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K F Hilgers

Publications and source records attributed to K F Hilgers.

At least 37 records · Page 2Linked to original sources
PubMed1999

1166 A/C polymorphism of the angiotensin II type 1 receptor gene and the response to short-term infusion of angiotensin II.

BACKGROUND: Previous studies reported an association of the 1166 A/C polymorphism of the angiotensin II (Ang II) type 1 receptor gene with high blood pressure and cardiovascular disease. We tested the hypothesis that this polymorphism affects the blood-pressure, renal hemodynamic, and aldosterone response to infused Ang II. METHODS AND RESULTS: Young, male, white volunteers (n = 116) with normal (n = 65) or mildly elevated (n = 51) blood pressure on a high salt intake were genotyped for the 1166 A/C polymorphism. Two doses of Ang II (0.5 and 3 ng x kg(-1) x min(-1) over 30 minutes each) increased blood pressure, plasma aldosterone, glomerular filtration rate, and filtration fraction and decreased renal blood flow. The blood-pressure, renal hemodynamic, and aldosterone responses were not significantly different between subjects homozygous for the A allele (n = 56) and heterozygous subjects (n = 47) or subjects homozygous for the C allele (n = 13). Comparison of A allele homozygotes with all C allele carriers pooled (n = 60) or restriction of the analysis to normotensive volunteers also revealed no significant differences between genotypes. CONCLUSIONS: The 1166 C variant of the Ang II type 1 receptor does not lead to a greater blood-pressure, aldosterone, or renal vascular response to infused Ang II in young, male, white subjects. We conclude that the 1166 A/C polymorphism does not have a major effect on these actions of Ang II.

Adult↗
PubMed1999

825T allele of the G-protein beta3 subunit gene (GNB3) is associated with impaired left ventricular diastolic filling in essential hypertension.

OBJECTIVE: Recently, a novel C825T polymorphism in the gene (GNB3) encoding for the G-protein beta3 subunit was identified. The 825T allele is associated with the generation of a novel splice variant, enhanced intracellular signal transduction, and arterial hypertension. In this study, we investigated the impact of the 825T allele on left ventricular structure and function in mild to moderate essential hypertensive subjects. METHODS: In 34 white patients with established mild to moderate essential hypertension (World Health Organization stage I or II, mean age 52 +/- 9 years) genotype analysis of GNB3 C825T polymorphism, insertion/deletion polymorphism of the ACE gene and 1166 A/C polymorphism of the AT1 receptor gene was performed. In each patient, 24 h ambulatory blood pressure measurement (SpaceLabs 90207) and two-dimensional guided M-mode echocardiography combined with Doppler sonography were performed. RESULTS: In our homogenous study group, the GNB3 825T allele was not associated with casual and 24 h ambulatory blood pressure (CC versus TC/TT: 144 +/- 13/92 +/- 8 versus 151 +/- 14/97 +/- 7 and 143 +/- 11/92 +/- 7 versus 150 +/- 16/ 96 +/- 9 mmHg, respectively) or parameters of left ventricular structure (relative wall thickness: CC versus TC/TT, 0.48 +/- 0.1 versus 0.46 +/- 0.1; left ventricular mass: CC versus TC/TT, 281 +/- 65 versus 299 +/- 80 g). However, transmitral flow variables reflecting left ventricular diastolic filling were impaired in patients expressing the TC/TT genotype (ratio of peak late (A) to early (E) velocities: CC versus TC/TT, 0.95 +/- 0.24 versus 1.2 +/- 0.26, P< 0.02; velocity time integrals A/E: CC versus TC/TT, 0.57 +/- 0.16 versus 0.76 +/- 0.23, P< 0.01) while all co-variables such as age, body mass index, ambulatory blood pressure, heart rate and end-diastolic volume were similar between the two groups. If patients were stratified according to the I/D polymorphism of the ACE gene and the A1166C polymorphism of the AT1 receptor gene, no differences in blood pressure, left ventricular structure or systolic and diastolic function of the left ventricle were found between different genotypes. CONCLUSION: The GNB3 825T allele was associated with impaired left ventricular diastolic filling in hypertensive subjects in this study. Since alterations in left ventricular filling have been identified as an early marker of hypertensive heart disease, the GNB3 C825T polymorphism may influence cardiac adaptation to increased afterload.

Adult↗
PubMed1999

Effects of human prorenin in rats transgenic for human angiotensinogen.

The physiological role of prorenin is unknown; however, the possibility that prorenin inhibits renin locally has been suggested. We tested the hypothesis that prorenin may be an endogenous competitor for renin uptake in the tissue. We also investigated whether prorenin can be activated to active renin and affect mean arterial pressure (MAP). Isolated perfused hindquarters of rats transgenic for human angiotensinogen were infused with human renin and/or prorenin. The plateau phase of angiotensin (Ang) I release 15 minutes after cessation of infusions was used as a parameter for renin uptake. Renin (10 ng/mL for 15 minutes) caused sustained release of Ang I (153+/-16 fmol/mL). Coinfusion with a 15-fold excess of prorenin did not affect local Ang I formation (153+/-19 fmol/mL). Prorenin infusion alone showed no activation to active renin. In addition, we investigated MAP and plasma Ang II levels after injection of saline (DeltaMAP, -1+/-2 mm Hg; 40+/-5 fmol/mL Ang II), 9 ng renin (DeltaMAP, +37+/-3 mm Hg; 378+/-39 fmol/mL), and 144 ng prorenin (DeltaMAP, +10+/-5 mm Hg; 61+/-5 fmol/mL) and the coinjection of renin and prorenin (DeltaMAP, +41+/-4 mm Hg; 305+/-23 fmol/mL) in anesthetized rats. The data show that prorenin was not activated to active renin and did not affect MAP in short-term experiments. Renin-induced Ang formation was not affected by prorenin. Renin may have been taken up specifically because of its physical and chemical properties or because of nonspecific sequestration in the extravascular space. We conclude that prorenin does not act as an endogenous antagonist for the long-lasting effects of renin in the vascular wall. Moreover, prorenin does not affect acute renin-related effects on blood pressure.

Angiotensin I↗
PubMed1999

Inhibition of the renin-angiotensin system upregulates cyclooxygenase-2 expression in the macula densa.

The expression of cyclooxygenase 2 (COX-2) in the late thick ascending limb, including the macula densa, is found to be upregulated in an activated renin-angiotensin system. How this upregulation is managed is not yet known. We therefore considered the possibility that the stimulation of COX-2 expression is triggered by the activation of the renin-angiotensin system. For this purpose, we treated male Sprague-Dawley rats with the angiotensin I-converting enzyme inhibitor ramipril (10 mg/kg per day), the angiotensin II type 1 (AT(1)) receptor blocker losartan (30 mg/kg per day), and the angiotensin II type 2 (AT(2)) receptor blocker PD123319 (6 mg/kg per day) for 4 days. We determined the expression of COX-2 mRNA and protein in the renal cortex. We found that ramipril and the AT(1) receptor blocker losartan increased COX-2 mRNA and COX-2 immunoreactivity in the macula densa approximately 4-fold, whereas the AT(2) blocker PD123319 showed no effect. A low-salt diet (0.02% wt/wt) stimulated COX-2 expression in the kidney cortex <2-fold. The combination of a low-salt diet with ramipril led to a further increase of COX-2 mRNA and COX-2 immunoreactivity compared with low salt or ramipril alone. These data indicate that endogenous angiotensin II apparently inhibits COX-2 expression in the macula densa via AT(1) receptors and can therefore not account for the stimulation of COX-2 expression associated with an activated renin-angiotensin system. Because macula densa-derived prostaglandins are considered stimulators of renin secretion and renin synthesis, inhibition of macula densa COX-2 by angiotensin II could form a novel indirect negative feedback control of the renin system.

Angiotensin II↗
PubMed1998

Endogenous angiotensin II and the reflex response to stimulation of cardiopulmonary serotonin 5HT3 receptors.

1. Angiotensin (Ang) II modulates cardiovascular baroreflexes; whether or not the peptide influences chemosensitive cardiovascular reflexes is not known. We tested the hypothesis that Ang II modulates the reflex control of sympathetic nerve activity exerted by 5-hydroxytryptamine 3 (5HT3) cardiopulmonary receptors. 2. The 5HT3 receptor agonist phenylbiguanide (PBG), infused intravenously for 15 min, elicited a sustained reflex decrease of renal sympathetic nerve activity (RSNA) but only transient (<3 min) changes of arterial blood pressure (BP) and heart rate (HR) in methohexital-anaesthesized rats. 3. Infusion of Ang II at a dose that did not affect baseline BP, HR and RSNA enhanced the PBG-evoked reflex decrease of RSNA (-54+/-5% in Ang II treated versus -33+/-6% in control rats after 15 min PBG, P<0.05, n = 6 each) in methohexital-anaesthetized rats. 4. The angiotensin converting enzyme (ACE) inhibitor lisinopril blunted the reflex responses to PBG in anaesthetized as well as conscious animals. The effect of the ACE inhibitor was abolished by concomitant infusion of Ang II. 5. The reflex response to stimulation of cardiopulmonary 5HT3 afferents was also impaired by the Ang II type 1 receptor (AT1) blocker ZD7155 but not by the type 2 (AT2) blocker PD 123319. 6. Infusion of a volume load to stimulate cardiopulmonary baroreceptors induced a gradual decrease of RSNA which was impaired by exogenous Ang II (RSNA -26+/-6% in Ang II treated versus -47+/-6% in control rats after volume load, P<0.05, n = 6 each) but unaffected by ACE inhibition. 7. The reflex control of RSNA by cardiopulmonary 5HT3 receptors is enhanced by Ang II via AT1 receptors. Thus, Ang II facilitates a chemosensitive cardiovascular reflex, in contrast to its inhibitory influences on mechanosensitive reflexes.

Anesthesia↗
PubMed1998

Molecular cloning of KS, a novel rat gene expressed exclusively in the kidney.

BACKGROUND: We aimed to identify genes with kidney specific, developmentally regulated expression. Here we report the cDNA sequence and expression pattern of KS, a novel kidney-specific rat gene. METHODS: A partial cDNA was identified by differential display polymerase chain reaction (PCR) of a renal cell fraction enriched for proximal tubular and renin-expressing cells. Using the partial cDNA as a probe, a rat kidney cDNA library was screened. The full-length KS sequence was obtained by PCR amplification of cDNA ends. The expression pattern of KS was investigated by Northern blot. RNA was extracted from several organs of newborn and adult rats, as well as from the kidneys of rats with altered tubular function, that is, rats that had undergone unilateral nephrectomy, unilateral ureteral obstruction, neonatal losartan treatment, and the appropriate control animals. The expression of KS was also investigated in the kidneys of rats with spontaneous or renovascular hypertension. RESULTS: The KS cDNA (2426 bp) contained one open reading frame encoding a predicted 572 amino acid protein. The derived peptide sequence displayed approximately 70% similarity to the hypertension-related SA gene product and approximately 50% similarity to prokaryotic and eukaryotic acetyl-CoA synthases (EC 6. 2.1.1). KS was expressed in the kidney and not in any other organ assayed. KS RNA was not detected in fetal and newborn rat kidney but became apparent after one week of postnatal life. Gene expression was downregulated in rat models of altered tubular function. KS expression was decreased in spontaneously hypertensive rats but not in renovascular hypertension. CONCLUSION: KS, a novel rat gene, exhibits a unique tissue-specific expression exclusively in mature kidneys. The data suggest KS may encode an adenosine monophosphate binding enzyme.

Amino Acid Sequence↗
PubMed1998

Angiotensin-dependent gene expression in the developing rat kidney.

We aimed to identify genes involved in the growth effects of angiotensin II (Ang II) during kidney development. In rats treated from birth with the Ang II type-1 receptor blocker losartan, expression of transforming growth factor beta1 (TGF-beta1), platelet-derived growth factor B (PDGF-B), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF), as measured by Northern blot, did not change significantly (N = 4 to 6 per group each). Differential display methods, used to identify genes with Ang II-dependent expression, produced mostly false positives. We identified one novel rat partial cDNA, termed AD.5, that is related to a human orphan receptor. AD.5 was expressed in a developmentally regulated pattern and may be involved in kidney development and/or the trophic actions of Ang II.

Amino Acid Sequence↗
PubMed1998

Coordinate expression of cyclooxygenase-2 and renin in the rat kidney in renovascular hypertension.

Prostaglandins contribute to the regulation of renin synthesis and secretion. We tested the hypothesis that the inducible isoform of prostaglandin G/H synthase, cyclooxygenase-2, contributes to the stimulation of renin synthesis in renovascular hypertension. The expression of cyclooxygenase-2 and renin was investigated in the kidneys of rats with two-kidney, one-clip renovascular hypertension or sham operation. Systolic blood pressure was increased 2 weeks after clipping (153+/-7 versus 112+/-4 mmHg in controls, n=6 each, P<.05) and continued to rise until 4 weeks. Cyclooxygenase-2 mRNA levels were increased in clipped kidneys but remained unchanged or slightly decreased in nonclipped kidneys. Cyclooxygenase-2 protein was expressed mainly in the macula densa and occasionally in distal tubular cells not associated with the macula densa. Two weeks after clipping, the percentage of juxtaglomerular apparatus staining positive for cyclooxygenase-2 was 27.8+/-3.6 in clipped kidneys, 3.1+/-0.4 in contralateral kidneys, and 8.0+/-1.3 in controls; the percentages for immunoreactive renin staining in the afferent arteriole were 33.6+/-2 in clipped kidneys, 1.9+/-0.5 in contralateral kidneys, and 12.4+/-4.0 in controls, respectively. Similar parallel changes in renin and cyclooxygenase-2 staining were observed 4 weeks after clipping. The percentage of cyclooxygenase-2-positive juxtaglomerular apparatus correlated positively with the percentage that was renin positive (r=0.78, P<.05). Double immunostaining showed coexpression of cyclooxygenase-2 and renin protein in the same juxtaglomerular apparatus. Our data are consistent with a role for macula densa cyclooxygenase-2 in the regulation of renin in renovascular hypertension.

Animals↗
PubMed1998

Angiotensinases restrict locally generated angiotensin II to the blood vessel wall.

We tested the hypothesis that angiotensinases limit the spillover of locally formed angiotensin II into the circulation. The release of angiotensin peptides from isolated rat hindquarters perfused with an artificial medium was measured by high-performance liquid chromatography and radioimmunoassay. The spontaneous release of angiotensins was increased by the angiotensinase inhibitors phenanthroline (850+/-195 versus 95+/-33 fmol of angiotensin I per 30 minutes in controls, P<.05, n=5 each) and amastatin (P<.05, n=5 each). Infusion of renin induced sustained local angiotensin I formation, which was also increased by phenanthroline. Stimulation of local angiotensin formation by renin infusion was compared with infusion of exogenous angiotensin II. Renin caused similar increases of perfusion pressure (11.1+/-2.2 versus 7.6+/-1.9 mm Hg after angiotensin II, P>.05) despite lower angiotensin II levels in the venous effluent than during infusion of exogenous angiotensin II (65+/-2 versus 482+/-33 fmol/mL, P<.05, n=7 each). Thus, renin must have caused higher angiotensin II tissue levels than indicated by the measurements in the venous effluent. The pressor response to renin was abolished by the type 1 angiotensin II receptor antagonist losartan. We conclude that the major part of locally generated angiotensins is not released into the circulation but degraded by angiotensinases within the tissue compartment.

Angiotensin I↗
PubMed1997

Endogenous erythropoietin correlates with blood pressure in essential hypertension.

Patients on maintenance hemodialysis with a family history of essential hypertension are at higher risk for increased arterial blood pressure when treated with erythropoietin than patients without family history. This study was performed to elucidate the role of endogenous erythropoietin in essential hypertension. We conducted a study in 42 untreated patients (mean age, 51 +/- 9 years) with essential hypertension World Health Organization stages I or II. Ambulatory 24-hour blood pressure (Spacelab 90207), cardiac output (2D guided M-mode echocardiography and CW Doppler sonography), renal hemodynamics (para-aminohippurate and inulin clearance), and endogenous erythropoietin (radioimmunoassay) together with erythrocyte count, hemoglobin, and hematocrit were measured in parallel. Mean 24-hour systolic blood pressure was 145 +/- 13 mm Hg, and mean diastolic blood pressure was 93 +/- 8 mm Hg. The average erythropoietin concentration was 15.3 +/- 3.7 mU/mL and within the normal range. We found that the higher erythropoietin concentrations, the more elevated was both 24-hour ambulatory systolic (r = 0.51, P < 0.005) and diastolic blood pressure (r = 0.49, P < 0.005). Also, the concentration of endogenous erythropoietin was correlated with total peripheral resistance as noninvasively determined by echocardiographic and Doppler sonographic measurements (r = 0.40, P < 0.02 and r = 0.49, P < 0.02, respectively). With increasing erythropoietin concentrations, renal plasma flow and renal blood flow were found to be progressively reduced (r = -0.32, P < 0.05 and r = -0.35, P < 0.05, respectively) and renal vascular resistance increased (r = 0.41, P < 0.01). Neither hematocrit nor hemoglobin nor erythrocyte count were related to endogenous erythropoietin concentrations. In human essential hypertension, the level of arterial blood pressure is related to endogenous erythropoietin, which is hemodynamically mediated by an increase of total peripheral resistance. Because erythropoietin has shown proliferative and vasoconstricting effects on the endothelium in experimental studies, we suggest that endogenous erythropoietin might be an aggravating or even a promoting factor in the pathogenesis of essential hypertension.

Adult↗
PubMed1997

Pulmonary serotonin 5-HT3-sensitive afferent fibers modulate renal sympathetic nerve activity in rats.

Cardiopulmonary reflexes with vagal afferents may control volume homeostasis by influencing renal nerve activity. Such reflexes can be stimulated mechanically and chemically, e.g., by serotonin 5-HT). We have demonstrated that stimulation of epicardial 5-HT3 receptors inhibits renal sympathetic nerve activity (RSNA) by a cardiorenal reflex. We now tested the hypothesis that pulmonary 5-HT3-sensitive vagal afferent fibers participate in the control of renal nerve activity. Two sets of experiments were performed. First, the responses of multifiber RSNA, heart rate (HR), and blood pressure (BP) to the 5-HT3-receptor agonist phenylbiguanide (PBG; 10 microg iv) were recorded in the presence of intact pulmonary afferents. Abdominal afferents were removed by subdiaphragmatic vagotomy. Cardiac afferents were blocked by intrapericardial injection of 10% procaine. Second, the responses of 25 single vagal pulmonary afferent C fibers to PBG were assessed. PBG decreased BP, HR, and RSNA (-90 +/- 8%). When cardiac afferents were blocked by procaine, BP and HR failed to decrease in response to PBG; however, the RSNA decrease was still -48 +/- 8%. Single fibers generally responded to PBG by a slight increase in firing rate. A distinct subset of fibers (5 of 25) showed an activity increase of >15 Hz that preceded changes in BP and HR. The decreased RSNA in the absence of cardiac and abdominal vagal afferents and the strong response of 20% of pulmonary single fibers to intravenous PBG suggest that pulmonary fibers play a role in a 5-HT3 serotenergic reflex. Thus pulmonary serotonin could influence the neural control of renal function.

Afferent Pathways↗
PubMed1997

Aberrant renal vascular morphology and renin expression in mutant mice lacking angiotensin-converting enzyme.

To determine whether angiotensin-converting enzyme plays a role in the development and maintenance of normal renal architecture, the renal morphology of 10- to 12-month-old female mice homozygous for a disruption of the converting enzyme gene was compared with that of age-matched wild-type mice. Tubular obstruction, dilatation, and atrophy were present in all kidneys from the homozygous mutant mice but absent in wild types; two kidneys from 4 mutant mice but none from the wild types were hydronephrotic. The entire arterial vascular tree, microdissected from mice with no converting enzyme, was grossly distorted in comparison to the vasculature of wild-type mice; all intrarenal arterial vessels were widened and thickened, including the terminal (afferent) arterioles. In wild-type mice kidneys, renin-positive cells were detected exclusively in a juxtaglomerular localization. In contrast, abnormal distribution of renin immunostaining was observed in mice without converting enzyme; scattered renin-positive cells were seen along the arterial vessels, often in a perivascular localization, and interstitial renin-positive cells surrounded glomeruli. Kidney renin mRNA was increased more than 32-fold in the mutant mice compared with wild types. Northern blot analysis revealed that this increase included the accumulation of large amounts of smaller renin RNA transcripts. In summary, mice lacking the converting enzyme exhibit abnormal renal vessels and tubules. Renin synthesis is increased, accompanied by the presence of small renin mRNA species, and renin is present mainly in interstitial and perivascular cells. We conclude that angiotensin-converting enzyme is necessary to preserve normal kidney architecture and the normal pattern of renin expression.

Animals↗
PubMed1997

Vascular angiotensin-converting enzyme expression regulates local angiotensin II.

We tested the hypothesis that changes in angiotensin-converting enzyme (ACE) gene expression can regulate the rate of local vascular angiotensin II (Ang II) production. We perfused isolated rat hindlimbs with an artificial medium and infused renin and Ang I via the perfusate. Ang I and II were measured by radioimmunoassay. We then increased ACE gene expression and ACE levels in the rat aorta by producing two-kidney, one clip (2K1C) hypertension for 4 weeks. Gene expression was measured by RNAse protection assay, and ACE activity in the vessel wall was measured by the Cushman-Cheung assay. Angiotensin I infusion at 1, 10, 100, and 1000 pmol/mL led to 371 +/- 14 (+/-SEM), 3611 +/- 202, 44,828 +/- 1425, and 431,503 +/- 16,439 fmol/mL Ang II released, respectively, from the hindlimbs (r = .98, P < .001). Thus, the conversion rate did not change across four orders of magnitude, and the system was not saturable under these conditions. In 2K1C hindlimbs, Ang I infusion (0.5 pmol/mL) resulted in increased Ang II generation (157 +/- 16 versus 123 +/- 23 fmol/mL, P = .014 at minute 10) compared with controls. ACE gene expression and ACE activity were increased in 2K1C hindlimbs compared with controls (36 +/- 4 versus 17 +/- 1 mU/mg protein, P < .001). Ang II degradation in the two groups did not differ. To investigate the conversion of locally generated Ang I, we infused porcine renin (0.5 milliunits per mL) into 2K1C and control hindlimbs. Despite markedly higher Ang I release in sham-operated than in 2K1C rats (71 +/- 8 versus 37 +/- 6 pmol/mL, P = .008 at minute 12), Ang II was only moderately increased (36 +/- 3 versus 25 +/- 6 pmol/mL, P = .12 at minute 12). This difference between 2K1C rats and controls reflected a higher rate of conversion in 2K1C rats. Thus, Ang I conversion in the rat hindlimb is linear over a wide range of substrate concentrations and occurs at a fixed relationship. Nevertheless, increased ACE gene expression and ACE activity in the vessel wall lead to an increase in the conversion of Ang I to Ang II. We conclude that local ACE gene expression and ACE activity can influence the local rate of Ang II production.

Angiotensin I↗
PubMed1997

Angiotensin's role in renal development.

All the components of the renin-angiotensin system (RAS) are highly expressed in the developing kidney in a unique spatial and temporal pattern that is associated with nephrogenesis, vascularization, and the proper architectural and functional development of this organ. Pharmacological inhibition of the RAS results in structural and functional developmental abnormalities of the kidneys in several animal species, including humans. Similarly, altered renal morphology and functional abnormalities have been described in mice with targeted inactivation of the angiotensinogen (Agt) and the angiotensin-converting enzyme (ACE) genes. In contrast, inactivation of angiotensin receptors have not resulted in renal morphological abnormalities, suggesting a redundancy at this level of the RAS cascade that prevents the development of renal pathology. More importantly, inactivation of the ACE or Ao genes results in a renal phenotype remarkably similar to that obtained with pharmacological inhibition of the RAS. Taken together, the available information suggests that angiotensin is necessary for normal kidney development and for the maintenance of the functional and structural integrity of the adult kidney.

Adult↗
PubMed1996

Subthreshold stimulation of a serotonin 5-HT3 reflex attenuates cardiovascular reflexes.

Volume-sensitive and chemosensitive cardiopulmonary reflexes modulate volume homeostasis via renal sympathetic nerve activity (RSNA). Blunting of volume-sensitive cardiopulmonary reflexes is associated with volume retention, e.g., in hypertension, whereas the role of chemosensitive cardiopulmonary reflexes is largely unknown. To elucidate the possible role of chemosensitive cardiopulmonary reflexes in control of volume homeostasis, we investigated whether subthreshold stimulation of 5-HT3 receptors modulates the control of RSNA by volume-sensitive cardiopulmonary reflexes or the arterial baroreceptor reflex in rats. Phenyl biguanide (PBG) was infused intravenously to stimulate 5-HT3 receptors. Higher doses of PBG lowered RSNA, but a dose of 6 micrograms/min, given as a background infusion throughout the experiment, did not change arterial pressure, heart rate (HR), or RSNA. Ten minutes after beginning the 6 micrograms/min PBG infusion, a 15-min volume expansion (0.9% saline, 5 or 10% body weight) was started to stimulate volume-sensitive cardiopulmonary reflexes. In separate experiments, 5-min ramp infusions of methoxamine and nitroglycerin to stimulate the arterial baroreceptor reflex (evaluated by a 4-parameter logistic regression) were performed 15 min after beginning the PBG background infusion (6 micrograms/min). During PBG infusion, the RSNA responses to volume expansions were significantly impaired (5% body weight: PBG -6 +/- 6%, n = 7 vs. control -39 +/- 9%, n = 6, P < 0.001; 10% body weight: PBG -33 +/- 6%, n = 8 vs. control -52 +/- 5%, n = 7, P < 0.05). The 5-HT3 receptor antagonist odansetron (GR-38032F) abolished these effects of PBG. The maximum HR gain of the arterial baroreceptor reflex was impaired but the arterial baroreceptor control of RSNA was unaffected by PBG background infusion. We conclude that 5-HT3-serotonergic cardiopulmonary chemoreceptors blunt the RSNA decrease to volume loading. This mechanism may facilitate volume retention when cardiac serotonin is increased.

Animals↗
PubMed1996

Role of angiotensin II in glomerular injury: lessons from experimental and clinical studies.

Angiotensin (Ang) II is generated within the kidney via a complex transcellular pathway. Renin release is not the sole determinant of Ang II levels; the expression of angiotensinogen, Ang-converting enzyme, and angiotensinases may also regulate local Ang II. The Ang II levels in some intrarenal compartments are several orders of magnitude higher than in plasma; plasma measurements may not always predict local Ang II levels. Besides its effects on systemic blood pressure, Ang II modulates glomerular hemodynamics by constricting preferentially the efferent arteriole. The evidence available indicates that both the hemodynamic and nonhemodynamic effects of Ang II are mediated by the type 1 Ang II receptor. Nonhemodynamic effects of Ang II include stimulation of the growth of renal vascular and glomerular cells, increased synthesis of matrix molecules, and possibly a stimulation of monocyte/macrophage infiltration. These effects of the octapeptide may contribute to glomerular sclerosis and interstitial fibrosis. Intervention studies have shown that blockade of Ang II formation by Ang-converting enzyme inhibition reduces proteinuria and delays the progression of renal insufficiency in patients with diabetic and nondiabetic glomerular diseases.

Angiotensin II↗
PubMed1996

Epicardial bradykinin B2 receptors elicit a sympathoexcitatory reflex in rats.

Bradykinin may be generated in the heart during ischemia and is involved in nociception. We tested the hypothesis that bradykinin elicits a sympathoexcitatory reflex in rats by stimulating cardiac afferent nerve fibers. Rats were implanted with femoral catheters for measurement of blood pressure and heart rate, a bipolar electrode for measurement of renal sympathetic nerve activity, and a pericardial catheter for intrapericardial injection of substances. Rats were slightly anesthetized with hexobarbital so pain reactions were prevented. Graded doses of bradykinin (2.5, 12, 25 micrograms) were injected intravenously or intrapericardially into control rats, intrapericardially after vagotomy, intrapericardially after intrapericardial pretreatment with the bradykinin B2 receptor antagonist Hoe 140, and intrapericardially after cardiac autonomic blockade (intrapericardial pretreatment with 10% procaine). For comparison, the serotonin 5-HT3 agonist phenylbiguanide, a substance known to elicit sympathoinhibitory reflexes by cardiac vagal afferents, and adenosine, putatively inducing sympathoexcitatory responses via the heart, were applied intrapericardially. Bradykinin increased blood pressure when administered intrapericardially but decreased blood pressure when injected intravenously; both intrapericardial and intravenous bradykinin increased renal sympathetic nerve activity. Intrapericardial adenosine had no effect on circulatory control. Intrapericardial pretreatment with the B2 receptor antagonist Hoe 140 completely inhibited the increases of blood pressure and renal sympathetic nerve activity in response to intrapericardial bradykinin but did not affect the responses to intrapericardial phenylbiguanide. Bilateral cervical vagotomy abolished the decreases of blood pressure, heart rate, and renal sympathetic nerve activity after intrapericardial phenylbiguanide but did not influence the responses to intrapericardial bradykinin. Cardiac autonomic blockade with intrapericardial procaine abolished all responses to bradykinin and phenylbiguanide. We conclude that cardiac bradykinin elicits a sympathoexcitatory reflex by epicardial B2 receptors in rats. The afferent portion of the reflex is most likely contained within sympathetic cardiac afferent fibers. Bradykinin may contribute to increased sympathetic nerve activity in pathophysiological situations of coronary artery disease and cardiac ischemia.

Adenosine↗