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Biomedical subjects

P Dominiak

Publications and source records attributed to P Dominiak.

At least 91 records · Page 5Linked to original sources
PubMed1991

Regression of left ventricular hypertrophy in hypertensive heart transplant recipients treated with enalapril, furosemide, and verapamil.

BACKGROUND: This prospective study was designed to examine whether left ventricular (LV) hypertrophy of the denervated transplanted heart may be reversed by medical therapy and, if so, to investigate the time course of this process and its effect on exercise capacity, myocardial function, and cardiac hemodynamics. METHODS AND RESULTS: Ten hypertensive heart transplant recipients with LV hypertrophy were evaluated before therapy with enalapril plus furosemide alone or combined with verapamil, at initial blood pressure (BP) control and after 3, 6, 9, and 12 months, using 24-hour noninvasive ambulatory BP monitoring, M-mode and two-dimensional echocardiography, and supine bicycle ergometry. Average 24-hour systolic and diastolic BP declined from 158 +/- 10 and 104 +/- 7 mm Hg to 129 +/- 9 and 84 +/- 10 mm Hg at initial BP control (p less than 0.005 and p less than 0.025, respectively) and total peripheral resistance from 1,687 +/- 177 to 1,376 +/- 122 dyne.sec.cm-5 (p less than 0.025), remaining normal thereafter. Exercise capacity remained unchanged during the study. LV mass, mass-to-volume ratio, and end-diastolic septal plus posterior wall thickness decreased progressively from 211 +/- 30 g, 2.49 +/- 0.62 g/ml, and 25.7 +/- 2.6 mm to 184 +/- 26 g, 2.22 +/- 0.46 g/ml, and 22.5 +/- 1.9 mm after 3 months (all p less than 0.025) and to 174 +/- 25 g, 2.07 +/- 0.38 g/ml, and 21.5 +/- 1.5 mm after 6 months (all p less than 0.005), remaining unaltered at 9 and 12 months. A correlation was found between the decrease in average 24-hour mean BP and LV mass after 3 months of antihypertensive therapy (r = 0.71, p less than 0.05). Systolic meridional wall stress, LV end-diastolic and stroke volume, ejection fraction, and cardiac output remained unchanged throughout the observation period. CONCLUSIONS: The results indicate that regression of LV hypertrophy is induced by effective antihypertensive therapy in the denervated transplanted heart. The extent of decrease in average 24-hour BP appears to be the main determinant for the extent of reduction in LV mass. LV afterload as characterized by systolic meridional wall stress, LV size and pump function, and physical exercise capacity of the transplant patients are not influenced by the therapeutic regimen chosen in this study.

Adult↗
PubMed1991

Plasma hormones in patients with chronic heart failure before and early after orthotopic heart transplantation.

The aim of this prospective study was to investigate both vasoconstricting and vasodilating plasma hormones and plasma factors regulating the circulatory homeostasis in patients with endstage congestive heart failure before and early after orthotopic heart transplantation and to evaluate factors which may influence their regulation. 19 patients with endstage congestive heart failure were analyzed serially before and 3-4 weeks after orthotopic heart transplantation. A significant decrease in plasma concentrations of noradrenaline (457 +/- 202 vs. 204 +/- 88 pg/ml; p less than 0.001), adrenaline (43 +/- 32 vs. 26 +/- 11 pg/ml), atrial natriuretic peptide (341 +/- 218 vs. 139 +/- 64 pg/ml; p less than 0.005), cyclic guanosine monophosphate (13.8 +/- 7.8 vs. 6.6 +/- 2.2 pmol/ml, p less than 0.05) and in plasma renin activity (16.6 +/- 13.0 vs. 2.0 +/- 2.4 ng AI/ml/h; p less than 0.01) was found after transplantation. The data indicate that the marked increase in plasma catecholamine concentrations and renin activity in endstage congestive heart failure is reversible as early as 3-4 weeks after heart transplantation. This is most likely the consequence of normalization of cardiac function. While elevation of atrial natriuretic peptide and cyclic guanosine monophosphate as well as increased vasoconstrictor activity in heart failure appear to be related to impaired ventricular function, the persistent moderate elevation of both vasodilating agents after transplantation may be compensatory to counteract cyclosporin-induced arterial hypertension after heart transplantation.

Adult↗
PubMed1990

Extended levodopa release from a subcutaneously implanted polymer matrix in rats.

It is well recognized that plasma fluctuations resulting from oral levodopa therapy may cause an unstable clinical response in parkinsonian patients. We have therefore developed a slow-release polymer matrix system that can deliver levodopa continuously for extended periods of time (at least 225 days) after subcutaneous implantation in rats. Advantages of this approach include (1) the elimination of levodopa plasma fluctuations and (2) the possibility of reducing the required dose due to constant plasma levels and because the gastrointestinal tract is circumvented. The peripheral implantation of polymer systems containing levodopa, dopamine receptor agonists, or other anti-Parkinson agents may constitute a novel technology of drug delivery to improve the care of patients with Parkinson's disease.

Animals↗
PubMed1990

[Hypertensive acting 5-(beta-aminoethyl)aminoisoxazoles: synthesis and screening of derivatives with with partially rigid C-5 side chains and omega-position heterocyclics].

Isoxazoles with a 1,2-diaminoethane side chain at C-5 are synthesized by nucleophilic substitution of 5-chloro derivatives. Using piperazine, imidazolidine and 1,2-diaminocyclohexane, resp., isoxazoles with partially rigid chains at C-5 are formed. The same procedure succeeds in the synthesis of isoxazoles having a heterocycle at the omega-position of the side chain. The hypertensive activity of all new compounds is shown for the pithed and the anaesthetized rat, resp. According to structure activity relationships the hypertensive activity of compounds 7 and 8, resp., is mainly determined by the heterocycle at the omega-position (piperazine greater than piperidine approximately pyrrolidine greater than morpholine). Derivatives 2-5 with partially rigid 5-(beta-aminoethyl)amino side chains show less hypertensive activity than the corresponding compounds without restrictions.

Anesthesia↗
PubMed1990

Levodopa delivery from controlled-release polymer matrix: delivery of more than 600 days in vitro and 225 days of elevated plasma levels after subcutaneous implantation in rats.

Parkinson's disease is commonly treated with orally applied levodopa (l-dopa). However, because this treatment modality is associated with a number of undesirable side effects, some due to plasma fluctuations, we have developed a slow-release polymer system that can be used to deliver l-dopa continuously for extended periods of time in vitro (greater than 600 days) and in vivo (at least 225 days) in rats. In vitro l-dopa release was evaluated using polymer matrices with appropriately selected parameters (loading and geometry), and zero-order (linear) release of l-dopa was observed for more than 600 days (in highly loaded, noncoated material first-order kinetics), in some instances in mg quantities per day. This was achieved even in polymer matrices, which did not possess a dissolution limiting barrier. Scanning electron-microscopic analysis suggests that the mechanism of release is dissolution through channels and pores within the polymer matrix. To assess in vivo release, l-dopa was quantified in plasma from rats given s.c. implants of l-dopa polymer matrices using high-performance liquid chromatography. We observed release of l-dopa for a period of at least 225 days after an initial burst of release. Continuous release of l-dopa from s.c. implanted slow-release polymer matrices has several advantages over oral delivery: 1) l-dopa plasma fluctuations are eliminated, 2) patient compliance issues are reduced and 3) the gastrointestinal tract is circumvented, thus requiring a lower dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Selective local action of angiotensin II on dopaminergic neurons in the rat hypothalamus in vivo.

Microdialysis was used to investigate whether angiotensin II modulates the basal and K+-induced release of endogenous noradrenaline, dopamine and their metabolites 3,4-dihydroxyphenylglycol (DOPEG) and 3,4-dihydroxyphenylacetic acid (DOPAC) from the anterior hypothalamus of the anaesthetized rat. The release of the amines was stimulated twice (ST1 and ST2) with either 50 mmol/l or 100 mmol/l K+. The release of each amine induced by K+ was reproducible and concentration-dependent. Angiotensin II when present in the perfusion fluid after ST1 at a concentration of 0.1 and 10 mumol/l (chosen after in vitro experiments had shown that the recovery of the peptide across the dialysis membrane was only 3.6%), had no significant effect on amine release. However, 10 mumol/l angiotensin II induced an immediate, significant increase in basal DOPAC outflow which reached a maximum of 89% in the 100 mmol/l K+ and 53% in the 50 mmol/l K+ experiments. No such effect was observed with DOPEG outflow. In a separate experimental series, addition of angiotensin II without a preceding K+ stimulation period did not significantly affect the outflow of the amines and metabolites. The results suggest that angiotensin II can selectively influence dopamine metabolism in the anterior hypothalamus in vivo but does not act locally to acutely facilitate the release of endogenous catecholamines from this brain area.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

[Circadian behavior of blood pressure and heart rate following orthotopic heart transplantation. Studies before and during antihypertensive therapy].

The de novo hypertension, which develops in most cardiac transplant recipients within the first postoperative months, is multicausal, though toxic side-effects of cyclosporin A seem to play a key role. In order to analyze the circadian behavior of arterial blood pressure and heart rate after cardiac transplantation (HTX) and to evaluate the effect of an antihypertensive regimen on these parameters, 24-h noninvasive ambulatory blood pressure and heart rate monitoring was performed in 10 hypertensive cardiac transplant recipients on cyclosporin A (mean age 42.3 +/- 11.2 years, 14.3 +/- 8.3 months after HTX) before antihypertensive therapy and after introduction of an antihypertensive regimen with the ACE-inhibitor enalapril plus furosemide alone or combined with verapamil. The study demonstrated a complete loss of the usual nocturnal decline in blood pressure in cardiac transplant recipients (mean systolic and diastolic blood pressure 149 +/- 8 and 102 +/- 7 mm Hg during daytime and 152 +/- 8 and 104 +/- 9 mmHg at night). Antihypertensive therapy lowered the blood pressure level effectively, but did not influence the circadian pattern (mean systolic and diastolic blood pressure 121 +/- 8 and 81 +/- 4 mmHg during daytime and 121 +/- 9 and 83 +/- 3 mmHg at night, all p less than or equal to 0.001). Heart rate, in contrast, showed a significant, though in comparison to normal, a blunted decrease at night (mean heart rate 94 +/- 6 beats per min during daytime and 84 +/- 8 beats per min at night, p less than or equal to 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

[Influence of baroreceptors on hypertension, pharmacotherapy with conversion enzyme inhibitors].

Baroreceptor reflex plays an important role in the pathophysiology of essential hypertension. Experiments in dogs could demonstrate that after complete denervation of sinoaortic and cardiopulmonar baroreceptors a long-lasting hypertension with labile blood pressure behavior occurred. The sympathetic tone was enhanced significantly when studied in denervated rats. In patients with essential hypertension no comparable conditions to the "neurogenic hypertension" of animals exist. Therefore, studies in patients after orthotopic heart transplantation are of interest because those patients develop severe hypertension even if cyclosporine is not administered. Preliminary results reported here support a participation of baroreceptors in hypertension of transplanted patients. A further reason of essential hypertension is found on baroreceptor resetting. Changed ion concentrations and/or wall thickness of the respective blood vessels could be the cause. The sympathetic system influences the renin-angiotensin-system and baroreflex activity by central and peripheral mechanisms. It, for example, attenuates Ang-II and the baroreflex via central actions. Converting-enzyme-inhibitors (CEI) act in part as peripheral vasodilators without affecting the heart rate significantly. This effect is possibly due to lacking Ang-II that is able to increase the sensitivity of baroreceptors. In the past it has been shown that the inhibition of tissue-converting enzyme is more responsible for the antihypertensive effects of CEI than that of plasma-converting enzyme. The cardioprotective effects of CEI are suggested to be an important advantage in the treatment of hypertension and heart failure. These cardioprotective actions are partly due to accumulated bradykinin, just as are the hypotensive effects of CEI. The interactions between CEI and the sympathetic system should be differentiated into pre- and postsynaptic actions.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

The absolute systemic availability of a new oral formulation of co-dergocrine in healthy subjects.

We have studied the absolute systemic availability (f) of an oral formulation (Hydergin spezial = Hydergine FASR 4 mg per tablet) of co-dergocrine by three different methods. Twelve healthy volunteers received single doses of 0.9 mg co-dergocrine intravenously and 8.0 mg orally in a randomized crossover design. The pharmacological effect of co-dergocrine was monitored as a reduction in plasma prolactin. Maximal plasma concentrations of co-dergocrine after oral dosing ranged between 0.181 and 1.307 ng.ml-1. Maximal urinary excretion ranged between 4.7 and 9.9 micrograms.h-1 and between 0.3 and 2.3 micrograms.h-1 after intravenous and oral doses respectively. Clearance was measured as 90 +/- 22 l.h-1 and the absolute systemic availability (f) as 2.25 +/- 0.65% by using the areas under the plasma concentration-time curves extrapolated to infinity. Calculation of f by comparing areas up to 32 h or the fractions of the dose excreted in urine led to identical results. The intravenous and oral doses produced similar pharmacological effects (reduction of plasma prolactin concentrations) despite the small value of f.

Administration, Oral↗
PubMed1987

Changes in cardiovascular adrenoceptor response in rats subsequent to myocardial infarction.

Since sympatho-adrenal activity was greatest on the second day after experimental myocardial infarction in the rat, we investigated the responsiveness of cardiovascular adrenoceptors in pithed rats at this time and also determined the number of beta-adrenoceptors in the myocardium of the rats. In addition, the sympathetic outflow was measured, as a presynaptic parameter for estimating sympathetic nervous activity. The number of beta-adrenoceptor binding sites and the frequency responses of the heart were unchanged by myocardial infarction on the second day. There was also no difference from control animals with respect to sympathetic outflow. However, the rise in diastolic blood pressure, caused by electrical stimulation of the sympathetic nervous system, was far more pronounced in animals with infarction than in controls. In contrast, rats with myocardial infarction exhibited an attenuated response of diastolic blood pressure to infused noradrenaline. The observed effects can possibly be explained by changes of alpha-adrenoceptors, or perhaps by an enhanced degradation of catecholamines in the endothelium.

Animals↗
PubMed1987

Biosynthesis of catecholamines and sympathetic outflow in spontaneously hypertensive rats (SHR) after chronic treatment with CE blocking agents.

It has been reported that acute administration of captopril is followed by a decrease of norepinephrine (NE) release from the sympathetic nerves. Therefore, we studied the interactions between converting enzyme (CE) blocking agents and the presynaptic sympathetic nervous system after chronic administration of various CE inhibitors. Captopril, enalapril, and ramipril were administered orally to male spontaneously hypertensive rats (SHR) for 14 days. As parameters for catecholamine biosynthesis and storage, the activity of tyrosine hydroxylase and the catecholamine content of the hearts and the adrenal medulla were measured by high performance liquid chromotography (HPLC) in treated and control SHR. As an index of sympathetic outflow, plasma NE and epinephrine (E) levels were determined during preganglionic stimulation (PS) of the spinal cord. After chronic administration, no differences between the treated and control animals could be observed, either in the biosynthesis and storage of catecholamines in the heart and adrenal medulla or in the sympathetic outflow. However, after acute infusion of ramipril, a significant decrease in NE release was obtained. The dose-response curves of blood pressure vs. PS were significant shifted to the right when CE inhibitors were administered. It is suggested that the acute effect of CE inhibition on NE and E release (decreased sympathetic outflow) is blunted after long-term treatment with CE inhibitors because of increased angiotensin I (Ang I) and probably bradykinin. Both are capable of releasing NE and E at least from the adrenal medulla, like angiotensin II (Ang II).

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Effects of chronic treatment with ramipril, a new ACE blocking agent, on presynaptic sympathetic nervous system of SHR.

Acute administration of captopril has been reported to decrease noradrenaline (NA) release from the sympathetic nerves. In this study the chronic effects of ramipril on the sympathetic nervous system of male spontaneously hypertensive rats (SHR) have been investigated and compared to those of captopril and enalapril. As parameters for catecholamine biosynthesis and storage, the activity of tyrosine hydroxylase and the catecholamine content of the hearts and the adrenal medulla were measured by HPLC in treated and control SHR. To assess sympathetic outflow plasma NA and adrenaline (A) levels were determined during preganglionic stimulation (PS) of the spinal cord. Under none of these drugs could differences be observed between the treated and control animals, neither in the biosynthesis and storage of catecholamines in the heart and adrenal medulla nor in the sympathetic outflow. However, the dose response curves of blood pressure vs PS were significantly shifted to the right when ACE-inhibitors were administered, most strongly by ramipril. In view of the unaltered presynaptic sympathetic function long term treatment with ACE-inhibitors is suggested to increase bradykinin and angiotensin I. Bradykinin and angiotensin I are capable of releasing NA and A from the adrenal medulla, like angiotensin II.

Adrenal Glands↗
PubMed1987

[Bioavailability of heptaminol in healthy subjects].

In ten healthy volunteers the plasma and urine concentrations of heptaminol (Heptylon) were determined by high-performance liquid chromatography after intravenous administration of 250 mg heptaminol and oral intake of 2 x 150 mg heptaminol in tablet form, and the pharmacokinetic parameters were calculated. Heptaminol was rapidly and entirely absorbed following oral administration of heptaminol. Mean plasma peak concentrations of 1.6 mg/l were reached after 1.8 h, the area under the plasma concentration-time curve was equal to that after intravenous administration. The dominant terminal plasma half-life was 2.5-2.7 h. The total clearance amounted to 700 ml/min, and nearly all the dose given was recovered unchanged in urine within 24 h, indicating renal elimination by glomerular filtration and tubular secretion without metabolization.

Administration, Oral↗
PubMed1986

Alterations of beta-adrenoceptors subsequent to myocardial infarction.

Elevations and reductions of the number of beta-adrenoceptor binding sites are dependent on the strength and the duration of receptor interaction with respective agonists. In the paper presented here, results obtained by the authors concerning biosynthesis, storage and release of catecholamines following experimentally induced infarction of the myocardium in rats are compared with those of other authors for other species. Principally, storage and release of noradrenaline from ischemic hearts do not differ with the mode of inducing tissue hypoxia (stopped-flow ischemia, coronary artery ligation, occlusion of the great cardiac vein), nor for various species (rat, dog, guinea-pig). Differences are, however, present in the results of several beta-adrenoceptor binding studies performed after experimental myocardial infarction. Following acute infarction, an increase in the number of beta-adrenoceptor binding sites is generally observed, which is explained on the basis of an externalization of receptors from the cytoplasm ot the sarcolemmal membrane. Results pertaining to 2-3 days after infarction are not uniform: in guinea-pig hearts a marked drop in the number of beta-adrenoceptors has been reported, a mild rise in the number has been detected in the left and right ventricle of rat hearts. These divergent observations could arise from the experimental protocol employed, for instance in the binding assay and in the pretreatment given to the hearts prior to assay.

Animals↗
PubMed1986

Inhibition of monoamine oxidase by viloxazine in rats.

Biochemical and pharmacological investigations about the effect of the antidepressant drug viloxazine (Vivalan) on catecholamine metabolism in rats led to the following results: Viloxazine exerts a dose and time dependent inhibition of monoamine oxidase activity of brain and liver mitochondrial fraction and tissue homogenates of hypothalamus, heart, liver, and adrenal glands, both in vitro and after oral and parenteral administration in vivo. Consequently, an increase in catecholamine concentrations in brain of rats could be observed after pretreatment with viloxazine. In addition brain serotonin concentrations rose and 5-hydroxy-indoleacetic acid was diminished. However, characterization of inhibition of monoamine oxidase activity by viloxazine in vitro revealed: Compared to the specific inhibitors clorgyline for MAO-A- and pargyline for MAO-B-activity, viloxazine was a very weak inhibitor both for MAO-A and MAO-B in vitro. The type of inhibition was competitive and reversible. From the presented results and the results obtained by other laboratories it is concluded that inhibition of monoamine oxidase activity by viloxazine, although clearly demonstrated in animal experiments, may not be the only mechanism for an antidepressant action of the drug in man.

Animals↗
PubMed1985

Effects of nicotine and its major metabolites on blood pressure in anaesthetized rats.

Blood pressure and heart rate in anaesthetized rats has been determined after i.v. injection of increasing doses of nicotine (NI) and its major metabolites, i.e. continine (CO), nornicotine (NOR), metanicotine (MN) and dihydrometanicotine (DMN). NI and MN elicited similar dose response curves, increasing blood pressure according to the dose injected. However, the dose response curve of MN was shifted to the right. Furthermore DMN caused similar pressor effects than MN and the pressor effects of NOR was even weaker. Only after injection of CO was a dose-dependent depressor effect observed and this was reversed after very high doses. CO also reduced heart rate in a dose-dependent manner, whereas NI and its other metabolites did not significantly change heart rate.

Animals↗