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Biomedical subjects

P Dominiak

Publications and source records attributed to P Dominiak.

At least 73 records · Page 4Linked to original sources
PubMed1995

[Evaluation of the antihypertensive drugs carvedilol, doxazosin and moxonidine].

Carvedilol, Doxazosin and Moxonidine are rather novel antihypertensive substances, which belong to "beta-adrenoceptor-antagonists", "alpha 1-adrenoceptor-antagonists" and "antisympathotonic substances" respectively. Besides its nonselective beta-adrenoceptor-antagonistic activity, Carvedilol possesses smooth vascular relaxant and alpha 1-antagonistic effects. Since beta-adrenoceptor-antagonists are, together with diuretics, the only antihypertensives for which a decrease in mortality rate has been verified, Carvedilol by its site of action also belongs to that antihypertensive family. Many investigations have shown that the alpha 1-adrenoceptor-antagonist Doxazosin is as effective in blood pressure lowering as other antihypertensive substances and has only a few side effects. With respect to the hypotensive action, the antisympathotonic substance Moxonidine is as effective as Clonidine is, but side effects occur 50% less in comparison to Clonidine. The 3 substances enlarge the antihypertensive therapy. However, mortality studies are required to test their comparability to the other first line antihypertensive substances.

Antihypertensive Agents↗
PubMed1995

[Antihypertensive therapy in elderly patients].

Arterial blood pressure increases with age. Because of the rapidly increasing number of elderly people, hypertension is a common problem in general medicine. The benefits of antihypertensive treatment in the elderly is nowadays well documented and has also proven in recent studies. Total mortality, cerebrovascular and cardiovascular events could be reduced by treating elderly patients with hypertension. However, some special features of elderly people must be considered, i.e. the alterations of the vessel wall reactivity, of decreased blood flow, of receptor function, of gastric, liver and renal function. Therefore, an altered pharmacokinetics can lead to an enhancement of the duration and potency of antihypertensive drugs. Initially, monotherapy with low doses of the five first line drugs is recommended: beta-blockers, diuretics, calcium channel blockers, ACE-inhibitors and alpha-1-blockers. Individual concomitant diseases and risk factors determine the choice of the drug. Because of the circadian blood pressure rhythm in primary hypertension with the highest values in the morning antihypertensive drugs should be given as early as possible. Drugs with a 24-hour duration of action should be preferred. Blood pressure should be carefully lowered into the desired range over a period of several weeks and months. Target is to lower diastolic blood pressure below 90 mmHg and systolic blood pressure below 160 mmHg in patients with initial values above 180 mmHg. In patients with initial values between 160-180 mmHg blood pressure should be reduced by nearly 20 mmHg.

Aged↗
PubMed1994

Historic aspects in the identification of the I1 receptor and the pharmacology of imidazolines.

The central nervous system is involved in the control of arterial blood pressure. Stimulation of central alpha 2-adrenoceptors in the nucleus tractus solitarii (NTS) decreases sympathetic outflow, resulting in a fall in arterial blood pressure. One of the first antihypertensive substances with actions on the alpha 2-adrenoceptors of the NTS was alpha-methylnoradrenaline. Later on the imidazoline clonidine was developed for which numerous effects, mediated by alpha 2-adrenoceptors, in the CNS could be demonstrated. Since the centrally acting alpha 2-adrenoceptor agonists possess severe side effects, the development of more specific and selective centrally acting imidazolines resulted in the derivatives moxonidine and rilmenidine. The effects of the "second-generation imidazolines" could not be fully understood as alpha 2-adrenoceptor agonists. In the meantime, the rostral ventrolateral medulla (RVLM) has been identified as the site of action of the imidazolines and an I1-imidazoline binding site was characterized in this region. For the antihypertensive action of the imidazolines, agonism at the I1-imidazoline subtype seems to be responsible. In addition, an acid- and heat-stable endogenous substance, called clonidine displacing substance (CDS), was reported to bind at the putative I receptor. In 1992 a receptor protein for I receptors (70 kD) could be separated that is different from that of alpha 2-adrenoceptors. However, up to now we are still lacking the amino-acid sequence of the I receptor and its second messenger system.

Animals↗
PubMed1993

Angiotensin II increases norepinephrine release from atria by acting on angiotensin subtype 1 receptors.

Norepinephrine stores in electrically driven guinea pig isolated atria were loaded with [3H]norepinephrine, and norepinephrine release was deduced from the radioactivity efflux. Electrical field stimulation of sympathetic nerve endings was applied during the refractory period of atrial contractions. The stimulation-induced release of norepinephrine was increased by angiotensin II (Ang II) (10(-8) to 10(-6) mol/L) in a concentration-dependent manner. The maximum observed effect was a 55% augmentation. The effects of 10(-7) and 10(-6) mol/L Ang II were abolished by 10(-6) and 10(-5) mol/L of the subtype 1 Ang II receptor antagonist losartan, respectively. Losartan by itself (10(-6) mol/L) caused a 14% reduction of norepinephrine release. The subtype 2 Ang II receptor ligand PD 123319 (1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)- 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate) in a concentration of 10(-4) mol/L had no detectable influence on transmitter release and did not antagonize the effect of Ang II. Angiotensin I (10(-6) and 10(-5) mol/L) increased norepinephrine release maximally by 23%. This effect was antagonized by 10(-5) mol/L losartan and did not appear in the presence of 10(-6) mol/L of the converting enzyme inhibitor ramiprilat. These results suggest that Ang II increases norepinephrine release by an activation of subtype 1 receptors, whereas angiotensin I is converted to Ang II to become effective.

Analysis of Variance↗
PubMed1993

Modulation of sympathetic control by ACE inhibitors.

ACE inhibitors may influence the actual concentrations of the peptides angiotensin I, angiotensin II and bradykinin. Since all three peptides are able to modulate catecholamine release, a change in noradrenaline and adrenaline release should be expected when angiotensin I converting enzyme (kininase II) is inhibited. Furthermore, converting enzyme inhibitors may also act indirectly on sympathetic membranes affecting, for instance, the reuptake mechanism of noradrenaline. It was shown that chronic ACE inhibition did not change biosynthesis, storage or release of catecholamines. However, the reuptake of noradrenaline was slightly but significantly diminished by ramipril. Whereas Ang I exerted no facilitating action on noradrenaline, bradykinin stimulated noradrenaline release dose-dependently, almost during converting enzyme inhibition. It is concluded that bradykinin may compensate for the lack of effect of converting enzyme inhibitors on catecholamine release.

Angiotensin I↗
PubMed1993

Hypertensive effects and structure-activity relationships of 5-omega-aminoalkyl isoxazoles.

Structure-activity and dose-response relationships of a series of novel 5-omega aminoalkyl and 5-omega-amino-heteroalkyl isoxazoles on blood pressure and heart rate of Sprague-Dawley rats have been investigated. To differentiate between peripheral and central cardiovascular actions of those compounds a pithed rat and anaesthetized rat preparation was used. Most of the compounds investigated exhibit potent hypertensive actions. The hypertensive effects of the tested compounds is depending on the amphiphilic character of the isoxazoles represented by a basic moiety in a definite distance to the phenyl substituents. To achieve high pharmacological activity a fully flexible side chain is requested, too. Possible mechanisms of action are discussed.

Animals↗
PubMed1992

Effects of graded exercise on blood pressure, heart rate, and plasma hormones in cardiac transplant recipients before and during antihypertensive therapy.

The effects of graded supine ergometry on blood pressure, heart rate, and plasma hormones were studied in 14 hypertensive heart transplant recipients before and after 2 weeks and 6 months of enalapril (20 mg/day) plus furosemide (20-80 mg/day) alone or combined with verapamil (120-360 mg/day). Each time, measurements were obtained at rest and at 25 and 50 W exercise. Antihypertensive therapy normalized blood pressure, while heart rate and the blood pressure response to exercise remained unaltered. Pretreatment resting plasma renin activity and catecholamine levels were normal, while atrial natriuretic factor and cyclic guanosine monophosphate concentrations were elevated. All hormones increased significantly with exercise. During treatment, plasma renin activity increased and atrial natriuretic factor and cyclic guanosine monophosphate levels decreased significantly, with a blunted exercise response; concentration of catecholamines increased significantly, with augmented exercise response. Thus, the chosen regimen allowed effective, lasting BP control in hypertensive transplant patients but was associated with significant changes in plasma hormones. Whereas the rise in plasma renin activity may be attributed to converting enzyme inhibition, the decreases in atrial natriuretic factor and cyclic guanosine monophosphate and increases in catecholamine levels seem to indicate marked changes in resting and particularly exercise hemodynamics during antihypertensive therapy.

Adult↗
PubMed1992

Changes in peripheral sympathetic outflow of pithed spontaneously hypertensive rats after bradykinin and DesArg-bradykinin infusions: influence of converting-enzyme inhibition.

Because converting enzyme and kininase II are identical enzymes and probably influence both the biosynthesis of angiotensin II and the metabolism of bradykinin, we investigated the effects of bradykinin and desArg-bradykinin on the sympathetic outflow of pithed spontaneously hypertensive rats (SHRs) before and after acute or chronic inhibition of the converting enzyme by ramipril. Sympathetic outflow was induced by preganglionic electrical stimulation of the spinal cord and measured as circulating, stimulation dependent norepinephrine and epinephrine by high-performance liquid chromatography (HPLC) and electrochemical detection. Bradykinin increased dose-dependently norepinephrine and epinephrine release, particularly when converting enzyme was inhibited. DesArg-bradykinin did not influence norepinephrine outflow but caused a dose-dependent increase in epinephrine release only after converting-enzyme inhibition. It is suggested that both bradykinin and desArg-bradykinin could compensate for the lack of effect of angiotensin II on sympathetic outflow.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Radiation-induced heart disease: morphology, changes in catecholamine synthesis and content, beta-adrenoceptor density, and hemodynamic function in an experimental model.

To study further the pathophysiology of radiation-induced cardiomyopathy, we investigated resting hemodynamics, myocardial catecholamine synthesis and storage, and beta-adrenoceptor density after local heart irradiation. In Wistar rats, a radiation dose of 20 Gy eventually leads to compromised myocardial function which is characterized by a reduction in cardiac output to 43 +/- 11% and in the left ventricular ejection fraction to 66 +/- 7.5%, and an increase in the left ventricular end-diastolic volume to 187 +/- 17% of control values. This reduction in function is correlated with focal degeneration of 23 +/- 4% of the myocardium. Measurement of tyrosine hydroxylase activity and catecholamine content revealed that catecholamine biosynthesis is unchanged in the adrenals but is significantly reduced in the hearts of irradiated animals, while cardiac beta-adrenoceptor density is increased to about 140% of that in age-matched controls. This is in contrast to findings in dilated or ischemic cardiomyopathy. Time-course studies showed that the development of myocardial degeneration starts simultaneously with the decrease in cardiac output and ejection fraction and the increase in beta-adrenoceptors at 50-80 days postirradiation. Myocardial degeneration is maximal in extent and severity at 100 days and does not progress thereafter. Cardiac output decreases at 80-100 days postirradiation to 60 +/- 7% of control values. A significant further decrease is seen only when congestive heart failure becomes manifest at 249 +/- 21 days after 20 Gy. Thus there is a delay between structural myocardial injury and hemodynamic deterioration which could be due to a compensatory increase in beta-adrenoceptor density during the initial stages of the cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Beta-adrenoceptor blocking effects of two bopindolol metabolites in isolated guinea-pig atria.

The beta-adrenoceptor blocking effects of the bopindolol (Wandonorm, CAS 62658-63-3) metabolites 18-502 (indole-2,4- methylaminopropoxy(N-tert.butyl)-tartrate) and 20-785 (indole-2,4-carboxyaminopropoxy(N-tert.butyl] were studied in electrically stimulated guinea-pig left atria and in spontaneously beating guinea-pig atria in vitro. Both compounds shifted the concentration-response curve of isoprenaline to the right, but did not reduce the maximum effect of this drug. For compound 20-785, pA2 values of 7.44 (left atrium, inotropic effect) and 7.58 (right atrium, chronotropic effect) were calculated. The metabolite 18-502 had a much greater beta-adrenoceptor blocking potency, as judged from its pA2 values of 9.53 and 9.48, resp., and in the concentration of 10(-8) mol/l it caused a significant flattening of the concentration-response curve of isoprenaline. From these results, compound 20-785 can be classified as a competitive beta-adrenoceptor antagonist, while for higher concentrations of the metabolite 18-502 additional noncompetitive mechanisms of action cannot be excluded.

Adrenergic beta-Antagonists↗
PubMed1992

Modulation of presynaptic sympathetic activity by kinins and related compounds: influence of converting enzyme inhibition.

Since converting enzyme and kininase II are identical enzymes and probably influences both, the biosynthesis of Ang II and the metabolism of bradykinin we investigated the effects of bradykinin, desArg-bradykinin and some bradykinin antagonists (desArg[9]-Leu[8]-bradykinin, HOE S 890307) on the sympathetic outflow of pithed SHR or Brown-Norway-Rats before and after acute or chronic inhibition of the converting enzyme by ramipril. bradykinin increased dose dependently the noradrenaline and adrenaline release in particular when the converting enzyme was inhibited. DesArg-bradykinin caused a dose-dependent increase in adrenaline release only after converting enzyme inhibition. The bradykinin-antagonists led to an increase in adrenaline release during ramipril administration. The weak but significant stimulation of adrenaline release by the bradykinin antagonists after converting enzyme inhibition might be due to unspecific actions on the adrenal medulla possibly induced by histamine release from mast cells.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Cardiovascular parameters and catecholamines in volunteers during passive orthostasis. Influence of antihypotensive drugs.

To evaluate the therapeutic value of various antihypotensive agents we investigated amezinium (AMZ; CAS 30578-37-1), dihydroergotamine (DHE; CAS 511-12-6), midodrine (MDD; CAS 42794-76-3), and oxilofrine (OXF; CAS 365-26-4) in volunteers during passive orthostasis in a randomized double-blind study against placebo (PCB). Blood pressure, heart rate, and circulating catecholamines were determined before and after i.v. injections of the mentioned agents before and during 10 min of passive orthostasis. Echocardiographic and venous plethysmographic data were obtained during resting before and after the administration of the drugs. Resting heart rate decreased after injection of PCB, AMZ, DHE, and MDD. During tilting no significant changes in heart rate could be observed. Blood pressure remained unchanged at rest and during orthostasis after all agents injected. DHE and MDD lowered circulating noradrenaline. Echocardiographic parameters were changed after administration of AMZ (increase in stroke volume index (SVI) and ejection fraction (EF)), MDD (increase in enddiastolic volume index and SVI), and OXF (increase in SVI, EF, and cardiac index). The venous capacity of the lower left leg was only significantly decreased after injection of DHE, indicating an increased venous tone of the leg veins. The observed changes in sympathetic and cardiovascular parameters are in agreement with their sympathomimetic actions and allow a differential therapeutic classification: DHE and MDD are suitable agents for patients with sympathotonic orthostatic reaction; if asympathotonic orthostatic reaction occurs MDD, AMX and OXF should be recommended to those patients.

Adult↗
PubMed1992

[ACE inhibitors].

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Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

[Therapy comparison between the combination hydergine/nifedipine and nifedipine alone in patients with isolated systolic hypertension].

The effect of Hydergine/Nifedipine (Pontuc) on blood pressure in supine or exercise blood pressure as well as subjective well-being was evaluated in a randomized, double-blind interindividual comparison with Nifedipine in 50 elderly out-patients (34 females, 16 males) with mostly pretreated isolated systolic hypertension. In addition to a nearly unchanged diastolic blood pressure during treatment the results prove that the drop in systolic blood pressure was statistically significant greater after treatment with Hydergine/Nifedipine and the normalization rate of the blood pressure was 81% in comparison to 69% after Nifedipine. Both drugs comparatively improved the subjective well-being of these geriatric patients. As drug specific adverse events flush symptoms were more frequent in the Nifedipine group, whereas in the Hydergine/Nifedipine group gastrointestinal symptoms occurred more often.

Aged↗
PubMed1991

[Hypertensive action of 5-(beta-aminoethyl)aminoisoxazoles: synthesis and screening of isoxazolopyrazines and isoxazolodiazepines].

The 5-aminoisoxazole 1 is converted via the 4-nitro derivative to the 4,5-diamino compound 4, which cyclises with glyoxal to yield the isoxazolo[4,5-b)pyrazine 5. Decomposition of the isoxazole moiety is always observed in experiments to hydrogenate partially the pyrazine ring and to phenylate the N-atom, respectively. Therefore, the corresponding tetrahydro derivative 6 is prepared from 4 and 1,2-ethandiol ditosylate. Starting with benzohydroxamic acid chloride and a cyanoacetic acid amide the tetrahydro isoxazolo[5,4-e]1,4-diazepinone-4 18 is synthesized. All new compounds are characterized by their spectroscopic data, the reaction mechanisms are discussed. Using the model of the pithed and the anaesthetized rat, resp., the pyrazino- and diazepino-isoxazoles (compounds 5, 6, 13, 18) have less or no hypertensive activity as compared to the corresponding derivatives with fully flexible side chains.

Animals↗
PubMed1991

Does converting enzyme inhibition change the neuronal and extraneuronal uptake of catecholamines?

In previous studies concerning the sympathetic outflow during converting enzyme inhibition, no significant changes after chronic treatment could be observed. Therefore, we investigated the effects of the long-acting converting enzyme inhibitor ramipril on the neuronal and extraneuronal uptake of SHR. Ramipril was administered either i.v. or orally to SHR, whereas desipramine or corticosterone were additionally infused to block the neuronal or extraneuronal uptake of catecholamines. As an index of sympathetic outflow, plasma noradrenaline and adrenaline concentrations were determined during preganglionic stimulation of the spinal cord using HPLC and ELCD. Blood pressure of SHR was measured in a carotid artery and was significantly decreased in the ramipril treated group under resting and stimulating conditions. Ramipril did not influence stimulated sympathetic outflow. However, in acute and chronic experiments ramipril led to an additive effect to desipramine concerning stimulated circulating catecholamines. Similar results could be obtained after blocking the uptake-2 with corticosterone. 3H-NA-uptake into the hearts of SHR was significantly diminished by about 10% after chronic ramipril administration. It is suggested that ramipril is able to decrease the neuronal and extraneuronal uptake of catecholamines by an unspecific effect due to the comparably high lipophilicity. The blood pressure lowering effect of ramipril is not supported by an inhibition of presynaptic noradrenaline release.

Angiotensin II↗