bluuebunny/crossref_metadata_2025 huggingface dataset:
Annexins V and VI: major calcium-dependent atrial secretory granule-binding proteins.
Authors: Doubell A F , Bester A J , Thibault G
Published: June 2012

Atrial natriuretic peptide is stored by atrial myocytes in secretory granules, known as atrial specific granules, and is released from these granules by exocytosis. We have isolated a group of atrial proteins by affinity chromatography that bind to atrial specific granules in a calcium-dependent manner. The two major proteins isolated (32.5 kd and 67 kd) are calcium-binding proteins and have been identified as annexins V and VI by immunoblotting with specific antisera. The calcium dependence of their binding to atrial specific granules has been characterized in vitro and indicates that this interaction takes place at micromolar levels of calcium. In addition, the group of proteins isolated includes another calcium-binding protein of 20 kd, as well as GTP-binding proteins of 22 to 26 kd. Membrane interactions during exocytosis are presumably mediated by the interaction of specific proteins with the granule membrane. The properties of the proteins described here, and their ability to bind to atrial specific granules in a calcium-dependent manner, make them likely candidates in the search for regulatory proteins mediating atrial natriuretic peptide secretion.
Increased vascular responsiveness to bradykinin in kidneys of spontaneously hypertensive rats. Effect of N omega-nitro-L-arginine.
Authors: Cachofeiro V , Nasjletti A
Published: June 2012

We investigated the role of nitric oxide (NO)-dependent and NO-independent mechanisms in mediation of renal vasodilatory responses to bradykinin in spontaneously hypertensive rats (SHR), rats with angiotensin II-induced hypertension (200 ng/min i.p. for 6 days) and the corresponding normotensive control Wistar-Kyoto (WKY) rats and sham-infused rats. To this end, we contrasted the effects of arterial injections of bradykinin and other vasodilators, acetylcholine and sodium nitroprusside, on perfusion pressure and output of cyclic GMP in isolated kidneys perfused with Krebs bicarbonate buffer containing phenylephrine, both with and without N omega-nitro-L-arginine (L-NOARG) (50 microM), an inhibitor of NO synthetase. In kidneys perfused without L-NOARG, all agonists increased the output of cyclic GMP and reduced perfusion pressure, indicative of vasodilation. In kidneys perfused with L-NOARG, vasodilatory responses to bradykinin and acetylcholine were attenuated, and associated effects on output of cyclic GMP were abolished, suggesting dependency on NO synthesis. Irrespective of whether kidneys were perfused with or without L-NOARG, kidneys of SHR were more responsive than kidneys of WKY rats with regard to bradykinin-induced vasodilation. In contrast, vasodilatory responsiveness to bradykinin was nearly equal in perfused kidneys of rats with angiotensin II-induced hypertension and in normotensive controls. Also, vasodilatory responsiveness to acetylcholine and sodium nitroprusside was similar in kidneys of normotensive and hypertensive rats. These data suggest that the renal vasculature of SHR is uniquely and selectively hyperresponsive to bradykinin, with regard to both the NO-dependent and NO-independent vasodilatory actions.
Sequence analysis of the alpha 1 Na+,K(+)-ATPase gene in the Dahl salt-sensitive rat.
Authors: Simonet L , St Lezin E , Kurtz T W
Published: June 2012

In the inbred Dahl salt-sensitive rat (SS/Jr strain), it has been proposed that a T for A transversion in the DNA sequence encoding amino acid 276 in the alpha 1 subunit isoform of Na+,K(+)-ATPase may impair ion transport and contribute to the pathogenesis of hypertension. This hypothesis is of major scientific interest because it represents the first attempt to explain the pathogenesis of salt-sensitive hypertension on the basis of a specifically defined mutation at the DNA level. We devised a polymerase chain reaction technique to screen the genomic DNA of multiple SS/Jr rats for the T for A transversion reported in the complementary DNA (cDNA) encoding the alpha 1 subunit of Na+,K(+)-ATPase. When eight Dahl SS/Jr rats from Harlan Sprague Dawley Inc. were tested with the polymerase chain reaction technique, we found no evidence of this mutation in the Na+,K(+)-ATPase gene. Direct sequence analysis of the gene in three SS/Jr rats also did not show the T for A transversion. These results 1) strongly suggest that commercially available Dahl SS/Jr rats do not carry a T for A transversion in the genomic DNA sequence encoding amino acid 276 in the alpha 1 subunit isoform of Na+,K(+)-ATPase and 2) raise the possibility that the previous finding of a mutation in the cDNA of the SS/Jr rat may have been due to a reverse transcriptase error during cDNA synthesis.
Effects of angiotensin subtype 1 and subtype 2 receptor antagonists in normotensive versus hypertensive rats.
Authors: Tofovic S P , Pong A S , Jackson E K
Published: June 2012

The purpose of this study was to examine in vivo the importance of angiotensin subtype 1 (AT1) versus subtype 2 (AT2) receptors in spontaneously hypertensive (hypertensive) versus normotensive Wistar-Kyoto (control) rats. Intravenous infusions of DuP 753, a selective AT1 receptor antagonist, abolished the pressor responses to intravenous infusions of angiotensin II in both strains, and the potency of DuP 753 in this regard was similar in the two strains. DuP 753 also abolished angiotensin II-induced aldosterone release in both strains; however, with respect to inhibiting angiotensin II-induced aldosterone release, DuP 753 was more potent in hypertensive compared with control rats. In hypertensive but not control rats, DuP 753 inhibited angiotensin II-induced aldosterone release at doses lower than required to inhibit angiotensin II-induced pressor responses. Intramesenteric infusions of DuP 753 abolished mesenteric vascular responses to intramesenteric infusions of angiotensin II with a similar potency in both strains. In control but not hypertensive rats, angiotensin II consistently potentiated noradrenergic neurotransmission in the mesenteric vascular bed, and this effect of angiotensin II was abolished by DuP 753. High doses of PD123177, a selective AT2 antagonist, did not influence any of the aforementioned effects of angiotensin II in either strain.(ABSTRACT TRUNCATED AT 250 WORDS)
Abnormal renal hemodynamics in black salt-sensitive patients with hypertension.
Authors: Campese V M , Parise M , Karubian F , Bigazzi R
Published: June 2012

African-Americans with essential hypertension are more prone to the development of renal failure and are frequently salt-sensitive as well. Because alterations of intrarenal hemodynamics are important in the progression of renal disease and because salt-sensitive animal models with hypertension manifest a greater propensity to develop glomerulosclerosis in association with a rise in glomerular capillary pressure, we tested whether the renal hemodynamic adaptation to high dietary Na+ intake differs in salt-sensitive and salt-resistant hypertensive patients. We studied 17 black and nine white patients with essential hypertension who were placed on a low Na+ diet (20 meq/day) for 9 days, followed by a high Na+ diet (200 meq/day) for 14 days. During the last 4 days of each diet regimen, they received 30 mg/day of slow-release nifedipine. Eleven blacks were salt-sensitive, and all whites were salt-resistant. During the low Na+ diet period, salt-sensitive and salt-resistant patients had similar mean arterial pressure, glomerular filtration rate, effective renal plasma flow, and filtration fraction.(ABSTRACT TRUNCATED AT 250 WORDS)
Epinephrine and the genesis of hypertension.
Authors: Floras J S
Published: June 2012

Several lines of evidence suggest a psychophysiological link between stress, adrenomedullary activation, and the genesis of hypertension. Experimental data support four important concepts: 1) epinephrine stimulates prejunctional beta 2-adrenergic receptors that facilitate norepinephrine release from sympathetic nerve endings; 2) epinephrine can be converted into a cotransmitter by neuronal uptake and on subsequent release augment the simultaneous discharge of norepinephrine; 3) exogenous epinephrine can induce sustained hypertension in rats; and 4) there is a period of critical sensitivity to endogenous epinephrine in a genetic model of rat hypertension. Plasma epinephrine concentrations are elevated in many young subjects with borderline or mild hypertension. The hypothesis that intermittent surges in epinephrine could initiate or promote the development of primary hypertension by amplifying peripheral neurotransmission, both directly (facilitative effect) and indirectly (cotransmitter action), is supported by reports that hemodynamic and noradrenergic responses to sympathetic activation can be augmented by increases in endogenous epinephrine or by its local or systemic (up to 30 ng/kg/min) infusion. Such responses have been documented in both normotensive and hypertensive subjects and can be blocked by propranolol. Although the weight of evidence (mostly indirect) indicates that epinephrine can augment norepinephrine release in humans, the epinephrine hypothesis, itself, remains unproven. Expression of hypertension by this mechanism may be restricted to a specific epinephrine-sensitive subset of individuals with a genetic predisposition to high blood pressure.
Potentiation of inositol trisphosphate production by dexamethasone.
Authors: Sato A , Suzuki H , Iwaita Y , Nakazato Y , Kato H , Saruta T
Published: June 2012

One of the mechanisms of glucocorticoid-induced hypertension has been thought to be the enhancement of vascular responsiveness to vasoconstrictors. In this regard, the effects of glucocorticoids on inositol trisphosphate production in vascular smooth muscle cells were studied. Angiotensin II and arginine vasopressin transiently increased inositol trisphosphate formation in a dose-dependent manner. Pretreatment with dexamethasone for 48 hours shifted the dose-response trisphosphate curves of angiotensin II- and arginine vasopressin-induced inositol trisphosphate production to the left, that is, it significantly reduced the half-maximal effective concentrations of angiotensin II (from 25 nM to 5 nM) and arginine vasopressin (from 50 nM to 25 nM). These effects of dexamethasone required a minimum of 12 hours of incubation; maximum effect was observed after 24 hours of treatment. A glucocorticoid antagonist, RU 38486, completely blocked these effects. To elucidate the interaction with prostaglandin, we used indomethacin, a potent inhibitor of prostaglandin synthesis. Treatment with indomethacin shifted the dose-response curves of angiotensin II- and arginine vasopressin-induced inositol trisphosphate production to the left. However, this shift was less than that seen after dexamethasone treatment. Indomethacin alone did not completely reproduce dexamethasone effects, and no additive effect between indomethacin and dexamethasone was observed. These results suggest, at least in part but not entirely, that the effects of dexamethasone depended on prostaglandin synthesis inhibition. We concluded that glucocorticoids altered the responsiveness of vascular smooth muscle cells to angiotensin II and arginine vasopressin through a glucocorticoid-specific receptor. These actions strongly support the mechanism by which the glucocorticoid induced hypertension through the increased sensitivity to vasoconstrictors.
Modulation of potassium channels by antiarrhythmic and antihypertensive drugs.
Authors: Sanguinetti M C
Published: June 2012

Agents that modulate cardiac and smooth muscle K+ channels have stimulated considerable interest in recent years because of their therapeutic potential in a number of cardiovascular diseases. Foremost among these drugs are the so-called Class III antiarrhythmic agents, which act by prolonging cardiac action potentials, and K+ channel openers, which hyperpolarize and thereby relax smooth muscle cells. Many of the newly developed Class III antiarrhythmic agents probably act by specific block of one subtype of delayed rectifier K+ current, IKr, whereas other agents block more than one type of cardiac K+ current. Much controversy exists over the specific type of K+ channel (or channels) in smooth muscle that are activated by the K+ channel openers. Both groups of K+ channel modulators have great therapeutic promise, but the Class III antiarrhythmic agents may suffer from a side-effect that is directly linked to their specific mechanism of action.
Higher blood pressure in adults with less education. Some explanations from INTERSALT.
Authors: Stamler R , Shipley M , Elliott P , Dyer A , Sans S , Stamler J
Published: June 2012

An inverse association between social class and disease has frequently been reported; education, an indicator of social class, was negatively related to blood pressure in several studies. Reasons are not clear. INTERSALT, an international study on electrolytes and blood pressure, obtained data on years of education for 10,079 adults in 52 centers in 32 countries. Data presented here are for 47 centers, omitting five where the population in the sample had no education or no differences in educational level. Regression coefficients were calculated for the education-blood pressure association in each center. An inverse association was found for men in 28 centers and for women in 38. Center coefficients were combined to give a studywide estimate of that association. When adjusted only for age, systolic pressure in men was 1.3 mm Hg higher for 10 fewer years of education (p less than 0.05) and for women 4.5 mm Hg higher (p less than 0.001). However, when adjusted also for five lifestyle factors (24-hour sodium and potassium excretion, body mass index, alcohol intake, and smoking), these estimates were reduced by about one half, and the inverse association was no longer significant for men. Similar findings were obtained for diastolic pressure. Those with less education had on average higher sodium excretion, lower potassium excretion, greater body mass, and higher alcohol intake, all factors tending to increase blood pressure. Improvement of these factors, which help explain the differences in blood pressure related to years of education, has the potential to reduce the blood pressure disadvantage associated with lower socioeconomic status.
Disturbed calcium metabolism in offspring of hypertensive parents.
Authors: Yamakawa H , Suzuki H , Nakamura M , Ohno Y , Saruta T
Published: June 2012

To assess a possible heritability of a disturbed calcium metabolism in relation to blood pressure regulation, 28 young normotensive offspring of either hypertensive or normotensive parents were studied while administered a defined diet with daily sodium chloride of 6 and 20 g/day for 7 days each. Before the high salt diet was begun, the cytosolic calcium concentration ([Ca2+]i) in platelets was elevated in offspring of hypertensive parents, whereas serum electrolytes, plasma renin activity, plasma catecholamines, and 24-hour urinary excretion of sodium and calcium showed no difference between the two groups. On exposure to a high salt diet, the mean blood pressure increased (from 80 +/- 2 to 85 +/- 2 mm Hg, p less than 0.05) in offspring of hypertensive parents. These changes in mean blood pressure were positively correlated with the basal platelet [Ca2+]i (r = 0.61, p less than 0.01), whereas [Ca2+]i did not demonstrate any significant changes. When the subjects were administered the high salt diet, plasma ionized calcium decreased (from 2.37 to 2.21 meq/l, p less than 0.05) and 1,25-dihydroxyvitamin D3 increased (from 32.7 to 40.8 pg/ml, p less than 0.05) with a transient relative hypercalciuria in offspring of hypertensive parents. This increase of 1,25-dihydroxyvitamin D3 was significantly correlated with the changes in mean blood pressure (r = 0.62, p less than 0.01). Disturbed intraplatelet and systemic calcium metabolism may be of predictive value in the development of hypertension.
Beneficial effects of a potassium- and magnesium-enriched salt alternative.
Authors: Mervaala E M , Himberg J J , Laakso J , Tuomainen P , Karppanen H
Published: June 2012

The effects on blood pressure and the development of cardiac hypertrophy of sodium chloride (regular salt) and a novel potassium-, magnesium-, and l-lysine-enriched salt alternative, which in a previous study prolonged the life span of hypertensive rats nearly threefold as compared with the animals receiving regular salt, were compared both in spontaneously hypertensive rats and their hypertension-resistant genetic controls. In particular, the possible protective effect of increased intakes of potassium, magnesium, and l-lysine during a high intake of sodium chloride was examined. Therefore, the salt alternative was added at 1.75 times higher levels to produce the same dietary levels of sodium chloride in the regular salt and the salt alternative groups. Regular salt produced a remarkable left ventricular hypertrophy in both rat strains, but as compared with the respective control groups, it induced an increase of blood pressure only in the spontaneously hypertensive rats. The salt alternative did not induce a rise in blood pressure in either of the rat strains, nor did it produce left ventricular hypertrophy in the hypertension-resistant rats and, in the spontaneously hypertensive animals, significantly less hypertrophy than regular salt. The salt alternative appeared to prevent the sodium chloride-induced volume load since plasma levels of atrial natriuretic peptide were increased in the regular salt groups but remained normal in the salt alternative groups. Therefore, potassium, magnesium, and/or l-lysine of the salt alternative produced a powerful protection against the harmful effects of sodium chloride.
Rat adrenal cortex is a source of a circulating ouabainlike compound.
Authors: Ludens J H , Clark M A , Robinson F G , DuCharme D W
Published: June 2012

To determine if the adrenal gland may be the source of plasma-borne ouabainlike compound (OLC) in rats, we 1) measured immunoreactivity expressed as OLC equivalents in extracts from a wide variety of central and peripheral tissues and, for adrenal cortex and medulla, chromatographed the extracts to determine to what extent immunoreactivity in the adrenal was OLC, and 2) measured OLC in the plasma of adrenalectomized and adrenal demedullectomized rats. The highest levels of immunoreactivity were found in adrenal cortex, adrenal medulla, atria, and the pituitary. Based on high-performance liquid chromatographic retention time, immunoreactivity in the adrenal cortex was almost exclusively immunoreactive OLC. Removal of this rich source of OLC from rats resulted in an approximate 50% decrease in circulating levels of OLC by 6 days after removal. Furthermore, although adrenal demedullectomy also caused a decrease in OLC 3 days after surgery, the decline was sustained only with total adrenalectomy, in that plasma levels of OLC in demedullectomized rats 6 days after surgery had returned to levels equal to those of sham controls. Taken together, these findings strongly suggest that the adrenal cortex is a major contributor to circulating OLC in the rat.
Attenuated afferent arteriolar response to acetylcholine in Goldblatt hypertension.
Authors: Ortenberg J M , Cook A K , Inscho E W , Carmines P K
Published: June 2012

We tested the hypothesis that endothelium-dependent afferent arteriolar vasodilation is impaired in the nonclipped kidney of two-kidney, one clip Goldblatt hypertensive rats relative to sham-operated controls. Five to six weeks after positioning of a 0.25-mm clip on the left renal artery, systolic pressure averaged 173 +/- 10 mm Hg in Goldblatt rats and 118 +/- 4 mm Hg in controls (p less than 0.01). The right kidney was harvested for videometric study of the microvasculature using the in vitro blood-perfused juxtamedullary nephron technique. Kidneys from Goldblatt and control rats were perfused at renal arterial pressures of 150 and 110 mm Hg, respectively. Afferent arteriolar inside diameter did not differ between control (20.3 +/- 0.7 microns) and Goldblatt (21.1 +/- 1.7 microns) kidneys. Determination of afferent responses to increasing concentrations of the endothelium-dependent vasodilator acetylcholine (1 nM to 10 microM) in the bathing solution unveiled a shift to the right in the dose-response relation in Goldblatt rats. Afferent arterioles from control kidneys dilated significantly when exposed to 1 nM acetylcholine, whereas a 1,000-fold higher concentration was required to dilate arterioles from Goldblatt rats. Sodium nitroprusside, an endothelium-independent vasodilator, increased afferent diameter to a similar extent in both groups. In a separate group of normal kidneys, vasodilator responses to 10 microM acetylcholine were completely blocked by 1,000 microM nitro-L-arginine, an inhibitor of nitric oxide synthesis. Thus, endothelium-dependent afferent vasodilation appears to be impaired in the nonclipped kidney of Goldblatt hypertensive rats. This phenomenon could contribute to the altered renal hemodynamic status characteristic of Goldblatt hypertension.
Cardiac pumping ability following reversal of hypertrophy and hypertension in spontaneously hypertensive rats.
Authors: Spech M M , Ferrario C M , Tarazi R C
Published: June 2012

Direct measurements of arterial pressure, stroke volume (SV), and cardiac output (CO) were obtained in ether-anesthetized rats with established spontaneous hypertension (SHR) treated with alpha-methyldopa and compared to both untreated hypertensive and normotensive Wistar-Kyoto (WKY) rats. Left ventricular pumping ability was determined by the maximum levels of SV and CO reached during rapid intravenous volume loading with blood. Treatment with methyldopa reduced the SHR arterial blood pressure (average 57 mm Hg) and reversed the cardiac hypertrophy toward normal. In comparison to untreated SHR, therapy increased heart rate and CO and decreased peripheral resistance. During volume-loading, the levels of SV and CO at matched left ventricular end-diastolic pressures were significantly higher in treated vs untreated SHR. To evaluate the role of blood pressure in the improved peak pumping ability observed in treated rats, a phenylephrine infusion was used to equalize pressures while repeating cardiac function studies. In normotensive WKY and untreated SHR, left ventricular pump function was not greatly affected. A pronounced depression in peak SV and peak CO was observed only in treated SHR. The data indicate that treatment with methyldopa is associated with improved ventricular function in part related to the reduction in arterial pressure.
Hypotensive action of captopril and saralasin in intact and anephric spontaneously hypertensive rats.
Authors: Hutchinson J S , Mendelsohn F A , Doyle A E
Published: June 2012

Intravenous injection of the converting enzyme inhibitor SQ14,225 (captopril, 2 mg/kg) reduced the blood pressure of anesthetized, spontaneously hypertensive rats (SHR) progressively over a 3-hour period. An indistinguishable fall in blood pressure occurred in SHR that were bilaterally nephrectomized 1 hour prior to injection of the converting enzyme inhibitor. In the nephrectomized animals, plasma renin activity (PRA) had fallen to less than 30% of its initial values at the time of injection. Injection of the vehicle alone had no effect on blood pressure in either anephric or intact SHR. The converting enzyme inhibitor produced no significant change in the blood pressure of either intact or anephric normotensive Wistar-Kyoto (NT-WK) rats. Infusions of Sar1-Ala8-angiotensin II (saralasin, 10 micrograms/kg-1/min-1) similarly reduced blood pressure of both intact and anephric SHR. These results indicate that captopril and saralasin lower blood pressure in the SHR by some mechanism(s) independent of the kidneys, circulating renin, or bradykinin potentiation. It is suggested that angiotensin II, locally produced at some critical tissue site(s), is involved in the maintenance of raised blood pressure in SHR.
Effect of converting enzyme inhibitor (SQ14,225) on myocardial hypertrophy in spontaneously hypertensive rats.
Authors: Sen S , Tarazi R C , Bumpus F M
Published: June 2012

The potent converting enzyme inhibitor (CEI) SQ14,225, which is known to prevent the formation of angiotensin II (AII) has been used to evaluate the role of AII in the development and reversal of cardiac hypertrophy. The present study describes the effect of CEI on blood pressure (BP) and myocardial hypertrophy (prevention and reversal) in the spontaneously hypertensive rat (SHR). A group of 3-week- and 8-week-old male SHR was treated with CEI (30 mg/kg in drinking water) for 6 weeks. An additional group of SHR was also treated with a combination of CEI and a diuretic (hydrochlorothiazide, 500 mg/liter). Heart weight, BP, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), hydroxyproline, myocardial catecholamines, and plasma renin activity (PRA) were determined. In the prevention study, we found a significant reduction in the ratio of heart weight to body weight along with the prevention of hypertension (200 vs 145 mm Hg, p less than 0.001). Similar reductions in BP and heart weights were obtained with the reversal group. A better BP control was noted in the CEI and hydrochlorothiazide group. The reduction of heart weight was associated with a reduction in RNA and hydroxyproline content. In all groups, we found a significant increase in PRA (p less than 0.001) and a slight increase in tissue catecholamine concentration. No change in kidney weight was found in any group. Data clearly showed that oral administration of CEI prevented and reversed cardiac hypertrophy in SHR. Reversal was associated with a decrease in myocardial collagen content. These data indicate that prevention of AII formation in combination with BP control can prevent and reverse cardiac hypertrophy in SHR. Of course, whether or not CEI acts only through the renin angiotension system is still speculative.
Discrepancy between antihypertensive effect and angiotensin converting enzyme inhibition by captopril.
Authors: Waeber B , Brunner H R , Brunner D B , Curtet A L , Turini G A , Gavras H
Published: June 2012

Captopril, an inhibitor of angiotensin converting enzyme, was administered twice daily to 13 hypertensive patients for a mean period of 9 weeks. Continuous blood pressure control in the ambulatory patients was established with a portable blood pressure recorder. Notwithstanding, in eight patients with normal renal function, plasma converting enzyme was found to resume normal activity before administration of the morning dose of captopril. Only in 5 patients with impaired renal function did some blockade of plasma converting enzyme persist for more than 12 hours. Measured plasma converting enzyme activity seemed to reflect total conversion of angiotensin I, including conversion in the pulmonary vascular bed, since changes in its activity were closely paralled by changes in plasma aldosterone levels. Bradykinin accumulation seems unlikely when converting enzyme and thus, presumably, kininase II has resumed normal activity. Captopril administration does not seem to alter plasma epinephrine or norepinephrine levels. Blood pressure reduction in the face of normal angiotensin converting enzyme activity is probably due to hyporesponsiveness of the arterioles to pressor hormones, which may be due to specific renin-related and/or nonspecific effects of captopril.
Review of the role of the central serotonergic neuronal system in blood pressure regulation.
Authors: Kuhn D M , Wolf W A , Lovenberg W
Published: June 2012

Alterations in the dynamics of brain serotonin biosynthesis can lead to changes in cardiovascular function. It appears that the activation of cerebral serotonin receptors produces a pressor effect in normotensive rats but produces a depressor effect in normotensive cats or dogs. On the other hand, reductions in the levels of serotonin can prevent the onset of hypertension in some experimental hypertensive models and lower the blood pressure of organisms with established hypertension. The ability of brain serotonin to modulate arterial blood pressure may be mediated by the influences of the serotonergic neuronal systems on efferent sympathetic activity. Finally, the reduction in sympathetic outflow produced by increasing brain serotonin levels in dogs protects the heart against ventricular fibrillation and may, therefore, constitute a reasonable adjunct in the management of high-risk, cardiac-arrest patients.
Pressure-independent increases in vascular resistance in hypertension: role of sympathoadrenergic influences.
Authors: Overbeck H W
Published: June 2012

Experimental aortic coarctation in rats is accompanied by non-pressure-related increases in hindlimb total vascular resistance and its neurogenic and structural components. To investigate the role of the sympathoadrenergic system, we partially constricted or sham-constricted the abdominal aorta in rats age 6 weeks that had had adrenal demedullation and guanethidine injections to produce peripheral sympathectomy (SYMP rats, N = 13-coarcted, 14-sham-coarcted) and in sham-sympathectomized, sham-demedullated control rats (SHAM rats, n = 14-coarcted, 11-sham-coarcted). In both SHAM and SYMP rats with coarctation, tail and femoral arterial pressures did not increase but carotid pressures rose by 18-25% (p less than 0.01), accompanied by significant increases in heart weight/body weight. However, arterial pressures in SYMP were 30% lower than those in SHAM rats (p less than 0.005). In the pump-perfused (blood, 1 ml/min), innervated, isolated hindlimbs of SYMP, compared to SHAM rats, the effect of acute section of local nerves on resistance was reduced and denervation hypersensitivity was documented. In contrast to SHAM, coarctation in SYMP rats was not accompanied by increases in total hindlimb resistance and its neurogenic component; there were, however, significant rises in the humoral-myogenic (p less than 0.01) and structural (p less than 0.05) components. Thus, the sympatho-adrenergic system influences arterial blood pressure and accounts for the elevated neurogenic component of peripheral vascular resistance in coarctation hypertension rats, but does not account for the elevated structural component of resistance. An unknown humoral factor, or factors, may be incriminated in the latter.
Desensitization of adenylate cyclase and increase of Gi alpha in cardiac hypertrophy due to acquired hypertension.
Authors: Böhm M , Gierschik P , Knorr A , Larisch K , Weismann K , Erdmann E
Published: June 2012

The present study investigated whether reduced adenylate cyclase activity and an increase in inhibitory guanine nucleotide binding proteins (Gi alpha), which have been observed in the failing human heart, already occur in myocardial hypertrophy before the stage of heart failure. In membranes of hypertrophic hearts from rats with different forms of experimentally induced hypertension without heart failure (one-kidney, one clip rats, deoxycorticosterone-treated rats, and rats with reduced renal mass), basal as well as isoprenaline-, 5'-guanylylimidodiphosphate-, and forskolin-stimulated adenylate cyclase activity was reduced. The activity of the catalyst was depressed in deoxycorticosterone but unchanged in one-kidney, one clip and reduced renal mass compared with controls. The number of beta-adrenergic receptors was similar in all groups. Radioimmunological quantification of Gi alpha proteins revealed an increase by 73% in one-kidney, one clip, 67% in reduced renal mass, but only 20% in deoxycorticosterone compared with sham-operated, age-matched control rats. The increase of Gi alpha was accompanied by smaller changes of pertussis toxin-induced [32P]ADP-ribosylation of a 40-kd membrane protein. It is concluded that Gi alpha contributes to the reduced adenylate cyclase activity in cardiac hypertrophy in one-kidney, one clip and reduced renal mass and to a smaller extent in deoxycorticosterone. It is suggested that an enhanced expression of Gi alpha could occur not only in severe heart failure but also in cardiac hypertrophy and could, therefore, contribute to myocardial depression and progression of disease in heart failure. In addition, Gi alpha might represent an important regulatory mechanism for cardiac adenylate cyclase activity and thus, might play an important role in various cardiac diseases.
Role of neutral endopeptidase in the metabolism of endothelin.
Authors: Abassi Z A , Tate J E , Golomb E , Keiser H R
Published: June 2012

Endothelin is a potent vasoconstrictor produced by endothelial cells. Although endothelin has been studied extensively, little is known about its metabolism in vivo. Neutral endopeptidase EC.3.4.24.11 is reported to degrade endothelin in vitro. Therefore, we studied the effect of neutral endopeptidase inhibition by SQ29,072 on plasma levels and urinary excretion of endogenous and exogenous endothelin. Injection of 30 or 60 mg/kg SQ29,072 into anesthetized rats increased the urinary excretion of endothelin nearly 14-fold. The response was maximal during the first 30 minutes of collection and lasted for 90 minutes. The larger dose of inhibitor caused a 37-43% increase (p less than or equal to 0.05) in the plasma concentration of endothelin. Only 0.20 +/- 0.04% of the total radioactivity injected as 125I-endothelin (1 microCi; 1,308 pg) into normal rats was recovered in the urine within 30 minutes. Urinary radioactivity increased to 0.54-0.63% (p less than or equal to 0.05) of the total infused in rats pretreated with SQ29,072. Chromatographic analysis of radioactivity in the urine revealed that intact endothelin accounted for only 6-9% of the total counts in control rats but 50-56% in rats pretreated with the inhibitor. We also studied the effects of another inhibitor of neutral endopeptidase, SQ28,063, on the distribution of radioactivity in the urine, kidney, and lung of rats injected with 125I-endothelin. SQ28,063 increased urinary excretion of labeled endothelin and increased total radioactivity accumulated in the lung and kidney from 157 and 105 pg to 234 and 157 pg, respectively. Intact endothelin accounted for 90% or more of the accumulated counts in both tissues. These results indicate that 1) little circulating endothelin is cleared into the urine, 2) endothelin in the urine is likely of renal origin, and 3) neutral endopeptidase EC.3.4.24.11 plays a major role in the inactivation of endothelin.
Tissue renin-angiotensin systems in renal hypertension.
Authors: Nishimura M , Milsted A , Block C H , Brosnihan K B , Ferrario C M
Published: June 2012

Angiotensinogen messenger RNA (mRNA) levels were measured in the brain (hypothalamus, lower brain stem, cerebellum), liver, kidneys, and adrenal glands of rats made hypertensive by ligation of the aorta between the renal arteries. We also measured renin mRNA in the kidneys of these renal hypertensive rats. The early phase of hypertension (day 6) was associated with significant increases in plasma renin activity and levels of circulating angiotensin II. The circulating renin-angiotensin system was not activated in the later phase of hypertension (day 24). Angiotensinogen mRNA levels were elevated in the lower brain stem of hypertensive rats at both stages of hypertension. In contrast, angiotensinogen mRNA levels in the hypothalamus were increased only at day 6 after aortic ligation. Decreased levels of angiotensinogen mRNA were observed in the cerebellum in both the early and later phases of the hypertension. Angiotensinogen mRNA levels in the adrenal gland below the ligature fell in the early phases but rose in the later phases of hypertension. Renin mRNA levels of the ischemic kidney remained elevated at both the early and later phases, whereas in both ischemic and nonischemic kidneys, levels of angiotensinogen mRNA remained below sham values throughout the period of study. These results indicate differential expression of renin-angiotensin system mRNAs in tissues of renal hypertensive rats. The differential changes in the expression of angiotensinogen mRNA over the course of development and maintenance of renal hypertension suggest that factors in addition to angiotensin II are important in modulating the expression of renin-angiotensin system genes.
Captopril improves impaired endothelium-dependent vasodilation in hypertensive patients.
Authors: Hirooka Y , Imaizumi T , Masaki H , Ando S , Harada S , Momohara M , Takeshita A
Published: June 2012

Animal studies suggest that some angiotensin converting enzyme inhibitors augment endothelium-dependent vasorelaxation. We aimed to determine if captopril augments endothelium-dependent vasodilation in middle-aged hypertensive patients. By using strain-gauge plethysmography, forearm vasodilation evoked with intra-arterial acetylcholine (4, 8, 16, and 24 micrograms/min) or nitroprusside (0.2, 0.4, 0.8, and 1.2 micrograms/min) was examined before and after captopril administration (25 mg per os). Before captopril, forearm vasodilation with acetylcholine was less in hypertensive patients (n = 12) than in age-matched (n = 7) or young (n = 7) normotensive subjects, but forearm vasodilation with nitroprusside did not differ among the three groups. Captopril improved forearm vasodilation in hypertensive patients (n = 7) with acetylcholine but nitroprusside did not. In contrast, nifedipine (10 mg per os) did not alter forearm vasodilation with acetylcholine or nitroprusside in hypertensive patients (n = 5). The decreases in mean blood pressure caused by captopril and nifedipine in hypertensive subjects were comparable. Captopril did not alter forearm vasodilation with acetylcholine or nitroprusside in young normotensive subjects (n = 7). These results suggest that captopril in hypertensive patients may acutely improve impaired endothelium-dependent forearm vasodilation that does not result from reduction in blood pressure per se.
Lewis K. Dahl Memorial Lecture. The renin system and four lines fo hypertension research. Nephron heterogeneity, the calcium connection, the prorenin vasodilator limb, and plasma renin and heart attack.
Authors: Laragh J H
Published: June 2012

As the major regulator of arterial blood pressure and sodium balance, the renin axis supports normotension or hypertension via angiotensin-mediated vasoconstriction and angiotensin plus aldosterone-induced renal sodium retention. In this endocrine servo control, renal renin is released by hypotension or salt depletion; conversely, with hypertension or volume excess, plasma renin activity falls to zero. Accordingly, any renal renin secretion is abnormal in the face of arterial hypertension. Human hypertensive disorders comprise a spectrum of abnormal vasoconstriction-volume products (renin-sodium profiles). Excess plasma renin activity for the sodium balance is created by nephron heterogeneity in which a subpopulation of ischemic nephrons hypersecretes renin and retains sodium. This excess renin impairs adaptive natriuresis of neighboring normal nephrons. Research defining the pivotal role of vascular cytosolic calcium for transducing sodium or renin-mediated vasoconstriction explains the selective value of calcium antagonists for correcting the sodium-volume-mediated, and beta-blockers or angiotensin converting enzyme inhibitors for correcting renin-mediated, arteriolar vasoconstriction. The renin precursor prorenin appears to be physiologically active, causing selective vasodilation that offsets renin-mediated vasoconstriction. Overactivity of prorenin may be involved in the hyperperfusion vascular injuries of diabetes mellitus and toxemias. Prorenin underactivity may facilitate renin-mediated ischemic vascular injury. In essential hypertension, undue plasma renin activity is powerfully and independently associated with heart attack risk. Conversely, patients with low renin activity are protected from heart attack despite higher blood pressures and greater age. Also, renin or angiotensin administration consistently causes vascular injury in the heart, brain, and kidneys of animals. These data suggest new potentials for the prevention of cardiovascular sequelae (heart attack and stroke) by using explicit strategies to curtail plasma renin activity.
Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension.
Authors: Ribeiro M O , Antunes E , de Nucci G , Lovisolo S M , Zatz R
Published: June 2012

Recent studies have indicated that acute inhibition of nitric oxide biosynthesis in the rat promotes arterial hypertension and renal vasoconstriction. We evaluated the renal and systemic effects of 4-6 weeks of nitric oxide blockade in Munich-Wistar rats receiving the nitric oxide inhibitor nitro-L-arginine orally. Age-matched untreated rats were used as controls. In an additional seven rats, nitric oxide blockade was carried out in conjunction with oral administration of the novel angiotensin II antagonist losartan potassium. Tail-cuff pressure rose progressively in nitro-L-arginine-treated rats, reaching 164 +/- 6 mm Hg at 4-6 weeks, compared with 108 +/- 3 mm Hg in controls. In rats concomitantly receiving losartan, tail-cuff pressure reached 125 +/- 6 mm Hg, still elevated compared with rats receiving losartan alone (98 +/- 3 mm Hg). Nitro-L-arginine-treated rats presented marked renal vasoconstriction and hypoperfusion, as well as a 30% fall in glomerular filtration rate and a 39% increase in filtration fraction. Treatment with Losartan normalized glomerular filtration rate, but not filtration fraction or renal vascular resistance. Plasma renin activity was elevated after nitro-L-arginine treatment. Renal histological examination revealed widespread arteriolar narrowing, focal arteriolar obliteration, and segmental fibrinoid necrosis in the glomeruli. In a separate group of rats, nitro-L-arginine administered for 1 week induced hypertension that was partially reversed by acute L-arginine, but not D-arginine or L-glycine, infusions. We conclude that chronic nitric oxide blockade may constitute a new model of severe arterial hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
Variability between current definitions of 'normal' ambulatory blood pressure. Implications in the assessment of white coat hypertension.
Authors: Verdecchia P , Schillaci G , Boldrini F , Zampi I , Porcellati C
Published: June 2012

The assessment of white coat hypertension is complicated by the lack of generally agreed-on normal limits of ambulatory blood pressure. To assess the influence of four of these limits on the prevalence of white coat hypertension and the corresponding distribution of left ventricular hypertrophy, we performed 24-hour ambulatory blood pressure monitoring and echocardiographic studies in 346 untreated patients with essential hypertension and 47 age-matched normotensive control subjects. The upper limits of normal daytime ambulatory blood pressure were lower using standards drawn from clinically normotensive populations than using standards drawn, partly or entirely, from general populations. The prevalence of white coat hypertension differed markedly using the different standards, being 12.1%, 16.5%, 28.9%, and 53.2% (chi 2 = 346.0, p less than 0.0001). Left ventricular mass index averaged 77 g/m2 in the control group, 85 g/m2 in the two groups with white coat hypertension defined by using standards drawn from normotensive populations (both comparisons not significant versus control group), and 90 and 98 g/m2 in the two groups with white coat hypertension defined by using the other two standards (both p less than 0.01 versus control group). The prevalence of echocardiographic left ventricular hypertrophy was 0% in the control group, 2.4% and 3.5% in the two groups with white coat hypertension defined by using standards drawn from normotensive populations, and 9.0% and 14.7% in the other two groups with white coat hypertension (p less than 0.05 and p less than 0.01, respectively, versus control group).(ABSTRACT TRUNCATED AT 250 WORDS)
Blood pressure response to hyperinsulinemia in salt-sensitive and salt-resistant rats.
Authors: Tomiyama H , Kushiro T , Abeta H , Kurumatani H , Taguchi H , Kuga N , Saito F , Kobayashi F , Otsuka Y , Kanmatsuse K
Published: June 2012

We investigated the role of insulin in salt-sensitive hypertension in Dahl salt-sensitive and salt-resistant rats. The rats were kept in metabolic cages, and sodium intake and urinary sodium excretion were measured. In salt-sensitive rats receiving a 0.3% NaCl diet, sodium retention was significantly greater at weeks 1 and 2 in rats that received an insulin infusion than in those receiving a saline infusion. Mean arterial blood pressure and plasma norepinephrine levels were significantly higher at week 3 in insulin-treated rats than in saline-treated rats (mean arterial pressure, 137 +/- 3 mm Hg versus 119 +/- 3 mm Hg, p < 0.05; plasma norepinephrine, 0.40 +/- 0.02 ng/ml versus 0.27 +/- 0.01 ng/ml, p < 0.05). Insulin did not influence sodium retention, mean arterial pressure, or plasma norepinephrine in salt-resistant rats. Coadministration of an alpha-blocker (bunazosin, 10 mg/kg per day for 3 weeks) in salt-sensitive rats abolished the insulin-induced elevations in mean arterial pressure and sodium retention. When salt-sensitive rats were fed a low salt diet (0.03% NaCl), insulin did not raise mean arterial pressure. Thus, insulin elevated blood pressure only in the salt-sensitive model. The sympathetic nervous system and sodium retention in the early phase of insulin overload may contribute to elevation of mean arterial pressure in this model.
Increased response to physical and mental stress in men with hypertensive parents.
Authors: Widgren B R , Wikstrand J , Berglund G , Andersson O K
Published: June 2012

Blood pressure and heart rate responses to isometric handgrip exercise were studied at age 31 and after 5 years in young nonhypertensive men with positive family histories of hypertension (n = 13) and in those with negative family histories of hypertension (n = 13) for two generations to test whether subjects with positive family histories established a pattern of increased blood pressure and heart rate responses during the 5-year follow-up period. At follow-up the response to mental stress (Stroop's color word test) was also studied. Baseline blood pressure and heart rate at rest did not differ, initially or at follow-up, between the groups. At the initial examination, absolute blood pressure levels were significantly higher during isometric handgrip exercise just before exhaustion in subjects with positive family histories. At follow-up the absolute blood pressure level (p < 0.001) and the blood pressure responses (p < 0.01-0.001) were found to be significantly increased during handgrip exercise in subjects with positive family histories compared with subjects with negative family histories. In subjects with positive family histories the diastolic blood pressure response was significantly higher (p < 0.01) at follow-up than initially and was significantly related (r = 0.70, p < 0.01) to changes in baseline diastolic blood pressure during the follow-up period. In subjects with negative family histories the systolic blood pressure response was somewhat lower at follow-up than initially. During the mental stress test, the blood pressure response was significantly greater in subjects with positive than with negative family histories.(ABSTRACT TRUNCATED AT 250 WORDS)