cyclic-gmp and Hypertension--Renal

In the present study, we tested the hypothesis that inhibition of renal phosphodiesterase type 5 (PDE5) in patients with liver cirrhosis and ascites increases sodium excretion. The effect of sildenafil citrate was studied in a randomized double-blind. placebo-controlled crossover study. Diuretics were withdrawn, and a fixed sodium diet (100 mmol/day) was given to the patients for 5 days before both study days. After a 60-min basal period, eight patients received either oral sildenafil (50 mg) or placebo. Glomerular filtration rate (GFR) and renal blood flow (RBF) were determined by 99mTc-diethylenetriamine-pentaacetate and (131)I-hippuran clearances. In human nephrectomy specimens, PDE5 mRNA was expressed at similar levels in the cortex (n = 6) and inner medulla (n = 4). Histochemical staining showed PDE5 immunoreactivity in collecting ducts and vascular smooth muscle. At baseline, cirrhotic patients exhibited elevated plasma concentrations of ANP, renin, ANG II, and aldosterone that did not differ on the 2 study days. Basal sodium excretion was similar at the 2 study days (median 17 and 18 mmol, respectively), and patients were in positive sodium balance. Sildenafil increased heart rate, plasma renin activity, plasma ANG II, and aldosterone concentrations significantly after 60 min. Plasma cGMP concentration was increased after 120 and 180 min, and urinary sodium excretion and mean arterial blood pressure were decreased significantly at 120 and 180 min. Plasma ANP concentration, GFR, and RBF did not change after sildenafil. In patients with ascites and cirrhosis, inhibition of PDE5 did not promote natriuresis but led to increased plasma levels of the renin-angiotensin-aldosterone system.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Animals; Ascites; Blood Pressure; Cross-Over Studies; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Gene Expression Regulation, Enzymologic; Hormones; Humans; Hypertension, Renal; Kidney Medulla; Liver Cirrhosis; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Potassium; Purines; Rats; Sildenafil Citrate; Sodium; Sodium Chloride, Dietary; Sulfones; Water

To investigate whether the administration of the anti-oxidant vitamin C could prevent the systemic and renal effects of nicotine in healthy non-smoker volunteers.. The acute effects of oral, 4 mg, nicotine gum (n = 10), intravenous vitamin C (12 mmol, n = 8) or both (n=9) on mean arterial pressure (MAP), heart rate, glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and urinary cyclic guanosine monophosphate (cGMP) were assessed in non-smokers.. In subjects receiving nicotine, MAP (+8 +/- 4 mmHg, P<0.0001) and HR (+13 +/- 8 beats/min, P < 0.001) increased whereas ERPF (-65 +/- 69 ml/min per 1.73 m2, P < 0.01), GFR (-14.5 +/- 16.8 ml/min per 1.73 m2, P < 0.01) and cGMP (-180 +/- 173 pmol/min, P < 0.01) decreased as compared to baseline values. The concomitant administration of nicotine and vitamin C caused similar haemodynamic changes; however, cGMP remained unchanged. In subjects receiving only vitamin C, there were no significant changes in MAP, heart rate, ERPF, GFR and cGMP.. The present findings indicate that vitamin C was unable to prevent the renal vasoconstriction, but it prevented the fall in cGMP provoked by nicotine in non-smokers. This suggests that nicotine induces a degradation of nitric oxide mediated by oxygen-derived free radicals which may be prevented by vitamin C administration. The nicotine-induced renal vasoconstriction may be related to other mechanism(s).

Topics: Adult; Antioxidants; Ascorbic Acid; Blood Pressure; Cyclic GMP; Female; Glomerular Filtration Rate; Heart Rate; Humans; Hypertension, Renal; Male; Nicotine; Nicotinic Agonists; Renal Circulation; Smoking

Topics: Cyclic GMP; Disease Progression; Endothelins; Glomerulonephritis, IGA; Glomerulonephritis, Membranoproliferative; Humans; Hypertension, Renal; Isosorbide Dinitrate; Nitric Oxide; Pilot Projects; Vasodilator Agents

To examine the vasodilatation induce by the NO donors, [Ru(terpy)(bdq)NO](3+) (TERPY) and sodium nitroprusside (SNP), and to compare their effects in aortic rings from hypertensive 2K-1C and normotensive 2K rats.. Vascular reactivity was performed in aortic rings pre-contracted with phenylephrine (Phe 100nM). We have analyzed the maximal relaxation (Emax) and potency (pD(2)) of NO donors.. Potency of SNP was greater than TERPY in both arterial groups. The vasodilatation induced by TERPY was greater in 2K than in 2K-1C, and it was inhibited by sGC inhibitor ODQ in 2K and in 2K-1C aortic rings. ODQ did not alter the efficacy to SNP, but it reduced its potency in 2K and 2K-1C. The blockade of K(+) channels reduced the potency of TERPY only in aortic rings of 2K. On the other hand, the potency of SNP was reduced in both 2K and 2K-1C. The combination of ODQ and TEA reduced the relaxation induced by TERPY and SNP in 2K and reduced the efficacy to SNP in 2K-1C aortic rings but it had no additional effect on the TERPY relaxation in 2K-1C aortas. The production of cGMP induced by TERPY was greater than that produced by SNP, which was similarly increased in 2K and 2K-1C. Sarcoplasmic reticulum Ca-ATPase inhibition only impaired the relaxation induced by SNP in 2K aortic rings.. Taken together, our results provide evidences that in this model of hypertension, impaired K(+) channels activation by TERPY and SERCA activation by SNP may contribute to decreased vasodilatation.

Topics: Animals; Aorta; Cyclic GMP; Guanylate Cyclase; Hypertension; Hypertension, Renal; Male; Nitric Oxide Donors; Nitroprusside; Organometallic Compounds; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Wistar; Ruthenium; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Vasodilation

The negative functional effects of cyclic GMP are controlled by the sarcoplasmic reticulum calcium-ATPase (SERCA). The effects of cyclic GMP are blunted in cardiac hypertrophy. We tested the hypothesis that the interaction between cyclic GMP and SERCA would be reduced in hypertrophic cardiac myocytes. Myocytes were isolated from 7 control and 7 renal-hypertensive hypertrophic rabbits. Control and hypertrophic myocytes received 8-bromo-cGMP (8-Br-cGMP; 10(-7), 10(-6), 10(-5) mol/l), the SERCA blocker thapsigargin (10(-8) mol/l) followed by 8-Br-cGMP, or the SERCA blocker, cyclopiazonic acid (CPA; 10(-7) mol/l) followed by 8-Br-cGMP. Percent shortening and maximal rate of shortening and relaxation were recorded using a video edge detector. Changes in cytosolic Ca2+ were assessed in fura 2-loaded myocytes. In controls, 8-Br-cGMP caused a significant 36% decrease in percent shortening from 5.8 +/- 0.4 to 3.7 +/- 0.3%. Thapsigargin and CPA did not affect basal control or hypertrophic myocyte function. When 8-Br-cGMP was given following thapsigargin or CPA, the negative effects of 8-Br-cGMP on control myocyte function were reduced. In hypertrophic myocytes, 8-Br-cGMP caused a smaller but significant 17% decrease in percent shortening from 4.7 +/- 0.2 to 3.9 +/- 0.1%. When 8-Br-cGMP was given following thapsigargin or CPA, no significant changes occurred in hypertrophic cell function. Intracellular Ca2+ transients responded in a similar manner to changes in cell function in control and hypertrophic myocytes. These results show that the effects of cyclic GMP were reduced in hypertrophic myocytes, but this was not related to SERCA. In presence of SERCA inhibitors, the responses to cyclic GMP were blunted in hypertrophic as well as control myocytes.

Topics: Animals; Calcium; Cyclic GMP; Heart Ventricles; Hypertension, Renal; Hypertrophy; In Vitro Techniques; Indoles; Myocytes, Cardiac; Rabbits; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Thapsigargin

This study addresses the hypothesis that renal interstitial (RI) cGMP, a modulator of pressure-natriuresis, exerts its effect through a relationship with renal interstitial hydrostatic pressure (RIHP). Increasing renal perfusion pressure in Sprague-Dawley rats led to increases in RIHP (5.2+/-0.6 to 10.9+/-1.6 mm Hg; P<0.01), urine sodium excretion (0.062+/-0.009 to 0.420+/-0.068 micromol/min per gram; P<0.01), and RI cGMP (3.5+/-0.8 to 9.5+/-1.7 fmol/min; P<0.01), and these effects were blocked by partial renal decapsulation. Infusion of cGMP into the RI compartment of decapsulated animals restored natriuresis (0.067+/-0.010 to 0.310+/-0.061 micromol/min per gram; P<0.01). These changes were independent of changes in glomerular filtration rate . Artificially increasing RIHP in normotensive animals increased RI cGMP (4.1+/-0.6 to 6.9+/-0.7 fmol/min; P<0.01) and urine sodium excretion (0.071+/-0.013 to 0.179+/-0.039 micromol/min per gram; P<0.05). Coinfusion of organic anion transport-inhibitor probenecid, or soluble guanylyl cyclase inhibitor 1-H(1,2,4) oxadiazolo-(4,2)quinoxalin-1-one, abolished these effects. Infusion of cGMP into the RI compartment of normotensive animals increased RIHP (6.7+/-0.4 to 10.3+/-0.9 mm Hg; P<0.001). Exogenous RI cGMP delivery did not affect total, cortical, or medullary renal blood flow. These studies suggest that extracellular RI cGMP is required for the natriuresis observed after increases in renal perfusion pressure and RIHP and that cGMP acts via a tubule mechanism. The results support an intrarenal positive-feedback loop wherein RI cGMP increases RIHP, which, in turn, increases RI cGMP, contributing to the reinforcement of pressure-natriuresis.

Topics: Albumins; Animals; Blood Pressure; Cyclic GMP; Enzyme Inhibitors; Feedback, Physiological; Female; Glomerular Filtration Rate; Hydrostatic Pressure; Hypertension, Renal; Kidney; Natriuresis; Oxadiazoles; Quinoxalines; Rats; Rats, Sprague-Dawley; Renal Circulation; Urine

Oxidative stress causes changes in angiotensin (Ang) type 1 receptor (AT1R) function, which contributes to hypertension. Ang II affects blood pressure via maintenance of sodium homeostasis by regulating renal Na(+) absorption through its effects on Na/K-ATPase (NKA). At low concentrations, Ang II stimulates NKA; higher concentrations inhibit the enzyme. We examined the effect of oxidative stress on renal AT1R function involved in biphasic regulation of NKA. Male Sprague-Dawley rats received tap water (control) and 30 mmol/L of L-buthionine sulfoximine (BSO), an oxidant, with and without 1 mmol/L of Tempol (antioxidant) for 2 weeks. BSO-treated rats exhibited increased oxidative stress, AT1R upregulation, and hypertension. In proximal tubules from control rats, Ang II exerted a biphasic effect on NKA activity, causing stimulation of the enzyme at picomolar and inhibition at micromolar concentrations. However, in BSO-treated rats, Ang II caused stimulation of NKA at both of the concentrations. The effect of Ang II was abolished by the AT1R antagonist candesartan and the mitogen-activated protein kinase inhibitor UO126, whereas the Ang type 2 receptor antagonist PD-123319 and NO synthase inhibitor N(G)-nitro-L-arginine methyl ester had no effect. The inhibitory effect of Ang II was sensitive to candesartan and N(G)-nitro-L-arginine methyl ester, whereas PD-123319 and UO126 had no effect. In BSO-treated rats, Ang II showed exaggerated stimulation of NKA, mitogen-activated protein kinase, proline-rich-tyrosine kinase 2, and NADPH oxidase but failed to activate NO signaling. Tempol reduced oxidative stress, normalized AT1R signaling, unmasked the biphasic effect on NKA, and reduced blood pressure in BSO-treated rats. In conclusion, oxidative stress-mediated AT1R upregulation caused a loss of NKA biphasic response and hypertension. Tempol normalized AT1R signaling and blood pressure.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Antioxidants; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Buthionine Sulfoximine; Cyclic GMP; Cyclic N-Oxides; Enzyme Inhibitors; Focal Adhesion Kinase 2; Hypertension, Renal; Kidney Tubules, Proximal; Male; Mitogen-Activated Protein Kinases; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Signal Transduction; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers; Sodium-Potassium-Exchanging ATPase; Spin Labels; Tetrazoles; Vasoconstrictor Agents

This study tested the hypothesis that the positive inotropic effect of beta-adrenoceptor stimulation would be inhibited by increases in cyclic GMP in control cardiomyocytes and that this response would be modified in hypertrophic cardiomyocytes. Cell functional data as well as GMP and cyclic AMP data were collected from 7 control and 7 1K1C (one-kidney-one-clip) renal hypertensive hypertrophic rabbits. Using isolated control and IKIC ventricular myocytes, data were obtained at baseline and after treatment with the beta-adrenoceptor agonist isoproterenol (10(-8, -6) mol/l) or the cyclic GMP-phosphodiesterase inhibitor zaprinast (10(-5) mol/l) followed by isoproterenol (10(-8, -6) mol/l). We found that in control rabbits, isoproterenol (10(-6) mol/l) increased percent shortening (4.8 +/- 0.2 to 6.4 +/- 0.3%) and cyclic AMP (2.3 +/- 0.3 to 5.0 +/- 0.7 pmol/10(5) cells). Zaprinast 10(-5) mol/l increased cyclic GMP (150 +/- 20 to 209 +/- 14 fmol/10(5) cells) and decreased percent shortening (6.2 +/- 0.4 to 5.2 +/- 0.3). Zaprinast 10(-5) mol/l prevented the functional response to isoproterenol in control (5.2 +/- 0.3 to 4.7 +/- 0.3), without changing cyclic AMP levels. In 1K1C rabbits, isoproterenol (10(-6) mol/l) increased cyclic AMP (4.9 +/- 0.8 to 7.6 +/- 1.4 pmol/10(5) cells) without changing function. Zaprinast 10(-5) mol/l increased cyclic GMP (182 +/- 23 to 233 +/- 24 fmol/10(5) cells) and decreased percent shortening (6.6 +/- 0.9 to 4.7 +/- 0.5), but did not alter the lack of effect of isoproterenol in 1K1C. In control cardiomyocytes, cyclic GMP blunted the isoproterenol contraction response without changing cyclic AMP levels, but isoproterenol's functional effect was not seen in 1K1C cardiomyocytes.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adrenergic beta-Agonists; Animals; Cardiomegaly; Cell Enlargement; Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; Hypertension, Renal; In Vitro Techniques; Isoproterenol; Myocardial Contraction; Myocytes, Cardiac; Purinones; Rabbits

We tested the hypothesis that the negative inotropic effects of C-type natriuretic peptide (CNP) would be diminished in renal hypertensive (one-kidney-one-clip, 1K1C) hypertrophic rabbit hearts and that this attenuated effect would be due either to decreased cyclic GMP production or to reduced signaling.. Using isolated control and 1K1C ventricular myocytes, cell shortening data (video edge detection) were collected: (1) at baseline and after CNP 10(-8,-7) M, followed by KT5823 (KT), a cyclic GMP-dependent protein kinase inhibitor; or (2) at baseline, following KT pre-treatment and subsequent CNP 10(-8,-7) M. In addition, cyclic GMP levels were determined by radioimmunoassay at baseline and CNP 10(-7) M.. In control myocytes, CNP decreased percent shortening (5.7 +/- 0.4 versus 4.0 +/- 0.4% at 10(-7) M), maximal rate of shortening (58.7 +/- 5.1 versus 45.2 +/- 3.6 microm/sec) and maximal rate of relaxation (57.1 +/- 4.9 versus 44.1 +/- 3.4 microm/sec) in a concentration-dependent manner. These effects were attenuated by subsequent KT administration. CNP failed to produce these negative functional effects in 1K1C myocytes. When pre-treated with KT, CNP had no negative functional effect in either normal and 1K1C myocytes. Basal levels of cyclic GMP were similar in control versus 1K1C myocytes; however, CNP produced a significant rise in cyclic GMP level in control (63.6 +/- 7.8 versus 83.5 +/- 11.3 pmol/10(5) myocytes) but not in 1K1C (49.2 +/- 2.6 versus 52.7 +/- 5.6) myocytes.. Thus, CNP acted through the cyclic GMP protein kinase in control myocytes. We conclude that in hypertrophic cardiac myocytes, the decreased effect of CNP was because of decreased production of cyclic GMP.

Topics: Animals; Carbazoles; Cardiomegaly; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Guanylate Cyclase; Heart Ventricles; Hypertension, Renal; Hypertrophy; Indoles; Myocardial Contraction; Myocytes, Cardiac; Natriuretic Peptide, C-Type; Protein Kinase Inhibitors; Rabbits; Signal Transduction; Surgical Instruments

ANG II activation of phospholipase D (PLD) is required for ERK and NAD(P)H oxidase activation, both of which are involved in hypertension. Previous findings demonstrate that ANG II stimulates PLD activity through AT(1) receptors in a RhoA-dependent mechanism. Additionally, endogenous AT(2) receptors in preglomerular smooth muscle cells attenuate ANG II-mediated PLD activity. In the present study, we examined the signal transduction mechanisms used by endogenous AT(2) receptors to modulate ANG II-induced PLD activity through either PLA(2) generation of lysophosphatidylethanolamine or Galpha(i)-mediated generation of nitric oxide (NO) and interaction with RhoA. Blockade of AT(2) receptors, Galpha(i) and NO synthase, but not PLA(2), enhanced ANG II-mediated PLD activity in cells rich in, but not poor in, AT(2) receptors. Moreover, NO donors, a direct activator of guanylyl cyclase and a cGMP analog, but not lysophosphatidylethanolamine, inhibited ANG II-mediated PLD activity, whereas an inhibitor of guanylyl cyclase augmented ANG II-induced PLD activity. AT(2) receptor- and NO-mediated attenuation of ANG II-induced PLD activity was completely lost in cells transfected with S188A RhoA, which cannot be phosphorylated on serine 188. Therefore, our data indicate that AT(2) receptors activate Galpha(i), subsequently stimulating NO synthase and leading to increased soluble guanylyl cyclase activity, generation of cGMP, and activation of a protein kinase, resulting in phosphorylation of RhoA on serine 188. Furthermore, because AT(2) receptors inhibit AT(1) receptor signaling to PLD via modulating RhoA activity, AT(2) receptor signaling can potentially regulate multiple vasoconstrictive signaling systems through inactivating RhoA.

Topics: Animals; Cells, Cultured; Cloning, Molecular; Cyclic GMP; Hypertension, Renal; Nitric Oxide; Nitric Oxide Synthase; Phospholipase D; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor Cross-Talk; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; rhoA GTP-Binding Protein; Signal Transduction

In DOCA-salt hypertension, renal kallikrein levels are increased and may play a protective role in renal injury. We investigated the effect of enhanced kallikrein levels on kidney remodeling of DOCA-salt hypertensive rats by systemic delivery of adenovirus containing human tissue kallikrein gene. Recombinant human kallikrein was detected in the urine and serum of rats after gene delivery. Kallikrein gene transfer significantly decreased DOCA- and salt-induced proteinuria, glomerular sclerosis, tubular dilatation, and luminal protein casts. Sirius red staining showed that kallikrein gene transfer reduced renal fibrosis, which was confirmed by decreased collagen I and fibronectin levels. Furthermore, kallikrein gene delivery diminished myofibroblast accumulation in the interstitium of the cortex and medulla, as well as transforming growth factor (TGF)-beta1 immunostaining in glomeruli. Western blot analysis and ELISA verified the decrease in immunoreactive TGF-beta1 levels. Kallikrein gene transfer also significantly reduced kidney weight, glomerular size, proliferating tubular epithelial cells, and macrophages/monocytes. Reduction of proliferation and hypertrophy was associated with reduced levels of the cyclin-dependent kinase inhibitor p27(Kip1), and the phosphorylation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). The protective effects of kallikrein were accompanied by increased urinary nitrate/nitrite and cGMP levels, and suppression of superoxide formation. These results indicate that kallikrein protects against mineralocorticoid-induced renal fibrosis glomerular hypertrophy, and renal cell proliferation via inhibition of oxidative stress, JNK/ERK activation, and p27(Kip1) and TGF-beta1 expression.

Topics: Animals; Cell Cycle Proteins; Cell Division; Cyclic GMP; Cyclin-Dependent Kinase Inhibitor p27; Desoxycorticosterone; Disease Models, Animal; Extracellular Matrix; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Gene Transfer Techniques; Genetic Therapy; Hypertension, Renal; Hypertrophy; JNK Mitogen-Activated Protein Kinases; Kallikreins; Male; Nitrates; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Suppressor Proteins

Inhibition of nitric oxide synthases causes systemic hypertension and renal injury in rats. Our objective was to examine whether omapatrilat, a vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase, could induce better regression of renal injury than ACE inhibitor alone. Ten groups of rats were studied. They were fed either a normal (0.8% NaCl) or a high (4% NaCl) sodium diet. Eight of these groups received NG-nitro-L-arginine methyl ester (L-NAME, 20 mg x kg(-1) x d(-1)) in their drinking water. After 4 weeks, 1 group on each diet was killed and considered the L-NAME group, whereas the others received L-NAME alone, captopril (200 mg x kg(-1) x d(-1)) plus L-NAME, or omapatrilat (80 mg x kg(-1) x d(-1)) plus L-NAME for 4 additional weeks. In rats receiving L-NAME alone for 8 weeks, the mortality rate was approximately 90%, irrespective of the diet. In contrast, all rats survived in the captopril and the omapatrilat groups. In rats fed a normal-sodium diet, captopril and omapatrilat normalized systolic blood pressure and induced a complete regression of renal injury. Creatinine clearance and proteinuria were also normalized. In the high-sodium-diet groups, both treatments were less efficient: blood pressure remained elevated, and the regression of renal fibrosis was only partial. Although proteinuria decreased significantly with captopril or omapatrilat, creatinine clearance remained lower than in the controls. These results demonstrate that, in nitric oxide-deficient rats fed a normal-sodium diet, ACE and vasopeptidase inhibitors exhibit a marked renoprotective effect, whereas these treatments are less efficient in rats fed a high-sodium diet.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Vessels; Captopril; Cyclic GMP; Endothelin-1; Enzyme Inhibitors; Fibrosis; Hypertension, Renal; Kidney; Male; Neprilysin; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Protease Inhibitors; Pyridines; Rats; Rats, Sprague-Dawley; Sodium Chloride; Survival Rate; Thiazepines

To investigate the changes in the angiotensin II (Ang II) receptors and nitric oxide (NO)-cGMP pathway in the rat kidney after nitric oxide synthase (NOS)blockade.. Captopril, an angiotensin-converting enzyme (ACE)inhibitor, 20 mg/100 ml; and/or L-158,809 (an Ang II AT1-receptor antagonist, 5 mg/100 ml) and L-NAME (NOS inhibitor, 50 mg/100 ml) were administered orally for 12 weeks. Blood pressure (BP),urinary albumin, urinary cGMP excretion, plasma ANP, and plasma renin activity were measured. In vitro autoradiography was used to locate the Ang II receptors in the kidney.. Captopril and L- 158,809 treatments normalised BP and prevented the appearance of albuminuria in rats receiving L-NAME. Urinary cGMP excretion was significantly increased in L-158,809-treated rats compared with the non-treated group, suggesting that the dysfunctional NO system may be activated by the treatment. AT1-receptor binding in the kidney was inhibited to about 40% of the control value after administration of L- 158,809. The AT2-receptor binding was inhibited to less than 15% of the control value. NOS inhibition had no effect on receptor binding.. Blockade of NOS causes hypertension and renal damage. Treatment with an ACE inhibitor and/or Ang II receptor antagonist prevented these changes equally effectively. The stimulatory effect of AT1-receptor antagonism on cGMP production was not mediated by AT2-receptor-dependent mechanisms, since renalAT2-receptor binding density was suppressed following treatment with L-158,809. AT1-receptor blockade per se favours activation of humoral pathways that stimulate cGMP production potentially contributing to renal and vascular protection in hypertension and chronic renal disease.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Autoradiography; Blood Pressure; Captopril; Cyclic GMP; Enzyme Inhibitors; Female; Hypertension, Renal; Imidazoles; Kidney; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Wistar; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; Tetrazoles

Fragments derived from the prohormone of alpha-human atrial natriuretic peptide (alpha-ANP) in patients with cardiac failure are more closely related to the disease state than intact alpha-ANP.. Specific immunoassays have been developed to detect proANP 1-30, proANP 31-67, and proANP 1-98. Plasma concentrations of these fragments were determined in 122 hemodialysis patients with and without cardiac dysfunction, with and without hypertension, as well as with and without dialysis-associated hypotensive episodes either before or after a regularly scheduled hemodialysis session. The effects of different dialyzer membranes were also evaluated. The results of these assays along with other markers of volume regulation such as alpha-ANP and cyclic 3',5' guanosine monophosphate (cGMP) were compared with those of healthy controls.. Predialytic and postdialytic plasma concentrations of the proANP fragments were markedly higher in uremic patients than in controls (98-fold for proANP 1-98, 56-fold for proANP 31-67, and 35-fold for proANP 1-30). All proANP fragments, alpha-ANP, and cGMP decreased during hemodialysis. A strong linear correlation was found between predialytic and postdialytic plasma levels. There was no correlation, however, with the amount of fluid removed during hemodialysis. Patients with altered left ventricular hemodynamics displayed significantly higher plasma concentrations of all proANP fragments and alpha-ANP, but not cGMP, than patients with normal cardiac function. Hemodialysis patients with moderate or severe hypertension had higher concentrations of proANP fragments, alpha-ANP, and cGMP than patients with normal blood pressure or patients with only mild hypertension. There was no significant difference in circulating levels of proANP peptides, alpha-ANP, and cGMP between patients with and without frequent dialysis-associated hypotensive episodes. Cellulose-triacetate dialyzers reduced plasma levels of proANP 1-30, proANP 31-67, and proANP 1-98 significantly more than polysulfone dialyzers, but alpha-ANP and cGMP levels were not different.. Circulating alpha-ANP and proANP fragments are influenced by a variety of factors such as end-stage renal disease, hemodialysis treatment, dialyzer membrane material, cardiac dysfunction, and hypertension. Therefore, these are not useful markers to accurately estimate volume status in hemodialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Pressure; Blood Volume; Cyclic GMP; Female; Heart Failure; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Membranes, Artificial; Middle Aged; Peptide Fragments; Protein Precursors; Renal Dialysis

Tissue kallikrein cleaves kininogen substrate to produce the potent vasodilating peptide kinin, which plays important roles in cardiovascular and renal function. To explore cardiac and renal potential protective effects of kallikrein gene delivery in chronic renal failure, we delivered adenovirus carrying the human tissue kallikrein cDNA (cHK) into rats with 5/6 reduction of renal mass.. Expression of human tissue kallikrein in rats was assessed by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR)/Southern blotting. Physiological parameters monitored in rats included systolic blood pressure, heart rate, and urinary excretion of protein, albumin, kinin, cGMP, cAMP, and nitrate/nitrites. Systemic and regional hemodynamics were measured by fluorescent-labeled microspheres. Heart weight and myocyte diameter were used to assess left ventricular hypertrophy. Quantitative and qualitative morphological analyses were used to evaluate histologic changes in kidney and heart sections.. Active tissue kallikrein reached a peak serum level of 463 +/- 76 ng/mL following gene delivery and returned to control levels within 21 days. A maximal blood pressure reduction of 37 mm Hg was observed within one week in rats receiving kallikrein gene delivery as compared with control rats receiving adenovirus containing the luciferase gene (159 +/- 5 vs. 196 +/- 6 mm Hg, N = 15, P < 0.001), and a significant blood pressure difference continued for five weeks postgene delivery. Kallikrein gene delivery significantly decreased total urinary protein and albumin excretion and increased levels of urinary kinin, nitrite/nitrate, and cGMP levels. Cardiac output and regional blood flow were also increased, while peripheral vascular resistance decreased. Kallikrein gene transfer reduced glomerular sclerotic lesions, tubular damage, lumenal protein cast accumulation, and interstitial inflammation in the kidney. Myocardial hypertrophy and fibrosis were also attenuated in rats receiving kallikrein gene delivery.. These findings indicated that kallikrein gene delivery attenuates hypertension and protects against renal injury and cardiac remodeling in the rat remnant kidney model of chronic renal failure.

Topics: Adenoviridae; Animals; Blood Pressure; Blood Urea Nitrogen; Cardiomegaly; Cyclic GMP; Fibrosis; Gene Expression; Genetic Therapy; Humans; Hypertension, Renal; Injections, Intravenous; Kidney Failure, Chronic; Kinins; Male; Nephrectomy; Nitrates; Nitrites; Rats; Rats, Wistar; Renal Circulation; Tissue Kallikreins; Vascular Resistance; Vasodilation; Ventricular Remodeling

The contribution of endothelial factors and mechanisms underlying decreased acetylcholine-induced relaxation and endothelial inhibitory action on phenylephrine-induced contraction were evaluated in aortas of two-kidney, one-clip hypertensive (2K-1C) and normotensive (2K) rats. Relaxation induced by acetylcholine in 2K-1C precontracted by phenylephrine was lower [Maximum Effect (ME): 71.33+/-3.36%; pD(2): 7.050+/-0.03] than in 2K (ME: 95.26+/-1.59%; pD(2): 7.31+/-0.07). This response was abolished by N(G)-nitro-L-arginine (L-NNA) in 2K-1C, but was only reduced in 2K (ME: 29.21+/-9.28%). Indomethacin had no effect in 2K-1C, and slightly attenuated acetylcholine-induced relaxation in 2K. The combination of L-NNA and indomethacin almost abolished acetylcholine-induced relaxation in 2K-1C, while in 2K, the inhibition (ME: 56.61+/-8.95%) was lower than the effect of L-NNA alone. During the KCl-induced precontraction, 2K and 2K-1C aortas showed similar acetylcholine-induced relaxation (43.50+/-5.64% vs. 41.60+/-4.36%), which was abolished by L-NNA. The levels of cGMP produced in response to acetylcholine were not different between 2K and 2K-1C. The sensitivity to sodium nitroprusside was lower in phenylephrine-precontracted aortas from 2K-1C than 2K, as showed by the pD(2) values (7.72+/-0.20 vs. 8.59+/-0.17), and this difference was abolished in aortas precontracted by KCl. The membrane potential was less negative in 2K-1C than in 2K (-41.57+/-1.19 vs. -51.00+/-1.13 mV) and hyperpolarization induced by acetylcholine was lower in 2K-1C than in 2K aortas (6.00+/-0.66 vs. 13.27+/-1.61 mV). Phenylephrine-induced contraction in aortas with endothelium was similar in both groups, and increased by the endothelium removal. This increase was lower in 2K-1C (from 1.32+/-0.06 to 1.90+/-0.21 g) than 2K (from 1.49+/-0.07 to 2.83+/-0.18 g). L-NNA and the endothelium removal had similar effect in 2K-1C (1.85+/-0.18 g) and were lower in 2K (2.18+/-0.20 g). Indomethacin decreased phenylephrine-induced contraction only in 2K. In conclusion, our major finding was a selective defect in smooth muscle membrane hyperpolarization, which could explain the decreased relaxation to acetylcholine and the attenuated inhibitory effect of endothelium on the contractile function in 2K-1C aortas.

Topics: Acetylcholine; Animals; Aorta; Biological Factors; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Hypertension, Renal; Hypertension, Renovascular; Indomethacin; Male; Membrane Potentials; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Phenylephrine; Rats; Rats, Wistar; Stimulation, Chemical; Vasodilator Agents

To investigate effects of angiotensin I converting enzyme (ACE) inhibition in experimental nephritis during chronic inhibition of nitric oxide (NO) synthase.. Rats with and without autoimmune Heymann nephritis were treated with a NO synthase inhibitor L-NAME (50 mg/100 ml) and/or an ACE inhibitor captopril (20 mg/100 ml) in drinking water for 12 weeks. Urinary cGMP excretion was used as an indirect measure of NO activity. Blood pressure, urinary albumin, nitrite and nitrate levels, plasma ANP, and plasma renin activity were measured. Kidneys were examined with light microscopy and immunohistochemical methods.. Captopril treatment protected rats receiving L-NAME and none of the captopril-treated rats died. Mortality was greatest in the nephritis-L-NAME (57%) and L-NAME (43%) groups. Captopril normalized cGMP excretion, blood pressure, and prevented partly the appearance of albuminuria. Peritubular infiltration of mononuclear cells was clearly enhanced in the nephritis-L-NAME group (found in 80% of the rats) as compared with the nephritis (20%), L-NAME (40%), and control (0%) groups. The peritubular cell infiltration caused by L-NAME was prevented by captopril treatment. L-NAME-induced hypertension was associated with cardiac hypertrophy and this was prevented by captopril.. NO may play an important renoprotective role in disease progression of chronic membranous glomerulonephritis. Captopril prevents L-NAME-induced hypertension, improves survival, and ameliorates renal damage in this type of nephritis. Dysfunction of renal NO pathways may be an important factor causing progressive renal damage in chronic nephritis. Our results suggest that the dysfunctional renal NO system may be beneficially activated by ACE inhibitors.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Captopril; Cyclic GMP; Enzyme Inhibitors; Female; Glomerulonephritis; Hypertension, Renal; Kidney Tubules; Myocardium; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Organ Size; Rats; Rats, Wistar; Renin

To test the hypothesis that nitric oxide (NO) deficiency occurs in end-stage renal disease (ESRD), NO oxidation products (NO2 + NO3 = NOx) and cGMP were measured in blood, urine, and dialysate effluent of peritoneal dialysis (PD) patients and compared with blood and urine of healthy subjects. All subjects were on a controlled low-nitrate diet (approximately 330 micromol/day). NOx and cGMP outputs were significantly reduced in PD patients (334 +/- 50 micromol/24 h and 55 +/- 13 nmol/24 h, respectively) vs. controls (823 +/- 101 micromol/24 h and 149 +/- 46 nmol/24 h). Plasma arginine was borderline low, plasma citrulline was elevated and plasma levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine were approximately five time higher in PD patients (2.2 +/- 0.3 microM) vs. controls (0.4 +/- 0.1 microM). Although blood pressure (BP) was not different between groups at the time of study, 10 of 11 PD patients were on medication for hypertension. These studies demonstrate that total NO production is low in ESRD, and with appropriate caution, we conclude that this NO deficiency may contribute to the increased BP that occurs in ESRD.

Topics: Adult; Aged; Arginine; Citrulline; Creatinine; Cyclic GMP; Female; Humans; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Oxidation-Reduction; Peritoneal Dialysis

This study examined the effect of N-ethylmaleimide (NEM, 10(-7) M) on agonist-induced contraction and the relaxation following drug-washout, of vascular smooth muscle (VSM) segments derived from hypertensive rabbits. Mean blood pressure increase was produced either by renal constriction plus contralateral nephrectomy, or by cadmium acetate ingestion. Freely-ionized calcium (45Ca)flux, cyclic 3':5'-guanosine monophosphate (cGMP), and cyclic 3':5' adenosine monophosphate (cAMP), were analyzed. NEM was used as a stereoselective probe to clarify the role of sulfhydryl (SH) groups in hypertension. Contractile response to norepinephrine (NE, 5.9 x 10(-7) M), angiotensin II (AT, 9.8 x 10(-8) M), and potassium chloride (KCl, 2.2 x 10(-2) M) were significantly depressed in hypertensive tissue. Exposure to NEM, before agonist challenge, caused an even greater depression in contractile response. As for the normotensive group, an inhibition of relaxation occurred when NEM was added after the development of a maximal contractile response to NE, AT or KCl. Changes in contractile ability and in relaxation were attributed to specific alterations in calcium distribution. These alterations were examined by 45Ca washout components and were related to cAMP and cGMP metabolism. These results suggest a regulatory role of SH groups in contraction and relaxation and a modification of this role in hypertension.

Topics: Acetates; Alkylation; Angiotensin II; Animals; Cadmium; Calcium; Cyclic AMP; Cyclic GMP; Ethylmaleimide; Female; Half-Life; Hypertension, Renal; Muscle, Smooth, Vascular; Norepinephrine; Potassium Chloride; Rabbits; Sulfhydryl Reagents; Vasoconstriction; Vasodilation

We tested the hypothesis that cardiac myocytes from hypertensive (one kidney, one clip; 1K,1C) cardiac-hypertrophied rabbits require higher guanosine 3',5'-cyclic monophosphate (cGMP) to similarly lower O2 consumption than control myocytes and that this effect is caused by differences in guanylate cyclase activity. Using isolated myocytes from control and 1K,1C New Zealand White rabbits, we obtained O2 consumption (nl O2 x min(-1) x 10(5) cells) and cGMP (fmol/10(5) cells) levels after stimulation of guanylate cyclase with nitroprusside, CO, or guanylin (10(-8)-10(-5) M). Soluble guanylate cyclase activity was also determined. Basal cGMP was elevated in 1K,1C vs. control (176 +/- 28 vs. 85 +/- 13) myocytes. cGMP increased in 1K,1C and control myocytes after stimulation with nitroprusside, CO, and guanylin. Guanylate cyclase activity in 1K,1C vs. control myocytes was not statistically different. Basal O2 consumption in 1K,1C vs. control myocytes was comparable (307 +/- 1 vs. 299 +/- 22). O2 consumption was similarly decreased when guanylate cyclase was stimulated. Control regression equations correlating cGMP and O2 consumption were O2 consumption = -1.46 x [cGMP] + 444.65 (r = 0.96) for CO, O2 consumption = -0.58 x [cGMP] + 328.48 (r = 0.82) for nitroprusside, and O2 consumption = -1.25 x [cGMP] + 389.15 (r = 0.88) for guanylin. The 1K,1C regression equations were O2 consumption = -1.36 x [cGMP] + 537.81 (r = 0.97) for CO, O2 consumption = -0.23 x [cGMP] + 307.30 (r = 0.88) for nitroprusside, and O2 consumption = -1.27 x [cGMP] + 502.91 (r = 0.89) for guanylin. These data indicate that 1K,1C hypertrophic myocytes had higher cGMP than controls at every level of O2 consumption. This effect was not caused by differences in basal or maximal guanylate cyclase activity.

Topics: Animals; Calcium; Carbon Monoxide; Cardiomegaly; Cyclic GMP; Gastrointestinal Hormones; Guanylate Cyclase; Hypertension, Renal; Myocardium; Natriuretic Peptides; Nitroprusside; Oxygen Consumption; Peptides; Rabbits

We tested the hypothesis that a reduction in myocardial cyclic GMP would increase myocardial O2 consumption and that renal hypertension (One Kidney-One Clip, 1K1C)-induced cardiac hypertrophy would change this relationship.. Either vehicle or LY83583 (10(-3) M, a guanylate cyclase inhibitor) was topically applied to the left ventricular surface of control of 1K1C anesthetized open-chest New Zealand white rabbits (N = 38). Coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry) were used to determine subepicardial (EPI) and subendocardial (ENDO) O2 consumption and myocardial cyclic GMP was determined by radioimmunoassay.. The heart weight/body weight ratio was greater in the 1K1C rabbits (3.16 +/- 0.20) than controls (2.58 +/- 0.08 g/kg). Systolic blood pressure was higher in 1K1C rabbits (116 +/- 8 mm Hg) than controls (80 +/- 6), but topical LY83583 had no significant hemodynamic effects. LY83583 significantly and similarly decreased EPI cyclic GMP in both control (7.9 +/- 1.2 to 6.0 +/- 1.0 pmol/g) and 1K1C (7.7 +/- 1.2 to 5.3 +/- 0.9) hearts and control ENDO (8.7 +/- 1.7 to 7.2 +/- 1.2) but not 1K1C ENDO (6.7 +/- 0.5 to 5.7 +/- 1.1). Myocardial O2 consumption was significantly increased in control with LY83583 (EPI 6.6 +/- 1.1 to 15.6 +/- 1.4 and ENDO 7.2 +/- 0.9 to 14.2 +/- 0.7 ml O2/min/100 g), but not in 1K1C hearts (EPI 12.1 +/- 1.0 to 12.9 +/- 1.2 or ENDO 11.4 +/- 0.7 to 12.9 +/- 0.9).. Thus myocardial O2 consumption was only increased by LY83583 in control hearts, but LY83583 decreased cyclic GMP similarly in both the control and 1K1C EPI. This indicated, at least in the EPI, a dissociation of the inverse relationship between the myocardial level of cyclic GMP and O2 consumption in the 1K1C rabbit heart.

Topics: Aminoquinolines; Analysis of Variance; Animals; Cardiomegaly; Coronary Circulation; Cyclic GMP; Enzyme Inhibitors; Guanylate Cyclase; Hypertension, Renal; Male; Myocardium; Oxygen Consumption; Pericardium; Rabbits

NG-nitro-L-arginine methyl ester (L-NAME) and 11-desoxycorticosterone plus salt intake (DOCA-salt) hypertensive rat models were compared to study the possible involvement of model-specific factors in the development of renal angiopathy and left ventricular hypertrophy (LVH). Blood pressure was measured in L-NAME, DOCA-salt hypertensive, and control Wistar rats, and the lesions of nephroangiosclerosis and left ventricular hypertrophy were evaluated after 7 weeks. Arterial wall cyclic guanosine monophosphate, plasma renin activity (PRA), and renal renin storage were assessed in parallel. For the same level of hypertension in the two models, the renal arterial fibrinoid necrotic lesions were significantly more frequent in L-NAME than in DOCA-salt hypertensive rats. In DOCA-salt hypertensive rats, PRA was decreased and arterial cGMP increased compared to controls. In the L-NAME model, arterial cGMP decreased and PRA showed a bimodal distribution in this intermediate stage of hypertensive disease. LVH was observed in DOCA-salt rats and only in the L-NAME rats with a high level of PRA. There was a close correlation between the lesions of nephroangiosclerosis, left ventricular index, and plasma renin activity in L-NAME rats. We therefore suggest that the activation of the renin-angiotensin system participates specifically in the development of the second stage of hypertension during chronic blockade of NO synthase involving nephroangiosclerosis and LVH.

Topics: Animals; Aorta; Arginine; Blood Pressure; Blood Urea Nitrogen; Body Weight; Creatinine; Cyclic GMP; Desoxycorticosterone; Disease Models, Animal; Hypertension, Renal; Hypertrophy, Left Ventricular; Male; Mortality; NG-Nitroarginine Methyl Ester; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System

To compare normal pregnancy with pregnancy-induced hypertension (PIH)/preeclampsia with respect to the effects of acute volume expansion on plasma atrial natriuretic peptide (ANP), cyclic guanosine monophosphate (cGMP) and fetal-maternal circulation.. Observational study.. University hospital.. Fifteen women with PIH/preeclampsia and 15 healthy pregnant controls.. Before and after 30 minutes' infusion of a crystalloid solution (15 ml/kg), maternal venous blood was sampled for ANP and cGMP analysis and echocardiographic and Doppler investigations were performed.. Basal median (range) ANP and cGMP levels were significantly higher in the PIH/preeclampsia group compared to the controls: 6.5 (3.8-30.4) compared to 3.9 (2.0-6.7) pmol/l, p < 0.01 and 5.8 (2.4-11.6) compared to 4.0 (2.3-10.8) nmol/l, p < 0.05. The response to volume load was enhanced: 4.6 (-4.5-21.8) compared to 0.7 (-4.1-8.8), p < 0.05 and 2.9 (0.1-10.9) compared to 1.2 (-5.0-6.0), p < 0.05, respectively. Systemic vascular resistance was initially higher in the patient group, 22.3 (14.1-36.7) compared to 15.6 (10.0-25.5) peripheral resistance units, p < 0.01 but the response to volume load was similar in both groups (12-13% decrease). The pulsatility index of the uterine artery, 0.85 (0.46-1.38) compared to 0.72 (0.49-1.26) and umbilical artery 0.89 (0.66-1.57) compared to 0.97 (0.74-1.31) did not differ between the groups. Volume expansion did not affect any of these variables.. The pulsatility index of the uterine artery remained unaffected in both preeclamptic patients and healthy controls despite an increase of ANP and cGMP concentration and a systemic vasodilatation during acute volume expansion. This finding may indicate the absence of a vasodilation of the uteroplacental vascular bed.

Topics: Atrial Natriuretic Factor; Blood Circulation; Blood Volume; Cyclic GMP; Female; Fetal Blood; Humans; Hypertension, Renal; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Pulsatile Flow; Vascular Resistance

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Cyclic AMP; Cyclic GMP; Diagnosis, Differential; Electrocardiography; Exercise Test; Humans; Hypertension; Hypertension, Renal; Male; Renin-Angiotensin System; Vasopressins

It has been suggested that the impaired natriuretic response of the clipped kidney in two-kidney, one clip hypertensive rats is related to downregulation of renal atrial natriuretic peptide receptors. To test this hypothesis, blood volume expansion and atrial peptide binding studies were performed in this model. Infusion of 1% and then 1.5% body weight donor blood (n = 6) caused a progressive increase in plasma immunoreactive atrial natriuretic peptide (107 +/- 26 to 168 +/- 31 to 427 +/- 154 pg/ml, p less than 0.001); the sodium excretion of the nonclipped kidney rose from 230 to 2,200 to 4,000 neq/min (p less than 0.01) but that of the clipped kidney did not rise significantly. There was a highly significant correlation between log cyclic guanosine monophosphate and log sodium excretion by the nonclipped (r2 = 0.749) but not the clipped (r2 = 0.046) kidney. Between clipped and nonclipped kidneys, the association constant (5.26 +/- 0.89 versus 5.17 +/- 0.64 x 10(9)/mol) and apparent binding site density (575 +/- 92 versus 500 +/- 74 fmol/mg protein) for atrial peptide binding in isolated glomeruli did not differ. Assay of atrial peptide-induced cyclic guanosine monophosphate release by isolated glomeruli showed that clipped and nonclipped kidneys were equally responsive. Binding affinity and receptor density did not differ in homogenates prepared from inner medullas of clipped and nonclipped kidneys. These results show that the blunted natriuretic response in clipped kidneys was not associated with any relative decrease in number or function of glomerular or papillary atrial natriuretic peptide receptors.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Glomerular Filtration Rate; Hypertension, Renal; Natriuresis; Rats; Rats, Inbred Strains; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface

To investigate the involvement of atrial natriuretic peptide (ANP) in secondary hypertension, we examined hormonal and renal responses to ANP infusion (0.025 microgram/kg/min) in 27 patients with renal parenchymal hypertension, 10 with primary aldosteronism, 8 with renovascular hypertension, and 15 normotensive subjects. The preinfusion plasma concentration of ANP was significantly higher in patients with renal parenchymal hypertension (120 pg/ml, p less than 0.01) and in patients with primary aldosteronism (98 pg/ml, p less than 0.05) than in the normotensive subjects (40 pg/ml), but it was not greater than in the patients with renovascular hypertension (73 pg/ml, NS). In the patients with renal parenchymal hypertension, plasma ANP correlated negatively with creatinine clearance (r = -0.76, p less than 0.001). Mean blood pressure (-5%, p less than 0.01) and plasma aldosterone (-40%, p less than 0.001) decreased to a similar degree in the four groups during ANP infusion. However, an increase in urinary sodium excretion caused by ANP was higher in the hypertensive than in the normotensive patients (+250% vs. +70%, p less than 0.01) and correlated positively with mean blood pressure during ANP infusion (r = 0.47, p less than 0.001). The removal of adenomas in the patients with primary aldosteronism significantly lowered both plasma levels of ANP and cyclic guanosine 2',3'-monophosphate and reduced an increase in sodium excretion during ANP infusion, whereas the responses of blood pressure and plasma aldosterone to ANP infusion were not altered by the operation. Thus, these results suggest that elevated ANP secretion and increased natriuretic responses to ANP may modify the blood pressure and body fluid volume status in some types of secondary hypertension.

Topics: Adrenal Gland Neoplasms; Aldosterone; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Hormones; Humans; Hyperaldosteronism; Hypertension, Renal; Hypertension, Renovascular; Kidney; Osmolar Concentration; Postoperative Period; Reference Values; Renin

Relaxation of spirally cut aortic strips was diminished in vessels from both spontaneously hypertensive rats and renal hypertensive rats. Aortic relaxation was decreased in response to the cyclic nucleotides and the beta adrenergic stimulant, isoproterenol, in both models, of hypertension. Defective aortic relaxation also occurred with two other vasodilators, nitroglycerin and adenosine. Further evidence for a reduced relaxant ability of blood vessels from hypertensive rats was obtained by measuring aortic relaxation after exposure and subsequent removal of vascular contractile agonists. The time for aortic preparations from spontaneously hypertensive rats to relax to base-line tension after maximum contraction with norepinephrine, serotonin and potassium chloride was significantly prolonged compared to recovery time for vessels from Kyoto Wistar normotensive rats. Treatment of the spontaneously hypertensive rat with reserpine, but not hydralazine, resulted in an improved ability of aortic preparations to relax. Based on these data, we propose that defects in vascular relaxation may contribute to hypertension and that some antihypertensive drugs may improve or facilitate vascular relaxation.

Topics: Adenosine; Animals; Aorta, Thoracic; Bucladesine; Cyclic GMP; Female; Hypertension, Renal; Isoproterenol; Male; Muscle Contraction; Nitroglycerin; Rats; Rats, Inbred Strains; Serotonin; Vasomotor System