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Notes: 1. Renal and total noradrenaline (NA) spillover rates were examined under control conditions and during graded infusions of gludopa (γ-l-glutamyl-l-dopa) in conscious rabbits.2. Gludopa infusion at 25 and 100 μg/kg per min did not alter mean arterial pressure (MAP) and heart rate (HR), but had significant dose-related effects on the renal dopamine (DA) system. At the high dose there were pronounced increases in urinary DA excretion (〉6000-fold) and renal DA content (〉 100-fold); renal NA content doubled.3. Renal venous DA increased after gludopa infusion, but arterial plasma DA concentrations were not significantly changed. Mean arterial plasma gludopa and l-dopa concentrations reached 890, 3190 ng/mL and 3, 10 ng/mL at low and high doses, respectively.4. Gludopa resulted in a pronounced dose-dependent fall in renal NA spillover, which at 100 μg/kg per min accounted for almost half of the reduction in overall NA spillover rate.5. The significant falls in renal and extrarenal NA spillover rate during gludopa infusion are consistent with suppression of renal and overall sympathetic activity. Gludopa-induced inhibition of renal NA spillover is likely to be due to the actions of DA generated in the kidney on presynaptic DA-2 and α-2 receptors. A central sympathoinhibitory mechanism may explain the reduced total NA spillover.

Notes: 1. To investigate the effects of angiotensin-converting enzyme inhibition (ACEI) on exercise performance, the following were measured in eight normal rabbits performing graded treadmill exercise during intravenous vehicle saline or enalaprilat infusion: haemodynamics, noradrenaline (NA) spillover, hindlimb oxygen consumption and lactate release.2. Blood pressure, heart rate (HR), femoral blood flow (FBF), hindlimb lactate release, hindlimb oxygen consumption and hindlimb NA spillover rate were all significantly increased during exercise and the changes during enalaprilat infusion were similar to control responses.3. At submaximal exercise (6 m/min), ACEI did not significantly alter the responses of hindlimb lactate release, NA spillover rate or oxygen consumption. At the higher exercise load (12 m/min), ACEI reduced hindlimb NA spillover rate (33.1 ± 4.2 vs 61.3 ± 17.1 ng/min) and significantly increased oxygen consumption (241 ± 53.4 vs 133 ± 23.396, P 〈 0.05). The ratio of hindlimb NA spillover rate to total NA spillover rate was markedly increased during exercise, with similar changes being observed in ACEI and control experiments.4. This study indicates that acute ACEI has a favourable effect on oxygen utilization in exercising muscle in the normal rabbit. Suppression of local sympathetic activation during exercising stress, as reflected in a reduced NA spillover response, may benefit the microcirculation in exercising muscles.

Notes: 1. Changes in renal sympathetic nerve activity (RSNA) were investigated during the development of congestive heart failure (CHF) in rabbits with doxorubicin-induced cardiomyopathy.2. Controls (saline treated, n= 5) and doxorubicin-treated rabbits (1 mg/kg administered intravenously twice weekly, n= 5) were studied after 4 and 6 weeks treatment.3. RSNA was estimated by measuring renal noradrenaline spillover rate under resting conditions and in response to changes in arterial pressure induced by phenylephrine and sodium nitroprusside infusions.4. In the doxorubicin-treated group, resting renal noradrenaline spillover was increased at 4 weeks (24.2 ng/min, s.e.m. = 2.5, n= 5) compared with controls (15.2 ng/min, s.e.m. = 2.4, n= 5; P〈0.01) and remained elevated.5. The baroreceptor–renal noradrenaline spillover curve showed a significant upward shift in the doxorubicin-treated group at 4 weeks. After 6 weeks both heart rate and renal noradrenaline spillover responses to hypotension were significantly blunted.6. It is suggested that increased RSNA occurs early during the development of CHF in doxorubicin-treated rabbits. The observed changes in the baroreflex responses suggest that different mechanisms may contribute to this increased RSNA at different stages of CHF.

Notes: 1. Non-invasive techniques to measure indices of arterial function and wall thickness are frequently used as surrogate markers of cardiovascular disease. Reproducibility of measurements of arterial compliance has been infrequently reported and little is known about the interrelationships of the various indices in vivo.2. The present study was designed to assess reproducibility and interrelationships of indices of systemic arterial compliance, pulse wave velocity, carotid compliance and intima-media thickness (IMT).3. Fifty healthy volunteers (20 male and 30 female; aged 20-70 years, mean 46.5 years), participated in the present study. Each subject was studied on two occasions by the same investigators, using an identical protocol at an interval of 1-5 weeks (mean 2.5 weeks) without lifestyle change.4. There were no significant differences between visits for any recorded general data, except resting blood pressure, which was lower on the second occasion. There were no systematic differences within each pair over the range of measurements for any of the variables. Bland-Altman plots of repeatability of changes in indices showed that the mean values between visits were not significantly different. All indices of central arterial compliance were significantly related to age and IMT.5. Thus, under controlled experimental conditions, there was satisfactory repeatability of measurements of indices of both intrinsic and functional arterial mechanical properties (central and carotid arterial compliance and IMT). This type of information will permit the construction of sample size tables for clinical trials using these indices.6. Central arterial compliance may be an important determinant of IMT.

Notes: Summary: Congestive heart failure (CHF) is a complex clinical syndrome in which the kidney has a central pathophysiological role. an imbalance between vasoconstrictor-antinatriuretic and vasodilator-natriuretic forces is a key feature of the pathophysiology of CHF. This review summarizes current understanding of disturbances in vasodilator-natriuretic systems in CHF. the key vasodilator systems involved are: the natriuretic peptide family atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), urodilatin, dopamine (DA), endothelium-derived relaxing factors and prosraglandins. Renal responses to ANP are blunted in CHF, under the influence of haemodynamic, neuro-humoral, receptor and post-receptor events. BNP, secreted in response to left ventricular load, may circulate in high concentrations in CHF, with similar effects to ANP. Urodilatin is a newly discovered peptide of renal origin whose physiological role is under investigation. Neural endopeptidase inhibitors have shown some promise in the treatment of human CHF, particularly when combined with ACE inhibition or angiotensin II receptor blockade. the renal DA system is influenced by sodium intake and DA metabolism is altered in CHF. the place of orally active DA prodrugs and DA agonist in the management of patients with CHF is still undecided. In CHF, basal release of nitric oxide may be preserved or even enhanced. However, stimulated release of nitric oxide may be reduced. Renal effects of nitric oxide or arginine in CHF have yet to be defined. Renal prostaglandins play an important role in offsetting renal and systemic vasoconstriction and fluid retention in CHF. the recent availability of specific receptor antagonist should lead to clearer definition of the relative roles of renal angiotensin II inhibition and bradykinin potentiation in the benefical responses to angiotensin converting enzyme (ACE-1) in CHF. Prostaglandin-E1 (PG-E1) and prostaglandin-E2 (PG-E2) infusion may have some benefit for the treatment of severe CHF. Adrenomedullin, a vasodilator-natriuretic peptide closely related to the calcitonin gene-related peptide family, is present in high concentrations in the kidney. Plasma concentrations of adrenomedullin are increased after acute cardiac injury and in CHF. Its roles in renal physiology and in the pathophysiology of CHF are under investigation. Overall, there is considerable potential to exploit these vasodilator-natriuretic systems in management strategies for CHF.

Notes: 1. This study was designed to investigate the effects of isotonic saline loading on renal tubular and neurogenic dopamine (DA) in conscious rabbits.2. Isotonic saline loading did not affect mean arterial pressure, heart rate or renal blood flow but markedly increased urine volume, sodium excretion and DA excretion.3. Renal DA spillover was not affected by venous emptying, while renal noradrenaline (NA) spillover tended to decrease during saline loading. The ratio of % renal DA spillover to % renal NA spillover increased to 2.3 ± 0.6 (P 〈 0.05) 3h after saline loading.4. Isotonic saline loading increased renal tubular DA production but had little effect on neurogenic DA release.

Notes: 1. To evaluate the effects of angiotensin-converting enzyme (ACE) inhibition on sympathetic nerve activity, renal and total norepinephrine (NE) spillover rates were examined under control conditions and during enalaprilat infusion at rest and in response to sodium nitroprusside (SNP)-induced hypotension.2. Resting renal and total NE spillover rate during enalaprilat infusion were similar to control values.3. During SNP infusion at 10 μg/kg per min, renal NE spillover rate increased by 26% in enalaprilat-treated group and by 39% in controls, in response to falls in mean arterial pressure (MAP) of 25 and 19% respectively.4. During sympathetic stimulation induced by SNP, total NE spillover rate was significantly increased in both groups, but the 50% (s.e.m. = 12) increase in the enalaprilat-treated group was less (P〈0.05) than the 97% (s.e.m. = 16) change observed in controls.5. Enalaprilat treatment resulted in a higher renal to total NE spillover ratio (P〈0.05). The ratio fell in parallel in both groups during SNP-induced hypotension.6. This study indicates that the sympathetic nervous system interacts dynamically with the renin-angiotensin system during hypotensive stimulation but this occurs predominantly at sites other than the kidney.

Notes: 1. Changes in plasma atrial natriuretic peptide (ANP) were examined in conscious rabbits in response to a 33% blood volume expansion in intact animals and after blockade of cardiac nerve activity.2. Blood volume expansion by one-third markedly increased right atrial pressure and resulted in a four-fold increase in plasma ANP.3. Cardiac nerve blockade with intrapericardial procaine had no effect on resting plasma ANP levels. The ANP responses to volume expansion in the presence of cardiac nerve blockade were similar to those seen in intact animals.4. Release of ANP from its cardiac stores in response to volume expansion is not influenced by cardiac nerve activity.

Notes: 1. The role of vasopressin in cardiovascular adaptation to sodium depletion was examined in rats after 6 days on a low sodium diet. Studies were performed after selective or combined blockade with d(CH2)5 Tyr(Me)AVP (AVPA), enalaprilat (CEI) and phentolamine (PHENTOL). AVPA alone had no effect on systemic haemodynamics or regional blood flow distribution. After CEI or PHENTOL pretreatment, AVPA led to significant falls in peripheral resistance and increases in cardiac output and renal blood flow. In sodium depletion, endogenous vasopressin acts as a vasoconstrictor hormone, particularly in the kidney, when either the renin-angiotensin or α-adrenergic system is inhibited.

Notes: 1. Renal sympathetic nerve activity (RSNA) in response to changes in mean arterial pressure (MAP) was examined by measuring renal norepinephrine (NE) spillover rate in conscious rabbits.2. A chronic renal vein catheter was implanted for sampling renal venous blood without stress in conscious animals.3. RSNA estimated by renal NE spillover rate significantly increased in response to moderate falls in MAP produced by sodium nitroprusside (SNP) infusion and decreased in response to moderate rises in MAP produced by phenylephrine (PE) infusion.4. The NE spillover method is sufficiently sensitive to detect responses of RSNA to physiological stimuli in conscious rabbits.