Renal Hemodynamic Function Research Articles

Endothelial Nitric Oxide Synthase Gene/Gender Interactions and the Renal Hemodynamic Response to Angiotensin II

Endothelial function is dependent on the generation of nitric oxide (NO) by the enzyme endothelial NO synthase (eNOS). One functional coding polymorphism of the eNOS gene (G894-->T) is associated with reduced enzyme activity, increased coronary heart disease, and the development of end-stage renal failure. Because gender and renin-angiotensin system activation also play key roles in the development of renal and cardiovascular disease and because NO plays a role in the response to angiotensin II (AngII), it was hypothesized that the eNOS gene G894-->T polymorphism would be a determinant of the systemic and renal vascular response to AngII. Fifty young, healthy, normotensive individuals who were on a controlled sodium and protein diet for 1 wk underwent assessment of BP and renal hemodynamic function at baseline and during AngII infusion (4 ng/kg per min for 45 min). Participants were genotyped for the eNOS gene G894-->T polymorphism and then segregated into groups on the basis of gender and genotype (GG versus GT/TT). Baseline values for renal blood flow, effective renal plasma flow, and GFR were lower in men with the T allele compared with men who were homozygous for the G allele (P = 0.03), but the polymorphism was not associated with renal hemodynamic function in women. The BP responses to AngII were similar in men and women regardless of genotype. Both multivariate linear regression and analysis of covariance (ANCOVA) revealed a relationship between gender and genotype. Men with the GT/TT genotype exhibited a significantly greater decrease in GFR (P = 0.04) in response to AngII than did those with the GG genotype. This association was not observed in women. The eNOS gene G894-->T polymorphism is a determinant of both baseline renal hemodynamic function and the hemodynamic response to AngII in men but not in women.

Increased Renal Tubular Reabsorption of Calcium and Magnesium by the Offspring of Diabetic Rat Pregnancy

Diabetic pregnancy has a marked influence on offspring calcium and magnesium homeostasis. Urinary excretion of calcium and magnesium is reduced, yet offspring of diabetic pregnancy exhibit hypomagnesemia and hypocalcemia. The aim of this study was to measure renal hemodynamic and tubular function in the offspring of diabetic (OD) and control, nondiabetic (OC) rats at 4 and 8 wk of age to determine the glomerular and tubular mechanisms through which renal calcium and magnesium handling are programmed in utero. The fraction of filtered calcium that was excreted was significantly lower in OD at both 4 and 8 wk of age [8 wk: OC (n = 6), 11.8 +/- 2.9 versus OD (n = 5), 4.3 +/- 0.6%; p < 0.05] and that of magnesium was lower at 8 wk of age [OC (n = 6), 42.4 +/- 7.5 versus OD (n = 5), 13.0 +/- 1.7%; p < 0.01]. This increased reabsorption occurred despite an elevated GFR in OD. These findings clearly indicate that tubular reabsorptive mechanisms for calcium and magnesium are increased markedly in OD. Serum PTH concentration was reduced in 8-wk-old OD [OC (n = 7), 539.4 +/- 142.1 versus OD (n = 9), 174.3 +/- 69.4 pg/ml; p < 0.05], consistent with previous reports in human infants. Taken together, these observations suggest that the basis for the altered renal magnesium and calcium handling in OD involves increased tubular transport activity and possibly increased sensitivity of these mechanisms to PTH.

Endothelin, Angiotensin, and Oxidative Stress in Hypertension

Endothelin (ET)-1 is a potent vasoconstrictor and mitogen, and because of these properties, it is thought to play a role in the development of hypertension.1,2 The vascular endothelium is a major source of ET-1 production, although a variety of other cell types also have been shown to synthesize and release ET-1. ET-1 is believed to act in a paracrine manner on ETA and ETB receptors on smooth muscle, which mediate contraction, cell proliferation, and hypertrophy. Activation of ETB receptors on endothelial cells stimulates the production of prostacyclin and nitric oxide to induce vasorelaxation and inhibition of sodium transport in renal tubules. Given these properties, considerable attention has been paid to the mechanisms of ET-1 action as it relates to the renal control of blood pressure and the pathogenesis of salt-dependent hypertension. Renal ET synthesis is increased in experimental animals maintained on a high-salt diet and ETA receptor antagonists lower arterial pressure primarily in salt-dependent models of hypertension.1,2 For the past 30 to 40 years, the actions of angiotensin (Ang) II has been arguably the most widely investigated factor in hypertension research. Although physiology textbooks agree on the major actions of Ang II, eg, vasoconstriction and release of aldosterone, recent attention has focused on its ability to stimulate the synthesis of ET-1,3–5 as well as reactive oxygen species.6 There are many reactive oxygen species such as superoxide, hydroxyl radical, and hydrogen peroxide that are produced by all cell types and can have profound effects on the vascular system to impact blood pressure regulation. Most recent attention has been paid to the role of superoxide. There are many enzymatic sources of superoxide including NADPH oxidase, xanthine oxidase, nitric oxide synthase, and cytochrome P450. The focus of the current review, however, is be on the …

Gender difference in response to thromboxane A2/prostaglandin H2 receptor antagonism in spontaneously hypertensive rats

Blood pressure (BP) is typically higher in men than in women. As in humans, BP is higher in male spontaneously hypertensive rats (SHRs) than in female SHRs. The mechanism(s) responsible for the higher BP in men and male rats has not been elucidated. The present study tested the hypothesis that thromboxane and/or the thromboxane A(2)/prostaglandin H(2) receptor (TxR) plays a role in the gender difference in BP in SHRs. Male and female SHRs were treated with the TxR antagonist SQ29548 (2 microg/kg/min into the jugular vein) via minipump for 2 weeks; mean arterial pressure (MAP) and renal hemodynamic function were measured. To determine whether thromboxane played a role in the higher MAP in SHRs, male and female rats were treated with the thromboxane synthase inhibitor (TxI) furegrelate, 30 mug/kg/min, via minipump, for 2 weeks. MAP was reduced with TxR antagonism in male but not in female SHRs. In addition, TxR antagonism in males caused renal vasodilation with increases in glomerular filtration rate and renal plasma flow, and reductions in renal vascular resistance. In contrast, MAP was not affected by the TxI in either males or females. These data support a role for TxR, but not thromboxane, in mediating the gender difference in BP in SHRs.

Renal and Systemic Effects of Chronic Blockade of ETA or ETB Receptors in Normal Rats and Animals with Experimental Heart Failure

Endothelin-1 (ET-1) is involved in the pathogenesis of cardiac and renal hemodynamic changes and impaired excretory function in congestive heart failure. It has previously been demonstrated that acute administration of ABT-627 (endothelin-A blocker) abolished systemic and renal vasoconstriction in controls and rats with congestive heart failure induced by a surgically created aortocaval fistula (Abassi et al. Clin Sci (Lond) 2002;103:S245-S248). In contrast, acute endothelin-B blockade by A-192621 exaggerated the ET-1 induced systemic and renal vasoconstriction. The present study examined the renal and systemic effects of chronically administered ABT-627 (24 mg/kg per day) or A-192621 (72 mg/kg per day) for 7 days via osmotic minipumps inserted intraperitoneally on the day of operation of sham controls and rats with congestive heart failure. Tailcuff measurements revealed that ABT- 627 significantly decreased mean arterial pressure from 108 +/- 2 mmHg to 87 +/- 2 mmHg (P < 0.05), whereas A-192621 significantly increased mean arterial pressure from 110 +/- 3 mmHg to 122 +/- 3 mmHg (P < 0.05) in controls. Despite the hypotensive effect of ABT-627, daily sodium excretion dramatically increased, but to a lesser extent in A-192621-treated controls. Furthermore, chronic administration of ABT-627 to controls attenuated the systemic and renal vasoconstriction induced by ET-1 (1 nmol/kg intravenous), whereas A-192621 augmented these effects. Similarly, chronic treatment with ABT-627 totally abolished the systemic and renal vasoconstriction caused by injected ET-1 in rats with congestive heart failure, whereas A192621 potentiated these effects. Chronic treatment of animals with congestive heart failure with ABT-627 did not influence daily sodium excretion, whereas treatment with A192621 significantly improved daily sodium excretion. Interestingly, treatment with either ABT-627 or A192621 significantly decreased cardiac hypertrophy in rats with congestive heart failure. In conclusion, in sham controls endothelin-B receptor mediated vasodilation and natriuresis, probably as a result of tubular action, whereas in congestive heart failure the excretory contribution of endothelin-B receptor was attenuated, resulting in Na+ retention.

Differential Regulation of ETA and ETB in the Renal Tissue of Rats with Compensated and Decompensated Heart Failure

Endothelin-1 (ET-1) exerts its biological actions through two receptor subtypes: endothelin-A (ETA) receptor and endothelin-B (ETB) receptor. We demonstrated previously that ET-1 induces systemic and renal cortical vasoconstriction via ETA whereas ETB mediates medullary vasodilation. Congestive heart failure (CHF) is characterized by increased vascular resistance and impaired renal hemodynamic and excretory function. While the pathophysiological effects of ET-1 in CHF are well established, the status of ETA and ETB in the kidney is poorly characterized. The present study examined the immunostaining and localization of ETA and ETB in the renal cortex and medulla of rats with experimental CHF induced by aorto-caval fistula. Rats with CHF were further subdivided, based on their daily urinary sodium excretion, into rats with compensated (urinary sodium excretion > 1200 microEq/day) and decompensated CHF (urinary sodium excretion < 200 microEq/day). ETA is predominantly localized to the cortex mainly in the peritubular capillaries, and is upregulated in rats with compensated and decompensated CHF compared with sham controls. In contrast, ETB is preferentially expressed in the outer and inner medulla, mainly in the vasa recta, the thick ascending limb of Henle's loop and the collecting duct. While compensated CHF is associated with upregulation of ETB in the collecting duct and vasa recta, decompensated CHF is accompanied with enhanced ETB abundance in the vasa recta and remarkable downregulation of this receptor subtype in the collecting duct. The findings suggest that upregulation of ETA may lead to a decrease in cortical blood flow while upregulation of ETB in the vasa recta probably contributes to the preservation of medullary blood flow. Furthermore, downregulation of ETB in the collecting duct, only in rats with decompensated CHF, could contribute to sodium retention in that subgroup.

Renal actions of the cancion® Cardiac Recovery System in severe experimental heart failure

Background: Congestive heart failure (CHF) is a complex disease in which cardiorenal dysfunction reflects clinical status and prognosis. Evidence suggests mechanical unloading of the heart leads to molecular and functional myocardial recovery. The Cancion® Cardiac Recovery System (CRS), a novel percutaneously inserted extracorporeal mechanical device, superimposes continuous aortic flow on existing pulsatile flow. Previous studies in experimental CHF report decreased left ventricular filling pressures with CRS. Early studies in human CHF report decreased pulmonary capillary wedge pressure (PCWP) and plasma creatinine after employment of the CRS. The mechanisms for cardiorenal improvement remain unclear. To further characterize renal resonses to CRS we evaluated renal excretory and hemodynamic function before and after 4 hrs. of CRS therapy in an established model of severe CHF. Methods: Adult male dogs (n = 4) were paced at 240 bpm for 10 days consistent with an established model of CHF characterized by neurohumoral activation, systemic vasoconstriction, impaired cardiac pump function, increased filling pressures, sodium retention and impaired glomerular filtration rate (GFR) and renal blood flow (RBF). Dogs were then anaesthetized and the CRS device inserted percutaneously via the femoral artery into the descending aorta. A baseline clearance for urinary sodium excretion (UNaV) and inulin clearance to measure GFR was obtained. Cardiac filling pressures were measured via a Swan-Ganz catheter, mean arterial pressure (MAP) monitored, and RBF measured with a flow probe. The CRS was activated for 4 hrs., then deactivated and another clearance obtained. Resuts: UNaV (μEq/min) increased (440%±134%, p<0.05 vs baseline) after 4 hours of CRS therapy. GFR (15±5 vs 24±6mL/mim, NS) and RBF (130±12 vs 145±34 mL/min, NS) were maintained and tended to increase despite decreases in MAP (114±10 vs 83±6 mmHg, p<0.05). Consistent with previous studies PCWP decreased (23±2 vs 15±1 mmHg, p<0.05). Conclusion: We report that CRS device activation promotes natriuresis in severe experimental CHF despite decreased MAP. GFR, an important prognostic predictor in CHF is maintained. Consistent with previous studies employment of the CRS results in decreased PCWP in experimental CHF. The time course of these cardiorenal findings suggests neurohumorally mediated mechanisms. Further studies are warranted to elucidate these mechanisms.

Differential regulation of renal endothelin eta and etb receptors in rats withexperimental heart failure

P-94 Key Words: Endothelin Receptors, Kidney, Heart Failure

Effects of oral contraceptive use on the renal and systemic vascular response to angiotensin II infusion.

We have previously shown that users of oral contraceptive (OC) medications exhibit increased plasma levels of angiotensin II (Ang II) with only modest hemodynamic consequences, suggesting estrogen-mediated Ang II type 1 (AT(1)) receptor downregulation. Accordingly, in 10 women who were OC users and 10 women who, as OC nonusers, served as controls, all mean age 26 +/- 1 yr, we examined the renal and peripheral hemodynamic response to graded Ang II infusion, plasma and urine cyclic guanosine monophosphate (cGMP) levels as a surrogate marker for AT(1) and/or AT(2) receptor-mediated activation of the nitric oxide pathway, and AT(1) receptor expression in skin biopsies. The OC nonusers were studied during the follicular and luteal phases of the menstrual cycle, whereas OC users were studied once during the 21-d medication phase. Subjects ingested a controlled sodium diet for 7 d before each study. Renal hemodynamic function was assessed using standard inulin and p-aminohippurate clearance techniques. AT(1) receptor mRNA levels in skin biopsy samples were assessed using a real-time PCR protocol. In response to graded Ang II infusion, OC users exhibited renal and peripheral hemodynamic responses that were augmented compared with those of OC nonusers, in conjunction with evidence of increased tissue AT(1) receptor expression. Plasma cGMP levels and 24-h urinary cGMP excretion did not differ. These data suggest that, contrary to our original hypothesis, OC use does not appear to be associated with AT(1) receptor downregulation. The factor protecting OC users from the hemodynamic impact of increased Ang II levels remains elusive.

AT 1 and AT 2 receptor in the kidney: role in health and disease

The renin angiotensin system plays an important role in the control of body fluid and electrolyte homeostasis and blood pressure regulation. Angiotensin II is the most effector hormone of this system and functions mainly through stimulation of its subtype receptors, namely, the AT 1 and AT 2 receptors. Most of the known physiological and pathologic effects of angiotensin II are mediated through stimulation of the AT 1 receptor. The knowledge about the involvement of the AT 2 receptor in physiological and pathologic processes is still evolving. In the kidney, both the AT 1 and AT 2 receptors contribute to the regulation of renal hemodynamic and tubular functions. Also, these receptors regulate renal cellular growth and matrix formation. However, AT 2 receptor possesses functions that counteract the effects of the AT 1 receptor. The balance between the AT 1 and AT 2 receptors can determine the renal status in health and disease.

Effect of endothelin antagonists on the renal haemodynamic and tubular responses to ischaemia-reperfusion injury in anaesthetised rats.

In this investigation we have evaluated whether blockade of endothelin receptors influenced the renal haemodynamic and excretory responses to a period of ischaemia and reperfusion in the anaesthetised rat. The renal artery was occluded for 30 min and renal haemodynamic and excretory function followed for 90 min of reperfusion while either saline, the non-selective endothelin 1 receptor (ET(A)/ET(B)) antagonist SB209670 or the selective ET(A) receptor antagonist UK-350,926 was infused. In the post-ischaemic period, renal cortical and medullary perfusions were reduced by 40-50 %. When SB209670 was administered (30 micro g kg(-1) min(-1) I.V.) for 30 min before, during and for 90 min after renal artery occlusion, cortical and medullary perfusions returned to baseline levels, responses different from those obtained during saline infusion (both P < 0.05). In the presence of UK-350,926 (30 micro g kg(-1) min(-1) I.V.), perfusion in the medulla returned to baseline on clamp removal whereas that in the cortex remained depressed (P < 0.05). Renal ischaemia for 30 min decreased glomerular filtration rate during reperfusion and increased urine flow and sodium excretion 5- to 15-fold. UK-350,926 (30 micro g kg(-1) min(-1) I.V.) reduced (P < 0.05) fluid excretion prior to ischaemia but during reperfusion, glomerular filtration rate returned to basal levels and there were progressive increases in fluid excretion which were smaller compared to the saline-treated group (all P < 0.05). The ischaemic challenge may cause release of endothelin, which acts on ET(B) receptors in the cortex and ET(A) receptors in the medulla to decrease perfusion. The blunted natriuresis and diuresis during blockade of ET(A) receptors may result from either a vascular or tubular action of endothelin.

Renal function and angiotensin AT1 receptor expression in young rats following intrauterine exposure to a maternal low-protein diet.

Recent studies have proposed a link between impaired nephrogenesis, decreased activity of the renin-angiotensin system and the onset of hypertension in rats exposed in the uterus to a maternal low-protein diet. However, there is no detailed information about renal function in this model; hence the aim of the present study was to assess renal function in young (4-week-old) rats exposed in the uterus to a maternal low-protein diet. Pregnant Wistar rats were fed isocalorific diets containing either 18% (normal protein; offspring denoted NP rats) or 9% (low protein; offspring denoted LP rats) (w/w) protein from conception until birth. At 4 weeks of age, male offspring were anaesthetized and prepared for the study of renal function, during which animals received saline alone, a bolus of enalapril (5 mg.kg(-1)) or a bolus of enalapril followed by an infusion of angiotensin II (30 ng.min(-1).kg(-1)). Under control conditions, renal haemodynamic and tubular function did not differ. However, when challenged with angiotensin II, LP rats responded with a greater decrease in glomerular filtration rate than did NP rats [NP, 2.0+/-0.2 ml.min(-1).g(-1) kidney weight ( n =9); LP, 1.0+/-0.2 ml.min(-1).g(-1) kidney weight ( n =5); P <0.05]. Renal electrolyte excretion did not differ. LP rats had significantly fewer glomeruli than NP rats ( P <0.01). Renal angiotensin II AT(1) receptor expression was increased ( P <0.01) by 24% in LP rats. It is concluded that blood pressure may be elevated in LP rats in order to maintain glomerular filtration rate against a background of fewer nephrons. Increased AT(1) receptor expression, which may arise as a result of the direct effect of protein restriction or in response to the reported decrease in renal tissue angiotensin II concentration, could also contribute to the elevated blood pressure of this model.

Interactions between gender and the angiotensin type 1 receptor gene polymorphism

The cardiovascular effects of angiotensin II are mediated by the angiotensin II type 1 receptor (AGT1R); one polymorphism of the AGT1R gene, A1166-->C, has been associated with hypertension. The hemodynamic response to angiotensin II is blunted in women compared to men, but interactions between gender, blood pressure, and AGT1R gene polymorphisms are unclear. A total of 81 young healthy normotensive individuals maintained regulated sodium and protein intake prior to study. They were divided into four groups based on gender and A1166-->C genotype (AA versus AC/CC); serial supine blood pressures were obtained. A subset of 52 individuals received graded infusions of angiotensin II. Inulin and paraaminohippurate clearance techniques were used to measure renal hemodynamic function at baseline and in response to the infusions. Men with the AC/CC genotype exhibited higher blood pressures than men with the AA genotype; however, this relationship was not found among women. Analysis of covariance revealed a significant interaction between gender and AGT1R genotype in the determination of blood pressure. Glomerular filtration rate (GFR) declined variably in the study subjects following infusion of angiotensin II, and a statistical model incorporating gender and genotype best predicted the fall in GFR. There was a trend for females of the AA genotype to have a greater fall in GFR in response to angiotensin II infusion, than any of the other groups. In young healthy subjects, there is an important interaction between gender, the AGT1R A1166-->C gene polymorphism, and blood pressure. In addition, the renal hemodynamic response to angiotensin II infusion is a function of both gender and the AGT1R genotype.

Platelet-activating factor and solute transport processes in the kidney.

We examined the hemodynamic and tubular transport mechanisms by which platelet-activating factor (PAF) regulates salt and water excretion. In anesthetized, renally denervated male Wistar rats, with raised systemic blood pressure and renal arterial blood pressure maintained at normal levels, intrarenal PAF infusion at 2.5 ng. min(-1) x kg(-1) resulted in a small fall in systemic blood pressure (no change in renal arterial blood pressure) and an increase in renal blood flow and urinary water, sodium, and potassium excretion rates. The PAF-induced changes in cardiovascular and renal hemodynamic function were abolished and renal excretory function greatly attenuated by treating rats with a nitric oxide synthase inhibitor. To determine whether a tubular site of action was involved in the natriuretic effect of PAF, cortical proximal tubules were enzymatically dissociated from male Wistar rat kidneys, and oxygen consumption rates (Qo(2)) were used as an integrated index of transcellular sodium transport. PAF at 1 nM maximally inhibited Qo(2) in both untreated and nystatin-stimulated (sodium entry into renal cell is not rate limiting) proximal tubules by approximately 20%. Blockade of PAF receptors or Na(+)-K(+)-ATPase pump activity with BN-52021 or ouabain, respectively, abolished the effect of PAF on nystatin-stimulated proximal tubule Qo(2). Inhibition of nitric oxide synthase or guanylate cyclase systems did not alter PAF-mediated inhibition of nystatin-stimulated proximal tubule Qo(2), whereas phospholipase A(2) or cytochrome-P-450 monooxygenase inhibition resulted in a 40-60% reduction. These findings suggest that stimulation of PAF receptors on the proximal tubule decreases transcellular sodium transport by activating phospholipase A(2) and the cytochrome-P-450 monooxygenase pathways that lead to the inhibition of an ouabain-sensitive component of the basolateral Na(+)-K(+)-ATPase pump. Thus PAF can activate both an arachidonate pathway-mediated suppression of proximal tubule sodium transport and a nitric oxide pathway-mediated dilatory action on renal hemodynamics that likely contributes to the natriuresis and diuresis observed in vivo.

Dopamine D4 receptor expression in rat kidney: evidence for pre- and postjunctional localization.

Dopamine D4 receptors mediate inhibition of vasopressin-dependent sodium reabsorption by dopamine in collecting tubules. At present, the distribution of D4 receptors in other renal districts remains an open issue. The renal distribution of D4 receptor was assessed in normally innervated and denervated male Sprague-Dawley rats by quantitative immunohistochemistry using an anti-dopamine D4 receptor rabbit polyclonal antibody. D4 receptor protein immunoreactivity was observed perivascularly in the adventitia and the adventitia-media border. The density of perivascular dopamine D4 receptor was higher in afferent and efferent arterioles than in other segments of the renal vascular tree. Renal denervation abolished perivascular dopamine D4 receptor protein immunoreactivity. In renal tubules, the epithelium of collecting tubules showed the highest dopamine D4 receptor protein immunoreactivity, followed by the epithelium of proximal and distal tubules. No dopamine D4 receptor protein immunoreactivity was observed in the epithelium of the loop of Henle. Denervation did not change dopamine D4 receptor protein immunoreactivity in renal tubules. These results indicate that rat kidney expresses dopamine D4 receptors located both prejunctionally and nonprejunctionally in collecting, proximal, and distal tubules. This suggests that the dopamine D4 receptor may be involved in the control of neurotransmitter release and in renal hemodynamic and tubule function.

Transfer of the Rf-1 region from FHH onto the ACI background increases susceptibility to renal impairment.

The genetically hypertensive fawn-hooded (FHH/Eur) rat is characterized by the early presence of systolic and glomerular hypertension, progressive proteinuria (UPV), and albuminuria (UAV), and focal glomerulosclerosis, resulting in premature death from renal failure. Previous studies showed that at least five genetic loci (Rf-1 to Rf-5) were linked to the development of renal impairment. Of these five, Rf-1 appears to play a major role. To study the impact of Rf-1 in the absence of the other loci, we transferred the Rf-1 region of chromosome 1, between the markers D1Mit34 and D1Rat156, Rf-1B for short, onto the genomic background of the normotensive August x Copenhagen Irish (ACI) rat. In this congenic strain, named ACI.FHH-D1Mit34/Rat156 or ACI.FHH-Rf1B, we challenged the renal hemodynamic function of these animals by studying the effects of unilateral nephrectomy (UNX) alone, or combined with N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Following UNX, the congenic strain developed significantly more UPV and UAV than the ACI progenitor. The differences were even more pronounced when UNX was combined with an L-NAME-induced rise in systolic blood pressure to about 150 mmHg, i.e., the level of hypertension present in the parental FHH strain. These findings indicate that the Rf-1B region of the FHH rat contains at least one gene affecting the susceptibility to progressive renal failure, especially in the presence of an increase in blood pressure.

Variation in the renin angiotensin system throughout the normal menstrual cycle.

It has been demonstrated elsewhere that circulating renin angiotensin system (RAS) components peak when plasma estrogen levels are highest, during the luteal phase of the normal menstrual cycle. This phenomenon has been attributed to "activation" of the RAS. The end-organ vasoconstrictive response to this phenomenon has not been well established. In two related experiments, the RAS was studied in healthy, premenopausal women during predefined phases of the normal menstrual cycle. In the first experiment, the circulating components of the RAS and the systemic hemodynamic response to incremental lower body negative pressure (LBNP) during the follicular and luteal phases of the menstrual cycle were examined. Response variables included mean arterial pressure (MAP), renin, plasma renin activity (PRA), angiotensin II (AngII), and aldosterone. Baseline levels of renin, PRA, and aldosterone were significantly higher in the luteal phase. In response to LBNP, there were significant increases in all variables in both phases; however, the humoral response to this stimulus was significantly augmented in the luteal phase compared with the follicular phase. Despite these elevations in circulating components of the RAS during the luteal phase, subjects were unable to maintain MAP in response to LBNP, exhibiting a dramatic depressor response that did not occur during the follicular phase. In the second experiment, renal and peripheral hemodynamic function at baseline, and in response to AngII blockade with losartan, were examined in women during these high and low estrogen phases of the menstrual cycle. The renal and peripheral hemodynamic responses were similar in the luteal phase and the follicular phase. These results demonstrate that, despite an increase in circulating RAS components during the luteal phase of the menstrual cycle, the system is blunted rather than "activated," at least at a tissue level. Further studies are needed to clarify this mechanism.

Pathophysiology of hypertension during preeclampsia linking placental ischemia with endothelial dysfunction.

Studies over the past decade have provided a better understanding of the potential mechanisms responsible for the pathogenesis of preeclampsia. The initiating event in preeclampsia has been postulated to be reduced uteroplacental perfusion as a result of abnormal cytotrophoblast invasion of spiral arterioles. Placental ischemia is thought to lead to widespread activation/dysfunction of the maternal vascular endothelium that results in enhanced formation of endothelin and thromboxane, increased vascular sensitivity to angiotensin II, and decreased formation of vasodilators such as NO and prostacyclin. These endothelial abnormalities, in turn, cause hypertension by impairing renal-pressure natriuresis and increasing total peripheral resistance. The quantitative importance of the various endothelial and humoral factors in mediating the reduction in renal hemodynamic and excretory function and elevation in arterial pressure during preeclampsia are still unclear. Results from ongoing basic and clinical studies, however, should provide new and important information regarding the physiological mechanisms responsible for the elevation in arterial pressure in women with preeclampsia.

Role of neuropeptide Y in renal sympathetic vasoconstriction: Studies in normal and congestive heart failure rats

Sympathetic nerve activity, including that in the kidney, is increased in heart failure with increased plasma concentrations of norepinephrine and the vasoconstrictor cotransmitter neuropeptide Y (NPY). We examined the contribution of NPY to sympathetically mediated alterations in kidney function in normal and heart failure rats. Heart failure rats were created by left coronary ligation and myocardial infarction. In anesthetized normal rats, the NPY Y1 receptor antagonist, H 409/22, at two doses, had no effect on heart rate, arterial pressure, or renal hemodynamic and excretory function. In conscious severe heart failure rats, high-dose H 409/22 decreased mean arterial pressure by 8 ± 2 mm Hg but had no effect in normal and mild heart failure rats. During graded frequency renal sympathetic nerve stimulation (0 to 10 Hz), high-dose H 409/22 attenuated the decreases in renal blood flow only at 10 Hz (–36% ± 5%, P < .05) in normal rats but did so at both 4 (–29% ± 4%, P < .05) and 10 Hz (–33% ± 5%, P < .05) in heart failure rats. The glomerular filtration rate, urinary flow rate, and sodium excretion responses to renal sympathetic nerve stimulation were not affected by high-dose H 409/22 in either normal or heart failure rats. NPY does not participate in the regulation of kidney function and arterial pressure in normal conscious or anesthetized rats. When sympathetic nervous system activity is increased, as in heart failure and intense renal sympathetic nerve stimulation, respectively, a small contribution of NPY to maintenance of arterial pressure and to sympathetic renal vasoconstrictor responses may be identified. (J Lab Clin Med 2001;138:119-29)

Pathophysiology of pregnancy-induced hypertension

Pregnancy-induced hypertension (PIH) is estimated to affect 7% to 10% of all pregnancies in the United States. Despite being the leading cause of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of PIH have not yet been fully elucidated. Studies during the past decade, however, have provided a better understanding of the potential mechanisms responsible for the pathogenesis of PIH. The initiating event in PIH appears to be reduced uteroplacental perfusion as a result of abnormal cytotrophoblast invasion of spiral arterioles. Placental ischemia is thought to lead to widespread activation/dysfunction of the maternal vascular endothelium that results in enhanced formation of endothelin and thromboxane, increased vascular sensitivity to angiotensin II, and decreased formation of vasodilators such as nitric oxide and prostacyclin. The quantitative importance of the various endothelial and humoral factors in mediating the reduction in renal hemodynamic and excretory function and elevation in arterial pressure during PIH is still unclear. Investigators are also attempting to elucidate the placental factors that are responsible for mediating activation/dysfunction of the maternal vascular endothelium. Microarray analysis of genes within the ischemic placenta should provide new insights into the link between placental ischemia and hypertension. More effective strategies for the prevention of preeclampsia should be forthcoming once the underlying pathophysiologic mechanisms that are involved in PIH are completely understood.