In vivo demonstration of H3-histaminergic inhibition of cardiac sympathetic stimulation by R-alpha-methyl-histamine and its prodrug BP 2.94 in the dog.
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1. The aim of this study was to investigate whether histamine H3-receptor agonists could inhibit the effects of cardiac sympathetic nerve stimulation in the dog. 2. Catecholamine release by the heart and the associated variation of haemodynamic parameters were measured after electrical stimulation of the right cardiac sympathetic nerves (1-4 Hz, 10 V, 10 ms) in the anaesthetized dog treated with R-alpha-methyl-histamine (R-HA) and its prodrug BP 2.94 (BP). 3. Cardiac sympathetic stimulation induced a noradrenaline release into the coronary sinus along with a tachycardia and an increase in left ventricular pressure and contractility without changes in mean arterial pressure. Intravenous administration of H3-receptor agonists significantly decreased noradrenaline release by the heart (R-HA at 2 micromol kg(-1) h(-1): +77 +/- 25 vs +405 +/- 82; BP 2.94 at 1 mg kg(-1): +12 +/- 11 vs +330 +/- 100 pg ml(-1) in control conditions, P < or = 0.05), and increases in heart rate (R-HA at 2 micromol kg(-1) h(-1): +26 +/- 8 vs +65 +/- 10 and BP 2.94 at 1 mg kg(-1): +30 +/- 8 vs 75 +/- 6 beats min(-1), in control conditions P < or = 0.05), left ventricular pressure, and contractility. Treatment with SC 359 (1 mg kg(-1)) a selective H3-antagonist, reversed the effects of H3-receptor agonists. Treatment with R-HA at 2 micromol kg(-1) h(-1) and BP 2.94 at 1 mg kg(-1) tended to decrease, while that with SC 359 significantly increased basal heart rate (from 111 +/- 3 to 130 +/- 5 beats min(-1), P < or = 0.001). 4. Functional H3-receptors are present on sympathetic nerve endings in the dog heart. Their stimulation by R-alpha-methyl-histamine or BP 2.94 can inhibit noradrenaline release by the heart and its associated haemodynamic effects. (+info)
Peripheral hemodynamics evaluated by acceleration plethysmography in workers exposed to lead.
(18/14436)
To clarify the effect of lead exposure on peripheral hemodynamics, acceleration plethysmography (APG) was performed for 48 male subjects occupationally exposed to lead (exposure group) and 43 male subjects with no history of occupational exposure to lead (control group). In the exposure group, the blood lead concentration (Pb-B) was also measured. Each APG parameter was assessed by comparing measured data with the standard aging curves. A significant negative correlation was obtained between the parameter--b/a and Pb-B. The exposure group showed significantly lower values of parameters--b/a (p < 0.01) and d/a (p < 0.05) than the control group. The parameter--b/a in the exposure group dose-dependently decreased with increases in length of working career (duration of exposure to lead) and Pb-B. The parameter--b/a significantly (p < 0.05) decreased in subjects with working careers of 5 years or more and in subjects whose Pb-B was 40 micrograms/100 ml or more. These results suggest that lead exposure affects peripheral hemodynamics as evaluated by APG. (+info)
Acute haemodynamic and proteinuric effects of prednisolone in patients with a nephrotic syndrome.
(19/14436)
BACKGROUND: Administration of prednisolone causes an abrupt rise in proteinuria in patients with a nephrotic syndrome. METHODS: To clarify the mechanisms responsible for this increase in proteinuria we have performed a placebo controlled study in 26 patients with a nephrotic syndrome. Systemic and renal haemodynamics and urinary protein excretion were measured after prednisolone and after placebo. RESULTS: After i.v. administration of 125-150 mg prednisolone total proteinuria increased from 6.66+/-4.42 to 9.37+/-6.07 mg/min (P<0.001). By analysing the excretion of proteins with different charge and weight (albumin, transferrin, IgG, IgG4 and beta2-microglobulin) it became apparent that the increase of proteinuria was the result of a change in size selectivity rather than a change in glomerular charge selectivity or tubular protein reabsorption. Glomerular filtration rate rose from 83+/-34 ml to 95+/-43 ml/min (P<0.001) after 5 h, whereas effective renal plasma flow and endogenous creatinine clearance remained unchanged. As a result filtration fraction was increased, compatible with an increased glomerular pressure, which probably contributes to the size selectivity changes. Since corticosteroids affect both the renin-angiotensin system and renal prostaglandins, we have evaluated the effects of prednisolone on proteinuria after pretreatment with 3 months of the angiotensin-converting enzyme inhibitor lisinopril or after 2 weeks of the prostaglandin synthesis inhibitor indomethacin. Neither drug had any effect on prednisolone-induced increases of proteinuria. CONCLUSIONS: Prednisolone increases proteinuria by changing the size selective barrier of the glomerular capillary. Neither the renin-angiotensin axis nor prostaglandins seem to be involved in these effects of prednisolone on proteinuria. (+info)
Antiproteinuric efficacy of verapamil in comparison to trandolapril in non-diabetic renal disease.
(20/14436)
BACKGROUND: Non-dihydropyridine calcium antagonists such as verapamil are equally effective in reducing proteinuria as ACE inhibitors in hypertensive patients with diabetic nephropathy. To date it is unknown whether verapamil elucidates such an antiproteinuric capacity in non-diabetic renal disease. METHODS: We performed a double-blind, placebo-controlled, random cross-over study which compared the antiproteinuric effect of 6 weeks treatment with verapamil SR (360 mg) to that of the ACE inhibitor trandolapril (4 mg), and their fixed combination vera/tran (180 mg verapamil SR and 2 mg trandolapril) in 11 non-diabetic patients with proteinuria of 6.6 (5.1-8.8) g/day, a creatinine clearance of 87 (74-106) ml/min, and a 24-h blood pressure of 136/85 (126/76-157/96) mmHg at baseline. RESULTS: Twenty-four-hour mean arterial pressure did not change during verapamil, whereas both trandolapril and vera/tran induced a significant reduction in MAP. Verapamil showed no significant effects on renal haemodynamics. Trandolapril and vera/tran did not significantly change GFR, but ERPF increased and FF decreased during both treatments (P<0.05). The antiproteinuric response of verapamil was significantly less compared to that of trandolapril and vera/tran (-12% (-17/-1) vs -51% (-56/-25) and -41% (-50/-19) respectively). The blood pressure and antiproteinuric response during verapamil tended to be greater in hypertensive patients than in normotensive patients, although this difference was not significant. Baseline blood pressure was related to the change in blood pressure during verapamil (r = -0.70; P < 0.02). CONCLUSIONS: The antiproteinuric and antihypertensive response of verapamil is less than that of the ACE inhibitor trandolapril in patients with non-diabetic renal disease. In contrast to the antiproteinuric response of trandolapril, the antiproteinuric reponse of verapamil seems to be completely dependent from effective blood pressure reduction. The fixed combination of verapamil and ACE inhibition at half doses has similar effects as ACE inhibition at full dose. (+info)
Differences in spontaneous breathing pattern and mechanics in patients with severe COPD recovering from acute exacerbation.
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The aims of this study were to assess spontaneous breathing patterns in patients with chronic obstructive pulmonary disease (COPD) recovering from acute exacerbation and to assess the relationship between different breathing patterns and clinical and functional parameters of respiratory impairment. Thirty-four COPD patients underwent assessment of lung function tests, arterial blood gases, haemodynamics, breathing pattern (respiratory frequency (fR), tidal volume (VT), inspiratory and expiratory time (tI and tE), duty cycle (tI/ttot), VT/tI) and mechanics (oesophageal pressure (Poes), work of breathing (WOB), pressure-time product and index, and dynamic intrinsic positive end-expiratory pressure (PEEPi,dyn)). According to the presence (group 1) or absence (group 2) of Poes swings during the expiratory phase (premature inspiration), 20 (59%) patients were included in group 1 and 14 (41%) in group 2. Premature inspirations were observed 4.5+/-6.4 times x min(-1) (range 1-31), i.e. 20+/-21% (3.7-100%) of total fR calculated from VT tracings. In group 1 the coefficient of variation in VT, tE, tI/ttot, PEEPi,dyn, Poes and WOB of the eight consecutive breaths immediately preceding the premature inspiration was greater than that of eight consecutive breaths in group 2. There were no significant differences in the assessed parameters between the two groups in the overall population, whereas patients with chronic hypoxaemia in group 1 showed a more severe impairment in clinical conditions, mechanics and lung function than hypoxaemic patients in group 2. In spontaneously breathing patients with chronic obstructive pulmonary disease recovering from an acute exacerbation, detectable activity of inspiratory muscles during expiration was found in more than half of the cases. This phenomenon was not associated with any significant differences in anthropometric, demographic, physiological or clinical characteristics. (+info)
Tumor necrosis factor-alpha contributes to ischemia- and reperfusion-induced endothelial activation in isolated hearts.
(22/14436)
-During myocardial reperfusion, polymorphonuclear neutrophil (PMN) adhesion involving the intercellular adhesion molecule-1 (ICAM-1) may lead to aggravation and prolongation of reperfusion injury. We studied the role of early tumor necrosis factor-alpha (TNF-alpha) cleavage and nuclear factor-kappaB (NF-kappaB) activation on ICAM-1 expression and venular adhesion of PMN in isolated hearts after ischemia (15 minutes) and reperfusion (30 to 480 minutes). NF-kappaB activation (electromobility shift assay) was found after 30 minutes of reperfusion and up to 240 minutes. ICAM-1 mRNA, assessed by Northern blot, increased during the same interval. Functional effect of newly synthesized adhesion molecules was found by quantification (in situ fluorescence microscopy) of PMN, given as bolus after ischemia, which became adherent to small coronary venules (10 to 50 microm in diameter). After 480 minutes of reperfusion, ICAM-1-dependent PMN adhesion increased 2.5-fold compared with PMN adhesion obtained during acute reperfusion. To study the influence of NF-kappaB on PMN adhesion, we inhibited NF-kappaB activation by transfection of NF-kappaB decoy oligonucleotides into isolated hearts using HJV-liposomes. Decoy NF-kappaB but not control oligonucleotides blocked ICAM-1 upregulation and inhibited the subacute increase in PMN adhesion. Similar effects were obtained using BB 1101 (10 microg), an inhibitor of TNF-alpha cleavage enzyme. These data suggest that ischemia and reperfusion in isolated hearts cause liberation of TNF-alpha, activation of NF-kappaB, and upregulation of ICAM-1, an adhesion molecule involved in inflammatory response after ischemia and reperfusion. (+info)
Regulation of myocardial blood flow by oxygen consumption is maintained in the failing heart during exercise.
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The hemodynamic abnormalities and neurohumoral activation that accompany congestive heart failure (CHF) might be expected to impair the increase in coronary blood flow that occurs during exercise. This study was performed to determine the effects of CHF on myocardial oxygen consumption and coronary blood flow during exercise. Coronary blood flow was measured in chronically instrumented dogs at rest, during 2 stages of graded treadmill exercise under control conditions (n=10), and after the development of CHF produced by 3 weeks of rapid ventricular pacing (n=9). In the normal dogs, coronary blood flow increased during exercise in proportion to the increase in the heart rate x the left ventricular systolic blood pressure product (RPP). After the development of CHF, resting myocardial blood flow was 25% lower than normal (P<0.05). Myocardial blood flow increased during the first stage of exercise, but then failed to increase further during the second stage of exercise despite an additional increase in the RPP. Myocardial oxygen consumption during exercise was significantly lower in animals with CHF and paralleled coronary flow. Despite the lower values for coronary blood flow in animals with CHF, there was no evidence for myocardial ischemia. Thus, even during the second level of exercise when coronary flow failed to increase, myocardial lactate consumption continued and coronary venous pH did not fall. In addition, the failure of coronary flow to increase as the exercise level was increased from stage 1 to stage 2 was not associated with a further increase in myocardial oxygen extraction. Thus, cardiac failure was associated with decreased myocardial oxygen consumption and failure of oxygen consumption to increase with an increase in the level of exercise. This abnormality did not appear to result from inadequate oxygen availability, but more likely represented a reduction of myocardial oxygen usage with a secondary decrease in metabolic coronary vasodilation. (+info)
Regulation of sympathetic nerve activity in heart failure: a role for nitric oxide and angiotensin II.
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The mechanisms by which sympathetic function is augmented in chronic heart failure (CHF) are not well understood. A previous study from this laboratory (Circ Res. 1998;82:496-502) indicated that blockade of nitric oxide (NO) synthesis resulted in only an increase in renal sympathetic nerve activity (RSNA) when plasma angiotensin II (Ang II) levels were elevated. The present study was undertaken to determine if NO reduces RSNA in rabbits with CHF when Ang II receptors are blocked. Twenty-four New Zealand White rabbits were instrumented with cardiac dimension crystals, a left ventricular pacing lead, and a pacemaker. After pacing at 360 to 380 bpm for approximately 3 weeks, a renal sympathetic nerve electrode and arterial and venous catheters were implanted. Studies were carried out in the conscious state 3 to 7 days after electrode implantation. The effects of a 1-hour infusion of sodium nitroprusside (SNP; 3 microgram . kg-1. min-1) on RSNA and mean arterial pressure (MAP) were determined before and after Ang II blockade with losartan (5 mg/kg) in normal and CHF rabbits. Changes in MAP were readjusted to normal with phenylephrine. Before losartan, SNP evoked a decrease in MAP and an increase in RSNA in both groups that was baroreflex-mediated, because both MAP and RSNA returned to control when phenylephrine was administered. In the normal group, losartan plus SNP caused a reduction in MAP and an increase in RSNA that was 152.6+/-9.8% of control. Phenylephrine returned both MAP and RSNA back to the control levels. However, in the CHF group, losartan plus SNP evoked a smaller change in RSNA for equivalent changes in MAP (117.1+/-4.1% of control). On returning MAP to the control level with phenylephrine, RSNA was reduced to 65.2+/-2.9% of control (P<0. 0001). These data suggest that endogenous Ang II contributes to the sympathoexcitation in the CHF state and that blockade of Ang II receptors plus providing an exogenous source of NO reduces RSNA below the elevated baseline levels. We conclude that both a loss of NO and an increase in Ang II are necessary for sustained increases in sympathetic nerve activity in the CHF state. (+info)