Biomedical subjects

G J Dusting

Publications and source records attributed to G J Dusting.

At least 37 records · Page 2Linked to original sources

PubMed1995

Endogenous nitric oxide in cardiovascular disease and transplantation.

Nitric oxide (NO), derived from the vascular endothelium and other cells of the cardiovascular system, has important roles in physiological regulation of blood flow and may have pathophysiological functions in cardiovascular disease. The mechanisms involved in NO-induced vasodilatation and cytotoxicity are briefly reviewed in the context of inflammatory reactions and cardiovascular function. Although NO can hyperpolarize vascular smooth muscle, activation of the endothelium can induce hyperpolarization and vasodilatation by other means. Endogenous inhibitors of NO generated by leucocytes may compromise blood flow distribution after ischaemia and reperfusion injury. Chronic heart failure is associated simultaneously with impairment of endothelium-dependent vasodilatation and with excess production of NO via the inducible NO synthase (iNOS), although it is unclear whether the latter ameliorates or exacerbates ventricular dysfunction. Excess NO production is also one of the earliest signs of transplant rejection, and suppression of iNOS expression by immunosuppressant drugs such as cyclosporin A might be one means by which these drugs protect allografts. Disturbances in the activity of NOS isoforms in the artery wall also accompany the development of atherosclerosis, providing conditions propitious for vasospasm and thrombosis. Reversing the NO defects with therapeutic agents, including angiotensin converting enzyme (ACE) inhibitors, offers promise in protecting against some manifestations of vascular disease.

Angioplasty↗

PubMed1994

Effects of ageing on sensory nerve function in rat skin.

Human studies have shown an age-related decrease in modulation of skin vascular reactivity by sensory nerves that correlates with a decline in wound repair efficacy. Using a vacuum-induced blister model in the rat hind footpad, we have investigated age-related changes in pre- and post-terminal activity of primary afferents involved in skin neurovascular function. Changes in local skin blood flow were monitored using a laser Doppler flowmeter. Pre-terminal stimulation was achieved by electrical stimulation of the distal end of the sciatic nerve (10 V, 15 Hz and 0.5 ms) in three groups of young, old and neonatally pretreated capsaicin rats (3, 24 and 3 months old, respectively). The effect of post-terminal stimulation, achieved using local perfusion of 1 microM substance P (SP) over the blister base, was examined in young (3 months old), mature (12 months old) and aged (24 months old) rats. In addition to changes in SP responsiveness, other post-terminal changes studied included changes in smooth muscle reactivity to sodium nitroprusside (SNP), which acts directly on smooth muscle and to endothelial cell function using N-nitro-L-arginine (L-NORAG), a selective inhibitor of nitric oxide synthesis and endothelium-dependent relaxation. Electrical stimulation of the sciatic nerve in young rats induced an increase in local blood flow (within 1 min) that was maintained during the stimulation period, while the capsaicin group and the old group showed a significantly increased latency and decreased amplitude of the response.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗

PubMed1994

Cholinergic neurogenic vasodilatation is mediated by nitric oxide in the dog hindlimb.

OBJECTIVE: The aim was to investigate the role of nitric oxide (NO) in cholinergic neurogenic vasodilatation in the dog hindlimb using the NO synthase inhibitor, N-nitro-L-arginine (NOLA), and the NO precursor, L-arginine. METHODS: 20 dogs were anaesthetised with thiopentone and alpha chloralose and experiments were performed in the presence of noradrenergic neurone blockade with guanethidine (15 mg.kg-1 subcutaneously). Using stereotaxic procedures, specific sites in the hypothalamus were electrically stimulated (HS) to produce depressor and hindlimb vasodilator responses. In each experiment, responses to intra-arterial (ia) injections of acetylcholine and glyceryl trinitrate produced increases in femoral blood flow similar to those caused by HS. RESULTS: Vasodilator responses to HS and acetylcholine but not glyceryl trinitrate were reduced by the muscarinic receptor antagonists tropicamide (3-12 mg ia) or atropine (0.5 mg.kg-1 intravenously, i.v.). Administration of NOLA (5-15 mg.kg-1 ia) significantly attenuated the HS induced decrease in arterial pressure [delta AP: control = -21 (SEM 3) mm Hg v NOLA treated = -9(3) mm Hg, p < 0.005] and the increase in femoral blood flow [delta FBF: control = 43(7) ml.min-1 v NOLA treated = 17(4) ml.min-1, p < 0.005]. NOLA also significantly inhibited femoral vasodilator responses to acetylcholine [delta FBF: control = 47(6) ml.min-1 v NOLA treated = 35(6) ml.min-1, p < 0.05] whereas responses to glyceryl trinitrate were enhanced [delta FBF: control = 54(9) ml.min-1 v NOLA treated = 69(9) ml.min-1, p < 0.005]. In addition L-arginine (150-300 mg.kg-1 i.v.), but not D-arginine (150 mg.kg-1 i.v.), reversed the inhibitory effect of NOLA on HS induced dilator responses [delta FBF: NOLA treated = 14(4) ml.min-1 v L-arginine treated = 35(8) ml.min-1, n = 8; greater than NOLA treated, p < 0.05]. CONCLUSIONS: Vasodilatation in the dog hindlimb evoked by activation of cholinergic nerves involves the synthesis of NO; however the source of this NO remains to be determined.

Acetylcholine↗

PubMed1994

Prolonged regional vasoconstriction produced by NG-nitro-L-arginine in conscious sheep.

Nitric oxide (NO) is a potent endothelium-derived vasodilator whose synthesis can be blocked both in vitro and in vivo by structural analogues of its precursor, L-arginine (L-ARG). We examined the dose-response profile of one such analogue, NG-nitro-L-arginine (NOLA) in conscious sheep (n = 4) and used continuous monitoring techniques to study long-term changes in mean arterial pressure (MAP), heart rate (HR), and cardiac output (CO) and the relative responsiveness of the coronary, mesenteric, renal, and hindlimb vascular beds to NOLA [10 mg/kg, intravenous (i.v.) bolus] in 5 sheep. NOLA (3 and 10 mg/kg) increased MAP at 1 h from 73 +/- 4 to 86 +/- 3 mm Hg (p < 0.05) and 73 +/- 1 to 106 +/- 8 mm Hg (p < 0.05), respectively. CO and HR decreased significantly after 10 mg/kg NOLA. Plasma endothelin (ET) level was unchanged after all doses of NOLA. Continuous monitoring of MAP, CO, and blood flow for 24 h before and after NOLA injection showed that MAP increased rapidly owing to a decrease in total peripheral conductance (TPC), with short-term reflex decreases in HR and prolonged decreases in CO and stroke volume (SV). Coronary and iliac conductances changed comparatively little. Renal conductance decreased by 43% at 80 min, but was not different from control after 6 h. The greatest and most sustained decrease in conductance, by a maximum of 55% of control levels at 110 min, occurred in the mesenteric bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Suppression of nitric oxide production by cyclosporin A and FK506A in rat vascular smooth muscle cells.

1. The effects of the immunosuppressants cyclosporin A (CsA) and FK506 on nitric oxide (NO) synthesis induced by lipopolysaccharide (LPS) or cytokines were examined in rat vascular smooth muscle cells (VSMC) in culture. 2. CsA inhibited by up to 90% the accumulation of nitrite induced by LPS, but FK506 had a weaker effect on nitrite accumulation induced by LPS in these cells. Both CsA and FK506 (at 1 mumol/L) significantly inhibited nitrite production induced by recombinant murine interleukin-1 beta (rIL-1 beta). 3. Given their differing potency, it is likely that CsA and FK506 suppress induction of NO synthase through different intracellular mechanisms. This action could contribute to the side effects of CsA therapy.

Animals↗

PubMed1994

Involvement of nitric oxide in coronary vascular responses to 5-hydroxytryptamine in the anaesthetized greyhound.

1. The effect of the intracoronary (i.c.) injection of 5-hydroxytryptamine (5-HT; 0.1-1.0 micrograms/kg) was examined before and after inhibition of nitric oxide (NO) synthesis with N-nitro-L-arginine (NOLA; 5 mg/kg i.c.) in nine anaesthetized greyhounds. Before administration of NOLA, 5-HT increased coronary blood flow (CBF) but decreased large coronary artery diameter indicating simultaneous dilatation of resistance vessels and constriction of large arteries. 2. The administration of NOLA significantly decreased large coronary artery diameter and increased systemic arterial pressure. There was no significant effect on coronary vascular resistance or heart rate. In the presence of NOLA, the 5-HT-induced constriction of the large coronary artery was enhanced and the dilatation of the resistance vessels was reduced. In addition there was a secondary reduction in CBF, a response that was not observed before NOLA treatment. 3. The response to NOLA suggests that a basal release of NO is important in the regulation of coronary and systemic vascular tone. Nitric oxide is an important mediator of coronary vasodilator responses to 5-HT, and in addition the release of NO modulates 5HT-induced constriction of large coronary arteries.

Amino Acid Oxidoreductases↗

PubMed1994

Requirement for endothelium-derived nitric oxide in vasodilation produced by stimulation of cholinergic nerves in rat hindquarters.

1. We aimed to determine whether nitric oxide (NO) and/or the endothelium is involved in cholinergic neurogenic vasodilatation in the rat isolated hindquarters. 2. The abdominal aorta was cannulated for perfusion of the rat hindquarters with Krebs bicarbonate solution containing phenylephrine, to induce basal constrictor tone. In the presence of noradrenergic neurone blockade with guanethidine (200 mg kg-1, i.p.) electrical stimulation of peri-aortic nerves induced frequency-dependent decreases in hindquarters perfusion pressure, indicating vasodilatation. Both the endothelium-dependent vasodilator, acetylcholine (ACh) and the endothelium-independent vasodilator, sodium nitroprusside (SNP) induced dose-dependent decreases in perfusion pressure. In each experiment, responses to either nerve stimulation, ACh or SNP were recorded before and after treatment with saline vehicle, atropine (1 microM), NG-nitro-L-arginine (L-NOARG, 100 microM), L-arginine (1 mM), L-arginine plus L-NOARG, or 3-3 cholamidopropyl dimethylammonio 1-propanesulphonate (CHAPS, 30 mg). Hindquarters dilatation after each treatment was expressed as a percentage of the control response. 3. Following treatment with saline, responses to nerve stimulation and ACh were 99 +/- 9% and 107 +/- 10% of control, respectively demonstrating the reproducibility of these responses. Nerve stimulation-induced dilation was abolished by atropine (0 +/- 0% of control, P < 0.05) or reduced to 14 +/- 10% of control by NO synthase inhibition with L-NOARG (P < 0.05). Dilator responses to ACh were also abolished by atropine (0 +/- 0% of control, P < 0.05) or inhibited by L-NOARG (59 +/- 10% of control, P < 0.05), indicating that the neurogenic dilatation is cholinergic and is mediated by NO. The administration of the NO precursor, L-arginine, prevented the inhibitory effect of L-NOARG on dilator responses to nerve stimulation and ACh (L-arginine plus L-NOARG: 89 +/- 13% and 122 +/- 24% of control, respectively). In addition CHAPS, which removes endothelial cells, inhibited responses to both nerve stimulation (0 +/- 0% of control, P <0.05) and ACh (33 +/- 8% of control, P <0.05). In contrast,no treatment significantly reduced the vasodilator responses to SNP.4. These observations suggest that cholinergic neurogenic vasodilatation in the rat isolated hindquarters requires the synthesis and release of NO from the endothelium.

Acetylcholine↗

PubMed1992

Baroreceptor reflexes and vascular reactivity during inhibition of nitric oxide synthesis in conscious rabbits.

The effect of the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine (NOLA) on vascular reactivity and the baroreceptor heart rate reflex was examined in chronically instrumented conscious rabbits. NOLA (15 mg/kg i.v.) significantly increased mean arterial pressure and hindlimb vascular resistance and decreased heart rate. Increases and decreases in arterial pressure were produced by the intravenous injection of phenylephrine and sodium nitroprusside respectively and the values obtained relating mean arterial blood pressure to heart rate were fitted to a sigmoid curve. NOLA significantly reduced the lower plateau of the arterial pressure--heart rate curve but did not significantly affect baroreceptor sensitivity. Depressor and hindlimb vasodilator responses to acetylcholine were significantly impaired by NOLA whereas responses to sodium nitroprusside were significantly enhanced. The pressor and hindlimb vasoconstrictor responses to phenylephrine were significantly enhanced in the presence of NOLA. We conclude that the bradycardia produced by NOLA does not result from a change in baroreceptor sensitivity. The continuous generation of NO appears to be important in regulating basal vascular resistance and in modulating vascular reactivity to both vasodilator and vasoconstrictor agents.

Acetylcholine↗

PubMed1992

Inhibition of NO synthesis has an additive effect on hypertension induced by ACTH in conscious rats.

1. The haemodynamic and metabolic effects of oral intake of approximately 30 mg/kg per day N-nitro-L-arginine (NOLA) were examined in sham and adrenocorticotrophin (ACTH, 0.5 mg/kg per day) treated conscious Sprague-Dawley rats (n = 33). 2. NOLA administration produced an increase in systolic blood pressure of 24 +/- 6 mmHg (P < 0.001), but did not alter food or water intake, urine volume or electrolyte excretion in rats not treated with ACTH. 3. Compared with sham injection, ACTH-treated rats demonstrated an increase in systolic blood pressure (water + sham, 3 +/- 1 mmHg; water + ACTH, 16 +/- 3 mmHg; P < 0.001), loss of bodyweight, and increases in water intake and urine volume. 4. The magnitude of the blood pressure rise in ACTH-treated rats was greater in those receiving NOLA than in those drinking water only (water + ACTH, 16 +/- 3 mmHg; NOLA + ACTH, 37 +/- 3 mmHg; P < 0.05). Metabolic changes were similar. 5. Inhibition of nitric oxide is unlikely to be a major determinant of ACTH-induced hypertension in the rat, since NOLA increased blood pressure whether or not ACTH was administered, indicating an additive effect of ACTH and NOLA administration.

Adrenocorticotropic Hormone↗

PubMed1992

Inhibition of nitric oxide synthase specifically enhances adrenergic vasoconstriction in rabbits.

1. The effect of inhibition of nitric oxide biosynthesis using N-nitro-L-arginine (NOLA) was examined in conscious rabbits and rabbit isolated aortae. 2. In autonomically blocked conscious rabbits intravenous infusion of NOLA (15 mg/kg) significantly increased arterial pressure and hindlimb vascular resistance but did not affect heart rate. Depressor and hindlimb vasodilator responses to acetylcholine (3-12 micrograms/kg per min) were significantly attenuated in the presence of NOLA. In contrast, NOLA significantly enhanced responses to intravenous infusion of glyceryl trinitrate (10-40 micrograms/kg per min) in vivo. 3. Infusion of noradrenaline (1-4 micrograms/kg per min) or the release of neuronal noradrenaline in response to the infusion of tyramine (80-320 micrograms/kg per min) increased arterial pressure and hindlimb vascular resistance in autonomically blocked conscious rabbits. After the administration of NOLA, the vasoconstrictor responses to both noradrenaline and tyramine were significantly enhanced. 4. In isolated rabbit aortae, NOLA (10 mumol/L) significantly impaired relaxant responses to acetylcholine but did not affect responses to glyceryl trinitrate. NOLA enhanced contractile responses to the adrenoceptor agonists noradrenaline and phenylephrine but did not affect the contractile responses to the thromboxane-mimetic U46619. 5. These data indicate that in autonomically blocked conscious rabbits, NOLA causes systemic vasoconstriction, impairs dilator responses to acetylcholine and enhances dilator responses to glyceryl trinitrate. In addition, NOLA enhances constrictor responses to both exogenous and neuronally-released noradrenaline. These results suggest that nitric oxide is important in the regulation of normal vascular tone and in the modulation of vascular responses to vasodilator and vasoconstrictor agents.

Acetylcholine↗

PubMed1992

Impaired endothelium-dependent relaxation of dog coronary arteries after myocardial ischaemia and reperfusion: prevention by amlodipine, propranolol and allopurinol.

1. Anaesthetized, open-chest dogs were subjected to 60 min of left circumflex coronary artery occlusion followed by 90 min of reperfusion. Endothelium-dependent and -independent relaxant responses of the isolated coronary arterial rings were then investigated. 2. The endothelium-dependent, acetylcholine-induced relaxation of ischaemic/reperfused arterial rings was significantly attenuated in comparison to control rings (1.9 fold rightward shift, ischaemic/reperfused maximum relaxation = 57 +/- 13% of control maximum relaxation; P less than 0.05). In contrast, glyceryl trinitrate produced similar relaxant responses in control and ischaemic rings. 3. Pretreatment of dogs with either amlodipine (3 micrograms kg-1 min-1, i.v.) or propranolol (1 mg kg-1, i.v.) completely prevented the postischaemic impairment of endothelium-dependent relaxant responses (100 +/- 3% and 90 +/- 5% of control maximum relaxation, respectively). 4. Allopurinol pretreatment (25 mg kg-1, p.o. 24 h previously, plus 50 mg kg-1 i.v. 5 min before arterial occlusion) partially protected against endothelial dysfunction by preventing the ischaemia-induced rightward shift of the acetylcholine relaxation curve and increasing the maximum relaxation response (83 +/- 7% of control rings). 5. These results confirm that endothelium-dependent coronary vascular relaxation is impaired by ischaemia and reperfusion, and that the ischaemia-induced impairment is reduced by pretreatment with amlodipine, propranolol or allopurinol.

Acetylcholine↗

PubMed1992

Nitric oxide and sensory nerves are involved in the vasodilator response to acetylcholine but not calcitonin gene-related peptide in rat skin microvasculature.

1. The contributions of sensory nerves and nitric oxide (NO) to vasodilator responses to acetylcholine (ACh) and calcitonin gene-related peptide (CGRP) were examined in rat skin microvasculature with a laser Doppler flowmeter to monitor relative blood flow. 2. Perfusion of ACh (100 microM; for 30 min) over a blister base on the rat hind footpad elicited microvascular vasodilatation and this response was not sustained. CGRP (1 microM; 10 min perfusion) also elicited vasodilatation and this response was maintained even when CGRP was no longer in contact with the blister base. 3. The vasodilator response to ACh was significantly smaller in rats pretreated as neonates with capsaicin to destroy primary sensory afferents than it was in age-matched controls. The vasodilator response to CGRP was unaffected by capsaicin pretreatment. 4. Selective inhibitors of NO synthase, NG-nitro-L-arginine (L-NOARG) and NG-monomethyl-L-arginine (L-NMMA) (both at 100 microM) attenuated the vasodilator response to ACh in control rats, but had no effect on the vasodilator response to CGRP. There was a significant L-NOARG-resistant component in control rats while in capsaicin-treated rats the vasodilator response to ACh was virtually abolished by L-NOARG. The inactive stereoisomer NG-monomethyl-D-arginine (100 microM) did not affect the vasodilator response to ACh. 5. The efficacy of L-NOARG and L-NMMA as inhibitors of endothelium-dependent responses was confirmed by use of an endothelium-dependent vasodilator, the calcium ionophore A23187 (100 microM; 10 min perfusion). Vasodilatation to A23187 was strongly attenuated by both L-NOARG and L-NMMA.6. These results suggest that sensory nerves and NO are both involved in the dilatation produced by ACh in rat skin microvasculature. A component of the vasodilator response elicited by ACh involves a direct action on the microvascular endothelium with subsequent generation of NO, while an additional component is elicited via activation of sensory nerves. The vasodilator mediator(s) released by ACh from sensory nerves acts largely independently of NO.7. The vasodilator response to CGRP is independent of a prejunctional action on sensory nerves and of NO.

Acetylcholine↗

PubMed1992

Tumour necrosis factor alpha augments the release of an endothelium-dependent vasoconstrictor from human polymorphonuclear leukocytes.

We have studied the effect of cytokine priming by recombinant human tumour necrosis factor alpha (rhTNF alpha) on the release of vasoactive mediators from human polymorphonuclear leukocytes (PMNs). Supernatants of human PMNs (100 microliters, 5 x 10(7) ml, from 12 donors) relaxed precontracted rabbit aortic rings. The relaxations were preceded by a transient contraction in four experiments. In contrast, supernatants of PMNs incubated with rhTNF alpha (0.3 nM, 30 min, 37 degrees C) elicited variable vascular responses that consisted of either a sustained contraction (n = 4), a transient contraction followed by a sustained relaxation (n = 2), or a sustained relaxation only (n = 6). The vascular tone produced by the rhTNF alpha-treated PMN supernatant was significantly greater over 30 min than that produced by the control supernatant (p < 0.01). Endothelium removal prevented the PMN-induced contractions and significantly decreased the vascular tone produced by all rhTNF alpha-treated PMN supernatants (p < 0.05). The PMN supernatants had no vasoactive effect on aortic rings at resting tension. Molecular size analysis indicated that the PMN-derived contractile mediator is > 30,000 Da. These results suggest that human PMNs, primed by rhTNF alpha, release a stable endothelium-dependent vasoconstrictor that opposes the action of a stable, spontaneously released direct vasodilator.

Acetylcholine↗

PubMed1991

Haemodynamic and hormonal effects of N-nitro-L-arginine, an inhibitor of nitric oxide biosynthesis, in sheep.

1. The haemodynamic and hormonal responses to N-nitro-L-arginine (NOLA), a potent inhibitor of nitric oxide biosynthesis in endothelial cells, were investigated in conscious sheep. 2. Mean arterial blood pressure (MAP), heart rate (HR) and cardiac output by thermodilution (CO) were measured in four oophrectomized ewes. Two other ewes were surgically implanted with aortic electromagnetic flow probes and an indwelling carotid arterial line for monitoring CO and MAP over 40 h. 3. After a control period, NOLA (10 mg/kg) was injected intravenously and MAP, HR and CO monitored and blood samples taken at intervals over the following 24 h. 4. NOLA increased blood pressure within minutes, from 76 +/- 4 to a maximum of 99 +/- 4 mmHg (P less than 0.001) at 6 h after injection. It remained elevated 24 h after injection. CO and HR fell but these falls were not sustained longer than 6 h. Calculated total peripheral resistance increased to a maximum of 2 h, but had returned to control levels 24 h after injection. There were no significant changes in plasma concentrations of renin, atrial natriuretic factor, vasopressin, noradrenaline or endothelin during the first hour. 5. NOLA may be a useful tool in understanding the role of the endothelium and nitric oxide in the control of blood pressure.

Acetylcholine↗

PubMed1991

Autoradiographic localization of angiotensin-converting enzyme and angiotensin II binding sites in early atheroma-like lesions in rabbit arteries.

1. Early atheroma-like lesions in rabbits are associated with increased sensitivity to serotonin. The localization and distribution of angiotensin-converting enzyme (ACE) and angiotensin II (AII) binding sites has been studied in these developing lesions by quantitative in vitro autoradiography. 2. In sham-operated control vessels, ACE was localized predominantly to intimal and adventitial sites, whereas in lesioned arteries the level of ACE detected in these regions was significantly reduced. 3. In control vessels AII receptor binding was distributed largely in the outer media, whereas in lesioned vessels AII receptor binding was dispersed throughout the media with the highest levels of binding in the outer media. 4. There was a significant amount of binding associated with ACE and with AII receptors in the extra-adventitial inflammatory tissue of lesioned arteries. 5. Apparent loss of ACE from intimal and adventitial sites may be a consequence of tissue remodelling and cellular proliferation, while the appearance of ACE in abnormal sites could play a role in AII production by the vessel wall. The role of ACE and AII in the developing atheroma-like lesions needs to be investigated further.

Angiotensin II↗

PubMed1991

Enhanced vasoconstriction by serotonin in rabbit carotid arteries with atheroma-like lesions in vivo.

1. In a new animal model which mimics the cellular events of early human atherosclerosis, atheroma-like lesions were produced by positioning a hollow silastic collar around the common carotid arteries of rabbits. The functional significance of these arterial lesions on blood flow responses to vasoactive agents was then studied in anaesthetized rabbits in vivo. 2. After 1 week of lesion development, resting blood flow was lower in atherosclerotic (cuffed) carotid arteries compared with the contralateral, sham-operated control arteries. 3. Intra-carotid injection of serotonin (0.01-1 microgram) produced dose-dependent increases in blood flow in control arteries, but produced either smaller increases or decreases in flow in cuffed arteries. Serotonin caused complete vasospasm (zero blood flow) in one of six rabbits. 4. Acetylcholine (0.0001-0.01 microgram, intra-carotid) produced smaller increases in blood flow in cuffed arteries compared with controls. 5. These data support the proposal that morphological and functional alterations in large arteries in the early stages of atherogenesis play an important role in determining blood flow in vivo. The increased vascular reactivity to serotonin which accompanies development of the lesions might contribute to vasospasm.

Acetylcholine↗

PubMed1991

Haemodynamic responses to N-nitro-L-arginine in conscious rabbits.

1. The effect of N-nitro-L-arginine (NOLA) on mean arterial pressure (AP), hindlimb vascular resistance (HVR) and heart rate (HR) was examined in conscious rabbits. 2. NOLA (15 mg kg, i.v.) increased AP (delta AP = 14 +/- 3 mmHg) and HVR (delta HVR = 0.8 +/- 0.3 U) and decreased HR (delta HR = -66 +/- 8 beats/min). AP remained elevated for at least 2 h following NOLA infusion but had returned to control levels after 24 h. In contrast, the hindlimb vaso-constriction and bradycardia were sustained for at least 48 h but had returned to control levels after 72 h. 3. In the presence of total autonomic blockade (hexamethonium 30 mg/kg; propranolol 1 mg/kg and atropine 0.1 mg/kg) NOLA continued to have a pressor (delta AP = 33 +/- 9 mm Hg) and hindlimb vasoconstrictor action (delta HVR = 0.4 +/- 0.1 U) but did not affect HR (delta HR = -1 +/- 3 beats/min). 4. NOLA has a prolonged pressor and vasoconstrictor action which is independent of any action in the central nervous system and which results in a marked reflex bradycardia. These results suggest that the peripheral biosynthesis of nitric oxide is important in regulation vascular tone and arterial pressure.

Animals↗

PubMed1991

Effect of tolerance to glyceryl trinitrate on vascular responses in conscious rabbits.

1. The effect of tolerance to glyceryl trinitrate (GTN) on vasodilator and vasoconstrictor responses was examined in conscious rabbits and isolated rabbit aortic rings. 2. In conscious rabbits, depressor responses to 5 min infusions of GTN (10-40 micrograms/kg per min intravenously (i.v.)), sodium nitroprusside (SNP, 5-20 micrograms/kg per min i.v.) and acetylcholine (ACh, 3-12 micrograms/kg per min i.v.) were examined before and after transdermal treatment with GTN (20 mg/48 h). GTN pretreatment significantly attenuated GTN-induced depressor responses, indicating the development of tolerance, but did not affect the reductions in arterial pressure induced by SNP or ACh. 3. Similarly, aortic rings taken from GTN pretreated rabbits exhibited tolerance to GTN but the relaxant responses to SNP or the calcium ionophore A23187 were not affected. In the aortic rings from GTN-tolerant rabbits contractile responses to serotonin or the thromboxane-mimetic U46619 were significantly attenuated, in contrast to the responses to the alpha 1-adrenoceptor agonist phenylephrine (PE) which were significantly enhanced. 4. Similarly, in conscious rabbits, PE-induced increases in arterial pressure and hindlimb vascular resistance were significantly enhanced by GTN pretreatment but the responses to the alpha 2-adrenoceptor agonist BHT 920 were unaffected. 5. In conclusion, tolerance to GTN does not affect endothelium-dependent vasodilatation but does cause a selective enhancement of alpha 1- but not alpha 2-adrenoceptor-mediated vasoconstriction.

Administration, Cutaneous↗