Medvedev Os

Simultaneous determination of plasma noradrenaline and adrenaline kinetics

SummaryLiquid chromatographic fractionation and detection of exogenous radiolabelled and endogenous catechols was used to examine simultaneously the plasma kinetics of noradrenaline and adrenaline in the conscious rabbit. Plasma clearances and release of noradrenaline and adrenaline into plasma were compared before and during nitroprusside-induced hypotension and 2-deoxyglucose-induced glucopenia, stimuli purported to differentially affect catecholamine release from sympathetic neurons and the adrenal medulla. Plasma concentrations of dihydroxyphenylglycol (DHPG) were also measured to assess presynaptic sympathetic function.Plasma clearances of adrenaline correlated with, but were significantly less than those of noradrenaline. Plasma clearances of both catecholamines showed significant decreases during nitroprusside-induced hypotension and 2-deoxyglucose-induced glucopenia. Glucopenia and hypotension increased the release into plasma of noradrenaline and adrenaline, but the adrenaline response relative to the noradrenaline response was greater during glucopenia than during hypotension. Plasma DHPG concentrations increased during glucopenia and hypotension, consistent with increased neuronal reuptake of noradrenaline and therefore a neuronal source — as opposed to an adrenal source — of most of the noradrenaline appearing in plasma during the stimuli. The increase in plasma DHPG relative to that of noradrenaline was greater after 2-deoxyglucose than after nitroprusside suggesting that the presynaptic handling of noradrenaline during glucopenia was different from that during hypotension or that the two stimuli released DHPG from regionally distinct sources.

Use of a smartphone for improved self-management of pulmonary rehabilitation

Patients suffering from chronic respiratory disease need to follow a rehabilitative exercise programme, in order to self-manage their illness and improve quality of life. Adherence to the programme is highly dependent on professional support from a physiotherapist and hence declines when patients seek to self-manage in the home. A number of requirements were identified for a Smartphone-based application in which patients are supported remotely and given automatic feedback during exercise. An application is described which will improve adherence during pulmonary rehabilitation.

Sympathoinhibitory action of rilmenidine in conscious sinoaortically denervated rats.

Summary: The responses of mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) to rilmenidine administration and changes in these responses after idazoxan or yohimbine pretreat-ment were investigated in conscious sinoaortically denervated rats. Intravenous (i.v.) injection of rilmenidine (300 and 600 μg/kg) dose-dependently reduced MAP (16 and 24%, respectively) and RSNA (31 and 56%, respectively), whereas bradycardia was similar at both doses of the drug. Intracisternal (i.e.) pretreatment with idazoxan (5 μg/kg), α2-adrenoceptor antagonist with a high affinity to imidazoline receptors (IR) prevented rilmenidine-induced decreases in MAP but not in RSNA and HR. Rilmenidine (300 μg/kg i.e.) significantly decreased MAP by 24%, RSNA by 32%, and HR by 13%. Pretreatment with idazoxan (1 μg/kg i.e.) significantly attenuated the hypotensive and sympathoinhibitory effects of rilmenidine, whereas i.e. pretreatment with equimolar to 10-fold higher doses of yohimbine, an a2-antagonist that binds poorly with IR, did not. Both idazoxan and yohimbine failed to affect the rilmenidine-induced bradycardia, however. We concluded that (a) rilmenidine exhibits more marked hypotensive effect when injected i.e. than when injected i.v., (b) a part of the inhibitory effect of i.v.-injected rilmenidine on RSNA may be exerted through idazoxan-insensitive mechanisms which might be activated by peripheral action of the drug, and (c) the hypotensive action of rilmenidine relates more to the interaction with IR than with α2-adrenoceptors.

Cardiac microdialysis measurement of extracellular adenine nucleotide breakdown products during regional ischemia and reperfusion in canine heart : protective effect of propranolol against reperfusion injury

Summary: Using cardiac microdialysis, we studied release of the adenine nucleotide breakdown products (ANBP) adenosine (ADS), inosine (INS), and hypoxanthine (HYP) into the interstitium of canine myocardium during 20- and 40-min occlusion of the anterior descending coronary artery and reperfusion. Dialysate ANBP concentrations reached maximum values not at the end of ischemia but in the first 10 min of reperfusion. The effect was more pronounced after 20-min ischemia. Further reperfusion led to an ANBP decrease that was more prolonged after 40-min ischemia. Pretreatment with dl-propranolol (0.5 mg/kg, intravenously, i.v.) given 40 min before coronary occlusion had no effect on adenine nucleotide catabolism rate during 20- and 40-min ischemia, but it facilitated washout of ANBP from ischemic zone immediately after the start of reperfusion. A similar effect was elicited by a d-stereoisomer of propranolol with no β-adrenoceptor blocking activity. Results suggest that the reperfusion injury and probably the no-reflow phenomenon were the cause of enhanced adenine nucleotide catabolism at the beginning of reperfusion and prolonged ANBP washout from the ischemic zone. Reduction of reperfusion injury by propranolol could be related to the membrane stabilizing and antioxidant activity of this agent. Examination of dl-propranolol kinetics in arterial and coronary venous blood plasma showed that drug accumulation in the myocardium was almost maximum at the start of ischemia; therefore, the efficiency of cardioprotection with dl-propranolol was not limited by pharmacokinetic causes. Insertion of an additional microdialysis probe in the myocardium allowed monitoring of extracellular propranolol concentrations.

2-Deoxy-D-Glucose-Induced Central Glycopenia Differentially Influences Renal and Adrenal Nerve Activity in Awake Shr Rats

2-deoxy-D-glucose (2-DG) evokes an increase in the efferent discharge rate of the adrenal nerve in narcotized rats and rabbits. The study reported here was undertaken to determine the sympathetic nerves and blood pressure responses to i.v. 2-DG administration in awake SHR rats. An increase in adrenal sympathetic nerve activity (adrSNA) by 63% was observed 15 min after 125 mg/kg 2-DG administration, but there were no changes in the renal sympathetic nerve activity (renSNA), blood pressure (BP) or the heart rate (HR). Additional administration of 375 mg/kg 2-DG (cumulative dose was 500 mg/kg) led to the increase in the adrSNA by more then 120%, and in BP by 20 mm Hg, whereas renSNA was increased only by 30%. These results indicate that 2-DG-induced neuroglycopenia evokes highly differential changes in adrenal and renSNA in awake SHR rats. Whether this explains the marked response in BP in SHR to 2-DG is to be established.

Systemic and regional hemodynamic effects of perindopril in experimental heart failure

The effects of converting-enzyme inhibition by perindoprilat (0.5 mg/kg, intravenously, short-term administration) or perindopril (2 mg/kg, orally, long-term administration once a day for 21 days) on systemic and regional hemodynamics were studied on a new rat model of heart failure, which was induced by microembolization of coronary vessels by 15 microns plastic microspheres. Cardiac output and regional blood flows were measured by microsphere technique; the tone of the venous vessels was determined as mean circulatory filling pressure in conscious, freely moving rats. Perindoprilat evoked a much more prominent increase in kidneys, adrenal glands, intestine, and skin blood flows in embolized rats than in sham-operated rats. The differences between the effects of long-term treatment with perindopril in sham-operated and embolized rats were highly significant. Mean circulatory filling pressure was decreased by short-term and long-term administration of an angiotensin-converting enzyme inhibitor. It is concluded that venous vessels could be one of the target sites for the effects of perindopril-like drugs.

Chronic administration of coenzyme Q10 limits postinfarct myocardial remodeling in rats

The effect of chronic coronary artery occlusion on the content of rat myocardial coenzymes Q (CoQ) and evaluation of the applicability of CoQ10 for limiting postinfarct remodeling have been investigated. Left ventricle myocardium hypertrophy was characterized by the decrease in CoQ9 (−45%, p < 0.0001), CoQ10 (−43%, p < 0.001), and α-tocopherol (−35%, p < 0.05). There were no differences between the parameters of postinfarction and sham-operated rats in plasma. Administration of CoQ10 (10 mg/kg) via a gastric probe for 3 weeks before and 3 weeks after occlusion maintained higher levels of CoQ in the postinfarction myocardium: the decrease in CoQ9 and CoQ10 was 25% (p < 0.05) and 23% (p < 0.05), respectively (versus sham-operated animals). Plasma concentrations of CoQ10 were more than 2 times higher (p < 0.05). In CoQ treated rats there was significant correlation between plasma levels of CoQ and the infarct size: r = −0.723 (p < 0.05) and r = −0.839 (p < 0.01) for CoQ9 and CoQ10. These animals were also characterized by earlier and more intensive scar tissue formation in the postinfarction myocardium and also by more pronounced cell regeneration processes. This resulted in the decrease in both the infarct size (16.2 ± 8.1 vs. 27.8 ± 12.1%) and also mass index of left ventricle (2.18 ± 0.24 vs. 2.38 ± 0.27 g/kg) versus untreated rats (p < 0.05). Thus, long-term treatment with ubiquinone increases plasma and myocardial CoQ content and this can improve the survival of myocardial cells during ischemia and limit postinfarct myocardial remodeling.

Effect of a prostacyclin derivative (iloprost) on regional blood flow, sympathetic nerve activity, and baroreceptor reflex in the conscious rat

Summary: We have investigated the hemodynamic actions of iloprost, a stable prostacyclin derivative, in conscious, chronically instrumented rats. Given intravenously by 10-min infusions at doses ranging from 0.0375 to 4 μg/min, iloprost lowered mean arterial blood pressure in a dose-dependent and reversible fashion. The effects on blood pressure were accompanied by increases in heart rate (HR); splanchnic nerve activity (SpNA, direct recording); and mesenteric, renal, and hindlimb blood flow (Doppler probes). Doses below the depressor threshold already reduced mesenteric and hindlimb vascular resistance without affecting HR. The reduction of hindlimb resistance outlasted the iloprost infusion period. Chronic sinoaortic deafferentation (SAD) almost abolished the tachycardic reflex responses to intravenous sodium nitroprusside. The reflex increases in SpNA to intravenous iloprost were also largely prevented in SAD animals, but the tachycardic effects of iloprost persisted. In addition, neither β1-adrenoceptor blockade alone nor complete cardiac autonomic blockade prevented the heart rate responses to iloprost. Our results show that iloprost is a potent vasodilator that preferentially reduces hindlimb vascular resistance. Low doses of the drug increase regional blood flow without affecting blood pressure or heart rate. The tachycardic effects at higher doses cannot be explained by baroreceptor reflex (BRR) activation alone; they instead suggest a direct action on the heart. The dissociation between vasodilator and depressor effects at low doses may contribute to the therapeutic benefit of the drug in the treatment of vascular disease.

Role of Reactive Oxygen Species in the Sensitivity of Rat Hypertrophied Myocardium to Ischemia

The relationship between hydroxyl radical (OH·) generation in the zone of ischemia/reperfusion and the size of infarction formed was investigated in 18-22-week-old anaesthetized male SHRSP and Wistar rats using a myocardial microdialysis technique. The marker of OH· generation, 2,3-dihydroxybenzoic acid (2,3-DHBA), was analyzed in dialyzates by high performance liquid chromatography with electrochemical detection. Myocardial ischemia was induced by ligation of the descending branch of the left main coronary artery for 30 min. The mean value of basal 2,3-DHBA level in the dialyzate samples from SHRSP (243 ± 21 pg for 30 min) was significantly higher than that from Wistar rats (91 ± 4 pg for 30 min, p < 0.0002); it positively correlated with left ventricular hypertrophy (r = 0.806; p < 0.05). During reperfusion total 2,3-DHBA output was 1.8-fold higher in SHRSP than in Wistar rats (659 ± 60 pg versus 364 ± 66 pg for 60 min, respectively, p < 0.0002). At the same time, 2,3-DHBA increase above the basal level was the same in Wistar and SHRSP rats (181 ± 25 and 172 ± 36 pg for 60 min, respectively). The infarct size in SHRSP (45.4 ± 4.3%) was significantly higher (p < 0.05) than in Wistar rats (32.8 ± 3.3%). There was a significant positive correlation between basal level of 2,3-DHBA and total reperfusion 2,3-DHBA content in SHRSP (r = 0.752; p < 0.05). Thus, data obtained clearly indicate that the hypertrophied myocardium of SHRSP was less tolerant to ischemia/reperfusion than that of Wistar rats due to chronically increased OH· production and enhanced total OH· output during reperfusion. Greater myocardial damage in SHRSP than in Wistar rats following the equal increase in OH· production above the basal level suggests the existence of deficit of the antioxidant defense in the hypertrophied myocardium.

Allopurinol: kinetics, inhibition of xanthine oxidase activity, and protective effect in ischemic-reperfused canine heart as studied by cardiac microdialysis

With microdialysis, we monitored cardiac interstitial fluid (ISF) levels of allopurinol, its metabolites, and the adenine nucleotide breakdown products (ANBP), inosine, hypoxanthine (HYP), xanthine (Xa), uric acid (UA) in dogs that received 1 and 10 mg/kg allopurinol intravenously (i.v.). Half-life (t1/2) of drug penetration into the heart was dose independent (1.8 min), whereas for the 10-mg/kg dose terminal elimination t1/2 (96 min) was much prolonged and ISF clearance (9.6 l/min kg) was reduced as compared with that induced by 1 mg/kg (28 min and 30.4 l/min kg) probably due to capacity limitation of allopurinol conversion to oxypurinol by Xa dehydrogenase/oxydase (Xa D/O). Inhibition of Xa D/O activity by allopurinol resulted in a dose-dependent increase in ISF HYP and Xa levels and a decrease in UA level. For a 10-mg/kg dose, maximal effect was attained approximately 40 min after drug injection. Allopurinol (1 mg/kg) given 30 min after the start of 40-min coronary artery occlusion during ischemia entered the ischemic zone ISF very slowly as compared with that of the control zone; the no-reflow phenomenon was evident because the levels became similar in both zones only 15 min after initiation of reperfusion. To examine cardioprotective efficiency, we administered allopurinol (10 mg/kg) 40 min before 40-min occlusion; it had little effect on total ANBP release during ischemia but facilitated washout of ANBP from the ischemic zone during reperfusion, thus manifesting protective efficacy against reperfusion injury and no-reflow. As shown by the lack of ischemia-induced increase in ISF Xa, myocardial Xa D/O activity was completely blocked by allopurinol.