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T M Griffith

Publications and source records attributed to T M Griffith.

At least 55 records · Page 3Linked to original sources
PubMed1996

Temporal chaos in the microcirculation.

In vivo, spontaneous rhythmic contraction and dilatation of the vessel wall and the nonlinear rheological properties of blood both contribute to irregular fluctuations in microcirculatory blood flow over time. In isolated vessels, vasomotion exhibits patterns of behaviour that are highly characteristic of many non-biological nonlinear systems, including exactly integral periodicity and well-characterized routes for the transition from periodic to chaotic dynamics such as period-doubling. Nonlinear mathematical analysis of the effects of specific pharmacological interventions suggests the participation of a minimum of 4 key control variables which, at the cellular level, appear to involve Ca(2+)-induced Ca2+ release from intracellular stores and inward Ca2+ and outward K+ fluxes at the cell membrane. Four dominant variables may thus be [Ca2+] in the cytosol, [Ca2+] in the sarcoplasmic reticulum, membrane potential and the open state probability of certain K+ channel subtypes. Nonlinear analysis also indicates that nitric oxide synthesis by the vascular endothelium and changes in intraluminal flow and pressure are not significant determinants of the complexity of the underlying dynamics. Chaotic systems exhibit extreme sensitivity to initial conditions and their behaviour may appear highly unpredictable. This potentially accounts for variability in response to both pharmacological interventions and altered conditions of perfusion. The sensitivity of chaotic systems to perturbation can nevertheless be exploited to bring about large changes in state with minimum expenditure of energy, so that chaotic dynamics may confer a high degree of flexibility in overall control. Indeed, relatively simple control techniques based on negative feedback can readily stabilize the irregular responses of isolated arteries as periodic or steady-state behaviour but, alternatively, may also lead to an increase in overall dynamical complexity. At the present time, however, it remains unknown whether the chaotic nature of vasomotion confers specific benefits over and above those obtainable with sinusoidal control of vascular calibre (e.g.) in the regulation of vascular resistance, mass transport and tissue pressure.

Humans↗
PubMed1996

Comparison of chaotic and sinusoidal vasomotion in the regulation of microvascular flow.

OBJECTIVE: In order to elucidate the physiological consequences of irregular vasomotion on microvascular flow we have compared the theoretical hydrodynamic consequences of sinusoidal and chaotic fluctuations in the diameter of a single resistance vessel. METHODS: In initial experimental studies vasomotion was induced by histamine in isolated rabbit ear resistance arteries (approximately 150 microns diameter) perfused with physiological buffer under both controlled-flow and controlled-pressure conditions. The phase relationships between the observed oscillations in flow and pressure were used to validate a theoretical electrical circuit in which vasomotion was simulated as sinusoidal or as chaotic fluctuations in distal resistance, with compliance incorporated as a parallel capacitance. RESULTS: In both the experimental and theoretical situation, oscillations in flow led those in pressure by approximately 90 degrees in controlled-flow mode, whereas they were approximately 180 degrees out of phase in controlled-pressure mode. In the theoretical model an increase in the amplitude of sinusoidal or chaotic diameter fluctuations enhanced flow, but "paradoxically" increased both time-averaged resistance and conductance. The model showed that with sinusoidal fluctuations the "efficiency" of perfusion (i.e., flow/viscous work expended in perfusing the vessel undergoing vasomotion) exhibited a peak whose magnitude was a function of vasomotion amplitude and the proximal capacitance in the circuit, and was attributable to transient release of charge from this capacitance. This phenomenon was not observed in simulations with chaotic vasomotion. Hydrodynamic effects specific to the presence of chaotic dynamics (e.g., abrupt increases or decreases in flow under the variation of a single parameter) were also evident when the intrinsic complexity of the vasomotion, rather than its amplitude, was varied. CONCLUSIONS: The model suggests (i) that vasomotion may serve to increase flow, (ii) that conductance provides a more accurate physiological measure of the functional consequences of active vasomotion than resistance, (iii) that chaotic vasomotion dissipates transients more readily than sinusoidal vasomotion, thereby conferring greater stability to microcirculatory perfusion and (iv) that specific modes of chaotic vasomotion may influence flow independently of their amplitude.

Animals↗
PubMed1995

Complexity of chaotic vasomotion is insensitive to flow and pressure but can be regulated by external control.

We have previously shown that irregular vasomotion induced by histamine in isolated rabbit ear resistance arteries is chaotic. Consistently, in the present study, such activity was found to respond in a highly unpredictable fashion to changes in flow under conditions of controlled-flow perfusion, although its fractal dimension, calculated by a standard correlation technique, was effectively independent of flow rate and remained < 4. As this statistic provides an estimate of the number of control variables that generate a chaotic time series, flow thus appears to modulate vasomotion without fundamentally contributing to its genesis. External modification of the dynamics was attempted by a negative feedback loop that regulated pump speed through an error signal derived from perfusion pressure. Irregular responses were converted to either periodic or steady-state behavior in approximately 60% of cases with an associated fall in fractal dimension. Conversely, unsuccessful control was often associated with an increase in fractal dimension, reflecting the additional complexity introduced by the feedback loop. Furthermore, control was more readily achieved in the presence of NG-nitro-L-arginine methyl ester, when time- and flow-dependent changes in endothelium-derived relaxing factor synthesis would not be expected to complicate the overall dynamics. The study suggests that vascular chaos may be economically "controlled" under both physiological and pathophysiological conditions.

Animals↗
PubMed1995

Effects of iodinated contrast media on peripheral blood flow.

All types of clinically employed iodinated roentgen contrast media (CM) cause vasodilatation after i.a. and i.v. administration, regardless of precise molecular structure. It is now apparent, however, that at iodine concentrations which provide equivalent angiographic contrast, this is significantly less with newer hexa-iodinated dimers, such as iodixanol and iotrolan, than older generations of compounds. The cellular mechanisms that underly the vasodilator effects of CM still remain to be fully elucidated but may include a) effects attributable to hyperosmolality; b) stimulation of the release of endogenous vasoactive mediators; and c) direct relaxant effects upon vascular smooth muscle. This review will discuss the possible contributions of these mechanisms to the vasodilatation observed in the clinical situation.

Animals↗
PubMed1995

Angiographic contrast media relax isolated rabbit aorta through an endothelium-independent mechanism that may not depend on the presence of the iodine atom.

Systemically administered iodinated angiographic contrast media evoke vasodilatation through mechanisms that are at present poorly understood. In the current investigation we have evaluated the role of the vascular endothelium in responses to an iso-osmolar formation of the non-ionic dimer iodixanol and a hyperosmolar formulation of the non-ionic monomer iopromide. Isolated rabbit aortic ring preparations with endothelium intact or removed by gentle abrasion were mounted in organ baths containing oxygenated Holman's solution, and cumulative concentration-response curves for relaxation to the contrast media were constructed after pre-constriction by phenylephrine (300 nM) in the presence of indomethacin to inhibit prostaglandin synthesis. Endothelial denudation did not influence the ability of either iodixanol or iopromide to relax the aortic ring preparations. Iopromide was significantly more potent than iodixanol when expressed in terms of iodine concentration (mg I ml-1), but both agents were equipotent when expressed in terms of molarity (mM). We conclude that relaxation of isolated rabbit aortic rings to iodixanol and iopromide under conditions where there is no fluid flow is endothelium-independent, and therefore not mediated by release of the potent endogeneous nitrovasodilator endothelium-derived relaxing factor (EDRF). Furthermore, their relaxant activity under the in vitro experimental conditions employed is attributable to a direct action on vascular smooth muscle by factors in addition to osmolality, and may depend on features that are not specifically associated with the presence of the iodine atom.

Angiography↗
PubMed1994

L-arginine reverses the impairment of nitric oxide-dependent collateral perfusion in dietary-induced hypercholesterolaemia in the rabbit.

1. We have used an isolated, buffer-perfused, rabbit ear model of acute arterial occlusion to investigate the effects of exogenous L-arginine on the severe impairment of collateral perfusion associated with dietary-induced hypercholesterolaemia. The effects of L-arginine on hypercholesterolaemia-related impairment of endothelium-dependent relaxations to acetylcholine were also investigated in unligated, isolated rabbit ears perfused with buffer. 2. Cholesterol feeding for 8 weeks (blood cholesterol level 66.5 +/- 5.3 versus 1.4 +/- 0.2 mmol/l, P < 0.001) was associated with almost complete impairment of collateral perfusion, an effect previously observed after inhibition of nitric oxide synthesis. The impairment of collateral perfusion found in hypercholesterolaemia was completely reversed by the addition of 10 mmol/l L-arginine to the perfusion fluid. In control preparations from rabbits fed a normal diet, the addition of 10 mmol/l L-arginine did not influence collateral perfusion. 3. Endothelium-dependent relaxation to acetylcholine was impaired in preparations from the rabbits fed the high cholesterol diet for 8 weeks: the maximum relaxation of tone was 24.6 +/- 0.8% and was significantly (P < 0.01) less than that in the controls (70.3 +/- 2.4%). Addition of L-arginine to the perfusion fluid caused a modest improvement in the endothelium-dependent relaxations to acetylcholine, with a maximum response of 43.2 +/- 1.3%. 4. We conclude that nitric oxide-dependent collateral perfusion is severely impaired in hypercholesterolaemia and that the addition of exogenous L-arginine fully reverses these changes. Endothelium-dependent relaxations to acetylcholine are similarly impaired by hypercholesterolaemia; however, this deficit was only partially reversed by L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

Modulation of vasodilatation to levcromakalim by adenosine analogues in the rabbit ear: an explanation for hypoxic augmentation.

1. We have used a rabbit isolated ear, buffered-perfused preparation to investigate the effects of adenosine analogues on the vasodilatation to the potassium channel opener, levcromakalim (the active (-)-enantiomer of cromakalim). We have examined the effects of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 antagonist, on vasodilatation to levcromakalim under hypoxic conditions and also following inhibition of nitric oxide synthesis. 2. Levcromakalim relaxed preconstricted preparations with an EC50 = 369 +/- 48 nM and maximum relaxation of tone (Rmax) = 81.0 +/- 3.2%. In the presence of 1 microM N6-cyclohexyladenosine (CHA) a selective adenosine A1 agonist, there was a significant (P < 0.01) leftward shift in the concentration-response curve with an EC50 = 194 +/- 54 nM and Rmax = 93.2 +/- 2.0%. Conversely, the presence of CHA did not influence vasodilatation to either pinacidil or sodium nitroprusside. 3. Hypoxia also significantly (P < 0.001) increased the vasodilator potency of levcromakalim (EC50 = 134 +/- 22 nM), and this enhancement was completely reversed (EC50 = 380 +/- 107 nM, P < 0.01) by pretreatment of the preparations with 5 microM DPCPX, a selective A1 adenosine antagonist. However, under normoxic conditions DPCPX did not influence vasodilatation to levcromakalim. 4. Inhibition of nitric oxide synthesis with 100 microM NG-nitro-L-arginine methyl ester (L-NAME) caused a significant (P < 0.001) leftward shift in the concentration-response curve to levcromakalim (EC50 = 73.0 +/- 7.6 nM). Pretreatment of preparations with DPCPX partially reversed the increase in potency found in the absence of nitric oxide synthesis (EC50 = 153 +/- 18 nM, P < 0.001). 5. We have shown that an adenosine Al agonist may increase the potency of levcromakalim indicating that adenosine receptor activation may augment the vasodilator activity of levcromakalim. That responses to levcromakalim but not those to pinacidil were affected by CHA points to further differences in the pharmacology of these potassium channel openers. The reversal by the adenosine Al antagonist of the hypoxic-potentiation of vasodilatation to levcromakalim, and also augmentation following inhibition of nitric oxide synthesis, suggests that under these conditions there is an endogenous release of adenosine which may enhance responses to levcromakalim. The findings of this study suggest that levcromakalim may selectively dilate vessels where there is elevated adenosine release.

Adenosine↗
PubMed1994

Abolition of flow-dependent EDRF release before that evoked by agonists in hypercholesterolaemic rabbits.

1. We have used a pulsatile cascade bioassay system to investigate the effects of dietary-induced hypercholesterolaemia on EDRF release evoked by acetylcholine and by the oscillatory and time-averaged components of flow, in isolated segments of rabbit abdominal aorta. 2. Flow pulsatility (frequency range 0.1-10 Hz) was studied with constant flow (9 ml min-1) at a pulse pressure amplitude of 2 mmHg. Frequency-related EDRF release, maximal at 6 Hz, was slightly attenuated after 4 weeks and abolished after 8 weeks of cholesterol feeding. 3. Time-averaged shear stress was manipulated with dextran (1-4% w/v, 80000 mol. wt.), to increase perfusate viscosity. EDRF release induced by increased perfusate viscosity was unaffected after 4 weeks but abolished after 8 weeks of cholesterol feeding. 4. Endothelium-dependent relaxations to acetylcholine (0.1-10 microM) were not influenced after 4 weeks and only partially attenuated (by 60% of the maximal response, EC50 unchanged at 6.45 +/- 0.04 vs. 6.4 +/- 0.1 microM) after 8 weeks of cholesterol feeding. 5. Blood cholesterol levels were significantly (P < 0.001) increased after 4 weeks (26 +/- 3.6 vs 2.6 +/- 0.6 mmol l-1) and 8 weeks (56.2 +/- 3.8 vs 1.3 +/- 0.1 mmol l-1) of cholesterol feeding but after 8 weeks plasma L-arginine levels were not significantly different from the age-matched controls (0.2 +/- 0.05 vs. 0.19 +/- 0.04 mmol l-1). 6. We conclude that hypercholesterolaemia impairs flow-related (pulsatile- and time-averaged shear-induced) EDRF release earlier than acetylcholine-induced relaxation in rabbit aorta. This is consistent with the view that different transduction mechanisms mediate EDRF release in response to agonists and flow.

Acetylcholine↗
PubMed1994

Heterogeneous populations of K+ channels mediate EDRF release to flow but not agonists in rabbit aorta.

We have investigated the role of Ca(2+)- and ATP-sensitive K+ channels (KCa and KATP, respectively) in flow- and agonist-stimulated release of endothelium-derived relaxing factor (EDRF). Segments of rabbit abdominal aorta, perfused at constant flow with buffer containing indomethacin, were used as a source of EDRF in cascade bioassay, and responses to endothelium-dependent agonists were studied isometrically in rings of the same tissue in the absence of flow. Apamin, charybdotoxin (ChTX), and tetraethylammonium (TEA) were used to block a variety of low, medium, and high conductance KCa channels, and glibenclamide was used to block KATP channels. The effects of flow pulsatility were studied at pulse frequencies ranging from 0.15 to 9.75 Hz, and time-averaged shear stress was manipulated by adding dextran (80,000 mol wt) to the perfusate to increase its viscosity. Frequency-related EDRF release was maximal at approximately 5 Hz and attenuated by apamin, TEA, and ChTX, but not by glibenclamide. EDRF release stimulated by increased viscosity was attenuated by TEA, ChTX, and glibenclamide, but not by apamin. In marked contrast, EDRF release stimulated by acetylcholine and ATP was unaffected by blockade of either KCa or KATP channels. We conclude that a spectrum of KCa channel subtypes mediates endothelial transduction of the oscillatory component of pulsatile flow and that KATP channels may be additionally involved in the transduction of time-averaged shear stress. In contrast, agonist-stimulated endothelium-dependent relaxation is independent of K+ channel activation in rabbit aorta.

Acetylcholine↗
PubMed1994

EDRF suppresses chaotic pressure oscillations in isolated resistance artery without influencing intrinsic complexity.

It is now widely recognized that nonlinear oscillatory systems can exhibit simple periodicity, characteristic repetitive patterns of odd and even integral periodicity and specific pathways for the transition to irregular, so-called "chaotic," dynamics. In the present study we have identified such behavior in the highly irregular rhythmic vasomotor activity induced by histamine in isolated rabbit ear resistance arteries, thus suggesting a deterministic rather than random etiology. In this experimental model nonlinearity arises at the level of the vascular smooth muscle cell, since oscillatory behavior was not abolished by endothelial denudation. To quantify the complexity of the responses induced by histamine, we applied the analysis of Grassberger and Proccacia (Physica D 9: 189-208, 1983) to calculate a scaling parameter known as fractal dimension, which estimates the minimum number of control variables participating in the genesis of an irregular time-varying signal. The findings suggest the involvement of at least three such variables, because its average numerical value was generally found to be between 2 and 3. Neither the absolute concentration of histamine employed nor pharmacological manipulation (i.e., stimulation/inhibition) of endothelium-derived relaxing factor (EDRF) activity significantly affected the fractal dimension of the pressure fluctuations, although both influenced their superficial form. Histamine and EDRF consequently do not determine the fundamental interactions responsible for generating the chaotic nature of the responses and may be regarded as permissive and modulatory influences, respectively. The well-known unpredictability of nonlinear systems to perturbation may explain why EDRF can either suppress or enhance rhythmic vasomotor activity in different artery types.

Acetylcholine↗
PubMed1994

Fractal analysis of role of smooth muscle Ca2+ fluxes in genesis of chaotic arterial pressure oscillations.

We have investigated the role of vascular smooth muscle Ca2+ fluxes in the genesis of chaotic pressure oscillations induced by histamine in isolated resistance arteries from the rabbit ear. The responses exhibited distinct "fast" and "slow" components, with periods of 5-20 s and 1-5 min, respectively, which could be dissociated pharmacologically. The fast subsystem involved ion movements at the cell membrane and was inhibited by both low (< 2 mM) and high (> 5 mM) extracellular Ca2+ concentration ([Ca2+]o) by verapamil (which inhibits voltage-dependent Ca2+ influx) and by charybdotoxin (ChTX) and apamin (which block Ca(2+)-activated K+ channels). In contrast, the slow subsystem was intracellular and was selectively attenuated by ryanodine, which inhibits Ca(2+)-induced Ca2+ release from sarcoplasmic reticulum. The effects of these interventions on the complexity of the responses were quantified by calculating their fractal dimension, a parameter that estimates the minimum number of independent variables contributing to an irregular time series. Its mean value was generally > 2 under control conditions but decreased to < 2 in a concentration-dependent fashion in the presence of verapamil, ChTX, apamin, or ryanodine and when [Ca2+]o was outside the range of 2-3 mM. Each intervention thus removed one dimension of complexity from the mechanisms generating the rhythmic activity. We conclude that the interaction of a fast membrane oscillator, which involves Ca2+ influx, Ca(2+)-activated K+ efflux, and therefore presumably changes in membrane potential, and a slow intracellular oscillator involving Ca2+ sequestration and release from stores is responsible for vascular chaos in our model. The coupling between these subsystems is likely to be mediated by cytosolic [Ca2+].

Animals↗
PubMed1993

Modulation of vasodilatation to levcromakalim by hypoxia and EDRF in the rabbit isolated ear: a comparison with pinacidil, sodium nitroprusside and verapamil.

1. We have used an isolated buffer-perfused preparation of the rabbit ear to investigate the effects of hypoxia and inhibition of endothelium-derived relaxing factor (EDRF) synthesis on the vasodilator responses to the potassium channel opener, levcromakalim (the active (-)-enantiomer of cromakalim). The results obtained with levcromakalim have been compared with those for pinacidil, sodium nitroprusside and verapamil. 2. Levcromakalim relaxed preconstricted preparations with an EC50 = 343 +/- 41 nM and Rmax = 80.3 +/- 6.4%. Under hypoxic conditions the concentration-response curve was significantly (P < 0.01) shifted to the left with an EC50 = 118 +/- 16 nM and Rmax = 89.9 +/- 2.7%. Hypoxia did not influence relaxation to either pinacidil, sodium nitroprusside or verapamil. 3. Inhibition of EDRF synthesis with 100 microM NG-nitro-L-arginine methyl ester (L-NAME) also significantly (P < 0.001) increased the vasodilator potency of levcromakalim (EC50 = 56 +/- 5 nM), and caused a similar shift in the concentration-response curve to sodium nitroprusside. It did not influence vasodilation to either verapamil or pinacidil. The potentiation of vasodilator responses to levcromakalim by L-NAME was reversed by an excess of L-arginine. 4. Impairment of oxidative phosphorylation with 400 nM carbonyl cyanide m-chlorophenylhydrazone significantly (P < 0.05) increased the potency of levcromakalim (EC50 = 120 +/- 20 nM) but did not influence vasodilation to pinacidil or endothelium-dependent relaxations to acetylcholine. 5. Vasodilatation to levcromakalim was augmented both by hypoxia and by inhibition of EDRF activity. Since impairment of oxidative phosphorylation increased the potency of levcromakalim but did not alter EDRF activity then the mechanism responsible for hypoxic facilitation of responses to levcromakalim is likely to be due to reduced ATP levels in hypoxic smooth muscle cells rather than a change in EDRF activity. These results suggest that levcromakalim may selectively dilate both hypoxic vessels and vessels with impaired EDRF activity. The results also point to important differences in the pharmacology of levcromakalim and pinacidil.

Acetylcholine↗
PubMed1993

Hypercholesterolaemia severely impairs EDRF-dependent collateral perfusion following acute arterial occlusion in rabbit isolated ear.

1. We have used a rabbit isolated buffer-perfused ear as a model of acute arterial occlusion to investigate the effects of dietary-induced hypercholesterolaemia on EDRF-dependent collateral perfusion. The effects of hypercholesterolaemia on endothelium-dependent relaxations to acetylcholine were also investigated in the unligated isolated buffer-perfused ear of the rabbit. 2. In rabbits receiving a high cholesterol diet (1%) for 4 weeks, blood cholesterol levels were significantly (P < 0.001) increased (26.0 +/- 3.6 vs. 2.6 +/- 0.6 mmol l-1), EDRF-dependent collateral perfusion was similar to that in age-matched controls for the first 15 min after occlusion but then decreased and was significantly (P < 0.01) less than control during the maintenance phase of collateral perfusion. 3. Cholesterol feeding for 8 weeks (blood cholesterol = 56.2 +/- 3.8 vs. 1.3 +/- 0.1 mmol l-1) was associated with almost complete impairment of collateral perfusion, an effect previously observed following inhibition of EDRF synthesis. 4. Endothelium-dependent relaxations to acetylcholine in isolated perfused ears were impaired in the rabbits fed the diet for 8 weeks but not those fed for 4 weeks. In the 8 week group, the maximum relaxation of tone was 32.6 +/- 11.6% and was significantly (P < 0.01) less than that in the controls (77.9 +/- 5.7%). 5. We conclude that EDRF-dependent collateral perfusion is severely impaired in hypercholesterolaemia and that the level of impairment is related to the duration of feeding.

Acetylcholine↗
PubMed1993

Modulation of chaotic pressure oscillations in isolated resistance arteries by EDRF.

By using non-linear techniques to analyse irregular histamine-induced pressure oscillations in an isolated rabbit ear resistance artery, we have shown that the pressure oscillations are generated by deterministic rather than stochastic mechanisms. The average fractal dimension of the oscillations was between 2 and 3, thus implying that three (or more) independent control variables were necessary to account for the complexity of the dynamics. EDRF suppressed the pressure oscillations, but their fractal dimension was not altered by graded stimulation of EDRF activity by acetylcholine, or by inhibition of EDRF activity with NG-nitro-L-arginine methyl ester (L-NAME) or haemoglobin. This implies that EDRF is not one of the primary control variables involved in the genesis of their dynamics. The oscillations exhibited distinct 'fast' and 'slow' components, with periods of 5-20 s and 1-5 min respectively. The fast subsystem involved ion movements at the cell membrane level, and was inhibited by low [Ca2+]o, by verapamil (which inhibits voltage-dependent Ca2+ influx) and by tetraethylammonium (TEA) and apamin (which block Ca(2+)-activated outward K+ channels). In contrast, the slow subsystem was selectively inhibited by ryanodine, and therefore involved intracellular Ca(2+)-induced Ca2+ release. Each of these interventions decreased the fractal dimension to < 2 and thus removed one degree of freedom from the dynamics. We conclude that the interaction of a fast membrane oscillator and a slow intracellular oscillator generates chaotic pressure oscillations which are modulated by EDRF.

Animals↗
PubMed1992

Collateral perfusion: the role of endothelium-derived relaxing factor and effects of vasodilators.

An in vitro rabbit ear model has been used to investigate the role of endothelium-derived relaxing factor (EDRF) in collateral perfusion after acute arterial occlusion and also the effects of vasodilators. Collateral perfusion of an arterial segment isolated between occlusions was assessed by x-ray microangiography and was found to develop in a time-dependent manner. Inhibition of EDRF synthesis with NG-nitro-L-arginine methyl ester (L-NAME) greatly impaired collateral perfusion, indicating that the development of collateral perfusion was dependent on EDRF activity. This inhibitory effect was reversed by an excess of L-arginine. Further studies using vasodilators with different modes of action indicated that BRL 38227 (the active enantiomer of cromakalim, a potassium channel activator) substantially enhanced collateral perfusion, sodium nitroprusside had early beneficial effects, and verapamil had no effect.

Animals↗
PubMed1992

Effects of BRL 38227, sodium nitroprusside and verapamil on collateral perfusion following acute arterial occlusion in the rabbit isolated ear.

1. We have used an isolated, buffer-perfused, rabbit ear model of acute arterial occlusion to investigate the effects of the nitrovasodilator sodium nitroprusside, the potassium channel activator BRL 38227 (the active (-)-enantiomer of cromakalim) and the calcium antagonist, verapamil, on collateral perfusion in the absence of pharmacological tone. 2. Verapamil was the most potent vasodilator (EC50 = 72.6 +/- 32.0 nM) of 5-hydroxytryptamine/histamine-induced tone in the rabbit isolated perfused ear. Sodium nitroprusside and BRL 38227 were less potent with respective EC50 values of 488 +/- 75 nM and 296 +/- 40 nM. Following inhibition of endothelium-derived relaxing factor (EDRF) synthesis, the potency of BRL 38227 was significantly (P less than 0.001) increased with an EC50 of 55.6 +/- 5.0 nM. 3. BRL 38227 at 500 nM and 3 microM induced substantial increases in collateral perfusion following arterial ligation in the absence of pharmacological tone compared to control. Furthermore 3 microM BRL 38227 completely reversed the attenuation of collateral perfusion which followed inhibition of EDRF synthesis with 100 microM NG-nitro-L-arginine methyl ester (L-NAME). 4. Sodium nitroprusside (500 nM and 3 microM) induced modest improvements in collateral perfusion in the early stages after arterial occlusion. 5. Verapamil did not influence collateral perfusion at either of the concentrations used (50 nM and 3 microM), even though it was a potent vasodilator. 6. The results of this study indicate that BRL 38227, and to a much lesser extent sodium nitroprusside, selectively improve collateral perfusion following arterial occlusion, even in the presence of effects of EDRF on acute collateralization, while verapamil has no effect. Furthermore, BRL 38227 also improves collateral perfusion following inhibition of EDRF synthesis. It remains to be established whether BRL 38227 has beneficial actions in acute arterial occlusion in vivo.

Animals↗
PubMed1992

Impaired cyclic nucleotide-mediated vasorelaxation may contribute to closure of the human umbilical artery after birth.

1. The mechanical and biochemical effects of agents that relax vascular smooth muscle either through elevation of guanosine 3':5'-cyclic monophosphate (cyclic GMP) or adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were compared in isolated ring preparations of human umbilical artery and rat aorta. Tone was established by preconstriction with 5-hydroxytryptamine. 2. The endothelium-dependent vasodilator calcium ionophore (A23187) (which stimulates endothelium-derived relaxing factor [EDRF] release and thus acts through soluble guanylyl cyclase), sodium nitroprusside (which stimulates soluble guanylyl cyclase directly), and atrial natriuretic peptide (which stimulates particulate guanylyl cyclase) relaxed rat aorta but not human umbilical artery. 3. Sodium nitroprusside, 10 microM, increased cyclic GMP levels from 10 to 390 pmol mg-1 protein at 2 min in rat aorta, as compared with a slower, relatively attenuated rise from 5 to 116 pmol mg-1 protein after 15 min in human umbilical artery. The rise in cyclic GMP in the umbilical artery was not significantly augmented by the cyclic GMP phosphodiesterase inhibitor, MB22948. Atrial natriuretic peptide increased cyclic GMP levels in rat aorta but not in human umbilical artery. 4. Forskolin, 10 microM, which stimulates both soluble and particulate adenylyl cyclase, maximally relaxed rat aorta and increased cyclic AMP levels from 15 to 379 pmol mg-1 protein at 15 min, but did not significantly relax or increase cyclic AMP levels in human umbilical artery. After preincubation with the cyclic nucleotide phosphodiesterase inhibitor, IBMX, 10 microM forskolin increased cyclic AMP levels to 1365 pmol mg-1 protein at 30 min in human umbilical arteries, but these high levels were not accompanied by mechanical relaxation.5. 8-Bromo-cyclic GMP and 8-bromo-cyclic AMP which are lipophilic analogues of cyclic GMP and cyclic AMP, both maximally relaxed the rat aorta at a concentration of 10 microM, but did not significantly relax the human umbilical artery.6. The findings indicate that elevated cyclic nucleotide levels are not associated with mechanical relaxation of the post-partum human umbilical artery, as in other vessels such as rat aorta. This impaired response to cyclic nucleotides may contribute to closure of the umbilical artery after birth.

8-Bromo Cyclic Adenosine Monophosphate↗