Effects of Erythropoietin Administration on Blood Pressure and Urinary Albumin Excretion in Rats

The effects of recombinant human erythropoietin (rHuEPO) administration on blood pressure and urinary albumin excretion were studied in normotensive Wistar-Kyoto rats (WKY), in spontaneously hypertensive rats (SHR), and in SHR rats treated with an angiotensin converting enzyme inhibitor (SHR-ACEi). Rats were housed in metabolic cages and treated with rHuEPO (150 U/kg body weight [bw] three times a week) for 6 weeks. Control animals received the vehicle only (0.25 mL of physiological saline). An angiotensin converting enzyme inhibitor was administered in the drinking water for 6 weeks (spirapril 5 mg/kg bw). Systolic blood pressure (SBP), and 24 h urinary albumin excretion (UAE) were measured once a week. No significant differences in SBP were observed between rHuEPO and vehicle-treated normotensive animals at the end of the treatment (171.9 ± 4.9 v 172.1 ± 5.6 mm Hg, respectively). After 6 weeks, SBP was significantly higher in SHR and SHR-ACEi groups treated with rHuEPO than in control groups (239.8 ± 7.3 and 243.0 ± 7.3 mm Hg v 218.1 ± 6.0 and 187.9 ± 4.6 mm Hg, respectively); UAE was significantly higher in groups treated with rHuEPO than in control groups (WKY: 265.9 ± 19.5 v 127.0 ± 12.3 μg/100 g bw, SHR: 1668.4 ± 564.6 v 234.8 ± 22.9 μg/100 g bw, and SHR-ACEi: 1522.7 ± 448.3 v 143.0 ± 18.9 μg/100 g bw, respectively). We concluded that erythropoietin treatment causes an increase in arterial pressure in SHR only, and an increase in UAE in both normotensive and hypertensive rats. The albuminuric effect was not entirely dependent on increased blood pressure. The treatment with an angiotensin converting enzyme inhibitor did not modify either the proteinuric or the pressor effects.     

Lovastatin reduces renal vascular reactivity in spontaneously hypertensive rats

We have reported that lovastatin attenuates the development of hypertension in spontaneously hypertensive rats (SHR). The fall in arterial pressure is associated with an elevation in renal medullary blood flow, normalization of the pressure-natriuresis relationship, and diminished hypertrophy of renal arterioles. However, the mechanism by which lovastatin alters renal vascular tone is unknown. The present study examined the effects of lovastatin on renal vascular tone and the expression of G proteins. Four-week–old SHR were chronically treated with lovastatin (20 mg/kg/day) or vehicle by gavage for 4 weeks. At the end of the study, mean arterial pressure averaged 131 ± 4 (n = 5) and 160 ± 4 mm Hg (n = 6) in lovastatin- and vehicle-treated SHR, respectively. Renal arterioles isolated from lovastatin-treated SHR were significantly less responsive to norepinephrine and vasopressin than those obtained from vehicle-treated rats (ED₅₀: 5.0 v 1.8 × 10⁻⁷ mol/L for norepinephrine, and 8.0 v 5.2 × 10⁻¹⁰ mol/L for vasopressin). The fall in renal vascular reactivity in lovastatin-treated SHR was associated with reduced levels of ras and rho proteins in renal arterioles, whereas the expressions of heterotrimeric G proteins (G_s, G_q, G_i) were similar in renal arterioles from vehicle- and lovastatin-treated SHR. Overnight culture of renal arterioles with media containing lovastatin also diminished the expression of ras and rho proteins and the response to vasoconstrictors. These findings indicate that lovastatin diminishes the response to vasoconstrictors and the expression of small G proteins in the renal vasculature of SHR and suggest that a fall in the levels of ras and rho proteins in these vessels may contribute to the antihypertensive effects of lovastatin.     

Is Insulin Resistance in the Spontaneously Hypertensive Rat Related to Changes in Protein Kinase C in Skeletal Muscle?

The mechanism of insulin resistance in the spontaneously hypertensive rat (SHR) has not been clearly identified, but protein kinase C (PKC) has been implicated as a mechanism of insulin resistance in obesity and diabetes mellitus and in a diet-induced (fructose-fed) model of insulin resistance and hypertension. This study compared PKC enzyme activity (cytosol and particulate fractions) and expression of the muscle-specific isoform, PKC-θ (Western blotting), in red (soleus) and white (tensor fascia latae) hindlimb muscles from SHR (n = 12) and WKY (n = 12) rats. SHRs were hypertensive and insulin resistant, as shown by higher insulin (188 ± 34 v 169 ± 22 pmol/L), triglycerides (1.65 ± 0.07 v 1.38 ± 0.06 mmol/L), and nonesterified fatty acids (0.99 ± 0.05 v 0.78 ± 0.04 mmol/L) concentrations. PKC activity was significantly greater in the membrane fraction, compared with the cytosol, but there were no significant differences either in PKC activity or subcellular distribution, or expression of PKC-θ, between the two strains. Thus, insulin resistance in the SHR (in contrast to the fructose-fed dietary model of insulin resistance and hypertension) is not related to changes in PKC signaling or expression of PKC-θ in skeletal muscle.     

Quinapril Inhibits c-Myc Expression and Normalizes Smooth Muscle Cell Proliferation in Spontaneously Hypertensive Rats

A number of data suggest that angiotensin II-dependent activation of the protooncogene c-myc participates in the proliferative response of smooth muscle cells (SMC) of rats with spontaneous hypertension (SHR). We therefore investigated the effects of chronic treatment with the angiotensin converting enzyme (ACE) inhibitor quinapril on the oncoprotein c-Myc and the proliferating cell nuclear antigen cyclin A in SMC of small intramyocardial arteries from the left ventricle of SHR. The expression of c-Myc and cyclin A was assessed by immunocytochemical analysis. The number of smooth muscle cells was assessed by morphometrical analysis. As compared to normotensive Wistar-Kyoto (WKY) rats, untreated SHR exhibited an increased percentages of cells expressing c-Myc (33% ± 4% v 19% ± 2%, mean ± SEM, P < .005) and cyclin A (25 ± 2 v 11% ± 1%, P < .001). In quinapril-treated SHR compared with untreated SHR, we found decreased expression of c-Myc (22% ± 2%, P < .005) and cyclin A (13% ± 1%, P < .001). No significant differences were found between WKY rats and quinapril-treated SHR in the above parameters. Cyclin A was directly correlated with the number of SMCs in each group of rats. These results suggest that an enhanced expression of c-Myc may be involved in the increased proliferation seen in SMCs from small arteries of SHR. Quinapril administration normalizes proliferation in the SMCs of SHR, possibly by inhibiting the expression of the oncoprotein c-Myc and its effects on the cell cycle.     

Altered insulin-like growth factor-1 and nitric oxide sensitivities in hypertension contribute to vascular hyperplasia

Vascular medial thickening, a hallmark of hypertension, is associated with vascular smooth muscle cell (VSMC) hypertrophy and hyperplasia. Although the precise mechanisms responsible are elusive, we have shown that strain induced regulation of autocrine insulin-like growth factor-1 (IGF-1) and nitric oxide (NO) reciprocally modulate VSMC proliferation. Therefore, we investigated potential IGF-1 and NO abnormalities in young (10-week-old) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and their respective VSMC ex vivo. The SHR had increased mean arterial pressure (173 ± 2 v 128 ± 3 mm Hg, n = 24, P < .05) but similar pulse pressures (31 ± 2 v 30 ± 3 mm Hg; P > .05) v WKY. The SHR exhibited increased aortic wall thickness in comparison with WKY (523 ± 16 v 355 ± 17μm; P < .05). No differences were seen in plasma combined NO₂ and NO₃ (NO_x) (0.48 ± 0.11 mmol/L for WKY v 0.58 ± 0.18 mmol/L for SHR) or plasma IGF-1 (1007 ± 28 ng/mL for WKY v 953 ± 26 ng/mL for SHR). Aortic VSMC from SHR displayed enhanced proliferation in comparison with WKY (P < .05). Underlying this enhanced proliferation was altered SHR VSMC sensitivity to the antiproliferative NO donor 2,2"[Hydroxynitrosohydrazono] bis-ethanimine (DETA-NO) (ID₅₀: 270 ± 20 mmol/L for SHR; 150 ± 11 mmol/L for WKY; P < .05). Basal cyclic guanosine monophosphate (cGMP) secretion from SHR VSMC was 65-fold greater than that seen from WKY (P < .001). In response to DETA-NO, cGMP secretion from SHR VSMC increased modestly (1.5-fold; P < .01), whereas treatment of WKY VSMC resulted in a 26-fold (P < .001) increase in cGMP. The SHR VSMC did not respond to exogenous IGF-1, whereas WKY VSMC exhibited a dose dependent increase in proliferation with IGF-1 (10⁻¹⁰ to 10⁻⁷ mol/L). These data suggest that VSMC hyperplasia in early hypertension is not reflected by imbalances in plasma IGF-1 or NO. Rather, altered SHR VSMC sensitivity to NO is likely responsible in part for the observed hyperproliferation seen in early stages of hypertension.     

In vivo and in vitro effects of nebivolol on penile structures in hypertensive rats

BACKGROUND: Erectile dysfunction is associated with high blood pressure and antihypertensive treatment, especially diuretics and traditional beta-blockers. Nevertheless, new beta-blockers such as nebivolol present some differences with respect to the classic beta-blockers. The aim of this study was to determine the functional and morphologic effects of nebivolol on penile structures in hypertensive rats. METHODS: During a 6-month period, male spontaneously hypertensive rat (SHR) and Wistar-Kyoto (WKY) rats were studied. The groups were as follows: 1) untreated SHR (Untreated-SHR); 2) SHR given nebivolol 10 mg/kg/day (SHR+N); 3) SHR given amlodipine 3 mg/kg/day (SHR+AML); and 4) untreated WKY (untreated-WKY). Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries, as well as collagen type III (COL III) in cavernous tissue, were evaluated. RESULTS: After 6 months, SHR groups given nebivolol and amlodipine showed similar reductions in blood pressure compared with untreated SHR. However, only SHR+N and control WKY showed significantly lower values of CSM (P < 01), VSM (P < 01), and COL III (P < 01) when compared with untreated SHR and SHR+AML. In addition SHR+N showed a higher endothelial nitric oxide synthase expression in sinusoidal endothelium compared with SHR, and SHR+AML (P < 01). In vitro studies revealed that SHR+N displayed a better relaxation response to acetylcholine than untreated-SHR and SHR+AML (P < 01). CONCLUSION: Nebivolol presented equivalent BP control compared with amlodipine. However, only nebivolol showed a significant better functional outcome with a protective role against structural changes in erectile tissue that are caused by arterial hypertension.     

Protection of cavernous tissue in male spontaneously hypertensive rats. Beyond blood pressure control

Male erectile dysfunction is increased in prevalence in patients with hypertension. Previous experiments from our group demonstrated morphologic changes in erectile tissue from male spontaneously hypertensive rats (SHR). The aim of the present study was to determine whether blood pressure (BP) control is enough to preserve cavernous tissue from the deleterious effect of arterial hypertension. Eight-week-old male SHR and normotensive Wistar-Kyoto rats (WKY) were studied during 6 months: Group 1 (n = 10) SHR; group 2 (n = 10) SHR with 7.5 mg/kg/d candesartan (C); group 3 (n = 10) SHR with 100 mg/kg/d atenolol (AT); and group 4 (n = 10) WKY. At the end of the experiment all the animals were killed for microscopic studies. Cavernous tissue was processed by hematoxylin-eosin, Masson's trichrome, monoclonal anti-alpha-smooth muscle actin, and anticollagen type III. Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries and the amounts of collagen type III were evaluated. At the end of the experiment, SHR with C and AT showed similar control in BP (group 2: 131.3 +/- 5.5 mm Hg; group 3: 136.5 +/- 2.9 mm Hg) compared with untreated SHR (group 1: 199.6 +/- 5.1 mm Hg). However, animals with C presented significantly lower values (P <.01) of CSM layer in cavernous space and VSM in cavernous arteries (P <.01), and lower amounts of collagen type III (P <.01) compared to SHR with AT and untreated SHR. We conclude that C provides a significant protective role against structural changes in vessels as well as in cavernous spaces of the erectile tissue, caused by arterial hypertension in SHR, beyond BP control.     

Alterations in Membrane Fatty Acid Unsaturation and Chain Length in Hypertension as Observed by 1H NMR Spectroscopy

Alterations in fatty acids of membrane phospholipids in essential hypertension may account for altered membrane ion transport, elasticity, and contractility properties of hypertensive tissues. To investigate the abnormalities in membrane fatty acids in essential hypertension, the degree of fatty acid unsaturation ([–CHCH–]/[–CH₃]), the average carbon chain length, ratio of glycerol to fatty acyl chains, ratio of phosphatidylcholine to fatty acyl chains, and the ratio of free and acylated cholesterol to fatty acyl chains in fatty acid fractions of membrane phospholipids of aorta, kidney, and heart were determined in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats by ¹H nuclear magnetic resonance (NMR) spectroscopy. The degrees of fatty acid unsaturation in the aorta and the kidney membranes were significantly lower in SHR than in WKY rats (aorta, 0.53 ± 0.01 v 0.63 ± 0.01, n = 5, P = .01; kidney, 0.70 ± 0.01 v 0.84 ± 0.03, n = 10, P = .01). No significant difference could be detected in fatty acid unsaturation in heart membranes between these two strains. For aorta, kidney, and heart membranes, the average carbon chain lengths of fatty acid fractions of membrane phospholipids were significantly shorter for SHR than for WKY rats (aorta, 15.1 ± 0.2 v 18.3 ± 0.7, n = 5, P = .02; kidney, 14.5 ± 0.2 v 16.4 ± 0.4, n = 10, P = .01; heart, 17.3 ± 0.5 v 18.8 ± 0.6, n = 10, P = .05). The lower unsaturated fatty acid content in membrane phospholipids of the aorta and the kidney, with concomitant reduction in average chain length, may arise from increased oxidation of fatty acid double bonds in hypertensive tissues and may account, in part, for the increased aortic stiffness and abnormal kidney function associated with essential hypertension. Whether the lower unsaturated fatty acid content and decreased carbon chain length of phospholipid membranes in the aorta and the kidney are a cause or a consequence of the high blood pressure, however, remains unknown.     

Vascular Growth Responses in SHR and WKY During Development of Renal (1K1C) Hypertension

Intrinsic differences between vascular smooth muscle cells (VSMC) in normotension and genetic hypertension may account for the exaggerated growth response often observed in the hypertensive vasculature. To test this hypothesis, in this study we compared the vascular growth response of the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) following induction of one kidney, one clip (1K1C) renal hypertension. SHR and WKY rats were uninephrectomized and renal hypertension (RH) induced using silver clips of 0.22 and 0.24 mm width. Four weeks later, vessel and VSMC growth were assessed in small mesenteric arteries. The systolic blood pressure (SBP) in the RH animals was significantly higher than in uninephrectomised controls, in RH-SHR with a 0.24 mm clip SBP averaged 215 ± 4 mm Hg and in RH-WKY with a 0.22 or 0.24 mm clip the SBPs averaged 214 ± 5 mm Hg and 190 ± 2 mm Hg, respectively. For the same SBP, there were no differences in medial cross-sectional areas of the small mesenteric arteries between RH-SHR and RH_0.22-WKY, which averaged 1.73 ± 0.19 × 10⁴ μm² and 1.66 ± 0.15 × 10⁴ μm², respectively. Likewise, the number of VSMCs (within a precise anatomical site of the mesenteric vasculature) were not different between the RH-SHR and the RH_0.22-WKY with VSMC number 7.6 ± 0.8 × 10⁴ cells and 6.9 ± 0.4 × 10⁴ cells, respectively. In the RH_0.22-WKY vascular growth responses were generally unchanged compared with the RH_0.24-WKY except for a further increase in the incidence of polyploid cells. In conclusion, the results of this study demonstrate that smooth muscle cells of the SHR are not hyperresponsive to all growth-promoting stimuli. Taken together with previous observations, it appears that sustained activity of the renin-angiotensin system may be required for exaggerated vascular growth responses in SHR.     

Impact of α- Versus β-Blockers on Hypertensive Target Organ Damage: Results of a Double-Blind,Randomized, Controlled Clinical Trial

In hypertensive disease, the extent of target organ damage determines the prognosis. We conducted a 6-month, double-blind randomized study to compare the effects of an α₁-adrenoreceptor blocker (bunazosin) with those of a β₁-adrenoreceptor blocker (metoprolol) on early hypertensive target organ damage at a similar level of blood pressure reduction. The study consisted of 43 patients (29 men and 14 women) of varying ages (mean age 52 ± 9 years) with essential hypertension World Health Organization stage I–II. Both the α- and the β-blocker lowered blood pressure to a similar extent measured by 24-h blood pressure monitoring. The left ventricular mass was comparably reduced in both cohorts (α-blocker 284 ± 80 v 259 ± 67 g, P < .05, β-blocker 282 ± 74 v 254 ± 70 g, P < .05). Treatment with the α-blocker led to reduced total peripheral resistance (22.9 ± 8.0 v 19.9 ± 5.3 U, P < .05), whereas therapy with the β-blocker resulted in an elevated total peripheral resistance (25.5 ± 8.4 v 28.5 ± 9.3 U, P < .10; P < .05 for the difference in both groups). Renal plasma flow remained constant in the α-blocker treated group but decreased in the β-blocker treated group (508 ± 141 v 477 ± 134 mL/min/1.73 m², P < .05). Glomerular filtration rate as measured by inulin clearance tended to increase after treatment with the α-blocker (112 ± 20 v 115 ± 18 mL/min/1.73 m², P < .10) in accordance with a decrease of serum creatinine (1.00 ± 0.14 v 0.93 ± 0.12 mg/dL, P < .001). Plasma cholesterol and LDL cholesterol was lowered after treatment with the α-blocker (238 ± 48 v 312 ± 37 mg/dL; P < .001, and 153 ± 32 v 130 ± 25 mg/dL; P < .05) while remaining unchanged in group treated with the β-blocker. Left ventricular hypertrophy was similarily reduced with α- and with β-blockade at a comparable reduction of 24-h blood pressure. α-Blockers effected a more favorable renal and systemic hemodynamic profile than β-blockers, but only long-term prospective studies will answer the question whether these hemodynamic effects result into a better cardiovascular prognosis.     

Reactivity of Mesenteric Arteries From Fructose Hypertensive Rats to Endothelin-1

We previously demonstrated that mesenteric arteries from hyperinsulinemic, insulin resistant fructose hypertensive (FH) rats contain a higher absolute amount of ET-1 and exhibit defective endothelium-dependent vasodilation. Furthermore, chronic ET receptor blockade with bosentan completely prevented the rise in blood pressure in these rats. The present study was undertaken to examine 1) whether the reactivity of mesenteric arteries to ET-1 is altered in FH rats, and 2) whether chronic bosentan treatment has any effect on ET-1 responsiveness and endothelium-dependent vasodilation. Male Sprague Dawley rats were divided into four groups: control (C), control bosentan-treated (CB), fructose (F) and fructose bosentan-treated (FB). Chronic oral bosentan treatment (100 mg/kg/day) was initiated in the CB and FB groups 1 week prior to initiating the fructose diet. At week 16, the F group was hyperinsulinemic and hypertensive when compared to the C group (plasma insulin: 5.8 ± 0.3 v C 3.2 ± 0.5 ng/mL, P < .001; systolic BP: 157 ± 5 v C 130 ± 4 mm Hg, P < .001). Treatment of the F group with bosentan prevented the rise in BP (FB: 133 ± 3 mm Hg; P < .001 v F). Analysis of the pressurized mesenteric resistance arterioles demonstrated that the wall thickness as expressed as percentage of internal diameter did not differ between arteries from C and F rats, when measured over a range of transmural pressures. Constrictor responses of resistance arterioles to NE were similar for C and F rats when studied at transmural pressures of either 120 mm Hg or 160 mm Hg, respectively. The maximum contractile response and the sensitivity of superior mesenteric arteries to NE did not differ between the groups, either with or without the endothelium. However, the maximum contractile response to ET-1 was depressed in the F group both with (+) and without (−) the endothelium [(+): 1.50 ± 0.11 v C 1.88 ± 0.1 g/mm³, P < .05, (−): 1.68 ± 0.11 v C 2.05 ± 0.1 g/mm³, P < .05.]. Furthermore, the endothelium intact F arteries exhibited a decreased sensitivity to ET-1 (pD₂ values F 8.36 ± 0.11 v C 8.83 ± 0.07). Chronic bosentan treatment of the F group restored the maximum tension responses of arteries to ET-1 [(+) in the FB group: 1.88 ± 0.12 g/mm³ v C, P > .05, (−): 1.95 ± 0.05 g/mm³ v C, P > .05] but had no effect on the responses of the CB group. In arteries with intact endothelium, bosentan treatment restored the sensitivity of the F arteries to ET-1 (pD₂ values FB 8.82 ± 0.05 v C, P < .05). Endothelium-dependent relaxation responses were diminished in the F group, which were unaffected by bosentan treatment. These data suggest that mesenteric arteries from FH demonstrate a specific alteration towards the reactivity to ET-1, which is restored by long-term bosentan treatment.     

Relationship Between the Response to the Angiotensin Converting Enzyme Inhibitor Imidapril and the Angiotensin Converting Enzyme Genotype

Insertion (I)/deletion (D) polymorphism of the angiotensin converting enzyme (ACE) gene has been reported to be involved in various cardiovascular diseases. We investigated prospectively whether the response to the ACE inhibitor imidapril varied according to the ACE genotype or plasma ACE activity in Japanese hypertensive patients. The study population consisted of 57 hypertensive patients. After a 4-week observation period, imidapril was administered at a dose of 5 mg/day and blood pressure was measured every 2 weeks for 6 weeks. The plasma ACE activity in patients with the DD or ID genotype was significantly higher than that in patients with the II genotype. Neither the reduction nor the percent reduction in systolic blood pressure was significantly different between patients with either the DD or ID genotype and patients with the II genotype (DD or ID v II, 18.8 ± 2.4 v 20.2 ± 3.3 mm Hg; P = NS, 10.9 ± 1.4 v 11.7 ± 1.9%; P = NS, respectively). However, both the reduction and the percent reduction in diastolic blood pressure tended to be higher in patients with the II genotype (DD or ID v II, 7.9 ± 1.2 v 12.4 ± 2.2 mm Hg; P = .0669, 8.1 ± 1.2 v 12.4 ± 2.2%; P = .0569, respectively). The reduction in diastolic blood pressure was inversely correlated with plasma ACE activity (r = 0.301, P = .0253). In conclusion, the response to imidapril in hypertensive patients is determined at least in part by the ACE genotype.     

Carotid thickening,cardiac hypertrophy,and angiotensin converting enzyme gene polymorphism in patients with hypertension

An insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene has been associated with increased risk for myocardial infarction, cardiomyopathy, carotid thickening, and cardiac hypertrophy. However, a conclusive agreement about the role of ACE genotype in the genetics of cardiovascular disease has not yet been reached. This study was undertaken to investigate the relationship of the I/D polymorphism of the ACE gene with carotid intima-media thickness (IMT) and left ventricular mass (LVM) in 175 Chinese patients with mild-to-moderate hypertension. The I/D genotypes were detected by the polymerase chain reaction using primers flanking the polymorphic region in intron 16 of the ACE gene. The IMT was measured in the common carotid and carotid bifurcation by B-mode ultrasound. The LVM was calculated with M-mode echocardiographic measures of the left ventricle. Patients with the DD genotype (n = 41) showed significant greater carotid IMT (1.593 ± 0.879 v1.309 ± 0.703 and 1.171 ± 0.583 mm, P = .01) but insignificant higher LVM index (123.8 ± 36.6 v 123.7 ± 37.4 and 118.2 ± 33.0 g/m², P = .61) than did those with the DI (n = 69) and II (n = 65) genotypes. The deletion polymorphism of the ACE gene (P = .04) was a significant predictor for carotid IMT on multiple regression analysis, controlling all the potential confounding factors including age (P = .001), systolic blood pressure (P = .09), smoking (P = .08), and plasma tissue plasminogen activator antigen (P = .03), but the LVM correlated only with age (P = .02), sex (P < .001), and body mass index (P < .001). These results indicated that the DD genotype of the ACE gene could be considered a risk factor for the development of early atherosclerosis in carotid arteries but not for left ventricular hypertrophy in the hypertensive population.     

Effect of Dietary Sodium on Insulin Sensitivity in Older,Obese, Sedentary Hypertensives

Increased dietary sodium intake has been associated with an increase in blood pressure as well as a decrease in insulin-mediated glucose disposal in young healthy adults. The purpose of this study was to determine whether dietary sodium intake is associated with changes in oral glucose tolerance, insulin sensitivity, and blood pressure in older, sedentary, overweight hypertensives. Eight older (70.0 ± 1.4 years, mean ± SEM), overweight (40.2 ± 3.1% body fat), mildly hypertensive (151 ± 8/82 ± 2 mm Hg) patients with a fasting plasma glucose < 7.8 mmol/L were studied after 2 weeks on low (3 g/day) and 2 weeks on high (10 g/day) sodium diets. To examine carbohydrate metabolism we performed a 2 h oral glucose tolerance test and a two-dose (240 and 600 pmol/m ²/min) hyperinsulinemic-euglycemic clamp at the end of each sodium diet. High sodium intake was associated with a significantly greater urinary sodium excretion (364 ± 45 mmol/day v 112 ± 21 mmol/day; P < .0001). The increase in dietary sodium from low to high did not result in significant differences in fasting plasma glucose (6.0 ± 0.2 v 5.8 ± 0.1 mmol/L, P = .20) or insulin (72.5 ± 7.8 v 69.9 ± 12.4 pmol/L, P = 0.71) levels or in the glucose (374.0 ± 50.8 v 493.2 ± 45.0 mmol/min/L, P = .12) and insulin (43,783 ± 10,278 v 44,110 ± 12,392 pmol/min/L, P = .96) areas determined during the oral glucose tolerance test. Similarly, there was no effect of dietary sodium on insulin-mediated glucose disposal at low (5.87 ± 1.02 v 5.60 ± 0.94 mg/kg LBM/min, P = .36) or high (12.15 ± 1.49 v 11.91 ± 1.49 mg/kg _LBM/min, P = .64) insulin infusion rates. Our findings suggest that, in insulin resistant hypertensives, increased dietary sodium does not affect either glucose or insulin responses during an oral glucose tolerance test or glucose disposal during a hyperinsulinemic euglycemic clamp.     

Race Affects the Decline in Blood Pressure With Hospitalization

Hospitalization routinely lowers blood pressure (BP). This study examined the effects of race and psychologic characteristics on this phenomenon. Data are reported from two separate cohorts of hypertensive and normotensive black and white men and women who were studied following a stay at a clinical research center where sodium intake was held constant. Blacks (N = 88), as compared to whites (N = 77), showed consistently smaller declines in systolic BP (P < .01) following hospitalization (−11.6 mm Hg SBP v −19.5 mm Hg SBP, respectively). A multiple regression model that treated BP as a function of physiologic and psychologic attributes indicated that preadmission BP level, body mass index, stress level, and anger expression were related to the drop in systolic (r² = 65%) and diastolic (r² = 45%) BP brought about by hospitalization (P < .0001). In blacks, high environmental stress ratings were unrelated to the change in BP with hospitalization. In contrast, whites with high environmental stress ratings lowered their BP noticeably with hospitalization. Given that the reduction in BP with hospitalization can be similar to that attained with pharmacologic therapy, these findings may have a bearing on studies examining BP in the hospital.     

Fibrinolytic function in diuretic-induced volume depletion

Accumulating evidence suggests that the renin-angiotensin system (RAS) may participate in the regulation of fibrinolytic function. In clinical studies, however, angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor antagonist losartan have failed to consistently affect endogenous fibrinolysis. Because such an effect may depend on the degree of prestimulation of the RAS, we have studied parameters of fibrinolytic function in 15 healthy volunteer subjects during baseline (day 1) and after 10 days of treatment with 25 mg of hydrochlorothiazide (HCT)/day (day 11). On the last day of the study (day 12), a single oral dose of 50 mg of losartan was given to the volunteers in addition to HCT and fibrinolytic function was assessed at the peak effect of losartan (5 h later). Plasma renin activity (PRA) was significantly stimulated during diuretic treatment (1.35 ± 0.21 v 0.34 ± 0.06 ng mL⁻¹ · h⁻¹ [P < .001]) and further increased after losartan (6.39 ± 1.16 ng mL⁻¹ · h⁻¹ [P < .001]). No effects of either the diuretic or losartan could be observed on tissue-type plasminogen activator (t-PA) antigen concentration and activity. However, 10 days of treatment with HCT significantly increased plasminogen activator inhibitor-1 (PAI-1) antigen (26.8 ± 5.8 v 21.1 ± 3.4 ng/mL [p = .037]). In addition, PAI-1 activity was also tentatively raised by HCT treatment (5.48 ± 1.82 v 3.88 ± 0.79 IU/mL [P = .067]). In spite of the marked further rise in PRA after losartan, the stimulation of PAI-1 antigen and activity was blunted by losartan (24.4 ± 3.6 ng/mL and 4.55 ± 0.99 IU/mL, respectively). Our results demonstrate that volume depletion induced by HCT treatment is associated with a rise in PAI-1. Acute administration of losartan is capable of blunting this effect, suggesting that the angiotensin II type 1 receptor may participate in this effect of angiotensin II.     

Effect of l-arginine infusion on systemic and renal hemodynamics in hypertensive patients

This study was designed to compare the renal endothelial function in patients with essential hypertension and normal renal function with that in hypertensive patients with renal insufficiency. We studied the effects of l-arginine (500 mg/kg intravenously over 30 min) on renal hemodynamics in 30 normotensive control subjects, 32 patients with mild to moderate essential hypertension who had normal renal function, and seven hypertensive patients with renal insufficiency who had a serum creatinine concentration >2.0 mg/mL and a glomerular filtration rate <50 mL/min/1.48 m². l-Arginine infusion similarly reduced the mean blood pressure between the three groups (normotensive: −9.7% ± 0.7%, hypertensives with normal renal function: −10.2% ± 0.8%, and hypertensives with renal insufficiency: −8.2% ± 1.3%). The l-arginine–induced decrease in renal vascular resistance was smaller in essential hypertensive patients than in normotensive subjects (−11.0% ± 2.2 v −19.8% ± 2.1%, P <.05). However, l-arginine had no effect on the renal vascular resistance in hypertensive patients with renal insufficiency (1.6% ± 4.8%). Urine nitrite/nitrate levels in response to l-arginine significantly increased in the three groups in the following order: patients with renal insufficiency (47% ± 15%), essential hypertensive patients (87% ± 10%), and normotensive subjects (129% ± 12%). The glomerular filtration rate was unaffected by l-arginine in normotensive and essential hypertensive patients (3.1% ± 2.4% and 4.2% ± 2.5%), but significantly decreased in hypertensive patients with renal insufficiency (−13.7% ± 6.1%). These findings suggest that the ability of the l-arginine–nitric oxide–cGMP pathway to relax the renal vascular tone may be impaired in essential hypertensive patients and more markedly blunted in hypertensive patients with renal insufficiency, in parallel with increasing serum creatinine concentrations.     

Inhibitors of Na-K-ATPase in human urine: effects of ouabain-like factors and of vanadium-diascorbate on calcium mobilization in rat vascular smooth muscle cells

Endogenous ouabain-like factors (OLF) may play a role in the pathogenesis of volume-dependent hypertension by raising intracellular free calcium ([Ca²⁺]_i) as a consequence of inhibition of the sodium pump. In previous studies we described the presence of two low molecular (Mr ≈ 400) inhibitors of Na-K-ATPase in human urine, ie, a more polar OLF-1 and a more apolar OLF-2. We subsequently identified the active compound in OLF-2 as vanadium (V^IV)-diascorbate (Mr 416). OLF-1, OLF-2, and V-diascorbate inhibited dose-dependently porcine Na-K-ATPase in vitro. In the present study we investigated the effects of urinary OLF-1, OLF-2, and V-diascorbate on calcium mobilization, ie, on [Ca²⁺]_i in cultured rat vascular smooth muscle (VSM) cells in comparison to the effects of ouabain, angiotensin II (A II), and arginine-vasopressin (AVP). [Ca²⁺]_i was determined by the fura-2 method. OLF-1 and OLF-2 (each ≈ 10⁻⁴ mol/L), obtained as single spots by thin-layer chromatography, produced a rise in [Ca²⁺]_i in VSM cells from 45 ± 7 to 99 ± 22 and from 48 ± 9 to 92 ± 2 nmol/L (each n = 5; P < .05), respectively, after 3 min. V-diascorbate also increased [Ca²⁺]_i slowly and dose-dependently, eg, from 56 ± 14 to 102 ± 15 nmol/L at a concentration of 10⁻⁶ mol/L (n = 5; P < .05) after 3 min. A similar slow rise in [Ca²⁺]_i from 53 ± 10 to 185 ± 3 nM (n = 5; P < .05) after 3 min was found with ouabain (10⁻⁶ mol/L). As standard vasoconstrictor, All (10⁻⁸ mol/L) rapidly increased [Ca²⁺]_i from 23 ± 4 to 846 ± 50 nmol/L (n = 7; P < .01) within 30 sec. This effect was enhanced to 1389 ± 161 nM (n = 7; P < .01) when VSM cells were preincubated with V-diascorbate (10⁻⁶ mol/L) for 10 min. AVP (10⁻⁷ mol/L) also rapidly increased [Ca²⁺]_i to 418 ± 11 nmol/L within 30 sec (n = 7; P < .01). This effect was enhanced in the presence of OLF-2 (≈10⁻⁴ mol/L) or ouabain (10⁻⁶ mol/L) to 523 ± 14 and 560 ± 19 nmol/L, respectively (each n = 7); P < .01). The calcium channel blocker verapamil, the intracellular calcium release blocker TMB-8, and the unselective cation channel blocker Ni²⁺ partly blunted the A II- or AVP-induced rise in [Ca²⁺]_i and prevented the OLF-2- and V-diascorbate–induced increase in [Ca²⁺]_i. Thus, OLF-1, OLF-2 and V-diascorbate, the active component of OLF-2, reveal effects similar to those of ouabain on [Ca²⁺]_i in VSM cells, ie, they produce a slow rise in [Ca²⁺]_i subsequent to inhibition of the sodium pump. The physiologic and pathologic roles of these and additional OLF in body fluid and blood pressure regulation and in hypertension have yet to be evaluated.     

Type 1A dopamine receptor expression in the heart is not altered in spontaneously hypertensive rats

We have recently demonstrated that type 1A dopamine (D_1A) receptor is expressed in the rat heart, but its function still remains unknown. In the present study, we investigated possible changes in the expression level and the distribution of the cardiac D_1A receptor in the development of left ventricular hypertrophy in spontaneously hypertensive rats/Izumo strain (SHR/Izm) at the ages of 4, 8, and 20 weeks. We examined D_1A receptor protein distribution by immunohistochemistry and gene expression by competitive polymerase chain reaction (competitive PCR). In SHR/Izm, compared with the age-matched Wistar Kyoto rats/ Izmo strain (WKY/Izm), blood pressure and heart/body weight ratio were significantly increased at 8 and 20 weeks. By immunohistochemistry, the D_1A receptor was localized in cardiomyocytes and vascular smooth muscle cells of coronary arteries, but not in interstitial fibrotic tissue. D_1A receptor distribution was not changed either by the strain or the age. Competitive PCR analysis showed that the D_1A receptor mRNA level was significantly higher at 4 weeks than at 8 and 20 weeks in both strains of rats and that there was no significant difference in D_1A receptor mRNA between SHR/Izm and WKY/Izm at any age ( 43.2 ± 10.4 attomol × 10⁻³/L v 43.1 ± 11.2 attomol × 10⁻³/L at 4 weeks, P = not significant, 3.9 ± 0.9 attomol × 10⁻³/L v 4.0 ± 1.3 attomol × 10⁻³/L at 8 weeks, P = not significant, 3.0 ± 1.2 attomol × 10⁻³/L v 1.9 ± 1.6 attomol × 10⁻³/L at 20 weeks, P = not significant). These results do not support the hypothesis that changes in D_1A receptor expression are associated with the development of left ventricular hypertrophy in SHR.     

Antihypertensive effect of α- and β-adrenergic blockade in obese and lean hypertensive subjects

The purpose of this study was to determine the contribution of the adrenergic system in mediating hypertension in obese and lean patients. Thirteen obese, hypertensive patients with a body mass index (BMI) ≥28 kg/m² (obese) and nine lean patients with a BMI ≤25 kg/m² (lean) were recruited. After a 1-week washout period, participants underwent daytime ambulatory blood pressure monitoring (ABPM). Participants were then treated with the α-adrenergic antagonist doxazosin, titrating to 4 mg QHS in 1 week. In the next week, the β-adrenergic antagonist atenolol was added at an initial dose of 25 mg/day and titrated to 50 mg/day within 1 week. One month after the addition of atenolol, all patients underwent a second ABPM session.There were no differences between the obese and lean subjects in baseline systolic (SBP), diastolic (DBP), or mean arterial pressures (MAP) measured by office recording or ABPM. However, obese subjects had higher heart rates than lean subjects (87.5 ± 2.4 v 76.8 ± 4.9 beats/min). After 1 month of treatment with the adrenergic blockers, obese patients had a significantly lower SBP (130.0 ± 2.5 v 138.9 ± 2.1 mm Hg, P = .02) and MAP (99.6 ± 2.3 v 107.0 ± 1.5 mm Hg, P = .02) than lean patients. Obese patients also tended to have a lower DBP than lean patients (84.3 ± 2.5 v 90.9 ± 1.6 mm Hg, P = .057), but there was no significant difference in heart rate after 1 month of adrenergic blockade.These results indicate that blood pressure is more sensitive to adrenergic blockade in obese than in lean hypertensive patients and suggest that increased sympathetic activity may be an important factor in the maintenance of hypertension in obesity.