl trinitrate (GTN), was studied in the rat isolated aorta. Nitrate tolerance induced by a 30 min incubation with GTN (30 or 100 μm) in vitro, was not affected by pretreatment with the intracellular superoxide anion scavenger, tiron (10 mm), or the intracellular scavenger of peroxynitrite anion and hydroxyl radical, dimethylsulphoxide (DMSO, 0.2% v v−1). In contrast, pretreatment with the intracellular sulphydryl donor, N‐acetyl‐l‐cysteine (NAC, 1 mm), significantly attenuated GTN‐induced tolerance. Pretreatment with a putative inhibitor of oxidant stress‐mediated, transcription factor NF‐κ B activation, pyrrolidine dithiocarbamate (PDTC, 50 μm), an inhibitor of gene activation by NF‐κB, dexamethasone (1 μm) or an inhibitor of protein synthesis, cycloheximide (10 μm), failed to affect tolerance development to GTN. Pretreatment with DMSO (0.2% v v−1) or PDTC (50 μm) depressed non‐tolerant vasorelaxation to GTN (1 nm1 μm) per se. Tiron (10 mm) abolished the reduction of ferricytochrome c by a superoxide anion generating system, assessed photometrically in vitro. In contrast, DMSO (0.2% v v−1), NAC (1 mm) and PDTC (50 μm) were without effect. Our data suggests that neither oxidant stress nor nuclear activation, is important in the development of cellular tolerance to GTN in rat isolated aortic smooth muscle. British Journal of Pharmacology (1997) 120, 1477–1482; doi: