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Biomedical subjects

P Hadházy

Publications and source records attributed to P Hadházy.

At least 19 recordsLinked to original sources
PubMed1997

Characteristics of coronary endothelial dysfunction in experimental diabetes.

OBJECTIVE: To study the influence of diabetes on the endothelium-dependent vasodilation in the coronary arterial bed. METHODS: The effects of acetylcholine (ACh 2-36 pmol.kg-1; 18 nmol.1(-1)-9.8 mumol.1(-1); 0.1-10 mumol.1(-1), L-arginine (1 mmol.1(-1) and sodium nitroprusside (1 nmol.1(-1)-100 mumol.1(-1)) were measured on coronary conductivity, vascular tone and cGMP release (RIA) in healthy and diabetic dogs. RESULTS: ACh-mediated (in cumulative intra-arterial infusion) increase in coronary conductivity was reduced (P < 0.01) in the diabetic dogs in vivo, whereas no increase in cGMP release was observed in isolated diabetic coronaries (P < 0.05) which could not be enhanced by L-arginine (P < 0.05). Inhibition of cyclo-oxygenase after 20 min further impaired (P < 0.01) responsiveness to ACh in vivo and diminished the ACh response in isolated coronary strips of the diabetic dogs, but not in those of the controls. Relaxation in response to sodium nitroprusside was not altered by diabetes. CONCLUSIONS: Diminished vasodilation in diabetes is due to a defect in endothelial nitric oxide production and action. Vasodilating prostanoids do not sufficiently compensate this defect.

Acetylcholine↗
PubMed1996

Comparison of the vasodilatory effects of bradykinin in isolated dog renal arteries and in buffer-perfused dog kidneys.

This study was undertaken to investigate the role of nitric oxide (NO), cyclooxygenase products and bradykinin (Bk) receptors in the Bk evoked responses of canine renal arteries and perfused kidneys. Rings of isolated canine renal arteries were mounted in organ chambers for measurement of isometric force. The isolated canine kidneys were perfused with Krebs-solution (constant flow) and the perfusion pressure was continuously recorded. The influence of the cyclooxygenase inhibitor indomethacin and the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginin (L-NOARG) on the vasocontractile responses to phenylephrine (PE) were examined in both preparations. Furthermore, the effects of Bk on the tone of canine isolated renal arteries and on the vasopressor responses of isolated buffer-perfused kidneys of dogs were tested in the absence and presence of enzyme inhibitors and the B2 kinin receptor antagonist HOE-140. It was found that indomethacin enhanced the contractile responses of large renal arteries to PE by 77 +/- 10%. In intact artery rings L-NOARG (0.1 mM) caused an additional potentiation of the PE-induced contractions in the presence of indomethacin (from 11.5 +/- 1.2 mN to 21.6 +/- 1.7 mN). However, L-NOARG failed to affect contractile responses to PE in endothelium-denuded rings. Bk produced a concentration-dependent relaxation of the precontracted endothelium-intact renal arteries. The IC50 value for Bk was 11.2 +/- 3.7 nM. The relaxant activity of the peptide in renal artery rings was not affected by indomethacin (3 microM). However, in the presence of L-NOARG a significantly higher concentration (IC50 = 860 +/- 300 nM) of Bk was required to relax renal arteries. The Bk receptor antagonist HOE-140 (10 nM for 40 min) attenuated the relaxant effect of Bk in renal artery rings (from an IC50 of 14.2 +/- 2.5 nM to 216 +/- 37 nM). Indomethacin (3 microM for 20 min) did not significantly alter the arteriolar vasoconstriction (from 45 +/- 4 mm Hg to 48 +/- 5 mm Hg, n = 5) evoked by PE. By contrast, L-NOARG (0.1 mM) potentiated (from 56 +/- 7 mm Hg to 94 +/- 11 mm Hg) the PE-induced vasopressor responses in perfused kidneys. Bk reduced the size of the pressor responses at relatively low concentrations (2-60 nM) but the dose-response curve was flat and the maximum inhibitory effect hardly exceeded 50 percent. Indomethacin (3 microM) did not modify the inhibitory effect of Bk in perfused kidney. In the presence of L-NOARG, Bk depressed the PE induced vasopressor effects with a maximum of 18 +/- 20%. Preincubation of the kidney preparations with the Bk antagonist HOE 140 (10 nM for 40 min) almost completely abolished the inhibitory effect of Bk on the PE induced vasopressor responses. The results suggest that the endothelial NO plays a fundamental role in the relaxant effect of Bk and considerably modulates vascular reactivity to PE in canine renal vasculature. Furthermore, significant difference exists between conduit and resistance vessels of dog's kidney in the effect of indomethacin on the adrenergic contractions.

Adrenergic beta-Antagonists↗
PubMed1992

Disturbed lipid metabolism in diabetic coronary vessels.

The aim of this study was to clarify whether or not arachidonic acid metabolic disorders are caused by a substrate inavailability and whether such disorders might contribute to circulatory disturbances in the diabetic myocardium. Norepinephrine induced a decrease in the conductivity of both coronary arterial bed and myocardial microcirculation in alloxan-diabetic dogs. It was markedly (p less than 0.05) attenuated both by indomethacin and acetylsalicylic acid pretreatments indicating an imbalance among the vasoactive prostanoids in diabetes. TXA2 release from the diabetic coronary rings was found to be elevated and could be normalized after the blockade of vascular adrenoceptors by phentolamine (p less than 0.05). PGI2 synthesis was also enhanced by adrenergic blockade in the diabetic arterial rings. After pretreatment with 14C arachidonic acid, in order to measure substrate availability, the arachidonic acid metabolic rate was less in the diabetic coronary arteries than in healty vessels (p less than 0.05). Ten mumol/l norepinephrine decreased arachidonic acid metabolism in the presence of prelabelled substrate in the diabetic animals, compared to an increase observed in metabolically healthy dogs. Therefore diabetes appears to diminish arachidonic acid metabolism and uptake independent of adrenoceptors and to induce an imbalance between vasoconstrictor and vasodilator cyclooxygenase products, resulting in elevated TXA2 release controlled by adrenergic mechanisms which may contribute to an impairment in myocardial microcirculation.

Alloxan↗
PubMed1990

Increased vasoconstrictor response to noradrenaline in femoral vascular bed of diabetic dogs. Is thromboxane A2 involved?

STUDY OBJECTIVE: The aim was to determine the role of cyclo-oxygenase products in the vasoconstrictor response of femoral arterial bed to noradrenaline and to analyse the role of vascular adrenoceptors in the synthesis of cyclo-oxygenase products. DESIGN: The influence of intra-arterially injected cyclo-oxygenase inhibitors indomethacin and acetylsalicylic acid on alterations in conductance of femoral arterial bed induced by noradrenaline was compared in metabolically healthy and alloxan diabetic dogs. PGI2 and TXA2 synthesising ability of isolated femoral arterial rings was measured with and without inhibition of alpha adrenoceptors by phentolamine. SUBJECTS: 18 metabolically healthy and 18 alloxan (560 mumol.kg-1) diabetic dogs of either sex, weight 16-28 kg, were studied. MEASUREMENTS AND MAIN RESULTS: Noradrenaline produced greater (p less than 0.01) pressor effects in the femoral arterial bed of alloxan diabetic dogs than in the hind limb of control animals. Blockade of cyclo-oxygenase either by indomethacin 10 mumol.kg-1 or by acetylsalicylic acid 140 mumol.kg-1 markedly reduced the response to noradrenaline in alloxan treated animals, but not in controls, thereby eliminating the different responsiveness of the two groups. Femoral arterial rings from diabetic animals synthesised similar amounts of PGI2 as control rings but formed more TXA2 (p less than 0.05). Phentolamine pretreatment (5 mumol.litre-1) markedly reduced the production of TXA2, but not of PGI2, in diabetic vessels. CONCLUSIONS: The results show an increased release of TXA2 by isolated diabetic femoral arteries. It is therefore suggested that an alpha adrenoceptor mediated increase in TXA2 biosynthesis may play a part in the vascular hyperreactivity of the diabetic femoral arterial bed.

Animals↗
PubMed1989

Altered responsiveness of diabetic dog renal arteries to acetylcholine and phenylephrine: role of endothelium.

The mechanical responses to acetylcholine (ACh), sodium nitroprusside and phenylephrine (PE) were determined in normal and diabetic dog renal arterial strips with and without endothelium. Experimental diabetes increased the sensitivity, IC50 = (2.9 +/- 0.4) X 10(-8) mol/l in normal and (9.6 +/- 1.5) X 10(-9) mol/l in diabetic (p less than 0.01, n = 6) to ACh of endothelium intact renal arterial strips without influencing the maximum relaxation induced by this agonist. In all intact vessels PE produced contractions of equal magnitude. Removal of the endothelium completely abolished the relaxant ability of ACh, and caused a slight increase in the contractile response of both diabetic and normal strips to PE. The maximum contractile force generated by the denuded diabetic vessels in response to PE was significantly (p less than 0.01) greater than the maximum tension produced by the denuded nondiabetic arteries. The sensitivity of the tissues to PE was, however, not modified by either diabetes or endothelium removal. The direct relaxant sodium nitroprusside elicited a similar degree of relaxation in the two groups of arteries. Cyclooxygenase blockade had no effect on either the relaxation or contractile responses of any of the preparations. These findings suggest that short-term diabetes makes dog renal arteries supersensitive to ACh and hyperreactive to PE.

Acetylcholine↗
PubMed1988

Relationship between vascular adrenergic receptors and prostaglandin biosyntheses in canine diabetic coronary arteries.

Before the onset of histologically detectable alterations of diabetic arteries, a considerable decrease of vasodilation ability develops. The role of an altered prostaglandin biosynthesis in this phenomenon was investigated in connection to the altered vascular adrenergic mechanisms. The effect of phenylephrine on prostacyclin production of isolated coronary arterial rings (100 mumol/l) as well as on conductivity of the coronary arterial bed (7.5-15-30-60 pmol. kg-1.min-1) were compared in 12 metabolically healthy and 12 alloxan-diabetic (560 mumol/kg) dogs. Furthermore, the effect of phentolamine (5 mumol/l) on the prostacyclin and thromboxane productions of the isolated vessels (coronary, femoral and basilar arteries) was investigated by radioimmunoassay. Although the basal prostacyclin amounts synthesized by healthy and diabetic coronary vessels were not different (5.1 +/- 1.6 and 4.9 +/- 1.4 pg/mg vessel/30 min), similarly to femoral and basilar arteries, the diabetic arterial rings produced significantly (p less than 0.05) more thromboxane than the control rings. The alpha-adrenergic blockade by phentolamine did not influence the prostacyclin production in the healthy arteries, but considerably (p less than 0.05) increased it in the diabetic coronary arteries. Phentolamine normalised the thromboxane synthesis in the diabetic group (p less than 0.01) and enhanced (p less than 0.05) it in the metabolically healthy group. Phenylephrine was ineffective (98 +/- 6%) on the prostacyclin production in vitro versus the stimulated (150 +/- 22%) prostacyclin synthesis detected in the metabolically healthy group; and in vivo induced a more significant (p less than 0.05) decrease in the coronary conductivity in diabetic than in control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Influence of experimental diabetes on the mechanical responses of canine coronary arteries: role of endothelium.

The influence of experimental diabetes on the endothelium mediated relaxation and contractile responses of canine isolated coronary arteries was studied in arteries removed from alloxan treated diabetic (280 mmol.kg-1) and control mongrel dogs. Strips with and without endothelium were suspended in Krebs bicarbonate solution for isometric recording. Relaxation responses to acetylcholine (1.8 X 10(-8) to 9.4 X 10(-6) mol.litre-1, A23187 (10(-8) to 1.28 X 10(-6) mol.litre-1), and sodium nitroprusside (10(-9) to 10(-7) mol.litre-1) as well as contractile responses to prostaglandin F2 alpha, (1.7 X 10(-7) to 5.6 X 10(-4) mol.litre-1) were determined. In all intact strips acetylcholine, and A23187 induced similar concentration dependent reduction of the prostaglandin F2 alpha (2 X 10(-6) mol.litre-1) evoked tone. No significant difference was observed between sodium nitroprusside evoked relaxations of normal and diabetic arteries. Cyclooxygenase blockade reduced the maximal relaxations induced by acetylcholine and A23187 in diabetic vessels, whereas it did not change the endothelium dependent relaxation of normal arteries. Diabetes increased significantly the sensitivity to acetylcholine (EC50 4.1(0.4) X 10(-7) mol.litre-1 in control and 6(0.7) X 10(-8) mol.litre-1 in diabetic arteries; p less than 0.01, n = 7) and to A23187 (EC50: 7(1) X 10(-8) mol.litre-1 in control and 3.8(0.3) X 10(-8) mol.litre-1 in diabetic vessels; p less than 0.01, n = 7); in contrast, prostaglandin F2 alpha remained an equiactive constrictor in normal and diabetic vessels with intact endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1988

Insulin induced reversibility of altered responsiveness in femoral arterial bed of diabetic dogs.

The altered reactivities of femoral arterial bed to noradrenaline, phenylephrine, adenosine and prostacyclin were compared in 18, clinically manifest but aketotic, alloxan diabetic mongrel dogs. Alloxan treatment markedly increased the vasoconstrictor responses to noradrenaline and phenylephrine, as well as the adenosine-induced vasodilation in the femoral vasculature. These changes were prevented or normalized, respectively, in the early or late insulin-treated alloxan diabetic animals. In the case of noradrenaline not only a normalization but also an explicit overcompensation could be observed by insulin treatment. The altered reactivity to prostacyclin could not be influenced by insulin therapy. These results indicate a significant difference in the effect of insulin treatment on the altered diabetic vascular responsiveness to catecholamines and adenosine or to prostacyclin.

Animals↗
PubMed1988

Effects of PGI2, CH-7284 and CH-7384 on spontaneous platelet aggregation and blood pressure of anaesthetized beagles.

Chinoin-7284 and Chinoin-7384 are chemically stable derivatives of prostacyclin. We compared the hypotensive and antiaggregatory effects of PGI2 and the two analogues using our computerized aggregometric system. The in vivo antiaggregatory activity was measured with a modified filtration pressure technique in anaesthetized beagle dogs: The change in arterial blood pressure was measured simultaneously. The dose-response relationship and the duration of action of prostacyclin and their analogues following bolus administration have been determined. The molar dose of PGI2, CH-7284 and CH-7384 that produced 25 mmHg reduction in filtration pressure were 0.3 +/- 0.06 nmol/kg; 7.37 +/- 0.94 nmol/kg; 17.19 +/- 1.76 nmol/kg respectively (n = 6). The molar doses that produced the same decrease in mean arterial pressure were 0.61 +/- 0.06 nmol/kg; 15.59 +/- 4.73 nmol/kg; 21.05 +/- 7.20 nmol/kg respectively (n = 6). There were no significant differences between equipotent doses of prostacyclin and its analogues with respect to the duration of antiaggregatory and hypotensive action. The in vivo selectivity ratios (hypotensive potency/antiaggregatory potency) of PGI2, CH-7284 and CH-7384 were 0.49, 0.47 and 0.85 respectively. The results indicate that these two PGI2 analogues have the same character as regards the in vivo duration of actions and in vivo selectivity, as has the parent compound.

Animals↗
PubMed1988

In vivo antiaggregatory effect of BM 13.177 on the spontaneous platelet aggregation in anaesthetized beagle dogs.

The arterial blood of anaesthetized heparin-treated beagle dogs was directed through a 30/um diameter pore size screen by a roller pump at a constant rate. As a result, the pressure proximal to the filter continuously increased. The filtration pressure stabilizing concentration of prostacyclin (infused proximal to the filter) was determined. BM 13.177 -similar to PGI2- was able to slow down and stop the increase of filtration pressure (final conc.: 1-10/uM). In addition it could reverse the filter occlusion process. The lowest concentration of BM 13.177 (0.1-1/uM) did not affect significantly the filter occlusion rate, but it markedly enhanced the antiaggregatory effect of PGI2 when these drugs were administered simultaneously. In summary, we can conclude that 1) generation of thromboxane and endoperoxide plays a key role in the mechanism of the spontaneous platelet aggregation on the filter; 2) BM 13.177 significantly potentiates the antiaggregatory effect of PGI2 in vivo.

Animals↗
PubMed1988

Relaxation by prostacyclin (PGI2) of human, dog and rabbit femoral artery strips. Interspecies difference.

Helically cut femoral artery strips from humans (bypass surgery), dogs and rabbit were set up for isometric recording. The endothelial layer was removed by rubbing, hence the vascular strips used in this study are considered to be arterial smooth muscle preparations without endothelium. The indomethacin-, prostaglandin F2 alpha- and PGI2-induced changes in tone were determined. Indomethacin (3/mumol/l) potentiated the contractile responses of human and canine vessels to PGF2 alpha by 60.0 +/- 10.4 and 108 +/- 12%, respectively. By contrast, the PGF2 alpha-induced contractions of rabbit arteries were not enhanced by the cyclooxygenase inhibitor. PGI2 diminished the tone of the PGF2 alpha-contracted vessels obtained from all the three species in a concentration-related manner. The potency of the relaxant prostanoid differed, however, markedly (p less than 0.02) from species to species. The IC50 values (molar concentrations of PGI2 producing 50 percent reduction in the PGF2 alpha-induced tone) were 20.8 +/- 1.9, 133 +/- 24 and 286 +/- 52 nmol/l for human, dog and rabbit arteries, respectively. The results clearly demonstrate a significant interspecies difference in the prostacyclin-sensitivity of the blood vessels studied. The differential responsiveness to indomethacin may reflect species-difference in the regulatory function of PGI2 in arterial smooth muscle tone.

Animals↗
PubMed1988

Actions of PGE2 and indomethacin on adrenergic neuroeffector transmission in the rabbit coeliac artery.

In the present study we have investigated the pre- and post-synaptic actions of PGE2 and indomethacin on the adrenergic transmission in isolated coeliac arteries of rabbits. The artery segment was preloaded with (3H)NA and suspended in an organ bath (37 degrees C, 5% CO2 - 95% O2, isometric recording). The preparation was superfused with Krebs-solution containing the uptake blockers cocaine and corticosterone. To release neurotransmitter, the artery was stimulated by electrical square-wave pulses (0.5 ms, 5 Hz, 60 s) using platinum wire electrodes. The perfusate was collected in 3 or 6 min samples. The outflow of labelled neurotransmitter was expressed in pmol/3 min. Inhibition of endogenous prostaglandin-biosynthesis by indomethacin (3/mumol/l) potentiated the contractile responses to nerve stimulation (57 +/- 15%, n = 4), but did not influence the release of NA (the release ratio was 1.02 +/- 0.03, n = 4). The endogenous prostaglandins may modulate vascular neuroeffector transmission postjunctionally, because cyclooxygenase inhibition did not cause any change in transmitter release. The effects of exogenous PGE2 on adrenergic transmission and contraction were also studied. In this case, indomethacin was present to minimize the potential complicating actions of endogenous prostanoids. At low concentrations (1, 3 and 10 nmol/l) PGE2 dose-dependently inhibited vasoconstrictor responses to nerve stimulation (IC50 = 4.7 +/- 1.5 nmol/l, n = 4), but was ineffective in influencing transmitter release (the stimulation evoked release ratios were 0.95 +/- 0.05, 1.00 +/- 0.00 and 0.93 +/- 0.11, n = 4, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Contractile and relaxant responses of diabetic dog femoral arteries.

Strips of femoral arteries of normal and alloxan-treated dogs were set up for isometric recording. The contractile response to phenylephrine and the relaxant response to acetylcholine were determined. Neither alloxan treatment nor mechanical removal of endothelium altered the EC50 value for phenylephrine. The slope of phenylephrine dose-response curves of diabetic and healthy vessels with intact endothelium was similar, whereas the slope of phenylephrine dose-response curves of endothelium-denuded diabetic arteries was significantly greater than that of the denuded healthy arteries. Removal of the endothelium completely abolished the relaxant effect of acetylcholine. The relaxant potency (IC50) of acetylcholine was not affected by alloxan treatment. The results suggest that in canine femoral arteries the relaxant activity of acetylcholine is unaffected in experimental diabetes and the damage of the arterial endothelium may play a role in the increased responsiveness of diabetic vessels to adrenergic agonists.

Acetylcholine↗
PubMed1987

Inhibition by quinine of endothelium-dependent relaxation of rabbit aortic strips.

1 The effects of quinine sulphate, tetramethylammonium chloride (TMA) and tetraethylammonium chloride (TEA) (all blockers of the Ca2+-activated K+ channels) on the relaxations induced by acetylcholine (ACh), calcium ionophore A23187 and sodium nitrite were studied in helical strips of rabbit aorta. 2 The strips were contracted to a moderate stable tone with phenylephrine (10(-7) M). ACh (4 X 10(-9) to 10(-6) M) as well as A23187 (10(-8) to 3 X 10(-7) M) reduced this tone in a concentration- and endothelium-dependent manner. 3 Pretreatment of the tissues with quinine (2.5 X 10(-5) to 10(-4) M) for 60 min produced a concentration-dependent inhibition of the relaxation induced by ACh. Also 90 min incubation of the strips with TMA (3 X 10(-3) to 6.5 X 10(-2) M) or TEA (10(-3) to 3 X 10(-2) M) inhibited the ACh-evoked relaxation in a manner similar to quinine. 4 Quinine (10(-4) M, 60 min), TMA (6.5 X 10(-2) M, 90 min) or TEA (3 X 10(-2) M, 90 min) produced 5 to 10 fold reductions in the relaxant EC50 values of A23187 and ACh and depressed (by 40 to 95%) the maximal relaxations to the ionophore and ACh. 5. On a molar basis, quinine was more effective than the two tetraalkylammonium ions in reducing the endothelium-dependent relaxations of the aortic strips induced by ACh or A23187. The inhibitory actions were reversible after 60 to 90 min washout. 6. Exposure of the strips to either quinine (10-4M, 60 min), TMA (6.5 x 10-2 M, 90 min) or TEA (3 X 10-2 M, 90 min), however, did not influence significantly the relaxations evoked by sodium nitrite, a direct smooth muscle relaxant. 7. These results suggest that stimulation of the Ca2+-activated K' channels could be, at least partially, responsible for the endothelium-dependent relaxations induced by ACh or A23 187. Their activation might not be required for the endothelium-independent relaxant effects of sodium nitrite.

4-Aminopyridine↗
PubMed1987

Differential contractile responsiveness of femoral arteries from healthy and diabetic dogs: role of endothelium.

Phenylephrine-induced contraction and acetylcholine-induced relaxation of isolated femoral arterial strips (with and without endothelium) of diabetic (alloxan-treated) and metabolically healthy dogs were determined. Alloxan treatment did not change the contractile responsiveness to phenylephrine (PE) of the arteries with intact endothelium. After mechanical removal of the endothelial layer, however, the maximum force generated by the diabetic vessels (22.0 +/- 2.0 mN.m-2) significantly exceeded the maximum contraction produced by the nondiabetic arteries (14.6 +/- 1.8 mN.m-2). The dose-response curve of diabetic arteries to PE was steeper than it was in non-diabetic strips. The EC50 values for PE were similar in these two groups (0.45 +/- 0.12 and 0.58 +/- 0.20 mumol/l in diabetic and nondiabetic vessels, respectively). In the arteries with intact endothelium, acetylcholine produced concentration-related reduction of PE-induced tone. This endothelium-dependent relaxant activity of acetylcholine was similar in the healthy and diabetic arterial strips, IC50 for acetylcholine being 0.17 +/- 0.02 and 0.20 +/- 0.03 mumol/l, respectively. These results suggest that functional alteration of endothelium (probably an increased release of EDRF) prevails in diabetes. This may be important in reducing the hyper-responsiveness of diabetic arterial smooth muscle to PE.

Animals↗