Influence of nitric oxide in the chronic phase of two-kidney, one clip renovascular hypertension

Chronic two-kidney, one clip (2K1C) renovascular hypertension is characterized by a largely angiotensin-independent elevated blood pressure (BP). We hypothesized that the long-term effect of hypertension would compromise endothelium-derived nitric oxide (NO) and diminish its influence in controlling renal perfusion. We determined the influence of endothelium-derived NO on renal hemodynamics and the angiotensin-NO interaction regulation of renal perfusion in rats with chronic 2K1C hypertension. Renal blood flow (RBF) was measured by radioactive microspheres in rats with either early-phase (4 weeks after clipping, n=7) or chronic-phase (13 to 16 weeks after clipping, n=7) 2K1C hypertension. The systemic and renal response to NO synthesis inhibition was determined with 10 mg/kg body wt N omega-nitro-L-arginine methyl ester (L-NAME). In rats with early-phase 2K1C hypertension, BP was 149+/-3 mm Hg, which increased by 42+/-3 mm Hg with L-NAME (P<.001). L-NAME decreased RBF by 20% (P<.02) and 17% (P<.005) and increased renal vascular resistance (RVR) by 58% (P<.005) and 62% (P<.02) in the nonclipped and clipped kidneys, respectively. In rats with chronic 2K1C hypertension, BP was 166+/-3 mm Hg, and L-NAME increased this by 35+/-6 mm Hg (P<.001). In the nonclipped and clipped kidneys of chronic 2K1C hypertensive rats, L-NAME decreased RBF by 20% (P<.01) and 17% (P<.01) and increased RVR by 51% (P<.005) and 60% (P<.02), respectively. There were no differences in L-NAME-induced changes between early- and chronic-phase 2K1C hypertensive rats. Next, we treated seven chronic-phase 2K1C hypertensive rats with 10 mg/kg body wt losartan, which reduced BP by only 7.7% (P<.005). After losartan, L-NAME increased BP by 41+/-3 mm Hg (P<.001), decreased RBF to the nonclipped kidney by 44% (P<.05), and increased RVR by 110% (P<.005); the decrease in RBF was significantly greater compared with untreated chronic-phase controls (P<.05). In the clipped kidney, L-NAME decreased RBF by 26% (P<.05) and increased RVR by 76% (P <.05). Thus, angiotensin blockade did not attenuate the systemic or renal vasoconstriction to L-NAME. Our results suggest that in both early and chronic phases of 2K1C hypertension, NO contributes significant dilator tone to buffer the hypertension and maintains perfusion of both kidneys by counterbalancing angiotensin-independent vasoconstriction.     

Major histocompatibility complex class II expression and parathyroid autoantibodies in primary hyperparathyroidism

We evaluated whether kinins exert a protective action against the development of two-kidney, one clip (2K1C) hypertension, a model characterized by an activated renin-angiotensin system in the ischemic kidney and increased expression of the bradykinin (BK) B2 receptor in the contralateral kidney. BK B2-receptor knockout (B2-/-), wild-type (B2+/+), and heterozygous (B2+/-) mice underwent clipping of the left renal artery, with the other kidney remaining untouched. Basal systolic blood pressure (SBP, via tail-cuff plethysmography) was higher in B2-/- mice than in B2+/- or B2+/+ mice (121+/-2 versus 113+/-2 and 109+/-1 mm Hg; P<0.05 for both comparisons). SBP did not change from basal values after sham operation, but it increased in mice that underwent clipping. The increase in SBP was greater in 2K1C B2-/- mice than in B2+/- or B2+/+ mice (28+/-2 versus 14+/-2 and 14+/-2 mm Hg, respectively, at 2 weeks; P<0.05 for both comparisons). Blockade of the BK B2 receptor by Icatibant enhanced the pressure response to clipping in B2+/+ mice (29+/-2 mm Hg at 2 weeks). Intra-arterial mean blood pressure (MBP) was higher in 2K1C than in respective sham-operated mice, with the MBP difference being higher in B2-/- mice (32 and 38 mm Hg, at 2 and 4 weeks, respectively), and higher in B2+/+ mice given Icatibant (30 and 32 mm Hg) than in B2+/+ mice without Icatibant (17 and 18 mm Hg). At 4 weeks, acute injection of an angiotensin type 1 receptor antagonist normalized the MBP of 2K1C hypertensive mice. A tachycardic response was observed 1 week after clipping in B2-/- and B2+/- mice, but this effect was delayed in B2+/+ mice. However, the HR response to clipping in B2+/+ mice was enhanced by Icatibant. Within each strain, heart weight to body weight ratio was greater in 2K1C hypertensive mice than in sham-operated control animals (B2-/-: 5.7+/-0.1 versus 5.2+/-0.1; B2+/+: 5.1+/-0.1 versus 4.5+/-0.1; P<0.01 for both comparisons). The clipped kidney weight to nonclipped kidney weight ratio was consistently reduced in mice with 2K1C hypertension. Our results indicate that kinins acting on the BK B2 receptor exert a protective action against excessive blood pressure elevation during early phases of 2K1C hypertension.     

Hemorheologic considerations in the pathogenesis of vascular occlusive events in polycythemia vera

Polycythemia vera (PV) commonly presents with vascular occlusion. Untreated patients have a poor prognosis due to the occurrence of thromboses. Treatment outcomes in PV and thrombotic events in other forms of polycythemia and in primary thrombocythemia lead to the conclusion that both raised packed cell volume (PCV) values and quantitative/qualitative platelet changes play a role in the pathogenesis of these vascular occlusive events. In vitro blood viscosity values are predominantly affected by the PCV, particularly at low shear rates and are thus high in untreated PV. Generally, under physiologic conditions blood flow is not governed by blood viscosity due to a number of factors, such as prevailing high shear rates, red cell axial migration, and adaptive vessel diameter changes. Peripheral blood flow is low in untreated PV. Whereas some untreated patients maintain adequate oxygen transport to the tissues, this may not apply in those with cardiac or local vessel disease. There is evidence that low flow rates predispose to occlusive events. Under pathologic low blood flow or static conditions, the rheologic blood changes of untreated PV, demonstrated in vitro, play a role in producing a more deleterious outcome of an occlusive event. Under blood flow conditions, red cell axial migration occurs. This leaves a plasmatic zone at the vessel wall into which platelets are dispersed and where shearing forces are maximal. These forces lead to platelet activation. Increased PCV values reduce the width of the plasmatic zone and lead to an increased possibility of platelet activation, platelet-platelet contact and platelet-vessel wall interaction, particularly when the platelet count is raised as well. These effects increase the likelihood of the initiation of thrombus formation in PV.     

Electromagnetic flow-probe implantation for cardiac output measurements in rabbits

A technique suitable for continuous measurement of beat-to-beat cardiac output in conscious rabbits for relatively longer periods is described. The method consists, essentially, of implanting a specially constructed electromagnetic flow probe around either the pulmonary artery or the aorta during left thoracotomy (second intercostal space) in animals anesthetized with hypnorm. With care, the procedure is successful in a large proportion of the animals. Little postoperative care is required and the flow probe remains functional for several weeks up until the animals were killed to recover the probe for reimplantation. The cardiac output values (ml/min/kg) in conscious rabbits were: normal 183 +/- 9; unilateral renal hypertensive animals, 108 +/- 10 and bilateral renal hypertensive animals, 153 +/- 15. Isoprenaline increased, and propranolol decreased, the cardiac output in conscious normotensive rabbits.     

Changes of plasma osmotic pressure during lactation in rats

It is known that blood and plasma volume increase during lactation. The present paper examines whether an increase in plasma volume is accompanied by the change in plasma composition or attributed to hydro-dilution. Six dam-nursed pups and six dam-removed pups housed individually were designated as lactating rats and control rats, respectively. The plasma osmotic pressure and hematocrit value (Ht) were measured in the rats on days 3, 5, 7, 10, 13 and 18 of lactation. The total plasma protein (TP) and serum sodium concentration were also measured as they are factors affecting the plasma osmotic pressure. In addition, milk yield was estimated by the Morag technique. On day 5 and after day 10, the osmotic pressure of the lactating rats was found to be significantly lower than that of the control rats. The serum sodium concentration (days 5 and after day 10) and Tp values (days 3, 10 and 18) of the lactating rats were significantly lower than those of the control rats. Except on day 5, the Ht values of the lactating rats were significantly lower than those of the controls. During the period between days 3 and 10, milk yield was increased and it become steady (18 g/12 hr) on days 10 and 18. On and after day 10 when rats secreted a large amount of milk, it is considered that a decrease in the plasma osmotic pressure was mainly attributed to the reduction of sodium concentration by hydro-dilution. The Ht values indicate that an increase in blood volume is mainly through plasma volume rather than blood cell volume in lactating rats.     

A new model of diabetic nephropathy with progressive renal impairment in the transgenic (mRen-2)27 rat (TGR)

BACKGROUND: The tissue renin-angiotensin system (RAS) may modulate the structural and functional changes that occur in the diabetic kidney. METHODS: Hypertensive transgenic (mREN-2)27 rat (TGR) that exhibit increased tissue renin expression were administered streptozotocin (STZ, diabetic) or citrate buffer (non-diabetic) at six weeks of age, and sacrificed 4 and 12 weeks later. Further groups were treated for 12 weeks post-STZ or vehicle with the angiotensin converting enzyme inhibitor, perindopril. Comparisons were made with 18-week-old non-diabetic and diabetic spontaneously hypertensive rats (SHR). RESULTS: In diabetic TGR, the most florid lesion was seen after 12 weeks of STZ, with kidneys exhibiting vacuolated tubules, hylanized arterioles, medullary fibrosis and necrosis and severe glomerulosclerosis. In contrast, only mild glomerulosclerosis was seen in non-diabetic TGR and diabetic SHR. Glomerular filtration rate was increased after four weeks of diabetes in TGR and 12 weeks of diabetes in SHR, but declined by greater than 50% after 12 weeks of diabetes in TGR. In both TGR and SHR, diabetes increased albuminuria but did not modify systolic blood pressure. Renal renin content increased progressively in diabetic TGR, and this was associated with increased renin immunolabeling in the juxtaglomerular apparatus (JGA) and the appearance of renin in proximal convoluted tubules. In contrast, renal renin content and JGA renin immunolabeling were unchanged in diabetic SHR. Perindopril attenuated renal pathology, improved renal function and abolished proximal tubular renin immunolabeling in diabetic TGR. CONCLUSIONS: This is the first report of a diabetic rodent model developing rapid onset renal impairment. Furthermore, this study suggests a role for an activated renal RAS in the acceleration of diabetic renal disease and confirms the benefit of drugs that inhibit this system.     

Preservation of endogenous antioxidant activity and inhibition of lipid peroxidation as common mechanisms of antiatherosclerotic effects of vitamin E, lovastatin and amlodipine

OBJECTIVES: We sought to document the common mechanisms of the antiatherogenic effects of the cholesterol-lowering hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin, the dihydropyridine Ca2+ blocker amlodipine and the antioxidant vitamin E. BACKGROUND: Vitamin E, HMG-CoA reductase inhibitors and Ca2+ blockers each inhibit atherosclerosis in hypercholesterolemic animals. METHODS: New Zealand White rabbits were fed regular chow (Group A), chow with 1% cholesterol (Group B), 1% cholesterol diet plus lovastatin (Group C), 1% cholesterol diet plus vitamin E (Group D) or 1% cholesterol diet plus amlodipine (Group E) for 12 weeks. The extent of aortic atherosclerosis was measured by planimetry of the sudanophilic area. Malondialdehyde (MDA) and superoxide dismutase (SOD) in blood were measured as indexes of lipid peroxidation and antioxidant activity, respectively. RESULTS: Group A rabbits showed no atherosclerosis, whereas Group B rabbits had 17.4 +/- 9.3% (mean +/- SD) of the aorta covered with atherosclerosis, and Groups C, D and E rabbits had significantly less atherosclerosis. Plasma SOD activity was lower in Group B than in Group A (6.9 +/- 1.1 vs. 12.8 +/- 1.5 U/ml, p < 0.01) and was preserved in the groups given lovastatin, vitamin E or amlodipine with a high cholesterol diet. The serum MDA level was higher in Group B rabbits than Group A rabbits (12.1 +/- 2.6 vs. 1.2 +/- 0.1 nmol/ml, p < 0.01) and increased minimally in rabbits given lovastatin, vitamin E or amlodipine with a high cholesterol diet. In in vitro experiments, both lovastatin and amlodipine preserved SOD activity and reduced the oxidizability of low density lipoproteins by rabbit leukocytes. CONCLUSIONS: This study suggests that a reduction in lipid peroxidation and preservation of SOD may be common mechanisms of antiatherosclerotic effects of lovastatin, vitamin E and amlodipine.     

Aneurysm clips: evaluation of MR imaging artifacts at 1.5 T

PURPOSE: Endothelin-1 (ET-1), a peptide produced by the vascular endothelium, causes profound renal vasoconstriction by binding to ET-A receptors. The present study examined the renal actions of ET-1 after ET-A receptors were blocked by BE-18257B to unmask the functions of ET-B receptors. MATERIALS AND METHODS: Renal hemodynamics and clearance measurements were obtained in anesthetized dogs after intrarenal infusion of BE-18257B at 100 ng./kg./min. (Group 1), after intrarenal infusion of ET-1 at 2 ng./kg./min. (Group 2), or after intrarenal infusion of ET-1 superimposed on BE-18257B (Group 3). RESULTS: In Group 1, BE-18257B infusion did not alter arterial pressure, renal blood flow (RBF), GFR or tubular function. In Group 2, ET-1 infusion led to a significant decrease in RBF and GFR (37 and 40%, respectively) without altering arterial pressure. Urinary volume and sodium excretion were not changed but osmolality decreased significantly. In Group 3, BE-18257B infusion significantly attenuated the decrease in RBF caused by ET-1 and increased GFR by 40% without altering arterial pressure, associated with significant diuresis and natriuresis. CONCLUSION: Renal vasoconstriction caused by ET-1 is attenuated by ET-A receptor blockade with BE-18257B, which unmasks the hemodynamic and tubular actions of ET-B receptors. As a result, it limits the ET-1 induced decrease in RBF and raises GFR, and leads to a diuresis and natriuresis.     

Protective effect of nicardipine treatment on renal microanatomical changes in spontaneously hypertensive rats

The effects of nicardipine administration on kidney morphology were studied in spontaneously hypertensive rats (SHR). Male 12-week-old SHR received an oral dose of 1 mg/Kg/day of nicardipine or vehicle for 8 weeks Age-matched Wistar-Kyoto rats were used as normotensive reference animals. At 20 weeks, the non treated SHR exhibited hypertension, albuminuria, decreased urinary sodium excretion and renal microanatomical changes. These changes were characterized by vascular alterations consisting in hypertrophy of the tunica media accompanied by a decrease of luminal surface. Glomerular changes consisting primarily in signs of glomerulosclerosis of varying degrees were noticeable in the kidneys of SHR. Treatment with nicardipine significantly reduced blood pressure and albuminuria and increased urinary sodium excretion. Moreover, hypertrophy of the tunica media and the luminal surface were decreased and increased respectively in nicardipine-treated SHR. The above results suggest that treatment with nicardipine reduces blood pressure in SHR and counteracts hypertension-dependent changes in the morphology of the kidney. The protective effect of the drug on hypertensive changes of renal microanatomy probably have functional relevance given of the influence of nicardipine treatment on albuminuria and urinary sodium excretion in SHR.     

Divergent effects of ACE-inhibition and calcium channel blockade on NO-activity in systemic and renal circulation in essential hypertension

OBJECTIVE: Nitric oxide is a vasodilating and blood pressure lowering substance. To investigate whether calcium antagonists or angiotensin-converting enzyme (ACE) inhibitors increase vascular nitric oxide activity, we assessed systemic and renal vascular sensitivity to nitric oxide synthase inhibition in hypertensives on and off medication. METHODS: Ten essential hypertensive patients, aged 22-51 years, were studied 3 times: > or = 4 weeks off medication, after 3 weeks treatment with enalapril 20 mg twice a day and after 3 weeks nifedipine 60 mg/day. Each time, 24-h blood pressure registration was performed, followed by a clearance study to obtain a 3-h dose-response curve for intravenously infused NG-monomethyl-L-arginine (L-NMMA, respectively 0.75, 1.5 and 3.0 mg/kg/h). RESULTS: L-NMMA dose-dependently increased mean arterial pressure with 5 +/- 2 mmHg and systemic vascular resistance with 24 +/- 5% at maximum dose, whereas cardiac output decreased (all P < 0.001). Enalapril and nifedipine treatment decreased blood pressure, while the L-NMMA-induced increase in systemic vascular resistance was potentiated (enalapril: 45 +/- 7% and nifedipine: 46 +/- 8%; both P < 0.01). L-NMMA also dose-dependently decreased renal blood flow by 58 +/- 8% at maximum dose (P < 0.001), but neither drug potentiated these effects. CONCLUSION: These results indicate that, in essential hypertensives, antihypertensive therapy with enalapril or nifedipine increases nitric oxide dependency of systemic vascular tone, which may play a role in the blood pressure lowering effect of these drugs. However, this phenomenon cannot be observed in the renal circulation, suggesting a different regulation of endothelium-dependent vasomotion in the hypertensive kidney.     

Tonic inhibition of renin secretion by the 12 lipoxygenase pathway: augmentation by high salt intake

Recent evidence suggests that lipoxygenase (LO) metabolites inhibit renin production in vitro. However, the physiological significance of this effect has not been determined. This study examined the role of the LO pathway in the regulation of plasma renin concentration (PRC) in vivo. The acute administration of two structurally unrelated LO inhibitors, phenidone (30 and 60 mg/kg) and esculetin (60 mg/kg), resulted in suppression of platelet 12 hydroxyeicosatetraenoic acid (12HETE) production, reduction in systemic arterial pressure and a 2- to 3-fold increase in PRC. To determine whether the esculetin-induced increase in PRC was secondary to hypotension, esculetin was also administered to rats preinfused with a pressor dose of norepinephrine. In these acutely hypertensive rats, esculetin still induced a 2.5-fold increase in PRC, whereas blood pressure remained over 40 mm Hg above basal levels. Further, esculetin (10(-6)M) increased renin release in renal slices from 150 +/- 10 to 310 +/- 20 ng/ml.h (P < 0.05) and this rise was entirely blocked in the presence of 12HETE (10(-7)M; 130 +/- 40 ng/ml.h). In rats placed on high salt intake, 12HETE concentration in renal slices from the outer cortex was considerably higher than in renal slices from salt-restricted rats (116.5 +/- 15.7 vs. 65 +/- 12 pg/mg protein; P < 0.05). Chronic administration of the LO inhibitor phenidone also resulted in an increase of PRC, which was independent of changes in blood pressure. On either high salt (3.15%0 or low salt (0.05%) diet phenidone-treated rats had higher PRC levels than the respective control groups [high salt 9.7 +/- 3.5 vs. 1.9 +/- 1.4 ng/ml.h; P < 0.05; low salt 33.2 +/- 5.3 vs. 19.4 +/- 3.10 ng/ml.h; P < 0.05]. The finding that LO blockers are potent stimulators of PRC in vivo suggests the existence of a physiological tonic inhibition of renin secretion by LO products that is operative under a wide range of salt intake. High salt intake enhances this inhibitory tone by increasing renal cortical 12 LO activity and, in fact, normal suppression of PRC during high salt diet does not occur in LO-blocked animals. Thus, the LO pathway exerts a tonic inhibitory effect on renin release, which appears particularly important for renin suppression during high salt intake.     

Catecholamine secretory vesicles. Augmented chromogranins and amines in secondary hypertension

Chromogranins A and B are major soluble proteins in chromaffin granules. Their adrenomedullary content is increased in the spontaneously (genetic) hypertensive rat. Is augmented catecholamine vesicular storage of the chromogranins a specific feature of genetic hypertension? To explore this question, we measured chromogranin A immunoreactivity, using a novel, synthetic peptide radioimmunoassay, in rat adrenal medullas 4-6 weeks after induction of the two-kidney, one clip Goldblatt model of renovascular hypertension and in unmanipulated control animals. We also measured messenger RNAs of chromogranins A and B and dopamine beta-hydroxylase by Northern blot. Immunoreactive adrenal chromogranin A was 3.3-fold higher (p < 0.01) in clipped rat adrenals. Adrenal catecholamine concentrations and phenylethanolamine-N-methyltransferase activity were also higher in clipped rats. Adrenal dopamine beta-hydroxylase activity (both membrane-bound and soluble forms) and corticosterone (glucocorticoid) concentration did not significantly differ between the groups. Adrenal medullary chromogranin A messenger RNA levels in clipped rats were 3.2-fold higher (p = 0.029) than those in the control group, and chromogranin B messenger RNA levels were 4.6-fold higher (p = 0.05). Dopamine beta-hydroxylase messenger RNA levels were 2.9-fold higher (p = 0.038). Thus, augmented synthesis and storage of adrenomedullary chromogranins A and B, catecholamines, and their biosynthetic enzymes appear to be characteristic of both acquired and genetic hypertension.     

Anti-hyperalgesic and anti-allodynic effects of intrathecal nociceptin/orphanin FQ in rats after spinal cord injury, peripheral nerve injury and inflammation

OBJECTIVE: To compare the acute and sustained renal hemodynamic effects on hypertensive patients of 100 mg irbesartan and 20 mg enalapril each once daily. PATIENTS: Twenty patients (aged 35-70 years) with uncomplicated, mild-to-moderate essential hypertension and normal serum creatinine levels completed this study. STUDY DESIGN: After random allocation to treatment (n=10 per group), administration schedule (morning or evening) was determined by further random allocation, with crossover of schedules after 6 weeks' therapy. Treatment and administration assignments were double-blind. Twenty-four-hour ambulatory blood pressure was monitored before and after 6 and 12 weeks of therapy. Renal hemodynamics were determined on the first day of drug administration and 12 and 24 h after the last dose during chronic treatment. RESULTS: Administration of each antihypertensive agent induced a renal vasodilatation with no significant change in glomerular filtration rate. However, the time course appeared to differ: irbesartan had no significant acute effect 4 h after the first dose, but during chronic administration a renal vasodilatory response was found 12 and 24 h after the dose; enalapril was effective acutely and 12 h after administration, but no residual effect was found 24 h after the dose. Both antihypertensive agents lowered mean ambulatory blood pressure effectively, with no significant difference between treatments or between administration schedules (morning versus evening). CONCLUSIONS: Irbesartan and enalapril have comparable effects on blood pressure and renal hemodynamics in hypertensive patients with normal renal functioning. However, the time profiles of the renal effects appear to differ, which might be important for long-term renoprotective effects.     

Blood viscosity in broilers: influence on pulmonary hypertension syndrome

Elevation in apparent blood viscosity may enhance the pulmonary hypertension that leads to pulmonary hypertension syndrome (PHS) and ascites in fast-growing broilers. We investigated the importance of packed cell volume (PCV) and shear rate in modifying apparent viscosity of the blood from broilers assigned to normal, preascites, and ascites groups. Apparent viscosity of broiler blood increased at all shear rates as PCV increased; the increase in apparent viscosity became greater as the shear rate decreased at PCV above 0.30. At the PCV of normal broilers (0.30 or below), apparent viscosity was nearly shear rate independent, at least down to 11.25 per second, the lowest shear rate studied. Apparent viscosity, at any given PCV and shear rate, was significantly lower in the blood of birds with ascites than in normal birds; however, the relative viscosity was not different between those groups, indicating that lower plasma viscosity in the birds with PHS was responsible for the finding. The results show that the principal factor responsible for increased apparent viscosity of blood in birds with PHS is the increase in PCV. The increased resistance to flow of blood as the result of higher blood viscosity may contribute to the pulmonary hypertension.     

Resistance to endotoxin shock in spontaneously hypertensive rats

Septic shock involves systemic vasodilation mediated by proinflammatory cytokines. In essential hypertension, vascular and immune dysfunctions are closely associated. The response of hypertensive animals compared with normotensive controls to endotoxin (lipopolysaccharide; LPS) challenge is not known. Age-matched (12 weeks) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were exposed to intravenous injection of 10 mg/kg LPS. Survival rate at 24 hours was markedly higher in SHR than in WKY (12 of 15 and 3 of 15, respectively; P<0.01). Survival of LPS-injected SHR was not related to their hypertension because hydralazine-treated SHR with normalized pressure had similar survival rates, and WKY made hypertensive by clipping of one renal artery showed fatality similar to that of normotensive WKY. Continuous arterial pressure and sequential plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured in LPS-treated SHR and WKY. Both the duration of the delayed hypotensive phase and the systemic release of IL-6 were much lower in SHR than WKY, whereas both acute hypotension and plasma TNF peak were equivalent. We further explored in vitro the inflammatory response and showed that LPS-activated whole blood from SHR produced less TNF and IL-6 than WKY LPS-activated whole blood. Our results indicate that SHR have a greater ability to resist endotoxic shock than WKY. This is not related to their hypertension but is associated with an attenuated inflammatory response to LPS.     

Sigmoidal curve-fitting of baroreceptor sensitivity in renovascular 2K1C hypertensive rats

The time course of changes in baroreceptor reflex sensitivity in Goldblatt two-kidney one clip (2K1C) hypertension was studied 3, 7 and 30 days after renal artery clipping by means of a sigmoidal curve-fitting analysis. Experiments were performed in 54 adult male Wistar rats (N = 9 per group) weighing 200-300 g. The reflex heart rate responses were elicited by alternate intravenous bolus injections of phenylephrine (delta +5 to +50 mmHg) and sodium nitroprusside (delta -5 to -50 mmHg). A clear upper and lower plateau (reflex tachycardia and bradycardia, respectively) was noted in both sham and hypertensive groups. Although the resting mean arterial pressure was significantly increased in all hypertensive groups (131 +/- 3, 149 +/- 7 and 168 +/- 11 mmHg, respectively, 3, 7 and 30 days after clipping), when compared to the sham group (108 +/- 2 mmHg), significant changes in baroreceptor reflex function were observed only in 7- and 30-day groups. Baroreflex sensitivity was markedly reduced in these hypertensive rats (2.3 +/- 0.3 and 1.9 +/- 0.3 bpm/mmHg, respectively) compared to the sham group (4.2 +/- 0.3 bpm/mmHg). In addition, a reduced baroreflex heart rate range was observed in these groups (117 +/- 12 and 107 +/- 10 bpm, respectively) compared to the sham group (165 +/- 11 bpm). These data indicate an impairment of baroreflex function in conscious 2K1C hypertensive rats which seems to be secondary to arterial hypertension.     

Effects of dipyridamole in spontaneously hypertensive rabbits with diffuse chronic cerebral ischemia

The effect of intravenous dipyridamole (0.7 mg/kg) on cerebral blood flow (CBF), mean arterial blood pressure (MABP), heart rate, respiration rate, cerebral electrical activity, arterial blood gases, pH, and glucose was investigated in 14 normotensive and 14 stroke-prone spontaneously hypertensive anesthetized rabbits. CBF was measured by hydrogen and heat clearance. In both groups, MABP decreased (normotensive: -24 mm Hg, hypertensive: -47 mm Hg; ANOVA: P < 0.0001) and CBF increased (normotensive: +59 ml/100 g/min, hypertensive: +72 ml/100 g/min; ANOVA: P < 0.0002). CBF returned to the initial level 21 min later in hypertensive than in normotensive rabbits. Changes in other parameters were insignificant. In additional experiments, 30 mg/kg theophylline entirely prevented the cerebral vasodilator and systemic hypotensive effects of dipyridamole in both normotensive and hypertensive rabbits. We conclude that, in stroke-prone spontaneously hypertensive rabbits, the longer-lasting and larger CBF increase in response to dipyridamole may be attributed to reversible functional changes in the cerebral vasculature resulting from hypertension.     

Effect of benidipine on microvascular remodeling and coronary flow reserve in two-kidney, one clip Goldblatt hypertension

OBJECTIVE: To determine whether chronic treatment with benidipine, a calcium antagonist, leads not only to regression of left ventricular hypertrophy, but also to an improvement in coronary flow reserve and microvascular remodeling. DESIGN AND METHODS: Two-kidney, one clip Goldblatt hypertensive rats were assigned either to a benidipine-treatment group or to a group without treatment after their kidneys had been clipped for 4 weeks. Benidipine was administered to rats in the treatment group for 6 weeks. At the end of the treatment, the systemic hemodynamics and coronary blood flow were determined in conscious unrestrained rats by using nonradioactive colored microspheres injected through the left atrium. The coronary blood flow was determined in rats of both groups with the rats at rest and after near-maximal vasodilatation induced by carbochrome. For evaluation of the microvascular remodeling capillary density, the wall : lumen ratio of arterioles and perivascular fibrosis were quantified by using an image analyzer after fixation of heart tissue. RESULTS: Benidipine treatment lowered the blood pressure significantly with a decrease in total peripheral resistance, and the left ventricular mass decreased markedly compared with that of untreated hypertensive rats. The coronary flow reserve of the untreated hypertensive rats was lower than that of the controls, but benidipine treatment improved the coronary flow reserve. We found a significant decrease in capillary density, and significant increases in wall : lumen ratio and perivascular fibrosis in untreated hypertensive rats. These changes in microvasculature were improved by benidipine treatment. CONCLUSION: Taken together, these results suggest that benidipine exerts favorable effects as an antihypertensive drug by reversing cardiac hypertrophy and improving the coronary flow reserve and microvascular remodeling.     

A longitudinal study of vessel wall properties in normotensive and hypertensive renal transplant recipients

The mechanisms responsible for reduced arterial distensibility in renal transplant recipients remain to be evaluated. The present longitudinal study was aimed to evaluate the effect of hypertension on the evolution of vessel wall properties in renal transplant recipients. The mechanical properties of the common carotid artery were determined in 24 normotensive and 24 treated hypertensive renal transplant recipients 6-12 weeks after transplantation. The measurements were repeated after 2 years. Arterial distension was determined by using a multigate pulsed Doppler system, blood pressure (BP) was measured by a mercury sphygmomanometer. BP was 127 +/- 3/80 +/- 2 mm Hg at entry and 133 +/- 3/82 +/- 2 mm Hg after 2 years in the normotensive group, 146 +/- 4/90 +/- 3 mm Hg at entry and 145 +/- 3/87 +/- 2 mm Hg after 2 years in the hypertensive group (P < 0.01, normotensives vs hypertensives). The distensibility coefficient (DC) decreased significantly after 2 years in the hypertensive group (DC 18.3 +/- 1.3 10(-3)/kPa before, 15.1 +/- 1.2 10(-3)/kPa after 2 years, P < 0.05) whereas no significant change was observed in the normotensive group (DC 19.0 +/- 1.4 10(-3)/kPa before, DC 17.8 +/- 1.3 10(-3)/kPa after 2 years, NS). There was a significant correlation between the change of the distensibility coefficient after 2 years and mean arterial pressure (n = 48, r = 0.42, P < 0.01). The results show that the decrease of arterial distensibility after 2 years is accelerated in hypertensive renal transplant recipients despite effective anti-hypertensive treatment. Since BP levels were not different at entry into the study and after 2 years, differences in distending pressure along cannot explain the more pronounced decrease of arterial distensibility over time in hypertensive renal transplant recipients.     

The effects of an outpatient practice guideline at a teaching hospital: a prospective pilot study

BACKGROUND: Platelet-activating factor (PAF) is a bioactive phospholipid which is a potent hypotensive agent. To investigate the role of PAF in renovascular hypertension, we determined the PAF concentration and its production level assessed by the activity of cholinephosphotransferase (CPT) in renal tissue and examined the effect of a PAF antagonist on the mean arterial pressure (MAP) in control and two-kidney with one clipped (2K1C) hypertensive rats. MATERIALS AND METHODS: The concentration of PAF and CPT in the renal medulla and cortex were determined by radioassay. Also, the effect of a PAF antagonist, CV-6209, on MAP was also examined in both 2K1C hypertensive and normal control rats. RESULTS: The PAF concentration and CPT activity were significantly higher in the medulla than in the cortex in both 2K1C hypertensive and normal control rats, and both values in the medulla were also significantly higher in the clipped kidney than in the contralateral unclipped kidney or in control rat kidneys. We also observed a significant negative correlation between the PAF concentration in the medulla, and the medulla weight in the clipped kidney of 2K1C hypertensive rats. Infusion of the PAF antagonist, CV-6209, did not affect MAP in 2K1C hypertensive rats, but was significantly increased (P < 0.05) in control rats. CONCLUSIONS: These findings suggest that PAF, whose production is induced by renal ischemia due to renal artery stenosis, plays an important role in the renomedullary vasodepressor system, but the effect of PAF as a vasodilator in the peripheral vessels is limited in 2K1C hypertension.