R. Dietz

Central blood pressure effects of substance P and angiotensin II: Role of the sympathetic nervous system and vasopressin

The role of the sympathetic nervous system and of arginine vasopressin (AVP) in the mediation of the central cardiovascular effects of angiotensin II (ANG II) and substance P (SP) was investigated. ANG II and SP caused dose-dependent blood pressure increases when injected into the lateral brain ventricle (i.c.v.) of conscious rats; ANG II was tenfold more potent than SP. Peripheral blockade of alpha-adrenoceptors with prazosin or blockade of the vasopressor action of AVP by the AVP antagonist d(CH2)5VDAVP both partially inhibited the pressor responses to central ANG II. Combined treatment with the two blockers produced almost complete inhibition of the central ANG I responses. Substance P injected i.c.v. produced increases in noradrenaline and adrenaline but not AVP in the plasma. Peripheral alpha-receptor blockade by prazosin reversed the central pressor effects of SP to depressor responses. The AVP antagonist did not alter the cardiovascular responses to SP. It is concluded that in conscious animals, stimulation of the sympathetic nervous system and release of AVP contribute to the central pressor action of ANG II to a similar extent and independently of each other. In contrast, the central pressor responses to SP appear to be exclusively mediated by the sympathetic nervous system without participation of AVP.

Emergency Coronary Stenting for Dissection During Percutaneous Transluminal Coronary Angioplasty : Angiographic Follow-Up After Stenting and After Repeat Angioplasty of the Stented Segment

OBJECTIVES The purpose of this study was to assess the angiographic results after emergency coronary stenting and after repeat angioplasty for restenosis within the stent. BACKGROUND There is still little angiographic information about lumen renarrowing and its correlates after emergency stenting, and data with regard to the angiographic outcome of repeat angioplasty within the stent are almost nonexistent. METHODS This study was based on the quantitative evaluation of angiograms performed before and immediately after intervention and at 6-month follow-up. The study included 164 of the 183 eligible patients with emergency Palmaz-Schatz stent implantation and 31 of those with restenosis within the stent who had repeat angioplasty. RESULTS Stenting produced an improvement in minimal lumen diameter from 0.82 +/- 0.41 to 2.76 +/- 0.47 mm (mean +/- SD) and in diameter stenosis from 74.9 +/- 11.5% to 18.3 +/- 8.1%. Elastic recoil was 0.51 +/- 0.34 mm, or 16%. At 6-month follow-up, 32.3% of the patients had restenosis (> or = 50% stenosis). Minimal lumen diameter decreased to 1.84 +/- 0.78 mm, and diameter stenosis increased to 41.7 +/- 21.0%. The degree of lumen loss correlated significantly with the length of the original stenosis and the initial lumen gain achieved by stenting. Thirty-one patients with in-stent restenosis underwent repeat angioplasty. The primary success rate was 100%, and no abrupt vessel closure was verified. Minimal lumen diameter increased from 0.85 +/- 0.35 to 2.18 +/- 0.39 mm, and diameter stenosis decreased from 69.7 +/- 12.9% to 28.6 +/- 9.4%. Elastic recoil was 0.82 +/- 0.38 mm, or 27%. At follow-up, 38.5% of the patients had restenosis. Minimal lumen diameter was reduced to 1.72 +/- 0.67 mm, and diameter stenosis increased to 42.4 +/- 18.1%. CONCLUSIONS Angiographic results of emergency coronary stenting compare favorably with those of conventional angioplasty. In-stent balloon redilation in patients with restenosis is associated with excellent short-term results and a restenosis rate not different from that reported for nonstented vessels.

ACE inhibition improves vagal reactivity in patients with heart failure

The deranged autonomic control of heart rate was studied in 34 patients with heart failure (New York Heart Association [NYHA] functional class II to III) by examining the carotid sinus baroreflex. The carotid sinus baroreceptors were stimulated by graded suction. The slope of the regression line between increases in cycle length and the degree of neck suction was taken as an index of baroreflex sensitivity. The reflex response is mediated by a selective increase of vagal efferent activity. Baroreflex sensitivity therefore represents a measure of vagal reactivity. Using multiple regression analysis, baroreflex sensitivity (BS) correlated positively to stroke volume index (SVI) and inversely to plasma renin activity (PRA) and to age: BS = 0.47 SVI - 0.38 PRA - 0.23 age + constant (r = 0.74; p less than 0.0005). In addition to digitalis and diuretics, angiotensin-converting enzyme (ACE) inhibitors (captopril or enalapril) were given to 16 patients for a mean of 17 +/- 3 days. The patients with hemodynamic improvement (group A) exhibited improved baroreflex sensitivity (1.4 +/- 0.4 to 3.6 +/- 1.2 msec/mm Hg; p less than 0.01). Baroreflex sensitivity remained unchanged (3.1 +/- 0.8 to 2.4 +/- 1.0 msec/mm Hg; n.s.) in the patients without hemodynamic improvement (group B). The increase in reflex sensitivity did not correlate with hemodynamic alterations. Baroreflex sensitivity during ACE inhibition (BSD) was only related to the baseline baroreflex sensitivity (BSB): BSD = 2.8 BSB - 0.46 (r = 0.84; p less than 0.005). In patients with heart failure, reflex bradycardia decreases with age and with PRA and increases with stroke volume. Chronic therapy with ACE inhibitors enhances vagal reactivity in patients with hemodynamic improvement.

The pharmacological relevance of vital staining with neutral red.

The uptake of neutral red into the renin-containing juxtaglomerular granules does not inhibit the release of renin either in basal or in stimulated states of renin secretion. The vasodilating effect of neutral red may be due to a non-specific binding to noradrenaline-receptors in the vascular smooth muscle cells.

Sympathetic vascular tone in spontaneous hypertension of rats

ZusammenfassungUnterschiede des sympathischen Gefäßtonus zwischen spontan hypertonen Ratten (spSHR) und Wistar Kyoto Ratten (WKR) wurden an Hand folgender Größen erfaßt:Die sympathische Aktivität wurde ermittelt durch die Bestimmung der Plasmakatecholamine (Noradrenalin, Adrenalin und Dopamin) bei gleichzeitiger Messung der neuronalen und extraneuronalen Wiederaufnahme von Noradrenalin im isolierten Präparat (Langendorff Herz). Die Ansprechbarkeit glatter Gefäßmuskulatur auf vasopressorische Substanzen wurde in der isoliert perfundierten Hinterextremität der Ratte gemessen.Die sympathische Aktivität war bei spSHR im Alter von 5, 12, 15 und 28 Wochen gesteigert, da die Konzentration von Noradrenalin im Plasma um 50% bei unveränderter neuronaler und extraneuronaler Wiederaufnahme erhöht war. Die Ansprechbarkeit der glatten Gefäßmuskulatur gegenüber Noradrenalin war bei spSHR verstärkt.Neben einer stärkeren maximalen Vasokonstriktion nach supramaximalen Dosen von Noradrenalin (10−3 mol/l) oder BaCl2 (20 mmol/l) fand sich eine spezifische Überempfindlichkeit der einzelnen glatten Muskelzelle gegenüber Noradrenalin bei 5 Wochen alten spontan hypertonen Ratten. Während nach Kaliumdepolarisation keine Unterschiede in der Schwellendosis oder der ED50 auftraten, waren diese bei spSHR für die Noradrenalin-induzierten Widerstandserhöhungen um 25% vermindert.Die stimulierte sympathische Aktivität sowie die erhöhte Ansprechbarkeit der Widerstandsgefäße gegenüber Noradrenalin bei spSHR sind Ursache des gesteigerten sympathischen Gefäßtonus, der über eine Erhöhung des peripheren Widerstandes die Entwicklung des hohen Blutdrucks bei der genetischen Hypertonie der Ratte verursacht.SummaryDifferences in sympathetic vascular tone between Wistar Kyoto rats (WKR) and stroke prone spontaneously hypertensive rats (spSHR) were determined by comparing the following parameters: sympathetic activity was evaluated by determinations of plasma catecholamines (noradrenaline, adrenaline, dopamine) combined with the measurement of the neuronal and extraneuronal uptake of noradrenaline using an isolated rat heart preparation. The responsiveness of vascular smooth muscle to vasopressor agents was tested in the isolated perfused hindlimb preparation.At the age of 5, 12, 15, and 28 weeks sympathetic nervous activity was significantly higher in spSHR than in WKR since plasma noradrenaline was elevated by almost 50% in the presence of an unaltered activity of the uptake mechanisms. The responsiveness of vascular smooth muscle to noradrenaline was markedly enhanced in spSHR. Besides increased maximal vasoconstriction in response to BaCl2 (20 mmol/l) after potassium chloride depolarization or supramaximal doses of noradrenaline (10−3 mol/l), a supersensitivity of vascular smooth muscle to noradrenaline could also be detected in spSHR (age 5 weeks). The threshold dose and the ED50 were reduced by 25% in spSHR in response to noradrenaline infusions. No changes in threshold or ED50 were found in response to potassium chloride depolarization.The stimulated sympathetic activity in spSHR and the increased responsiveness of resistance vessels to noradrenaline, both contribute to the rise in sympathetic vascular tone. The finding of an increased sympathetic vascular tone in very early stages of hypertension suggest that this factor, producing a primary increase in total peripheral resistance underlies the development of high blood pressure in spSHR.

Role of right and left atrial dimensions for release of atrial natriuretic peptide in left-sided valvular heart disease and idiopathic dilated cardiomyopathy

To evaluate the role of atrial dimensions for release of atrial natriuretic peptide (ANP), right and left atrial dimensions (cross-sections) were determined by 2-dimensional echocardiography in 50 patients with left-sided valvular heart disease or idiopathic dilated cardiomyopathy. All patients underwent right- and left-sided heart catheterization with measurement of central hemodynamics. Plasma samples for ANP were withdrawn from femoral vein (ANPv) and ascending aorta. An estimate of right and left meridional atrial wall stress was derived by multiplying cross-sectional areas with pressures of the respective atria. As expected ANPv was closely related to mean right (r = 0.63; p less than 0.001; n = 50) and left atrial pressures (r = 0.61; p less than 0.001; n = 47). Furthermore, a positive correlation between ANPv and right (r = 0.56; p less than 0.001; n = 48) and left (r = 0.30; p less than 0.05; n = 48) atrial cross-sections was obtained. Finally, an excellent relation was found between ANPv and right (r = 0.73; p less than 0.001; n = 48) as well as left (r = 0.58; p less than 0.001; n = 44) meridional atrial wall stress, indicating that atrial wall stress rather than atrial pressures or dimensions alone determines plasma ANP concentrations. However, for identical right and left meridional atrial wall stress 3- to 4-times higher plasma ANPv levels were obtained in patients with idiopathic dilated cardiomyopathy than in patients with left-sided valvular heart disease. This indicates that release of ANP to the same stimulus may be modulated by the nature of the underlying heart disease.

Angiotensin-converting enzyme inhibitors and renal function in heart failure

Patients with severe heart failure often exhibit signs of an impaired renal function. As judged from serum urea and creatinine concentrations, renal function may deteriorate further after the addition of angiotensin-converting enzyme (ACE) inhibitors to therapy. The beneficial effect of unloading the failing heart by reducing the systemic outflow resistance is opposed by a potentially harmful effect of unloading the kidney by preferentially reducing the outflow resistance of the glomerulus. However, development of functional renal insufficiency is unlikely and is a rare cause for withdrawing ACE inhibitors when certain precautions are considered: (1) The initial dose of the ACE inhibitor has to be reduced with increasing severity of heart failure (the titration period thereafter should be monitored carefully); (2) an increase in serum creatinine not exceeding 30% of the basal value may be taken as evidence for a beneficial action of the drug, which in addition to altering cardiac function alters kidney function (when the increase in serum creatinine is considered to be of clinical significance, it seems wise to reduce the dose of diuretics first--thereby neuroendocrine stimulation can be attenuated and the dependency of renal filtration from angiotensin II-induced efferent vasoconstriction can be reduced); and (3) the coadministration of inhibitors of prostaglandin synthesis (e.g., acetylsalicylic acid) appears to be associated with a higher risk of impairing renal function: the decrease in glomerular filtration rate is more marked and the compensatory increase in renal plasma flow following ACE inhibition is no longer observed.

Effects of cocaine and desipramine on the neurally evoked overflow of endogenous noradrenaline from the rat heart.

1 Stimulation of postganglionic cardiac sympathetic nerves produced a stimulation frequency‐dependent overflow of endogenous noradrenaline from the otherwise isolated rat heart. 2 Such nerve stimulation also produced increases in heart rate. There was significant correlation between heart rate increases and corresponding noradrenaline concentrations in the coronary venous effluent. 3 Cocaine (3 × 10−5 M) caused a significant reduction in both the noradrenaline overflow and the heart rate increase, produced by nerve stimulation for 1 min at 4 Hz. 4 Desipramine (10−6M) caused a significant increase in the noradrenaline overflow produced by stimulation for 1 min (4 Hz) with a mean increase of approximately 60%. There was no significant effect on the heart rate increase produced by such stimulation. 5 The opposite effects of cocaine (3 × 10−5M) and desipramine (10−6M) on noradrenaline overflow are attributed to differences in the local anaesthetic properties of these agents.

Intracerebroventricular angiotensin II increases arterial blood pressure in rhesus monkeys by stimulation of pituitary hormones and the sympathetic nervous system.

Intracerebroventricular injections of angiotensin II in anesthetized rhesus monkeys increase systemic blood pressure and heart rate. These effects are accompanied by an increase in plasma ADH, cortisol, adrenaline and noradrenaline. Angiotensin II may participate in central mechanisms of blood pressure regulation by its stimulatory effect on the sympathetic nervous system, on ADH and on ACTH release in primates.

Reversal of corticosterone-induced supersensitivity of vascular smooth muscle to noradrenaline by arachidonic acid and prostacyclin

In the isolated perfused hindlimb preparation of rats treated with corticosterone (2 x 20 mg/kg daily for 2 days), the dose-response curve to noradrenaline was shifted to the left, indicating supersensitivity of the vascular bed to noradrenaline. Perfusion with arachidonic acid (10(-5) M) and prostacyclin (10(-9) M) for 5 min reversed the supersensitivity induced by corticosterone. The metabolite of prostacyclin, 6-keto PGF1 alpha(10(-9) M), was ineffective in this respect. In rats which had received desoxycorticosterone acetate (2 x 5 mg/kg daily for 7 days), there was supersensitivity of the hindlimb preparation to noradrenaline similar to that in corticosterone-treated rats. In that case, however, administration of arachidonic acid did not reverse the leftward shift of the dose-response curve. Administration of indomethacin (2 x 2.5 mg/kg for 7 days) prior to the perfusion experiment also resulted in a shift of the noradrenaline dose-response curve to the left, which was less pronounced than the shift induced by corticosterone. Combined administration of corticosterone and indomethacin caused the same increase in noradrenaline sensitivity as did corticosterone alone. Since glucocorticoids inhibit the release of arachidonic acid from phospholipids, it is concluded that corticosterone may enhance the sensitivity to noradrenaline by affecting the biosynthesis of prostaglandins.