bluuebunny/crossref_metadata_2025 huggingface dataset:
Periventricular white matter lucency and cerebral blood flow autoregulation in hypertensive patients.
Authors: Matsushita K , Kuriyama Y , Nagatsuka K , Nakamura M , Sawada T , Omae T
Published: June 2012

The goal of this study was to elucidate the association between the development of periventricular white matter lucency and autoregulation of cerebral blood flow in hypertensive patients through the arteriovenous oxygen saturation difference method. We studied 51 hypertensive patients who had previously suffered from minor strokes (lacunar infarction, 43; deep basal minor hemorrhage, 8). Patients were divided into three groups based on the findings of periventricular white matter lucency. We measured the absolute value of resting cerebral blood flow using the argon inhalation method, and stepwise reduction of blood pressure was obtained with patients on a tilting table. Intracerebral venous blood sampling was accomplished by direct cannulation into the jugular vein up to the jugular bulb. We calculated several cerebral circulatory parameters, such as cerebrovascular resistance and cerebral oxygen consumption, and also delineated individual autoregulation curves. Cerebrovascular resistance was significantly greater in patients with severe periventricular white matter lucency than in patients without it (P < .05). Impaired autoregulation was also significantly more prevalent in patients with more severe periventricular lesions (P < .05). Multiple regression analysis revealed that the impaired autoregulation was significant and an independent determinant of the severity of such periventricular lesions (R = .34, P < .05). In conclusion, our findings indicated that hypertensive patients with severe periventricular white matter lucency were more likely to have impaired autoregulation of cerebral blood flow and suggest that stricter blood pressure control is required in such patients to prevent deterioration of the cerebral microcirculation.
Diurnal blood pressure variation and hormonal correlates in fatal familial insomnia.
Authors: Portaluppi F , Cortelli P , Avoni P , Vergnani L , Contin M , Maltoni P , Pavani A , Sforza E , degli Uberti E C , Gambetti P
Published: June 2012

Fatal familial insomnia is a prion disease in which a selective thalamic degeneration leads to total sleep deprivation, hypertension, dysautonomia, adrenal overactivity, and impaired motor functions. With patients under continuous recumbency and polysomnographic control, we assessed the changes in the 24-hour patterns of blood pressure, heart rate, plasma catecholamines, corticotropin, and serum cortisol in three patients at different stages of the disease. Six healthy volunteers were used as control subjects. A dominant 24-hour component was detected at rhythm analysis of all variables, both in patients and control subjects. In the patients, the amplitudes gradually decreased as the disease progressed, leading to the obliteration of any significant dirunal variation only in the preterminal stage. A shift in phase corresponded to the loss of the nocturnal fall in blood pressure in an early stage of the disease, when nocturnal bradycardia was still preserved. Plasma cortisol was high and became increasingly elevated, whereas corticotropin remained within normal levels; abnormal nocturnal peaks appeared in their circadian patterns. The disrupted patterns of cortisol and blood pressure preceded the development of hypertension and severe dysautonomia, which in turn were paralleled by increasing catecholamine and heart rate levels. Our data demonstrate that in patients with fatal familial insomnia the changes detectable in the rhythmic component of diurnal blood pressure variability result in a pattern of secondary hypertension. Disturbances in thalamic, pituitary-adrenal, and autonomic functions seem to be involved in mediating these changes.
Modulation of exogenous and endogenous atrial natriuretic peptide by a receptor inhibitor.
Authors: Stevens T L , Wei C M , Aahrus L L , Heublein D M , Kinoshita M , Matsuda Y , Burnett J C
Published: June 2012

Atrial natriuretic peptide is an important peptide hormone of cardiac origin that functions to regulate cardiac preload via the regulation of sodium excretion. This natriuretic action occurs through activation of the particulate guanylyl cyclase-linked natriuretic peptide-A receptor. HS-142-1 is a newly discovered antagonist of the natriuretic peptide-A receptor that permits insight into the functional role of atrial natriuretic peptide in cardiorenal homeostasis. The first objective of this study was to define for the first time the intrarenal action of HS-142-1 on exogenous atrial natriuretic peptide-mediated natriuresis in anesthetized normal dogs. In group 1 (n = 6), which received intravenous atrial natriuretic peptide at 100 ng/kg per minute, intrarenal HS-142-1 (0.5 mg/kg bolus) attenuated atrial natriuretic peptide-induced increases in glomerular filtration rate, urine flow, sodium excretion, and renal cyclic GMP generation and decreases in distal tubular sodium reabsorption. The second objective was to determine whether endogenous atrial natriuretic peptide participates in the regulation of basal sodium excretion. In group 2 (n = 6), intrarenal HS-142-1 alone decreased both absolute and fractional sodium excretion and renal cyclic GMP generation and increased distal tubular sodium reabsorption. These studies demonstrate that HS-142-1 markedly attenuates exogenous atrial natriuretic peptide-mediated natriuresis via enhancement of distal tubular reabsorption and blunting of increases in glomerular filtration rate. Second, the current studies support a functional role for endogenous atrial natriuretic peptide in the regulation of basal sodium excretion.
Renal effects of captopril and nitrendipine in transgenic rats with an extra renin gene.
Authors: Hirth-Dietrich C , Stasch J P , Ganten D , Luft F C
Published: June 2012

We investigated the acute effects of captopril and nitrendipine on renal function and sodium excretion in hypertensive, male, heterozygous transgenic rats harboring a mouse renin gene [TGR (mRen-2)27]. Both drugs reduced blood pressure dose dependently in conscious transgenic rats. The oral ED20 for captopril was 0.5 mg/kg and 2.7 mg/kg for nitrendipine. In orally salt-loaded (20 mL/kg saline) transgenic rats captopril (0.3 to 3.0 mg/kg) reduced sodium excretion by approximately 90% in the 6 hours after administration, whereas equally antihypertensive doses of nitrendipine increased sodium excretion by approximately 100%. The antinatriuretic effect of captopril was accompanied by a reduction in creatinine clearance and a decrease in the excretion of cyclic GMP. In orally water-loaded (20 mL/kg water) transgenic rats captopril also reduced sodium excretion by more than 90%, and nitrendipine slightly increased sodium excretion. In control Sprague-Dawley rats the effects were opposite; namely, captopril tended to increase natriuresis, and nitrendipine caused a small but distinct decrease in sodium excretion. Intravenous captopril in anesthetized transgenic rats caused an antinatriuresis with a decrease in inulin clearance but not in Sprague-Dawley rats. To control for non-renin-related effects of captopril, we gave transgenic rats oral losartan. Losartan also decreased urinary sodium excretion. The results suggest a role for the renin-angiotensin system in the maintenance of glomerular filtration rate and sodium excretion in transgenic TGR (mRen-2)27 rats.
Chronic inhibition of bradykinin B2-receptors enhances the slow vasopressor response to angiotensin II.
Authors: Madeddu P , Parpaglia P P , Demontis M P , Varoni M V , Fattaccio M C , Glorioso N
Published: June 2012

The contribution of endogenous kinins in the regulation of blood pressure of angiotensin-treated rats was evaluated using the new bradykinin B2-receptor antagonist Hoe 140 (D-Arg,[Hyp3,Thi5,D-Tic7, Oic8]-bradykinin). Chronic infusion of Hoe 140 at 75 nmol/d (a dose able to inhibit the vasodepressor effect of an intra-aortic bolus injection of 0.85 nmol/kg bradykinin) did not alter systolic blood pressure (tail-cuff plethysmography). Chronic infusion of angiotensin II (Ang II) induced a dose-related increase in systolic blood pressure and plasma Ang II levels. The vasopressor effect of 40 or 100 nmol/d Ang II was enhanced in rats given chronic infusion of Hoe 140 (by 12 and 14 mm Hg, respectively), whereas the increase in plasma Ang II levels remained unaltered. Furthermore, a low nonpressor dose of Ang II (20 nmol/d) was then able to increase blood pressure during chronic blockade of bradykinin receptors by Hoe 140 (from 126 +/- 3 to 137 +/- 3 mm Hg, P < .05). Combined infusion of 20 nmol Ang II and Hoe 140 did not alter the urinary excretion of sodium and water despite the fact that blood pressure was increased. Potentiation of the pressure effect of Ang II by Hoe 140 was confirmed by direct measurement of mean blood pressure (125 +/- 2 versus 108 +/- 2 mm Hg at 20 nmol, 123 +/- 2 versus 110 +/- 2 mm Hg at 40 nmol, and 139 +/- 2 versus 125 +/- 3 mm Hg at 100 nmol Ang II, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Ontogenesis of sympathetic responsiveness in spontaneously hypertensive rats. II. Renal G proteins in male and female rats.
Authors: Michel M C , Farke W , Erdbrügger W , Philipp T , Brodde O E
Published: June 2012

Previously we have reported an increased renal alpha 1- and beta-adrenergic receptor expression in male spontaneously hypertensive rats that occurred ontogenetically in parallel with blood pressure elevation. However, increased receptor numbers were not accompanied by enhanced stimulation of inositol phosphate and cyclic AMP formation, respectively, indicating relative desensitization. We have now quantified alpha-subunits of the G proteins Gs (Gs short and Gs long), G(i), and Gq by immunoblotting and pertussis toxin-catalyzed ADP-ribosylation in renal membranes from 3-, 6-, 8-, and 28-week-old normotensive and spontaneously hypertensive male Wistar-Kyoto rats; additionally, 28-week-old female normotensive and spontaneously hypertensive rats were studied. During ontogenesis of male normotensive rats, Gs short increased, Gs long remained unchanged, and G(i) alpha and Gq alpha decreased. In adult normotensive rats no sex differences were detected for Gs short, Gs long, and G(i) alpha. When male rats from the normotensive and spontaneously hypertensive strains were compared, all G protein alpha-subunits were similar in the prehypertensive phase (3 weeks). In established hypertension (28 weeks), Gs long and Gq alpha were reduced, whereas Gs short and G(i) alpha remained unchanged. Gs long was also reduced during the development of hypertension (6 and 8 weeks), whereas Gs short and G(i) alpha were not consistently altered in this phase. The reduction in Gs long seen in male adult hypertensive rats was not detectable in female hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Cell growth and Na-K-Cl cotransport responses of vascular smooth muscle cells of Milan rats.
Authors: Canessa M , Salazar G , Werner E , Vallega G , Gonzalez A
Published: June 2012

The present study examines the role of serum growth factors in the proliferative response and Na-K-Cl cotransport activity of vascular smooth muscle cells from Milan normotensive (MNS) and hypertensive (MHS) rats. Cells from thoracic aorta of both strains were cultured in 10% serum medium and made quiescent by 72 hours in 0.3% serum medium. MHS cells grown with 10% serum had a shorter population doubling time than MNS cells between passages 8 and 12 (13.8 +/- 1.7 versus 20.1 +/- 1.6 hours, P < .01, n = 4). MHS cells also exhibited a higher response of thymidine incorporation into nucleic acid to serum, epidermal, and platelet-derived growth factor BB. In MHS cells epidermal (100 ng/mL) and platelet (50 ng/mL) growth factors increased thymidine incorporation 2- and 10-fold, respectively. In MNS cells epidermal factor did not induce a significant response, and that of platelet factor was twofold lower than in MHS cells. Binding curves revealed a higher number of receptors for platelet than epidermal growth factor in both strains and a similar number of both receptors in MHS and MNS cells. Quantitative immunoblots of these receptor proteins confirmed the observation that the greater proliferation of MHS cells could not be related to a higher number of growth factor receptors. Cotransport activity (bumetanide-sensitive 86Rb influx in nanomoles per milligram protein per 5 minutes) was found to be significantly higher in MHS cells (16 +/- 3, n = 18) than MNS cells (8 +/- 3, n = 15) at confluence as well as in the log phase of serum-stimulated growth.(ABSTRACT TRUNCATED AT 250 WORDS)
Renal sensory receptor activation by calcitonin gene-related peptide.
Authors: Gontijo J R , Kopp U C
Published: June 2012

In anesthetized rats we examined whether calcitonin gene-related peptide activated renal pelvic sensory receptors and, if so, whether activation of renal pelvic calcitonin gene-related peptide receptors contributes to the inhibitory renorenal reflex response to renal mechanoreceptor stimulation. Calcitonin gene-related peptide (0.0026, 0.026, 0.26, and 2.6 mumol/L) administered into the renal pelvis increased ipsilateral afferent renal nerve activity in a concentration-dependent fashion (32 +/- 14%, 69 +/- 19%, 93 +/- 26%, and 253 +/- 48% [all P < .01], respectively). The increases in ipsilateral afferent renal nerve activity elicited by calcitonin gene-related peptide were associated with increases in contralateral urinary sodium excretion. The calcitonin gene-related peptide receptor antagonist human CGRP (h-CGRP) (8-37) (0.01, 0.1, 1.0, and 10 mumol/L) decreased the ipsilateral afferent renal nerve activity response to renal pelvic administration of calcitonin gene-related peptide (0.26 mumol/L) in a concentration-dependent fashion (29 +/- 4%, 33 +/- 12%, 76 +/- 9% [P < .01], and 86 +/- 13% [P < .01], respectively). In the presence of renal pelvic perfusion with vehicle, an increase in ureteral pressure of 5, 10, and 20 mm Hg increased ipsilateral afferent renal nerve activity by 13 +/- 7%, 41 +/- 7% (P < .01), and 95 +/- 15% (P < .01) and contralateral urinary sodium excretion by 8 +/- 1%, 24 +/- 4%, and 42 +/- 7% (all P < .05). The ipsilateral afferent renal nerve activity and contralateral natriuretic responses to graded increases in ureteral pressure (5 to 20 mm Hg) were unaltered by renal pelvic perfusion with h-CGRP (8-37) at 1.0 and 10 mumol/L.(ABSTRACT TRUNCATED AT 250 WORDS)
Decreased sensitivity to renal interstitial hydrostatic pressure in Dahl salt-sensitive rats.
Authors: Kato T , Kassab S , Wilkins F C , Kirchner K A , Granger J P
Published: June 2012

The ability of Dahl salt-sensitive (DS) rats to excrete a sodium load is significantly lower than Dahl salt-resistant (DR) rats. Because renal interstitial hydrostatic pressure (RIHP) is a major mediator of natriuresis in response to a sodium load, we proposed that the renal tubules of DS rats are less responsive to increases in RIHP than those of DR rats. To test this hypothesis, we determined the effect of direct increases in RIHP on renal excretory function in prehypertensive DS and DR rats. RIHP was directly increased by renal interstitial volume expansion via injection of 50 microL of a 2% albumin and saline solution into the renal interstitium through a chronically implanted renal interstitial catheter. RIHP, mean arterial pressure, glomerular filtration rate, urine flow rate, urinary sodium excretion, and fractional excretions of sodium, potassium, and lithium (an indicator of proximal tubule sodium handling) were measured before and after direct increases in RIHP in DS (n = 8) and DR (n = 8) rats. Baseline urine flow rate; urinary sodium excretion; fractional excretions of sodium, potassium, and lithium; RIHP; mean arterial pressure; and glomerular filtration rate were not different between DS and DR rats. Renal interstitial volume expansion in DS rats significantly increased RIHP (delta 4.7 +/- 0.8 mm Hg), urine flow rate (delta 14.5 +/- 3.4 microL/min), urinary sodium excretion (delta 2.62 +/- 0.62 mumol/min), and fractional excretions of sodium (delta 1.54 +/- 0.37%), potassium (delta 17.84 +/- 2.90%), and lithium (delta 19.68 +/- 3.52%).(ABSTRACT TRUNCATED AT 250 WORDS)
Cell-to-cell communication coordinates blood flow control.
Authors: Segal S S
Published: June 2012

The control of tissue blood flow is a dynamic process exemplified by the interaction among physical, chemical, and electrical events occurring within the vessel wall and between the vasculature and tissue parenchyma. The range of blood flow control achieved in vivo is illustrated by functional hyperemia in exercising skeletal muscle: maximal flow can exceed resting values by more than 50-fold. Blood flow control is integrated among many vessel segments, beginning with resistance arteries external to the muscle and encompassing the arteriolar network within the muscle. As metabolic demand increases, the locus of blood flow control shifts from distal arterioles, which control capillary perfusion and blood flow distribution within the tissue, to the proximal arterioles and resistance arteries, which control the total volume of flow into the muscle. A fundamental question centers on how this vasomotor activity is actually coordinated throughout the resistance network. The interaction within and among vascular segments can be explained by chemical and electrical signals to smooth muscle cells (SMCs) and endothelial cells (ECs) in response to changes in transmural pressure as well as luminal shear stress. Increasing pressure results in SMC contraction via the myogenic response. Increasing flow stimulates ECs to release autacoids (eg, nitric oxide), which relax SMCs. Pressure and flow thereby provide opposing mechanical stimuli that interact in the maintenance of vasomotor tone throughout the resistance network. Vasomotor signals are also conducted along arterioles through cell-to-cell coupling between ECs and SMCs, thereby coordinating vasomotor activity of cells within a branch and among branches.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension induced by brain grafts from fetal spontaneously hypertensive rats.
Authors: Deschepper C F , Li J S , Schiffrin E L , Welner S A
Published: June 2012

Hypothalami from fetal rats were grafted into the third ventricle of four strains of adult rats. Grafts from spontaneously hypertensive rats (SHR), in contrast to grafts from Wistar-Kyoto (WKY) rats, induced an elevation of systolic blood pressure and a thickening of the media of resistance arteries, along with corresponding alterations in the contractile properties of these vessels. However, no cardiac hypertrophy was observed. The resistance arteries of rats grafted with hypothalamic from SHR also displayed functional alterations that were similar to what is typically found in the resistance arteries of young prehypertensive SHR, ie, an increase in the sensitivity to cocaine and an impairment in the ability to relax in the presence of acetylcholine. This suggests that the brain may play a causal role in these alterations. Histological examination of sections of brains grafted with previously labeled tissue revealed that (1) there was no brain area that was systematically infiltrated by grafts from SHR and not by grafts from WKY rats; (2) the volume of the transplants appeared larger 2 weeks after the graft than the volume of the tissue originally implanted; and (3) grafts from SHR were slightly larger, displayed more individual foci, and extended farther along the anteroposterior axis than grafts from WKY rats. In addition, glial cultures derived from the hypothalami of SHR had a higher in vitro growth rate than equivalent cultures from WKY rats. It is therefore possible that the ability of brain grafts from SHR to induce hypertension is related to a higher proliferative and/or migratory potential of nonneuronal cells within the hypothalamus.
Inhibition of angiotensin-converting enzyme modulates the autoregulation of regional cerebral blood flow in hypertensive rats.
Authors: Sadoshima S , Nagao T , Ibayashi S , Fujishima M
Published: June 2012

The inhibition of angiotensin-converting enzyme activities is considered to favorably modulate the hemodynamics of the brain. We designed the present study to examine the effects of angiotensin-converting enzyme inhibitors on regional differences in the lower limits of cerebral blood flow autoregulation in spontaneously hypertensive rats. Angiotensin-converting enzyme inhibitors (either 10 mg/kg captopril or SQ 29,852 in saline) were intravenously injected 15 minutes before hemorrhagic hypotension was induced. Cerebral blood flows to the parietal cortex and thalamus were simultaneously measured by hydrogen clearance. Both captopril and SQ 29,852 significantly decreased mean arterial pressure by 14 to 18 mm Hg and also reduced calculated cerebral vascular resistance by 11% to 15% of resting values, which resulted in a well-maintained cerebral blood flow. The lower limits of autoregulation were 76 +/- 2% (mean +/- SEM) and 77 +/- 2% of resting values in the cortex and thalamus, respectively, in control rats. Administration of either captopril or SQ 29,852 significantly reduced the lower limits to 65 +/- 3% (P < .01 versus control) and 67 +/- 2% (P < .05), respectively, in the cortex, which were slightly but always larger than the 71 +/- 3% and 71 +/- 2% reduction, respectively, in the thalamus. The inhibition of angiotensin-converting enzyme activities thus may be more protective against acute hypotension for cerebral microcirculation in the cortex than in the thalamus.
Atrial natriuretic peptide and C-type natriuretic peptide in spontaneously hypertensive rats and their vasorelaxing actions in vitro.
Authors: Wei C M , Kim C H , Khraibi A A , Miller V M , Burnett J C
Published: June 2012

The present study determined circulating concentrations of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) and also investigated the vasorelaxing action of ANP and CNP on isolated contracted aorta. We also defined the vasorelaxing action of a novel and newly synthesized 27-amino acid chimera of ANP and CNP termed vasonatrin peptide (VNP), which we compared with ANP and CNP in WKY rats and SHR. Plasma and urinary cyclic GMP and sodium excretion were also investigated. Plasma ANP was increased in SHR in contrast to no change in circulating CNP. Plasma and urinary cyclic GMP and sodium excretion were no different between WKY rats and SHR. In WKY rats maximal relaxations to VNP in aortic rings without endothelium were greater than those to ANP and CNP. In SHR aortic rings the potency of VNP relaxation was preserved, the actions of ANP were enhanced, and the actions of CNP were markedly impaired. In association with these vasorelaxing actions, these data suggest that (1) circulating CNP is not different in SHR and WKY rats, but the aortic relaxing action of CNP is markedly impaired in SHR; (2) endogenous plasma ANP is significantly increased in SHR without associated increases in plasma or urinary cyclic GMP; (3) there is an increase in aortic relaxation to exogenous ANP in SHR; and (4) VNP has a potent endothelium-independent aortic relaxing action in both WKY rats and SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
Regulation of natriuretic peptide receptor A and B expression by transforming growth factor-beta 1 in cultured aortic smooth muscle cells.
Authors: Fujio N , Gossard F , Bayard F , Tremblay J
Published: June 2012

Two types of natriuretic peptide receptors (NPR-A and NPR-B) are membrane guanylate cyclases whose relative expression varies in different tissues. Because natriuretic peptides have been shown to inhibit aortic smooth muscle proliferation, we investigated the regulation of NPR-A and NPR-B in these cells under different proliferative conditions. NPR subtype mRNA levels were measured by our newly developed quantitative reverse transcription-polymerase chain reaction assay using mutated NPR-A and NPR-B cRNA as internal standards. The functional impact of their expression was determined by atrial natriuretic peptide (ANP)- and C-type natriuretic peptide (CNP)-induced stimulation of cyclic GMP production. In the intact aorta, NPR-B mRNA levels were found to be 10-fold higher than those of NPR-A. This dominance was further amplified (1000-fold) in long-term cultures (10 to 15 passages) of aortic smooth muscle cells (ASMC). Higher cyclic GMP production with CNP than with ANP was observed in cultured ASMC from Wistar-Kyoto (WKY) rats. Similar stimulation by the two agonists was noted in spontaneously hypertensive rat (SHR) cells, paralleled by a 10-fold increase in NPR-A mRNA levels and ANP stimulation of cyclic GMP in hypertensive cells. The present study also evaluated NPR-A and NPR-B mRNA control by transforming growth factor-beta 1 (TGF-beta 1), an important regulator of cell proliferation that is overexpressed in SHR ASMC. TGF-beta 1 decreased both NPR-A and NPR-B mRNA levels with a predominant effect in SHR cells at high cell density.(ABSTRACT TRUNCATED AT 250 WORDS)
Mechanisms involved in the cardiovascular-renal actions of nitric oxide inhibition.
Authors: Manning R D , Hu L , Williamson T D
Published: June 2012

The roles of the sympathetic nervous system, angiotensin II, and arginine vasopressin in the cardiovascular-renal responses to nitric oxide synthesis inhibition were examined in eight conscious dogs equipped with arterial and venous catheters and a nonoccluding bladder catheter. Nitric oxide inhibition was achieved by intravenous infusion of NG-nitro-L-arginine methyl ester (L-NAME) at 37.1 nmol/kg per minute for 140 minutes in the control group. The same dogs, after a 1-week recovery, were pretreated for 2 days with either prazosin for alpha 1 blockade, prazosin plus propranolol for alpha 1 plus beta blockade, L-158,809 for angiotensin receptor blockade, or d(CH2)Tyr(Me)arginine vasopressin for vasopressin-V1 blockade, and the L-NAME infusion was repeated. After 140 minutes of L-NAME infusion into the control group, mean arterial pressure and renal vascular resistance had increased 16% and 71%, and renal blood flow, glomerular filtration rate, urine flow, and urinary sodium excretion had decreased 33%, 16%, 61%, and 64%, respectively. The decrement in renal blood flow and glomerular filtration during L-NAME administration was unaffected by any of the neurohumoral blockers. During V1 blockade L-NAME resulted in only a 3% increase in arterial pressure, attenuation of the renal vascular resistance response, and almost total elimination of the decrease in urine flow. During angiotensin blockade the L-NAME-induced increase in arterial pressure was markedly attenuated, and the decrease in urinary sodium excretion was attenuated in the alpha 1 plus beta blockade group.(ABSTRACT TRUNCATED AT 250 WORDS)
Cyclosporine produces endothelial dysfunction by increased production of superoxide.
Authors: Diederich D , Skopec J , Diederich A , Dai F X
Published: June 2012

Vasoconstriction and hypertension are major side effects of cyclosporine therapy. The mechanism or mechanisms responsible for the vascular effects of cyclosporine are unclear. The vascular effects of cyclosporine may arise as a consequence of endothelial dysfunction induced by the agent. To test this possibility, we compared in vessels prepared in myographs endothelium-mediated relaxations of mesenteric resistance arteries of Wistar-Kyoto rats treated for 21 to 28 days with subcutaneous injections of cyclosporine (25 mg/kg per day), or vehicle. Endothelium-dependent relaxations in response to acetylcholine were impaired in arteries from cyclosporine-treated rats; the concentrations of acetylcholine required to produce 50% relaxation of norepinephrine activation (pD2) were 31.6 +/- 0.1 versus 5 +/- 0.1 nmol/L in control arteries (P < .05). Nitro-L-arginine produced comparable 10-fold decreases in sensitivity to acetylcholine in arteries from both rat groups, indicating that the relaxations were mediated by endothelium-derived nitric oxide. Acetylcholine-induced relaxations in cyclosporine-treated arteries were normalized by pretreatment of the arteries with superoxide dismutase (150 IU/mL; pD2, 3.6 +/- 0.1; P < .05); superoxide dismutase had no effect on relaxations in control arteries. SQ 29,548, an inhibitor of prostaglandin H2/thromboxane A2 receptors; H-7, an inhibitor of protein kinase C; and indomethacin did not alter relaxations in response to acetylcholine in either group of arteries. Cyclosporine-treated arteries were more sensitive than control arteries to nitroprusside, an agent that induces relaxation via nitric oxide (pD2, 1.3 and 6.2 mumol/L, respectively; P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Long-term nitric oxide synthase inhibition and distensibility of carotid artery in intact rats.
Authors: Delacrétaz E , Hayoz D , Osterheld M C , Genton C Y , Brunner H R , Waeber B
Published: June 2012

The goal of the present study was to evaluate the effect of long-term nitric oxide synthase inhibition by NG-nitro-L-arginine-methyl ester (L-NAME) on the morphology and viscoelastic properties of the carotid arteries in rats. Twelve-week-old Wistar-Kyoto rats were treated for 6 weeks with either the nitric oxide synthase inhibitor L-NAME (0.4 g/L in drinking water; L-NAME rats, n = 13) or tap water (control rats, n = 13). Age-matched spontaneously hypertensive rats (SHR, n = 14) received tap water for the same period. The internal diameter of the common carotid artery was measured continuously with an echo-tracking device with the rats under anesthesia with halothane. Intra-arterial pressure was monitored on the contralateral side. L-NAME rats exhibited arterial pressures similar to those of SHR. The distensibility pressure-curve determined in L-NAME rats was a direct continuation of that obtained in control rats. In contrast the distensibility in SHR was increased (P < .01, SHR versus L-NAME rats). Carotid artery cross-sectional area and left ventricular weight index were increased similarly in SHR and L-NAME rats compared with control rats. Thus the hypertension caused by long-term nitric oxide synthesis inhibition was not associated with the increased arterial distensibility observed in SHR despite similar blood pressure elevations, similar arterial hypertrophy, and consequently similar wall stress. This suggests a role for nitric oxide in regulating the mechanical behavior of arteries exposed to high blood pressure.
Antihypertensive effect of pioglitazone is not invariably associated with increased insulin sensitivity.
Authors: Zhang H Y , Reddy S R , Kotchen T A
Published: June 2012

Hypertension is often associated with insulin resistance, and several chemically diverse agents that increase insulin sensitivity attenuate the development of experimental hypertension. We undertook the present study to determine whether attenuation of hypertension by pioglitazone, a thiazolidinedione derivative that increases insulin sensitivity without increasing insulin secretion, is specifically related to its effect on insulin-mediated glucose uptake. Pioglitazone administered daily by oral gavage (20 mg/kg per day) for 3 weeks attenuated the development of hypertension in both the Dahl salt-sensitive (DS) rat (an insulin-resistant model of hypertension) and the one-kidney, one clip rat (a model of hypertension not associated with insulin resistance). Based on euglycemic insulin clamp studies in conscious animals, the glucose clearance rate was increased (P < .05) in pioglitazone-treated DS rats (36 +/- 3 mg/kg per minute) compared with control DS rats (27 +/- 1 mg/kg per minute). However, pioglitazone did not affect the glucose clearance rate in one-kidney, one clip hypertensive rats. Metformin, an unrelated agent that also improves glucose tolerance, had no significant effect on blood pressure or glucose clearance rate in either DS or one-kidney, one clip rats. Thus, the hypotensive effect of pioglitazone is not invariably associated with its capacity to improve insulin-induced glucose utilization.
Effects of aging on blood pressure variability in resting conditions.
Authors: Veerman D P , Imholz B P , Wieling W , Karemaker J M , van Montfrans G A
Published: June 2012

The objective of this study was to determine the effect of aging on beat-to-beat blood pressure and pulse interval variability in resting conditions and to determine the effect of aging on the sympathetic and vagal influence on the cardiovascular system by power spectral analysis of blood pressure and pulse interval. We studied three groups of healthy, normotensive subjects: young (10 to 15 years, n = 16), adult (20 to 40 years, n = 16), and elderly (70 to 90 years, n = 25). Beat-to-beat blood pressure was measured by Finapres during 20 minutes supine and 10 minutes standing. Overall systolic and diastolic blood pressures and pulse interval variability were determined as SD and as coefficient of variation. Also, relative powers of the mid-frequency (0.08 to 0.12 Hz) and high-frequency bands (0.15 to 0.40 Hz) were determined by spectral analysis. In these subjects no differences in blood pressure variability (either as SD or coefficient of variation) were found between age groups, except for the coefficient of variation of standing diastolic blood pressure, which decreased with aging. Pulse interval variability decreased with aging. Power of the mid-frequency band of systolic and diastolic blood pressures was markedly decreased in the elderly, especially in the standing position. Power of the high-frequency band of pulse interval was also decreased in the elderly. Baroreflex sensitivity calculated by fast Fourier transformation spectral analysis was decreased in the elderly subjects compared with the younger groups. In conclusion, we found no change in the overall variability of blood pressure with aging. Mid-frequency spectral power of blood pressure and mid- and high-frequency spectral powers of pulse interval variability were decreased in the elderly. These results suggest that aging does not merely influence the magnitude of blood pressure and pulse interval variability but causes a complex rearrangement of the variability pattern by changes in neurocardiovascular regulation.
Local renin-angiotensin system in the microcirculation of spontaneously hypertensive rats.
Authors: Vicaut E , Hou X
Published: June 2012

We studied the local renin-angiotensin system in the microcirculation of cremaster muscle in spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WKY) controls. We used intravital microscopy in an original preparation of cremaster isolated from its normal blood supply and externally perfused with physiological solution, thus allowing the exclusion of circulating converting enzyme, circulating renin, and circulating angiotensinogen. We classified arterioles studied as second-, third-, and fourth-order, with mean diameters, respectively, of 67 +/- 6, 35 +/- 2, and 17 +/- 1 microns in WKY controls and 61 +/- 5, 34 +/- 2, and 16 +/- 1 microns in SHR. No difference between WKY controls and SHR was found for arteriolar vasoconstrictions in response to topical administration of 0.01 to 1 nmol/mL angiotensin II. Conversely, in response to 0.01 to 1 nmol/mL angiotensin I, significantly more arteriolar vasoconstriction was found in SHR cremaster muscle. In both strains, responses to angiotensin I were significantly inhibited by 10 nmol/mL of the angiotensin-converting enzyme inhibitor lisinopril. When angiotensinogen-rich, renin-free plasma containing 2.3 nmol/mL angiotensinogen was administered, almost no vasoconstriction was found in WKY controls, but significant constrictions were observed in SHR (23 +/- 4%, 30 +/- 5%, and 41 +/- 4% for second-, third-, and fourth-order arterioles, respectively). In SHR, vasoconstriction in response to angiotensinogen-rich, renin-free plasma was dose dependent, was inhibited by lisinopril, and was not found 24 hours after bilateral nephrectomy. Topical administration of 1.2 micrograms/mL renin did not induce arteriolar vasoconstriction in either WKY or SHR cremaster muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
Lesions in rostral ventromedial or rostral ventrolateral medulla block neurogenic hypertension.
Authors: Varner K J , Vasquez E C , Brody M J
Published: June 2012

Neurogenic hypertension results from the removal of inhibitory baroreceptor afferent input to vasomotor systems in the central nervous system. We sought to determine whether the bilateral destruction of neurons in the rostral ventrolateral or rostral ventromedial medulla, made using microinjections of N-methyl-D-aspartic acid (30 nmol in 200 nL), would block the acute increase in arterial pressure after sinoaortic deafferentation in pentobarbital-anesthetized rats. Bilateral lesions of the rostral ventrolateral or rostral ventromedial medulla decreased mean arterial pressure (107 +/- 4 to 78 +/- 5 and 115 +/- 3 to 94 +/- 3 mm Hg, respectively). In rostral ventrolateral or rostral ventromedial medulla lesioned rats, sinoaortic deafferentation failed to increase arterial pressure. Sham lesions or lesions placed rostral to the rostral ventrolateral or rostral ventromedial medulla did not significantly lower arterial pressure. Subsequent sinoaortic deafferentation significantly increased mean arterial pressure (109 +/- 3 to 145 +/- 4 and 109 +/- 5 to 141 +/- 3 mm Hg, respectively). In eight rats we used an infusion of angiotensin II to return arterial pressure to control levels after lesion of the rostral ventrolateral (n = 4) or rostral ventromedial (n = 4) medulla. In these animals, sinoaortic deafferentation failed to increase arterial pressure. We conclude that neurons in the rostral ventrolateral and rostral ventromedial medulla are involved in the normal maintenance of arterial pressure and the development of hypertension after sinoaortic deafferentation in pentobarbital-anesthetized rats.
Inhibitory effect of ammonium chloride on acetylcholine-induced relaxation.
Authors: Ando K , Fujita T
Published: June 2012

We designed the present study to clarify whether the intracellular pH change by ammonium chloride influences endothelium-dependent relaxation in thoracic aorta of 9-week-old Sprague-Dawley rats. Intracellular alkalinization with 3 mmol/L ammonium chloride, which did not affect resting vascular tone, attenuated acetylcholine-induced relaxation but not nitroglycerin vasodilation. Acetylcholine relaxation was more inhibited by a shorter duration of treatment. Thus, change in intracellular pH may be important in the effect because the alkalinizing effect of ammonium chloride disappears gradually. In support of this, the proton ionophore nigericin abolished the effect. Also, amiloride shortened the effect of ammonium chloride, suggesting that intracellular pH plays a role: sodium-proton antiport antagonizes the disappearance of ammonium chloride-induced intracellular alkalinization. The synthesis of vasoconstrictor prostaglandins, such as thromboxane A2, may be stimulated during acetylcholine treatment, resulting in the attenuation of acetylcholine relaxation, because the relaxation was abolished by treatment with the phospholipase A2 inhibitor quinacrine, cyclooxygenase inhibitor indomethacin, prostaglandin H2/thromboxane A2 receptor antagonist S1452, and thromboxane A2 synthase inhibitor dazmegrel. Phospholipase A2 may contribute to the effect of intracellular alkalinization, which is compatible with the fact that the optimal pH of phospholipase A2 is neutral to alkaline. In addition, superoxide dismutase attenuated the effect of ammonium chloride. In conclusion, intracellular alkalinization by ammonium chloride attenuated acetylcholine-induced relaxation, possibly through the interrelated production of both thromboxane A2 and superoxide radicals.
Renal ablation acutely transforms 'benign' hypertension to 'malignant' nephrosclerosis in hypertensive rats.
Authors: Bidani A K , Griffin K A , Plott W , Schwartz M M
Published: June 2012

The present studies examine the consequences of the hemodynamic changes associated with approximately 5/6 renal ablation in the spontaneously hypertensive rat (SHR), a strain that normally does not exhibit evidence of vascular and/or glomerular injury until late in life despite significant hypertension. Control SHR with intact renal mass demonstrated normal renal autoregulation and an absence of vascular or glomerular injury. Renal mass reduction resulted in an initial expected decrease in renal blood flow to the remnant kidney at 5 days (2.8 +/- 0.3 mL/min) compared with control SHR (8.1 +/- 0.7 mL/min) at a mean arterial pressure of approximately 160 mm Hg (P < .01). By 10 to 14 days after renal ablation, marked renal vasodilation was observed (renal blood flow 8.3 +/- 0.8 mL/min at mean arterial pressure of approximately 160 mm Hg) along with severe impairment of autoregulatory ability. Striking and florid vascular injury to interlobular arteries and afferent arterioles had also developed by 10 to 14 days after approximately 5/6 renal ablation in a pattern similar to that observed in "malignant" hypertension, despite systolic blood pressures that were not significantly different from those in control SHR (168.2 +/- 6.4 versus 165.6 +/- 4.7 mm Hg). An additional group of SHR that were made normotensive with a triple-therapy antihypertensive regimen before and after approximately 5/6 renal ablation also exhibited hemodynamic changes similar to those in the untreated rats at 10 to 14 days but did not develop significant vascular or glomerular injury.(ABSTRACT TRUNCATED AT 250 WORDS)
Spontaneously hypertensive versus control rat aorta response to neutrophil-derived factors.
Authors: Nigro D , Sannomiya P , de Carvalho M H , Scivoletto R , Fortes Z B
Published: June 2012

We designed experiments to study the interaction of activated rat peritoneal neutrophils with aortas from spontaneously hypertensive rats (SHR) compared with those from normotensive rats. In aortic rings precontracted with phenylephrine, neutrophils obtained from normotensive rats caused a cell number-dependent relaxation of normotensive rat aorta with or without endothelium, whereas relaxation (at lower concentrations) followed by contraction (at higher concentrations) was observed in SHR aorta with endothelium. In SHR aortic rings denuded of endothelium, neutrophils did not induce contraction. The relaxation might be due to a factor indistinguishable from nitric oxide. The contraction might be due to prostaglandin H2 because it was blocked by indomethacin, a cyclooxygenase inhibitor, and ridogrel, a thromboxane A2 synthetase inhibitor/thromboxane A2-prostaglandin H2 antagonist, but not by superoxide dismutase, a superoxide anion scavenger, or dazoxiben, a thromboxane A2 synthetase inhibitor. SHR neutrophils caused a cell number-dependent relaxation of normotensive rat aorta with or without endothelium, whereas relaxation followed by contraction was observed in SHR aorta with endothelium. In SHR aortic rings denuded of endothelium, neutrophils did not induce contraction. The relaxation might be due to a factor indistinguishable from nitric oxide. The contraction seems to be due to superoxide anion because it was inhibitable by indomethacin and superoxide dismutase but not by dazoxiben and ridogrel. Equivalent amounts of superoxide anion were produced by unstimulated and phorbol myristate acetate-stimulated neutrophils obtained from either SHR or normotensive rats. Therefore, increased production of this anion could not explain the contraction observed in hypertensive aortas.(ABSTRACT TRUNCATED AT 250 WORDS)
Racial differences in the age-related increase in left ventricular mass in youths.
Authors: Harshfield G A , Koelsch D W , Pulliam D A , Alpert B S , Richey P A , Becker J A
Published: June 2012

We determined the factors related to left ventricular mass adjusted for body size in 60 black (mean age, 13 +/- 2 years) and 40 white (mean age, 14 +/- 2 years) normotensive youths. The factors examined included age, sex, systolic blood pressure, diastolic blood pressure, plasma renin activity, plasma aldosterone concentration, and sodium and potassium intake as determined by 24-hour excretion. Sex (beta = 13.3, P < .003), age (beta = 2.88, P < .001), and systolic blood pressure (beta = 0.41, P < .02) were independent predictors in the sample as a whole, accounting for 37% of the variance of left ventricular mass adjusted for height. Separate analyses were performed for black and white subjects. In the black subjects, age (beta = 4.4, P < .004) followed by sex (beta = 11.85, P < .02) were independent factors, accounting for 43% of the variance of left ventricular mass adjusted for height. In contrast, in white subjects systolic blood pressure (beta = 0.4, P < .003) followed by sodium excretion (beta = 0.13, P < .05) were independent factors, with gender (beta = 8.89, P < .07) tending to account for 36% of the variance. Similar results were observed for left ventricular mass adjusted for body surface area. In conclusion, the age-related increase in adjusted left ventricular mass in black but not white youths may in part account for the early development of cardiovascular disease among the black population.
Biochemical Effects of Losartan, a Nonpeptide Angiotensin II Receptor Antagonist, on the Renin-Angiotensin-Aldosterone System in Hypertensive Patients
Authors: Goldberg Michael R. , Bradstreet Thomas E. , McWilliams Edward J. , Tanaka Wesley K. , Lipert Stephanie , Bjornsson Thorir D. , Waldman Scott A. , Osborne Barbara , Pivadori Lisa , Lewis George , Blum Robert , Herman Theodore , Abraham Paul A. , Halstenson Charles N. , Lo Man-Wai , Lu Hannah , Spector Reynold
Published: June 2012

Abstract
We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n=51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist.