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Biomedical subjects

E Bassenge

Publications and source records attributed to E Bassenge.

At least 109 records · Page 6Linked to original sources
PubMed1989

Failure of the sulfhydryl donor N-acetylcysteine (NAC) to reverse nitrate tolerance in large epicardial arteries and the venous capacitance system of the dog.

NAC has been thought to reverse nitrate tolerance by replenishing depleted intracellular sulfhydryl groups, however data on interactions between N-acetylcysteine and nitrates in patients with stable angina are controversial and disappointing. Therefore, we studied the effect of NAC on nitrate responsiveness of epicardial arteries and of the venous system (assessed as changes in effective vascular compliance) in dogs (n = 12) during long-term nitroglycerine (GTN)-treatment (1.5 micrograms/kg/min for 5 to 6 days). In dogs with GTN-specific tolerance (shift of venous or epicardial artery dilation with 15- to 17-fold higher dosages), NAC (100 mg/kg i.v.) had no dilator effect and did not alter the dose response relations of nitroglycerin. However, in nontolerant dogs (n = 7) NAC augmented (1.5- to 2-fold) the reduction of peripheral vascular resistance induced by 0.5-1.5 microgram/kg/min GTN. In vitro, the augmentation of purified guanylate cyclase activity by GTN (100 microM) was potentiated by NAC (0.01-1.0 mM) in saline or in canine plasma, whereas NAC alone was ineffective. Therefore, NAC does not restore GTN-responsiveness in epicardial arteries or veins in vivo and a small, tolerance-independent augmentation of GTN-induced dilation may result from NAC-induced extracellular formation of a stimulant of guanylate cyclase from GTN.

Acetylcysteine↗
PubMed1989

Konkurrenz zwischen endothelabhängiger und Nitroglygerin-induzierter koronarer Vasodilatation [Competition between endothelium-dependent and nitroglycerin-induced coronary vasodilation].

UNLABELLED: Intact vascular endothelium can relax the smooth muscle by liberation of EDRF (endothelium-derived relaxing factor) and thus induce vasodilation. We investigated to what extent functional integrity of the endothelium modifies the dilatory capacity of coronary arteries and which influence nitroglycerin exerts on endothelium-dependent relaxation mechanism. In 74 coronary segments from eight patients with coronary artery disease, coronary artery diameters were measured before (C1) and 90 s after intracoronary infusion of the endothelium-dependent vasodilator bradykinin (0.1 mM) by means of a computer-assisted contour assessment system (CAAS). The same segments were then measured before (C2; 10 min after C1) and 90 s after an intracoronary infusion of the endothelium-independent vasodilator nitroglycerin (0.29 mM). By dividing diameter increases after bradykinin in group I less than 0.15 mm, n = 42 segments and group II: greater than 0.45 mm, n = 32 segments, the following diameters were obtained (mean +/- SD): (table; see text) CONCLUSION: In atherosclerotic coronary segments with impaired endothelium and consecutively reduced endothelium-dependent dilation the vasodilatory capacity of nitroglycerin is enhanced. Due to a competitive effect on the final common biochemical pathway, i.e., stimulation of soluble guanylate cyclase and elevation of intracellular levels of cyclic guanosylmonophosphate (cGMP) nitrovasodilators can facilitate insufficient endogenous relaxation of vascular smooth muscle.

Bradykinin↗
PubMed1989

[Inhibition of thrombocyte aggregation and adhesion by endothelium-derived relaxant factor (EDRF) and their pathophysiologic significance].

Changes in viscous drag acting upon the endothelial lining and a number of circulating agonists (ATP, ADP, serotonin, thrombin) stimulate the release of EDRF from intact endothelial cells. EDRF is probably identical with nitric oxide (NO), the vasoactive compound which is also formed in the metabolism of nitrovasodilators in the vasculature (some of them directly release NO without the essential foregoing bioconversion step). Albuminally released NO stimulates soluble guanylate cyclase (sGC) in the vasculature initiating vasodilation; luminally released NO stimulates, sGC in platelets and increases cyclic GMP inhibiting platelet activation and aggregation. Endothelial impairment brings about loss of dilator and antiaggregant capacity.

Animals↗
PubMed1989

Clinical tolerance to nitroglycerin is due to impaired biotransformation of nitroglycerin and biological counterregulation, not to desensitization of guanylate cyclase.

UNLABELLED: We studied the effect of nitroglycerin (NTG), endothelium-derived relaxing factor (EDRF), sydnonimine SIN-1, and sodium nitroprusside (SNP) on vascular tone, cyclic GMP content and activity of soluble guanylate cyclase (GC) (in homogenates) of tolerant (1 h 0.55 mM NTG) and non-tolerant (1 h vehicle) de-endothelialized rabbit aortae (RA) as well as on cyclic GMP content of cultured smooth muscle cells (SMC) from RA. Nitrate tolerance significantly attenuated NTG-induced vasodilation of precontracted (1.0 microM norepinephrine) RA, increase in cyclic GMP in RA and SMC, and activation of guanylate cyclase in homogenates as compared to controls. In contrast, vasodilation and cyclic GMP increases to NNP, SIN-1, and EDRF (from cultured bovine aortic endothelial cells) were not affected in RA and SMC, despite desensitization of guanylate cyclase to activation with SNP and SIN-1 in homogenized tolerant RA. CONCLUSION: A desensitization of soluble guanylate cyclase to activation with NO can be demonstrated under non-physiological conditions (disrupted cells) in homogenates from nitrate tolerant RA. However, in intact cells (in situ or in culture) soluble guanylate cyclase is not desensitized to EDRF, SIN-1 or SNP. Therefore reduced generation of NO from NTG because of impaired biotransformation of NTG must be regarded as the basis of nitrate tolerance.

Animals↗
PubMed1989

[Noninvasive, continuous measurement of finger artery pressure with the servo-plethysmo-manometer Finapres].

The servo-plethysmo-manometry, as described by Penaz, represents a method for noninvasive, continuous, true-phase measurement of the finger arterial pressure. PRINCIPLES OF MEASUREMENT The light transmission plethysmograph is integrated into a pneumatic cuff for the finger (Figure 1). The light intensity is a function of the instantaneous finger blood volume. It is assumed that the pulsatory volume fluctuations are a function of the instantaneous intra-arterial blood pressure. Since the elastic arterial walls counteract the volume fluctuations with resistance, for calibrated measurements, they must be in a fully relaxed state in the absence of transmural pressure. A criterium for assessment of the transmural pressure is the extent of the volume pulse amplitude which is relatively small in the presence of higher transmural pressure due to a lesser degree of distention of the arterial walls and which increases in association with higher extravascular pressure because of the lower transmural pressure. The registered photosignal is larger with continuous cuff pressure elevation and reduced when the intravascular pressure is exceeded. At maximal amplitude, that is, complete relaxation of the arterial wall and cessation of the transmural pressure, the servosystem is activated to regulate the cuff pressure such that the pressure in the finger cuff holds the finger blood volume constant during the pulse cycle with corresponding elevation during systole and reduction during diastole. Accordingly, the cuff pressure, with minimal delay, always can be equated with the intravascular pressure. MANOMETRY WITH THE FINAPRES Currently available Finapres models 4 and 5 are electronically similar, completely automatic and easy to handle. After positioning the finger cuff, the unit is adjusted automatically through comparison of the plethysmogram at each cuff pressure level with the predicted value stored as an algorhythm++.(ABSTRACT TRUNCATED AT 250 WORDS)

Arteries↗
PubMed1988

Desensitization of guanylate cyclase in nitrate tolerance does not impair endothelium-dependent responses.

Tolerance of vascular smooth muscle to nitroglycerin could be induced by an impaired biotransformation of nitroglycerin to nitric oxide, the activator of soluble guanylate cyclase, or by desensitization of guanylate cyclase to activation with nitric oxide. The latter would imply that there would also be tolerance to nitric oxide delivered from sodium nitroprusside or endothelial cells. Therefore, endothelium-denuded segments of rabbit aorta were treated with nitroglycerin to induce tolerance, and were then assessed for mechanical response, cyclic GMP content, and activity of soluble guanylate cyclase after addition of nitrovasodilators. Nitrate tolerance decreased the vasodilation and the increase in cyclic GMP elicited by nitroglycerin, but not that elicited by sodium nitroprusside or endothelium-derived relaxing factor, in norepinephrine-contracted segments. However, soluble guanylate cyclase in the supernatants of homogenates of nitrate-tolerant aortas was desensitized to activation with nitroglycerin and sodium nitroprusside. As the guanylate cyclase was still responsive to activation by nitric oxide in the intact, tolerant smooth muscle, an impaired biotransformation of nitroglycerin rather than desensitization of soluble guanylate cyclase may be the mechanism by which nitrate tolerance develops.

Animals↗
PubMed1988

Consideration of conduit and resistance vessels in regulation of blood flow.

In heart failure the maximal capacity for dilation, especially in skeletal muscle arteries, is reduced. This may be due to changes in sympathetic tone, in hormonal stimulation (both by circulating and intramurally released compounds like angiotensin II with additional presynaptic effects) or in endothelium mediated vasodilation. The loss of endothelium-mediated, flow-dependent dilation in large arteries may originate from endothelial impairment induced by, e.g., chronic hypoxia or hypercholesterolemia. Similar effects result from suppressed local dilator autacoid release brought about, e.g., by circulating atrial natriuretic factor in the presence of a fully functioning endothelium. Finally, attenuated augmentations in flow may be secondary to changes in muscular metabolism, and an increased alpha-adrenergic neurogenic constriction may be present. This may be further enhanced by a local, beta-receptor-mediated angiotensin II release. An impaired dilation at the level of resistance vessels may result from a combination of the mechanisms listed above.

Animals↗
PubMed1988

[Pharmacological bases of therapeutic tolerance].

The purpose of this review paper is to describe the various mechanisms that may lead to a decrease in the effectiveness of drugs during long-term treatment (the so-called "tolerance" or "escape phenomenon"). In addition, some precise recommendations will be made. Tolerance may be due either to degradation of the active substance by enzyme induction, as is the case e.g. with barbiturates (pharmacokinetic drug tolerance) or to down-regulation of receptors (e.g. beta-adrenergic drugs and opiates) or exhaustion of the metabolic pathways involved in pharmacological activation, as with nitrates and other drugs (pharmacodynamic drug tolerance). Whatever its mechanism, tolerance can be prevented by intermittent drug administration despite the problems inherent in the therapeutic gaps thus created. Another, more rational approach is to replace the drug concerned by a more appropriate drug which permits, or induces the restoration of receptor density when their number is reduced by the physiopathological situation (e.g. H2 stimulation instead of beta-adrenergic stimulation) or which reproduces the action of first physiological messengers, such as the endothelium-derived relaxing factor (EDRF), without requiring metabolic activation (e.g. SIN-1 or molsidomine instead of nitrates).

Animals↗
PubMed1988

Interdependence of pharmacologically-induced and endothelium-mediated coronary vasodilation in antianginal therapy.

Recent advances in the understanding of vascular physiology have furnished new aspects in the treatment of angina pectoris by various vasodilators. Upon stimulation by various factors (viscous drag from increased flow, pulsatile stretch, ADP/ATP, norepinephrine, serotonin), the coronary endothelium releases a vasodilator called endothelium-derived relaxant factor (EDRF). This factor has recently been shown to probably be nitric oxide (NO), which is identical to the active compound of nitroglycerin. EDRF (NO) dilates both large epicardial arteries and also coronary resistance vessels. It also has a strong platelet antiaggregant effect. The predominant effect of Ca2+ antagonists is on resistance vessels, increasing myocardial perfusion and viscous drag acting upon the endothelial lining. This, in turn, stimulates EDRF (NO) release in epicardial arteries and dilation. This additional nitrate-like effect augments the direct vasodilator effect of Ca2+ antagonists. Lack of normal endothelial function results in diminished capacity to dilate, and sometimes even in a shift from dilator to constrictor effects, paralleled by an increased tendency for platelet adhesion, activation, and thrombosis, which is still enhanced when plasma low density lipoprotein (LDL) is augmented. EDRF release, vasodilator capacity, and antiaggregant effects are reduced when LDL is high. Nitrates have a direct, endothelium-independent dilator effect, particularly on large coronary arteries, which seems even more pronounced when the endothelium is absent, but only when the vessel segment is still compliant. Therefore nitrates may particularly be effective in vessels with deficient EDRF release.

Angina Pectoris↗
PubMed1988

Endothelium-dependent hyperpolarization of smooth muscle cells in rabbit femoral arteries is not mediated by EDRF (nitric oxide).

Acetylcholine elicits an endothelium-dependent hyperpolarization of vascular smooth muscle cells. The experiments reported here tested the hypothesis that this hyperpolarization is mediated by the endothelium-derived relaxant factor (EDRF) identified as nitric oxide. Membrane potential was recorded with standard glass microelectrodes in smooth muscle cells in segments of rabbit femoral arteries. In endothelium-intact vessels, smooth muscle cells (resting potential: -67.0 +/- 1.3 mV) hyperpolarized significantly (P less than 0.001) by 5.7 +/- 0.9 mV in response to acetylcholine (1 microM). Inhibition of EDRF, either in the presence of hemoglobin or by pretreatment with gossypol, attenuated the relaxation elicited by acetylcholine in endothelium-intact segments precontracted with 0.1 microM noradrenaline but had no significant effect on either the control membrane potential (-62.2 +/- 1.9 mV and -68.5 +/- 2.1 mV, respectively) or the hyperpolarization in response to acetylcholine (5.0 +/- 1.6 mV and 5.8 +/- 1.6 mV, respectively). In contrast, in vessel segments with the endothelium removed, the hyperpolarization in response to acetylcholine was abolished although the control membrane potential (-68.0 +/- 5.1 mV) was not significantly different from that in endothelium-intact vessels. Sodium nitroprusside, an endothelium-dependent vasodilator and exogenous analog of EDRF, also had no significant effect on membrane potential. The lack of response to acetylcholine was not merely the result of nonspecific damage to the smooth muscle cells: vessel segments without endothelium were still able to hyperpolarize in response to various other vasodilators. These results suggest that the endothelium-dependent hyperpolarization of vascular smooth muscle cells in response to acetylcholine is not mediated by EDRF.

Acetylcholine↗
PubMed1988

Discrepancy between initial and steady-state resistance vessel responsiveness to short-term nitroglycerin exposure in the hindlimb of conscious dogs.

Since much of the antianginal efficacy of nitroglycerin can be ascribed to its ability to dilate large arteries and venous capacitance vessels at dosages that have little steady-state effect on vascular resistance, we re-examined the reasons for low responsiveness of resistance vessels to nitroglycerin in a peripheral vascular bed in vivo. In chronically instrumented conscious dogs, intra-iliac nitroglycerin (0.15, 0.5, and 1.5 micrograms/kg/min) resulted in substantial dose-dependent initial increases in iliac flow (35% +/- 7%, 60% +/- 11%, and 106% +/- 12%, respectively). However, unlike the responses of iliac large artery diameter, these dilations were not sustained during a 6-min infusion. In contrast, doses of nitroprusside, acetylcholine, and adenosine, which gave initial dilations comparable to nitroglycerin, resulted in considerably greater steady-state responses (p less than 0.001). Nitrate tolerance, autoregulatory escape, reflex vasoconstriction, and the influence of cyclooxygenase products were ruled out as potential explanations of this selective pattern of nitroglycerin response. It is proposed that the rapid attenuation of nitroglycerin-induced dilation in a representative peripheral vascular bed cannot be attributed to currently accepted hypotheses and contributes more to the unique and beneficial spectrum of nitrate vascular action than an a priori lack of sensitivity of resistance vessels.

Acetylcysteine↗
PubMed1988

Free radicals inhibit endothelium-dependent dilation in the coronary resistance bed.

Oxygen free radicals contribute significantly to ischemia-reperfusion myocardial damage in vivo. We studied the effect of reactive products of O2 generated by electrolysis of the saline perfusate on coronary vasomotor tone and endothelium-mediated vasodilator responsiveness in 41 isolated rabbit hearts. Under constant flow conditions, electrolysis induced a progressive increase in perfusion pressure associated with a modest reduction in myocardial contractile function. The responses to the endothelium-independent vasodilators papaverine and adenosine tended to be increased by 1.5- to 2-fold, indicating that the increase in perfusion pressure was due, at least in part, to increased resistance vessel tone. However, resistance vessel dilations to the endothelium-dependent agents acetylcholine and serotonin were markedly reduced. Various degrees of protection against increases in perfusion pressure and inhibition of endothelium-dependent dilation during electrolysis were obtained with catalase, a scavenger of hydrogen peroxide; superoxide dismutase, a scavenger of superoxide; and desferrioxamine, which chelates iron and thereby inhibits hydroxyl radical production. Furthermore the action of nitroprusside, a direct-acting stimulator of soluble guanylate cyclase, was not diminished during the electrolytic treatment. We conclude that inhibition of endothelium-dependent dilation is a prominent action of reactive products of O2 in the coronary resistance bed. In combination with a free radical-induced increase in resistance vessel tone this might limit recovery of myocardial perfusion post ischemia.

Acetylcholine↗
PubMed1988

Preferential venoconstriction by cyclooxygenase inhibition in vivo without attenuation of nitroglycerin venodilation.

Because prostacyclin is a rather potent venodilator in vivo, we analyzed the effect of cyclooxygenase inhibition on venous tone in 14 anesthetized dogs during ganglionic and beta-adrenergic blockade and atraumatic conditions. Effective vascular stiffness (a reciprocal of effective vascular compliance) as a variable of integrated venous tone was 0.30 +/- 0.01 mm Hg.kg/ml (n = 35) and was augmented up to twofold by diclofenac (1, 3, and 10 mg/kg i.v.), ibuprofen (6 and 60 mg/kg), or indomethacin (5 mg/kg) parallel to augmentations in central venous pressure, while the rise in arterial pressure was less than half of the increase induced by equivenoconstrictor dosages of norepinephrine. After preconstriction by indomethacin or diclofenac, nitroglycerin (1.5 micrograms/kg/min) lowered effective vascular stiffness (by 24 +/- 2% or 23 +/- 5%, respectively), similarly as during preconstriction by norepinephrine (by 24 +/- 4%). Long-term cyclooxygenase inhibition (diclofenac 2 x 1 mg/kg/day for 4 days) did not modify arterial pressure, heart rate, or hematocrit levels in conscious dogs at rest, but it lowered plasma volume to 52.5 +/- 1.9 ml/kg (sham treatment: 59.1 +/- 1.6 ml/kg, p less than 0.05, n = 4). In conclusion, venoconstriction by clinical dosages of cyclooxygenase inhibitors does not interfere with the venodilator action of nitroglycerin and is compensated chronically by adjustments of plasma volume.

Animals↗
PubMed1988

Sympathoadrenal activity and sympathoinhibitory hormones during acute and chronic nicotine application in dogs.

Though acute nicotine administration results in increased blood pressure and heart rate, previous work has shown that chronic nicotine treatment does not result in significant hypertension. In fact, surprisingly it has been shown to produce hypotension. We performed the present experiments to further analyze the effects of chronic nicotine treatment. In untreated dogs (n = 7) under pentobarbital anesthesia (with adrenal hormone release measured directly by cannulation of the adrenolumbar veins) cumulative nicotine infusions (1-24 micrograms/kg/min i.v.) caused dose-dependent release of epinephrine (from 3.0 +/- 0.7 to 111 +/- 30 micrograms/kg/min) and norepinephrine (from 0.4 +/- 0.1 to 11.2 +/- 3.1). However, significant release of leu-enkephalin and met-enkephalin immunoreactivity was observed only with the highest nicotine infusion (24 micrograms/kg/min). In untreated conscious dogs (n = 12), nicotine test infusions (3 and 10 micrograms/kg/min), 15 min, yielded smoking relevant plasma nicotine levels and augmented heart rate, mean arterial pressure, plasma catecholamine levels, and adrenal epinephrine release. Plasma-enkephalin immunoreactivities were only marginally elevated with the higher nicotine test infusion. Chronic nicotine treatment (1.5 micrograms/kg/min s.c. for 5 weeks, n = 7), only transiently (first 1-2 weeks) augmented mean arterial pressure, heart rate, and epinephrine release, but during the plateau phase of treatment, hemodynamics and catecholamine parameters were identical to the pretreatment period. Acute responses of hemodynamics and catecholamines to nicotine test infusions declined progressively during chronic treatment, but the time course of this attenuation seemed not related to the reversal of the transient hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

[Cardiac mechanisms for the development of angina pectoris pain].

Despite numerous experimental and clinical investigations, the exact mechanisms involved in the development of cardiac pain are not completely understood. Sensory receptors for painful stimuli, presumably sympathetic sensory nerve endings, are located in the atria, the ventricles, and in the walls of the coronary arteries. These receptors fire at a background rate under normal hemodynamic conditions. They respond to chemical stimuli and are therefore similar to polymodal nociceptors. The afferent fibers (slow-conducting, unmyelinated group IV-fibers, or fast-conducting myelinated group III-fibers) run in the cardiac sympathetic nerves and converge with somatosensory fibers on the same ascending spinothalamic neurons, which may explain the phenomenon of "referred pain". Still unknown is the role of the afferent vagal fibers in pain perception; however, a modulating influence on pain threshold and characteristics seems possible. Two main mechanisms may be responsible for cardiac pain during ischemic periods: a) chemical excitation of free sensory nerve endings by substances such as bradykinin, PGE2, adenosine, histamine, serotonin, or K+; b) abnormal motion of ischemic segments (dyskinesia, bulging) during systole and excitation of mechanical receptors by passive stretching, and probably a combination of a) and b): the release of chemical substances sensitizes mechanical receptors and lowers their threshold for nociceptive stimuli. These can be suppressed at various spinal or supraspinal levels.

Afferent Pathways↗
PubMed1988

[Quality assurance in Riva-Rocci blood pressure measurement: simultaneous sphygmomanometry with open and covered pressure display].

The indirect measurement of arterial blood pressure according to Riva-Rocci is one of the most frequently performed medical diagnostic procedures. When properly performed, this method yields accurate readings compared with intraarterial measurements. However, measurements by means of conventional sphygmomanometers are subject to observer error and variability. Therefore, to eliminate important sources of bias (terminal digit preference of the observer, rate of inflation and deflation of the cuff), and to quantify interobserver variability, a new sphygmomanometer has been developed. The new instrument makes possible "simultaneous-blind" blood pressure readings by two observers, according to the Riva-Rocci method. Simultaneous-blind blood pressure readings were made by four observers with experience in blood pressure determination. In 448 measurements made under resting conditions, values obtained by different observers with the new device were very consistent with each other: there were no differences in 50% of systolic and 43% of diastolic measurements. Differences of more than 5 mmHg were observed only in 9% of the systolic and 11% of the diastolic measurements. In 165 measurements made during exercise, the differences between blood pressure readings by different observers were larger (more than 5 mmHg in 40% of systolic and 35% of diastolic values). This variability among observers may be substantial in blood pressure readings made in therapeutic and epidemiologic studies, even when the observers are carefully selected and trained. Compared with the conventional open measurements, blind measurements (n = 100) gave mean values 2 mmHg lower, depending on heart rate and cuff deflation rate. The new sphygmomanometer allows quantification and control of the variability among observers during both open and blind measurements.

Adult↗