Molecular basis of cardioprotection by erythropoietin.

Erythropoietin (EPO), a glycoprotein essential for red blood cell production acts on several non-erythropoietic tissues. The EPO receptor (EPOR) is expressed in a variety of cell types including neurons, endothelial cells, and cardiomyocytes. Recently, a number of reports have indicated that EPO preserves heart function in models of cardiac ischemia-reperfusion (I/R) injury. A diverse range of cellular/physiological processes is modulated by EPO and are thought to play a role in the preservation of heart function. In vivo, reductions in infarct size, apoptosis, oxidative stress, and inflammation have been reported. More recently, increases in angiogenesis and reductions in arrhythmias have been implicated in the cardioprotective effects of EPO. In vitro, EPO reduces apoptosis, oxidative stress, and inflammation. These cardioprotective effects appear to be mediated by a receptor interaction that is distinct from that responsible for EPO's erythropoietic effects. Downstream of receptor interactions, the activation of phosphatidylinositol-3 kinase (PI3-kinase) and Akt appear to mediate many of EPO's cardioprotective effects. However, there is emerging evidence for Akt-independent mechanisms of cardioprotection including the inhibition of glycogen synthase kinase 3beta, as well as the activation of potassium channels, protein kinase C, and protein kinases such as ERK1/2. This review focuses on the effects of EPO in the heart and the molecular mechanisms by which EPO achieves its cardioprotective effects.

Nitric oxide depresses connexin 43 after myocardial infarction in mice.

AIMS: Heart failure (HF) is a major cause of death and morbidity. Connexin 43 (Cx43) content is reduced in the failing myocardium, but regulating factors have not been identified. In HF, inducible nitric oxide synthase (iNOS)-induced high levels of nitric oxide (NO) cause apoptosis and cardiac dysfunction. However, a direct iNOS-Cx43 link has not been demonstrated. We investigated this relationship in mice after myocardial infarction. METHODS: Effects of myocardial infarction were evaluated 2 weeks after coronary artery ligation in wild-type C57BL/6 (WT) and iNOS(-/-) knockout mice. Myocardial Cx43 and Cx45 content were assessed by immunofluorescence confocal imaging and western blotting. Cardiac function was evaluated in anaesthetized mice using a micro pressure-tipped catheter inserted into the left ventricle. RESULTS: Despite similar infarct size, deficiency in iNOS resulted in significantly lower plasma nitrate/nitrite levels, better haemodynamic performance and lower mortality 2 weeks after coronary ligation. Myocardial Cx43, but not Cx45, content was lower in WT mice following ligation. The reduction in Cx43 was less in iNOS(-/-) compared with WT mice. To assess the direct effect of NO on Cx43 expression, cultured neonatal mouse cardiomyocytes were employed. Incubation with the NO donor, S-nitroso-N-acetylpenicillamine, elicited a dose-dependent decrease in Cx43 content in cultured neonatal cardiomyocytes. CONCLUSIONS: Increased NO production from iNOS depressed cardiac performance and contributed to the decreased myocardial Cx43 content 2 weeks after myocardial infarction.

The effects of age on human venous responsiveness to neuropeptide Y.

AIMS: Neuropeptide Y (NPY) is a sympathetic neurotransmitter released with noradrenaline during sympathetic stimulation. Ageing has been shown to be associated with a reduction in alpha2 and beta-adrenoceptor mediated responses in veins, but it is not known whether NPY responsiveness is also altered with increasing age. METHODS: Using a dorsal hand vein technique, we examined NPY receptor responsiveness in 24 normal, healthy subjects (20-72 years; 10 males, 14 females). Graded infusions of NPY (25-2000 pmol min(-1)) were administered (5 min at each dose) into a dorsal hand vein. Venous distension at 45 mmHg was measured at 3-5 min of each infusion. Dose-response curves to NPY were constructed and the peak venoconstriction was calculated. RESULTS: Dose-dependent venoconstriction was seen in all but one subject. The peak venoconstriction observed with NPY was significantly and negatively correlated with the age of the normal subjects (r=-0.63, P<0.01). When subjects were ranked from youngest to oldest and divided into tertiles, (20-40 years, n = 8; 41-55 years, n = 8; 56-72 years, n = 8), mean dose-response curves were different with the oldest tertile being significantly less responsive (P<0.05). The peak venoconstriction observed (% of control) was 65.1+/-7.0, 46.5+/-9.4, and 24.4+/-4.8%, respectively. The oldest tertile had a significantly decreased peak venoconstriction compared with the youngest tertile (P<0.01). Infusion of NPY into a dorsal hand vein had no systemic effects on heart rate or blood pressure in any of the subjects studied. CONCLUSIONS: Hand vein responsiveness to exogenously infused NPY in normal subjects is decreased as age increases. The reduction of NPY-receptor-mediated responses with age may influence sympathetic nervous system control of the venous system with advancing age.

Cardiovascular responses and interactions by neuropeptide Y in rats with congestive heart failure.

Neuropeptide Y (NPY) has been shown to potentiate the effects of various vasoactive agents in both in vitro and in vivo experiments. The present study was designed to investigate the potentiation effects of NPY on various vasoconstrictive agents and the influence of NPY on the dilatation effects of endothelin-1 in rats with congestive heart failure (CHF). CHF was induced by left coronary artery ligation. Sham-operated rats subjected to thoracotomy served as normal controls. Experiments in conscious rats were performed 4-6 weeks after coronary artery ligation or sham operation. The pressor responses of intravenous phenylephrine (12.5 nmol/kg), endothelin-1 (400 pmol/kg) and angiotensin II (10 ng) but not tyramine (40 micrograms) were significantly decreased in CHF rats compared with sham-operated rats (p < 0.01). In sham-operated rats, subthreshold dose of NPY (0.1 microgram/kg/min) potentiated the pressor responses of all the agonists (p < 0.05). In CHF rats, significant enhancement of mean arterial pressure (MAP) by subthreshold dose of NPY was observed with angiotensin II (p < 0.05). The MAP was enhanced by 45.4% in CHF and 40.6% in sham-operated rats respectively. NPY did not enhance the pressor responses induced by phenylephrine, endothelin-1 or tyramine in CHF rats. The initial decrease of MAP after bolus injection of endothelin-1 was observed in both CHF and sham-operated control rats, and magnitude of this response was similar in both groups. Subthreshold dose of NPY significantly reduced the vasodilatation effect of endothelin-1 in CHF (p < 0.05) but not in normal control rats. We conclude that NPY potentiates pressor effects of angiotensin II and reduces vasodilatation effects of endothelin-1 in rats with CHF. These effects of NPY may contribute to the increased vascular tone in CHF.

Vascular alpha-2 adrenoceptor function is decreased in rats with congestive heart failure.

OBJECTIVE: Vascular alpha-2 adrenoceptor function of rats with congestive heart failure (CHF) was characterized in both in vivo and in vitro experiments. METHODS: CHF was induced in Sprague-Dawley rats by coronary artery ligation. Sham-operated rats served as normal controls. Postjunctional alpha-2 adrenergic responsiveness was assessed in vivo using the pithed rat model and in vitro in organ bath. Vascular alpha-2 adrenoceptor density was studied by receptor binding assay. RESULTS: Four to 6 weeks after this surgical procedure, plasma catecholamines were markedly increased in CHF rats. In vivo vascular responses to alpha-2 adrenoceptor agonists BHT933 and clonidine were significantly decreased in CHF rats (P < 0.001). Clonidine elicited dose-dependent responses in endothelium intact mesenteric arteries in both CHF and sham-operated rats. The dose-response curve in CHF was shifted to the right with a pD2 value of 5.5 +/- 0.2 compared with control rats 6.2 +/- 0.2 (P < 0.05). The response to clonidine was selectively blocked by an alpha-2 adrenergic antagonist rauwolscine in both groups. Endothelium denuded arteries showed an enhanced response to clonidine in both CHF and control rats. However, the response to clonidine is still decreased in CHF compared to sham-operated rats (P < 0.05). Alpha-2 adrenoreceptor density, as determined by [3H]yohimbine binding in membrane preparations from mesenteric arteries was decreased in CHF compared to sham-operated rats (Bmax 43 +/- 6 vs. 104 +/- 20 fmol/mg protein, P < 0.05). CONCLUSIONS: Vascular alpha-2 adrenoceptor function is decreased in rats with CHF.

Autonomic dysreflexia in tetraplegic patients: evidence for alpha-adrenoceptor hyper-responsiveness.

A controlled study of acute pharmacological intervention was designed to determine whether decreased sympathetic nerve activity in tetraplegic patients results in increased responsiveness of alpha-adrenoceptors which might contribute to vascular hyperreactivity and the clinical scenario of autonomic dysreflexia. The study took place in a university teaching hospital and included six male tetraplegic patients and six age-matched normal male controls. All tetraplegics were 5 months or longer post-traumatic spinal cord injury and all had experienced symptoms of autonomic dysreflexia on at least one occasion. The dorsal foot vein diameter was recorded with a tonometer during local infusions of noradrenaline 0.125-256 ng/min given through a short intravenous needle. In tetraplegic patients, there was a significant shift to the left of the dose-response curve indicating increased venous responsiveness to noradrenaline. The concentration of noradrenaline required to cause a 50% reduction of the resting vein diameter was decreased in tetraplegics (1.6 ng/min, geometric mean) compared to normal controls (10.9 ng/min, p < 0.02). alpha-Adrenoceptor responsiveness in dorsal foot veins is increased in patients with tetraplegia. Hypersensitivity of vascular alpha-adrenoceptors may contribute to autonomic dysreflexia in patients with high spinal cord injury.

Modulation of vascular contractile responses to alpha 1- and alpha 2-adrenergic and neuropeptide Y receptor stimulation in rats with ischaemic heart failure.

In order to evaluate adaptational changes in vascular function in congestive heart failure (CHF), we studied the contractile responses of isolated arterial and venous blood vessels from rats suffering from CHF induced by coronary artery ligature, resulting in a myocardial infarction. The contractile responses of the basilar, femoral and renal arteries and of the iliac vein were examined in relation to adrenergic and neuropeptide Y (NPY) receptor function by the action of the alpha 1 agonist phenylephrine, the alpha 2 agonist clonidine and NPY. The contractile force was measured (in mN) and in % of K(+)-induced contraction as well as pD2 to each agonist. When stimulated by a 60 mM K(+)-buffer solution, the femoral and renal arteries from CHF rats responded with a stronger contraction (Emax; 9.4 +/- 0.6 and 9.8 +/- 0.6 mN) than the corresponding Sham vessels (Emax; 6.2 +/- 0.7 and 5.6 +/- 0.4 mN respectively, P < 0.001). On the contrary, the iliac vein of CHF responded less to K+ than the Sham iliac vein (Emax 2.5 +/- 0.2 and 3.7 +/- 0.5 mN, P < 0.01). The CHF iliac vein responded with a weaker contraction when stimulated with phenylephrine (Emax 1.9 +/- 0.4 mN) and showed a lower sensitivity (pD2 5.6 +/- 0.1) than the corresponding sham vessel (Emax 5.7 +/- 2.3 mN and pD2 6.3 +/- 0.5, P < 0.05). The CHF renal artery was less sensitive to clonidine (pD2 6.4 +/- 0.6) than the Sham renal artery (pD2 7.2 +/- 0.1, P < 0.05). The results indicate differences between CHF and Sham vessel segments according to both contractile capacity induced by K(+)-depolarization and to agonist induced contractile capacity and sensitivity. The differences are not of general nature but vary according to the vascular bed examined.

Cardiovascular and renal effects of alpha-trinositol in ischemic heart failure rats.

Previous studies have demonstrated that alpha-trinositol (D-myo-inositol-1.2.6-trisphosphate; PP56) may act as a functional neuropeptide Y (NPY) inhibitor. Because NPY is known to be a potent vasoconstrictor, the effects of alpha-trinositol on renal function, vascular responses and the potentiating effects of NPY were investigated in rats with congestive heart failure (CHF) induced by ligation of the left coronary artery. Incremental doses of alpha-trinositol were given to conscious rats (bolus 2, 4 or 10 mg/kg i.v. followed by a 15-minute infusion 20, 40 and 100 mg/kg/h, respectively). Urinary volume, sodium and potassium excretions were significantly increased in both CHF and sham-operated control animals after alpha-trinositol administration compared with saline. Diuresis and natriuresis were observed also during co-administration of alpha-trinositol with NPY but not with norepinephrine (NE). In the pithed CHF rats, threshold doses of NPY potentiated the pressor effects of endothelin-1 (ET-1) and angiotensin II (AII), but not preganglionic nerve stimulation or phenylephrine administration. Alpha-trinositol antagonized both the pressor response to NPY and the potentiation by NPY of pressor responses to effects of ET-1 and AII. Our data show that alpha-trinositol exhibis diuretic and natriuretic effects as well as vascular antagonistic effects on NPY in normal and CHF rats. These effects of alpha-trinositol may be due to an interaction with NPY mediated antidiuresis and antinatriuresis.

Characteristics of renal sympathetic nerve activity in experimental congestive heart failure in the rat.

Recently emerging evidence has indicated that efferent renal sympathetic nerve activity (RSNA) is increased in congestive heart failure (CHF). In the present study the cyclic activity of the renal nerve in the normal and CHF rat was studied. An ischaemic myocardial lesion resulting in CHF was induced by left coronary artery ligation. Sham-operated rats subjected to thoracotomy served as normal controls. Renal sympathetic nerve activity was recorded under chloralose anaesthesia. The neural cycle activity was significantly higher in CHF (47 +/- 3%) compared with sham-operated rats (34 +/- 3%, P < 0.005). Baroreceptor control of RSNA was significantly attenuated in CHF compared with normal control rats (P < 0.005). In response to noxious thermal stimulation by 48 degrees C water immersion of the tail tip, the increase of RSNA was significantly higher in CHF compared with sham-operated rats. A stepwise 15% blood volume expansion over 5 min which induced no alterations of blood pressure or heart rate (HR) resulted in a gradual decrease of RSNA in control rats by approximately 25% at the end of the volume expansion procedure. In CHF rats however, there was no significant change in RSNA during volume expansion. It is concluded that in CHF rats: (1) efferent RSNA is increased; (2) baroreceptor control of RSNA is decreased; (3) RSNA in response to cutaneous thermal noxious stimulation is exaggerated; and (4) RSNA inhibition by cardiopulmonary receptors is blunted.

Cardiac neuropeptide Y and noradrenaline balance in patients with congestive heart failure.

OBJECTIVE: To measure plasma concentrations of noradrenaline and neuropeptide Y-like immunoreactivity in relation to cardiac function in patients with congestive heart failure. DESIGN: Retrospective analysis of plasma noradrenaline concentrations and neuropeptide Y-like immunoreactivity in the arterial and coronary circulations, in patients with a high or low ejection fraction (31.3% (1.3%) or 17.7% (1.1%) respectively) and in healthy volunteers. SETTING: Cardiology department of a university hospital. PATIENTS: 41 patients with congestive heart failure with various aetiologies. Ten healthy volunteers served as a reference group. MAIN OUTCOME MEASURES: Concentrations of noradrenaline measured by high performance liquid chromatography and of neuropeptide Y-like immunoreactivity measured by radioimmunoassay. Cardiac index, pulmonary capillary wedge pressure, pulmonary vascular resistance, and systemic vascular resistance were derived by catheterisation of the right heart. Ejection fraction was measured by radionuclide angiography, cineangiography, or M mode echocardiography. RESULTS: There were pronounced and significant increases in circulating arterial concentrations of neuropeptide Y-like immunoreactivity and noradrenaline in both the high and low ejection fraction groups compared with the healthy subjects. In the patients myocardial release of neuropeptide Y-like immunoreactivity tended to be greater compared with normal subjects, but not significantly so. While normal subjects showed myocardial noradrenaline uptake, patients with congestive heart failure showed significant and progressive myocardial noradrenaline release. Arterial as well as coronary sinus concentrations of neuropeptide Y-like immunoreactivity correlated significantly with plasma noradrenaline concentrations from the respective sites. Plasma noradrenaline concentrations in the artery and coronary sinus were negatively correlated with ejection fraction and cardiac index; no such relations were found for concentrations of neuropeptide Y-like immunoreactivity. CONCLUSIONS: Both circulating concentrations of neuropeptide Y-like immunoreactivity and noradrenaline are significantly increased in moderate to severe forms of congestive heart failure. Plasma concentrations of neuropeptide Y-like immunoreactivity correlated with plasma noradrenaline concentrations, but plasma noradrenaline concentrations alone correlated with ejection fraction and cardiac index. Thus plasma noradrenaline concentration seems to be a more sensitive index of cardiac dysfunction than the concentration of neuropeptide Y-like immunoreactivity in congestive heart failure.

Hypersensitivity of Gi protein mediated muscarinic receptor adenylyl cyclase in chronic ischaemic heart failure in the rat.

OBJECTIVE: The aim was to study the Gi protein mediated muscarinic signalling system in the myocardium of rats with chronic ischaemic heart failure. METHODS: Chronic ischaemic heart failure was induced by myocardial ischaemia (four weeks after coronary artery ligation) in rats. The densities and agonist affinities of muscarinic receptors, and the functional activity and concentration of Gi proteins were studied. RESULTS: In failing hearts, the activity of adenylyl cyclase stimulated by guanyliminodiphosphate (Gpp(NH)p) was decreased by 46%. Stimulated activities of adenylyl cyclase by both sodium fluoride and forskolin, however, remained unchanged. Carbachol depressed forskolin stimulated adenylyl cyclase more in membranes from failing hearts than those from normal hearts. The functional level of Gs protein as measured by a reconstitution assay in sarcolemmal membrane did not differ between the two groups. Furthermore, muscarinic receptors exhibited superhigh and low affinities for agonist in failing hearts whereas those in control hearts displayed only high and low affinities. No significant difference in the peptide equivalent amount of membrane bound Gi protein was found in either group. CONCLUSIONS: The experimental chronic failing heart due to myocardial ischaemia showed a depressed myocardial adenylyl cyclase signalling system. This may be due to the hypersensitivity of the Gi protein mediated muscarinic receptor-adenylyl cyclase system as shown by the increased inhibition of Gpp(NH)p mediated adenylyl cyclase, more potent inhibition of stimulated adenylyl cyclase by carbachol, and the superhigh affinity of the muscarinic receptors for carbachol.

Decreased density of mesenteric arteries but not of myocardial endothelin receptors and function in rats with chronic ischemic heart failure.

Mesenteric artery and cardiac ventricular endothelin receptors and endothelin-1-induced pressor responses were studied in normal rats and rats with chronic congestive heart failure induced by myocardial ischemia (4 weeks after coronary artery ligation). In mesenteric arteries of rats with chronic ischemic heart failure, endothelin receptor density was significantly decreased by 59%, whereas the dissociation constant was increased 2.8-fold, as compared with controls. There were, however, no changes in endothelin-receptor density or the dissociation constant in cardiac ventricular membrane preparations from rats with congestive heart failure as compared with controls. In pithed rats with congestive heart failure there was a reduced pressor response to a bolus injection of endothelin-1 (800 pmole/kg body weight), while the vasodilatory response was unaltered as compared with sham-operated controls. These results demonstrate that there is a decreased vascular endothelin-receptor function due to a down-regulated endothelin receptor. The in vivo data indicate that this is due to impaired endothelin A but not endothelin B receptor function. Thus, there is an impaired arterial but not cardiac ventricular endothelin receptor-mediated signalling system in the rat with chronic ischemic heart failure.

Effects of clonidine on renal sympathetic nerve activity, natriuresis and diuresis in chronic congestive heart failure rats.

The differential effects of the alpha-2 adrenergic agonist, clonidine, on blood pressure, renal sympathetic nerve activity (RSNA) and renal responses were investigated in conscious as well as anesthetized congestive heart failure (CHF) rats and normal control animals. After the stepwise increments of i.v. clonidine infusion (5, 15 and 30 micrograms/hr for 1 hr), mean arterial pressure gradually decreased in CHF, but increased significantly in the control animals at the higher doses. Urinary volume, sodium and potassium excretions were significantly higher in the normal control animals after the clonidine 30-micrograms/hr infusion compared with the CHF rats. There were almost immediate decreases in RSNA in both the CHF and control groups. Although the control animals reduced RSNA to about 5%, the CHF rats retained 36.5% of their respective control values after clonidine administration. Base-line plasma immunoreactive atrial natriuretic peptide were increased 7-fold in the CHF rats compared to controls. After clonidine, immunoreactive atrial natriuretic peptide increased more than 3-fold in the normal rats, whereas no changes were observed in the CHF group. Our data show that clonidine decreases RSNA in CHF and that the natriuretic and that diuretic effects of an alpha-2 receptor agonist are blunted in experimental CHF. Furthermore, the different mean arterial pressure response in the CHF and control groups at higher doses of clonidine may suggest down-regulation of the vascular alpha-2 adrenergic receptor in CHF.

Synthesis, characterization, and antibacterial activity of transition metal complexes with 5-hydroxy-7,4'-dimethoxyflavone.

Complexes of CuII, NiII, CoII, ZnII, FeIII, CrIII, CdII, and MnII with the natural product 5-hydroxy-7,4'-dimethoxyflavone have been synthesized and the probable structures of these complexes have been proposed on the basis of elemental analyses, molecular weight determination, magnetic moments, and electronic and IR spectral data. The presence of coordinated and crystal water molecules was demonstrated by thermal studies. The antibacterial activity of the ligand and all the complexes has been determined on gram positive and gram negative bacteria.

Cardiovascular and renal effects of gamma-MSH in spontaneously hypertensive and normotensive Wistar Kyoto rats.

The objective of this study was to compare the cardiovascular and renal effects of the two gamma-melanocyte-stimulating hormone (MSH) peptide sequences in the pro-opiomelanocortin prohormone structure in conscious, anesthetized, and pithed spontaneous hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) controls. In the conscious but not in the pithed rats, intravenous injection of gamma 2- and gamma 1-MSH induced a rapid and dose-dependent increase in mean arterial pressure (MAP), and gamma 2-MSH was more potent than gamma 1-MSH. The pressor response was more pronounced and more sustained in the SHR compared with the WKY. There were dose-dependent and significant increases in heart rate (HR) after gamma 2- and gamma 1-MSH in the SHR. At intravenous infusions of low doses of gamma 2-MSH, which did not significantly influence MAP or HR, urinary sodium excretion was significantly increased in both SHR and WKY. In conscious, but not in anesthetized rats, intracerebroventricular administration of the gamma 2-MSH peptide induced sustained increases in MAP in both SHR and WKY. After intrathecal administration, there were transient pressor effects of gamma 2-MSH. We conclude that the pro-opiomelanocortin-derived gamma 2- and gamma 1-MSH peptide sequences possess potent rapid pressor actions. The pressor effects, which require an intact sympathetic nervous system, are more pronounced in the SHR strain. Moreover, gamma 2-MSH induces natriuresis when administered in nonpressor doses in WKY and SHR.

Nifedipine pharmacodynamics and pharmacokinetics in treatment of congestive heart failure.

In 22 of 27 cases of congestive heart failure (CHF) treated with nifedipine (NIF), significant improvements in resting hemodynamics were noticed. The higher the basal systemic vascular resistance (SVR) and pulmonary artery end diastolic pressure (PAEDP), the greater the magnitude of reduction was achieved (r = 0.84 and 0.77, P less than 0.01, respectively). Exercise hemodynamic investigation showed that NIF lowered SVR, PAEDP and pulmonary vascular resistance (PVR), with an increase in stroke volume (SV) at the serum concentration of 5-10 ng/ml. Maximum effect was observed at the concentration of 20 ng/ml. No further vasodilation was attainable with serum concentrations above 20 ng/ml. No remarkable deviation of NIF pharmacokinetic parameters from the normal ranges was found in CHF patients. The plasma norepinephrine level decreased markedly 2 and 7 hours after the use of NIF. It is concluded that oral NIF is beneficial to severe CHF patients with low cardiac output and high SVR.

Blunted renal response to atrial natriuretic peptide in congestive heart failure rats is reversed by the alpha 2-adrenergic agonist clonidine.

We wished to determine whether pharmacologic inhibition of the exaggerated sympathetic nerve activity in congestive heart failure (CHF) could restore the renal response to exogenous atrial natriuretic peptide (ANP) administration. Left ventricular (LV) myocardial infarction was induced in Sprague-Dawley rats (n = 16) by coronary artery ligature. Four to 6 weeks postoperatively, an isotonic saline (controls) or clonidine 5 micrograms/h infusion was given. Four hours later, all animals received incremental doses of rat ANP (99-126) (0.25, 0.5 and 1.0 microgram/kg/min). The continuous clonidine infusion transiently increased urinary volume (UV) as compared with the saline controls. Mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine (NE) were significantly decreased by clonidine. The graded ANP infusions significantly increased UV (saline 39.13 +/- 12.45 and clonidine 90.25 +/- 13.69 microliters/min, p less than 0.05) and UNaV (saline 4.26 +/- 1.10 and clonidine 8.81 +/- 1.59 mumol/min, p less than 0.05) in clonidine-pretreated rats as compared with saline-pretreated rats. We conclude that the diuretic and natriuretic responses to ANP are significantly increased in CHF after presynaptic inhibition of NE release by low-dose clonidine.

[Pharmacodynamics and pharmacokinetics of nifedipine in patients with congestive heart failure].

Twenty-seven cases of congestive heart failure (CHF) were treated with nifedipine (Nif) 20 mg po. Significant improvements in resting hemodynamics were found in 22 cases. The higher the basal systemic vascular resistance (SVR) and pulmonary artery end diastolic pressure (PAEDP) were, the greater the magnitudes of reduction found (r = 0.84 and 0.77, P less than 0.01, respectively). Exercise hemodynamic investigation showed that Nif led to a lowering of SVR, PAEDP and pulmonary vascular resistance (PVR), with increases in SV and concentration of 5-10 ng/ml, with a maximum being observed at the concentration of 20 ng/ml. No further vasodilation was found when the plasma concentration exceeded 20 ng/ml. No remarkable deviations from the normal ranges of Nif pharmacokinetics were found in CHF patients. The plasma norepinephrine level decreased markedly 2 and 7 h after Nif. Thus, it is concluded that oral Nif is beneficial in severe CHF patients having low cardiac output and high SVR.