Significant Elevation Of Blood Pressure Research Articles

Role of alpha(2)-adrenergic receptor subtypes in the acute hypertensive response to hypertonic saline infusion in anephric mice.

Experimental evidence suggests that the acute hypertensive response induced in anephric animals by infusion of a hypertonic saline solution is mediated by disinhibition of the presynaptic sympathoinhibitory alpha(2)-adrenergic receptors (alpha(2)-AR) of the central nervous system. The purpose of the present experiments was to dissect the role of the 3 distinct alpha(2)-AR subtypes (alpha(2A)-, alpha(2B), - and alpha(2C)-AR) in this response. Groups of genetically engineered mice deficient in each one of these alpha(2)-AR subtype genes were submitted to bilateral nephrectomy followed by a 0.4-mL infusion of 4% saline over a 2-hour period, with constant direct blood pressure (BP) monitoring. The alpha(2A)-AR-deficient and alpha(2C)-AR-deficient mice responded with significant BP elevations (by 11.8+/-2.5 and 16.7+/-1.7 mm Hg, respectively), and so did their wild-type counterparts (17.8+/-2.5 and 11.8+/-2.0 mm Hg, respectively) and the wild-type alpha(2B) +/+ (13.1+/-2.4 mm Hg). However, the alpha(2B)-AR-deficient mice were unable to raise their BP and had a slightly lowered BP (by -3.0+/-4. 0 mm Hg) at the end of the infusion period. All 6 groups exhibited elevated plasma norepinephrine levels ranging between 0.8 and 1.8 ng/mL at the end of the infusion. In all cases, the alpha(2)-AR-deficient groups tended to have higher norepinephrine levels than their wild-type counterparts. Surprisingly, this difference was significant only in the alpha(2B)-AR-deficient mice, which, despite the elevated norepinephrine, were unable to raise their BP. The data suggest that a full complement of the alpha(2B)-AR is needed to mediate the hypertensive response to acute saline load, even though its absence does not prevent the release of norepinephrine under these conditions.

Cold-induced hypertension and diuresis

Chronic exposure of rats to mild cold (5°C) resulted in a significant elevation of blood pressure (BP) within 4 days. Peripheral administration of losartan (AT 1 receptor antagonist) could decrease the elevated BP to the control level. AT 1 receptor mRNA was significantly increased in resistance arteries by exposure to cold. Chronic exposure to cold was accompanied by diuresis and a decrease in urine osmolality. The circulating level of arginine vasopressin (AVP) was not affected significantly by cold exposure. It is concluded that cold-induced hypertension may be maintained by up-regulation of AT 1 receptors. Cold-induced diuresis may be due to decreased renal responsiveness to AVP rather than inhibition of AVP release.

The pharmacological effects of an aqueous extract from Acacia nilotica seeds.

An aqueous extract of the seed of Acacia nilotica was investigated for its pharmacological profile. On the isolated guinea-pig ileum, the extract displayed sustained dose-related contractile activity. The contractions which were reduced by hexamethonium, promethazine or atropine were completely abolished by nifedipine. The intravenous (i.v.) administration of the extract (11, 22, 44, 55 microg/kg) to anaesthetized cats produced a dose-related significant elevation of blood pressure. The mechanisms of the spasmogenic and vasoconstrictor actions of the extract have not been determined, however, the results suggest the involvement of calcium.

Identification of a polymorphic glutamic acid stretch in the α 2b-adrenergic receptor and lack of linkage with essential hypertension

Essential hypertension, a clinically significant elevation in blood pressure with no recognizable cause, is believed to be attributable to the collective effect of genetic predisposing factors in combination with specific environmental factors, such as diet and stress. Of the genetic causes, genes coding for proteins involved in blood pressure regulation, such as the α- and β-adrenergic receptors, are obvious candidates. The α 2-adrenergic receptor plays a key role in the sympathetic nervous system by mediating the effects of epinephrine and norepinephrine. To evaluate the potential role between the α 2B receptor and essential hypertension, we scanned the α 2B-receptor gene for genetic variation in 108 affected sibling pairs. The screening revealed two major forms of the receptor. They differ by the presence of either 9 or 12 glutamic acid residues in the acidic domain of the third cytoplasmic loop of the protein. Investigation of the pattern of this variation in hypertensive sibling pairs suggests that the α 2B receptor locus does not contribute substantially to genetic susceptibility for essential hypertension.

Alpha1-adrenergic plus angiotensin receptor blockade reduces atherosclerosis in apolipoprotein E-deficient mice.

-We have used the apolipoprotein E (apoE)-deficient mouse model to determine whether both the angiotensin II type 1 (AT1) and the alpha1-adrenergic receptors influence arteriosclerotic changes in this hyperlipidemic animal model. Mice were treated with antihypertensive drugs beginning at 9 weeks of age, and aortic atherosclerosis was measured after 12 weeks of treatment. Systolic blood pressure in the untreated apoE-deficient mouse averaged 104 mm Hg throughout the treatment period. Prazosin at a dose of 7.5 mg. kg-1. d-1 was ineffective in attenuating atherosclerosis and did not significantly reduce blood pressure. Losartan, at dosages of either 20 or 30 mg. kg-1. d-1, also did not influence atherosclerosis and had only a slight blood pressure-lowering effect. However, combined treatment with both prazosin and losartan markedly reduced atherosclerotic lesion development from an average lesion size per section of 2.6 to 1.5x10(5) microm2 (P<0.001) and significantly reduced blood pressure to 85+/-5 mm Hg. Treatment with NG-nitro-L-arginine methyl ester (40 mg. kg-1. d-1) produced significant elevations of blood pressure (127+/-3.8 mm Hg) but had no effect on the development of atherosclerosis. None of the treatments used affected plasma cholesterol throughout the 12-week period. These studies suggest that the vascular changes associated with atherosclerosis are influenced by a combination of AT1 and alpha1-adrenergic receptor activation.

Remission of hypertension: retrospective observations over a period of 20 years.

To clarify the background and outcome of hypertensive patients who have remission of their elevated blood pressure (BP) after a course of antihypertensive drug therapy, we designed a retrospective observational study. The clinical records of 106 hypertensive men and women (BP, 164.3/104.4 mmHg) given antihypertensive drug treatment and subsequently examined every 1 to 3 mo for more than 20 yr were reviewed. The patients were divided into two groups: those who had remission (R-group) and those who did not have remission (N-group). Patients were considered in remission if no significant elevation in BP was observed for more than 1 yr after withdrawing their medication. Remissions ranging in duration from 1.6 to 21.7 yr (average duration, 6.3 yr) occurred in 19 of 106 patients (17.9%). However, anti-hypertensive drug treatment was eventually restarted in 17 of the 19 patients. Before treatment, comparison of the R-group and N-group revealed no differences with respect to age, body weight, BP, or serum creatinine. In contrast, the proportion of patients who lacked high-voltage deflections in their electrocardiograms (ECG) as well as that of patients whose BP was well-controlled by a single medication was significantly greater in the R-group than in the N-group (12/19 vs. 22/87, p < 0.05 and 10/19 vs. 13/87, p < 0.001, respectively). In addition, body weight in the R-group decreased significantly by the time drug therapy was withdrawn (p < 0.01). Finally, significantly more patients (14 of 19 patients) entered remission in the spring and summer (p < 0.05) than at other times of the year. We conclude that remission occurs in a subset of well-controlled hypertensive patients and may persist for several years or more. However, in the majority of patients, antihypertensive drug treatment will usually need to be restarted at some point. Patients who lack ECG high-voltage deflections and who are successfully treated with a single therapeutic agent are most likely to experience remission. Moreover, it appears that withdrawing patients from drug therapy in the spring or summer is more likely to yield a favorable outcome than at other times of the year.

ATTENUATION IN RAT BRAIN NITRIC OXIDE SYNTHASE ACTIVITY IN THE COARCTATION MODEL OF HYPERTENSION

The correlation of brain nitric oxide synthase (NOS) activity with renal hypertension has been investigated in rats. NOS activity was measured by oxyhaemoglobin and by conversion of radioactive arginine to citrulline. There was significant elevation of blood pressure (54% increase) along with left ventricular hypertrophy (26% greater than the control) 8 weeks after coarctation. The brain NOS activity was also significantly reduced in coarctated animals (45% of the control value). Treatment with captopril (angiotensin converting enzyme inhibitor) or centhaquin (centrally acting antihypertensive agent) led to significant reduction of left ventricular hypertrophy and a marked recovery in the brain NOS activity (to 92% and 135% of the control, respectively). Nifedipine (a calcium channel blocker) also brought about normalization of blood pressure but the left ventricular hypertrophy was not prevented. The brain NOS activity in the nifedipine treated group also showed a significant trend of recovery (to 73% of the control NOS activity). The results suggested that there is an inverse correlation between brain NOS activity and blood pressure level.

Progesterone up-regulates vasodilator effects of calcitonin gene–related peptide in N G-nitro- l-arginine methyl ester–induced hypertension

OBJECTIVE: We recently reported that calcitonin gene–related peptide can reverse the hypertension produced by N G-nitro- l-arginine methyl ester in pregnant rats. In the current study we investigated whether these vasodilator effects of calcitonin gene–related peptide were progesterone dependent. STUDY DESIGN: Calcitonin gene–related peptide or N G-nitro- l-arginine methyl ester was infused through osmotic minipumps, either separately or in combination, to groups of five pregnant rats from day 17 of gestation until day 8 post partum or to nonpregnant ovariectomized rats for 8 days. Progesterone was injected during days 1 to 6 post partum and for 6 days after ovariectomy. Systolic blood pressure was measured daily. RESULTS: Animals receiving N G-nitro- l-arginine methyl ester exhibited significant elevations of blood pressure during pregnancy and post partum. Coadministration of calcitonin gene–related peptide to these rats reversed the hypertension during pregnancy but not during the postpartum period. At the dose used in this study calcitonin gene–related peptide administered alone was without significant effects on blood pressure. However, it reduced both the mortality and growth restriction of the fetus associated with N G-nitro- l-arginine methyl ester in these animals. Calcitonin gene–related peptide reversed the hypertension in N G-nitro- l-arginine methyl ester–infused postpartum rats during the periods of progesterone treatment only, and these effects were lost when progesterone treatment was stopped. Neither progesterone nor calcitonin gene–related peptide alone were effective. To further confirm these observations, progesterone effects were tested in ovariectomized adult rats. Similar to the findings in postpartum rats, calcitonin gene–related peptide completely reversed the elevation in blood pressure in N G-nitro- l-arginine methyl ester–treated rats receiving progesterone injections. The effects of calcitonin gene–related peptide were apparent only during the progesterone treatment period, and these effects were lost when progesterone treatment was stopped. Again, at these doses calcitonin gene–related peptide and progesterone were each ineffective alone. Conclusions: Calcitonin gene–related peptide reverses the N G-nitro- l-arginine methyl ester–induced hypertension during pregnancy, when progesterone levels are elevated, but not post partum or in ovariectomized nonpregnant rats. The blood pressure–lowering effects of calcitonin gene–related peptide were restored in both postpartum and ovariectomized rats with progesterone treatment. Therefore we conclude that progesterone modulates vasodilator effects of calcitonin gene–related peptide in hypertensive rats. (Am J Obstet Gynecol 1997;176:894-900.)

Endogenous 11 beta-hydroxysteroid dehydrogenase inhibitors and their role in glucocorticoid Na+ retention and hypertension.

11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) metabolizes active glucocorticoids to their inactive 11-dehydro products and protects renal mineralocorticoid receptors from the high circulating levels of endogenous glucocorticoids. 11 beta-HSD has been suggested to be important not only in the control of renal sodium retention but also blood pressure. We had previously shown that 11 alpha- and 11 beta-hydroxyprogesterone (11 alpha- and 11 beta-OHP) were (I) potent inhibitors of 11 beta-HSD (Isoforms 1 and 2) activity in vitro, (ii) able to confer mineralocorticoid (MC) activity upon corticosterone (B) in vivo and (iii) hypertensinogenic when chronically infused into Sprague-Dawley (SD) rats. In addition we also showed that 3 alpha,5B-tetrahydroprogesterone (3 alpha,5B-THP) and chenodeoxycholic acid (CDCA) were potent inhibitors of 11 beta-HSD1 activity but not 11 beta-HSD2 activity, however, these substances were still able to confer MC activity upon B in the adrenalectomized rat. To assess the possible blood pressure modulating effects of 3 alpha,5B-THP and CDCA we have now infused these substances into intact SD rats continuously for 14 days. Both 3 alpha,5B-THP and CDCA caused a significant elevation in blood pressure within seven days, an effect that persisted throughout the 14-day infusion. These results show that both 3 alpha,5B-THP and CDCA are hypertensinogenic in the rat and that the inhibition of either 11 beta-HSD2 or 11 beta-HSD1 activity by endogenous progesterone metabolites and CDCA may be involved in the pathology of hypertension.

Acute cardiovascular effects of intravenous cyclosporine.

The acute effects of intravenous (i.v.) cyclosporine A (CsA) on blood pressure and other haemodynamic parameters were examined in 8 patients with end-stage renal disease on haemodialysis (HD). The study was performed after the mid-week haemodialysis session, when the patients were on their dry body weight. Each patient received an i.v. infusion of 5 mg/kg of CsA in 120 ml of 5% dextrose in water during 2 hours. Heart rate, systolic and diastolic blood pressure (SBP, DBP) were monitored by the Holter system. An echocardiogram (M-mode 2-dimensional and Doppler sonography) was performed using an automatic device (Ultramark 6) before CsA administration, at 30, 60 and 120 minutes during CsA infusion, and at 30 minutes thereafter. SBP, DBP and calculated peripheral vascular resistance (CPVR) increased significantly in respect to basal values at 120 and 150 minutes (SBP: basal 130 +/- 21, 120 min: 136 +/- 20, 150 min: 140 +/- 18, p < 0.05 and p < 0.01, respectively. DBP: basal 80 +/- 9, 120 min: 86 +/- 13, 150 min: 88 +/- 13, p < 0.05 and p < 0.01, respectively. CPVR: basal 1000 +/- 228, 120 min: 1178 +/- 305, 150 min: 1236 +/- 270 dyne/s/cm5, p < 0.01). However, systolic volume (SV) and cardiac output (CO) showed significant decreases from the basal values (SV: basal 103 +/- 29, 120 min: 85 +/- 22, 150 min: 85 +/- 17, p < 0.05. CO: basal 8.2 +/- 2, 120 min: 7.3 +/- 1.1, 150 min: 7 +/- 1.2 l/min, p < 0.05). In conclusion, CsA infusion produces a significant elevation of blood pressure, which seems to be mediated by a direct action on peripheral vascular resistance.

Calcitonin gene-related peptide reverses the hypertension and significantly decreases the fetal mortality in pre-eclampsia rats induced by NG-nitro-L-arginine methyl ester

We recently established that the chronic inhibition of nitric oxide production with N(G)-nitro-L-arginine methyl ester (L-NAME) increases blood pressure and fetal mortality in pregnant rats. Using this animal model, we have investigated whether calcitonin gene-related peptide (CGRP) can reverse the pre-eclampsia-like conditions produced by L-NAME. CGRP and L-NAME were chronically infused s.c. into pregnant rats separately or together starting on day 17 of gestation; a control group was given saline infusions. Systolic blood pressure was measured on gestational days 17, 18, 19 and 22 and post-partum days 1 and 2. The weight and mortality of the pups were recorded immediately after spontaneous delivery. Animals treated with L-NAME exhibited significant elevations of blood pressure on days 18, 19 and 22 of gestation and during post-partum, increased pup mortality (18.4 versus 0.0%) and decreased pup weights (5.14 +/- 0.07 versus 6.20 +/- 0.06 g). The co-administration of L-NAME and CGRP prevented the gestational (not the post-partum) L-NAME hypertension and decreased pup mortality to 6.4% but did not reverse the decreased fetal weight (5.31 +/- 0.06 g). Our data indicate the CGRP (i) participates in regulation of the vascular adaptations that occur during normal pregnancy, (ii) has beneficial effects on the hypertension and increased mortality of experimental preeclampsia, and (iii) may exert differential effects on the systemic (i.e. maternal) and fetal components of utero-placental circulation. These findings may have important clinical implications.

11 alpha- and 11 beta-hydroxyprogesterone, potent inhibitors of 11 beta-hydroxysteroid dehydrogenase, possess hypertensinogenic activity in the rat.

The progesterone derivatives 11 alpha- and 11 beta-hydroxyprogesterone are potent inhibitors of 11 beta-hydroxysteroid dehydrogenase (isoforms 1 and 2) in vitro and can confer mineralocorticoid activity on corticosterone in the rat in vivo. 11 beta-Hydroxysteroid dehydrogenase metabolizes active glucocorticoids to their inactive 11-dehydro products and protects renal mineralocorticoid receptors from the high circulating levels of endogenous glucocorticoids. 11 beta-Hydroxysteroid dehydrogenase has been suggested to be important not only in the control of renal sodium retention but also of blood pressure. To assess the possible blood pressure-modulating effects of 11 alpha- and 11 beta-hydroxyprogesterone, we infused these substances into both intact and adrenalectomized Sprague-Dawley rats continuously for 14 days. Both 11 alpha- and 11 beta-hydroxyprogesterone caused a significant elevation in blood pressure within 3 days, an effect that persisted throughout the 14-day infusion. The hypertensive effects of 11 alpha-hydroxyprogesterone were abolished by adrenalectomy and significantly attenuated when 11 alpha-hydroxyprogesterone was infused together with the specific mineralocorticoid receptor antagonist RU28318. In an additional series of experiments, 11 alpha-hydroxyprogesterone significantly amplified the hypertensive effects of corticosterone in adrenalectomized spontaneously hypertensive rats but had no effects by itself in this experimental animal. These results demonstrate that both 11 alpha- and 11 beta-hydroxyprogesterone are potently hypertensinogenic in the rat and that this activity depends on an intact adrenal and at least in part on the activation of mineralocorticoid receptors. 11 beta-Hydroxyprogesterone, and similar endogenous progesterone metabolites that inhibit 11 beta-hydroxysteroid dehydrogenase, may be involved in the pathology of certain hypertensive states.

Silent Autonomic Dysreflexia During Voiding in Men with Spinal Cord Injuries

Purpose We determined whether symptoms of autonomic dysreflexia correlated with elevations in blood pressure in men with spinal cord injuries. Materials and Methods During a routine yearly urodynamic evaluation 45 consecutive men with complete spinal cord injuries above T6 underwent simultaneous monitoring of blood pressure and symptoms of autonomic dysreflexia. Those with systolic blood pressure of greater than 160 mm. Hg or diastolic blood pressure of greater than 90 mm. Hg during voiding were assigned to the hypertensive group. During voiding 35 men (78 percent) had significant hypertension. Results Before voiding there was no statistical difference in mean systolic blood pressure between men with and without hypertension (117 versus 110 mm. Hg, p = 0.28). During uninhibited contractions and voiding mean systolic blood pressure of the normotensive group (131 mm. Hg) versus the hypertensive group (169 mm. Hg) was statistically significant (p less than 0.0001). Of the 35 hypertensive patients 15 (43 percent) had no symptoms of autonomic dysreflexia. There was no correlation of autonomic dysreflexia with length of injury, maximum voiding pressure or bladder capacity (p = 0.59, 0.85 and 0.34, respectively). Conclusions Urodynamics are helpful to detect symptomatic and asymptomatic autonomic dysreflexia. Significant elevations in blood pressure can occur without the symptoms of autonomic dysreflexia.

Captopril and stress-induced hypertension in the borderline hypertensive rat

Daily exposure to air-jet stress (AJS) causes sustained elevations of blood pressure in borderline hypertensive rats (BHR). It is known that the renin-angiotensin system is activated during episodes of behavioral stress, and the purpose of this study was to assess the involvement of renin-angiotensin system in the development of stress-induced hypertension in the BHR. Four groups of 8- and 9-week-old rats were studied: they received, respectively, oral captopril and AJS; oral captopril without AJS; AJS without captopril; and neither AJS nor captopril. After 10 days of AJS and captopril conditions, femoral and jugular catheters were implanted for the measurement of mean arterial pressure and pressor responses to norepinephrine and tyramine. Blood samples were collected for the measurement of norepinephrine and plasma renin activity. Ten days of AJS caused a significant elevation of blood pressure in BHR exposed to AJS without receiving captopril but not in those animals given captopril concurrently with AJS. Circulating norepinephrine and blood pressure responses to exogenous norepinephrine and tyramine were similar across the four groups. Plasma renin activity was highest in BHR given captopril, and was significantly elevated during an acute episode of AJS. The renin-angiotensin system may be important in the development of stress-induced hypertension in the BHR.

In vivo and in vitro pressor effects of erythropoietin in rats.

Hypertension (HTN) is a common complication of recombinant erythropoietin (EPO) therapy, but the mechanism of the EPO-associated HTN is uncertain. In the present study we examined the effects of EPO and the vehicle alone on rat caudal artery contractile response and basal and thrombin-stimulated platelet cytosolic Ca2+ concentration ([Ca2+]i) in vitro and on blood pressure (BP) and heart rate in vivo. At high concentrations (200 U/ml) EPO caused a small but consistent contraction in the caudal artery rings (P < 0.01) without affecting the response to either angiotensin II (ANG II) or the alpha 1-agonist methoxamine. Incubation with EPO significantly increased basal platelet [Ca2+]i (P < 0.01) and augmented the thrombin-induced rise of [Ca2+]i in Ca(2+)-free medium (P < 0.05). Long-term EPO administration led to a significant elevation of BP within 2 wk regardless of whether the hematocrit was allowed to rise or was kept constant by dietary iron deficiency. In contrast, single intravenous administration of high-dose EPO (400 and 5,000 U/kg), estimated to yield plasma concentrations comparable with those employed in vitro, failed to either alter BP or modify the BP response to ANG II during a 60-min observation period. This was associated with a significant rise in plasma guanosine 3',5'-cyclic monophosphate but no discernible change in plasma atrial natriuretic peptide, suggesting enhanced nitric oxide (NO) release. Thus, at high concentrations, EPO appears to possess a fast-acting pressor effect in vitro but not in vivo. The observed discrepancy may be due to enhanced NO release with EPO administration in vivo. However, HTN does occur with repeated EPO administration in a time-dependent and hematocrit-independent manner. This suggest that expression of the hypertensive effect of EPO in vivo involves a gradual conditioning process.

Central nervous system mediates an antihypertensive property in glucocorticoid hypertension in dogs

To determine whether the central nervous system has a pressor or a depressor role in glucocorticoid-induced hypertension. Intracerebroventricular dexamethasone or its receptor antagonist, RU 38486, was administered in 20 trained conscious dogs. In addition, intracerebroventricular RU 38486 was administered in dogs treated with oral dexamethasone. Intracerebroventricular dexamethasone induced a dose-related reduction in blood pressure accompanied by decreased heart rate and cardiac output. In contrast, intracerebroventricular RU 38486 caused a slight but not significant elevation in blood pressure. Total peripheral resistance showed no significant change throughout the treatment with dexamethasone or RU 38486. In contrast, oral dexamethasone caused significant elevation of blood pressure associated with increased total peripheral resistance and reduced heart rate. In hypertensive dogs treated with oral dexamethasone, intracerebroventricular RU 38486 elicited a more severe form of hypertension accompanied by an attenuation of the heart rate and a reduction in cardiac output. Intracerebroventricular dexamethasone induced a significant reduction in plasma levels of adrenocorticotrophic hormone, cortisol, arginine vasopressin and noradrenaline. In addition, simultaneous central administration of RU 38486 with intracerebroventricular dexamethasone blocked the reduction in blood pressure and heart rate completely. The present data strongly suggest that endogenous glucocorticoid in the central nervous system may not have a role in the regulation of systemic haemodynamics and hormones under resting conditions, but does play an important part during the glucocorticoid excess state, for example glucocorticoid hypertension caused by oral treatment with dexamethasone. The glucocorticoid in the central nervous system opposed the elevation of blood pressure in glucocorticoid-induced hypertension by attenuating the reduction in heart rate and cardiac output via direct stimulation of glucocorticoid receptors in the brain.

Delayed platelet adhesion/aggregation at sites of endothelial injury in mouse cerebral arterioles after transient elevations of blood pressure and shear.

Prior research showed that injection of angiotensin II (Ang II) produces a transient elevation of blood pressure (BP) and shear in pial arterioles. This inhibited platelet adhesion/aggregation at a site of subsequently injured endothelium. The present study attempted to confirm the Ang II finding with a different method of endothelial injury, to test the hypothesis that the effect on adhesion/aggregation was a consequence of prolonged release of "classic" endothelium-derived relaxing factor (released by acetylcholine [Ach]; EDRFACh) produced by the preceding transient elevation in shear, and to show with the use of norepinephrine rather than Ang II that the effect of a preceding elevation of BP was independent of the pressor agent used. Focal platelet adhesion/aggregation was elicited in cerebral surface (pial) arterioles by producing minimal endothelial damage with a helium-neon laser/Evans blue dye technique. Vessels were observed by intravital microscopy. We recorded the time required for the laser to elicit adhesion/aggregation in control mice and in mice given Ang II in a dose of 16 micrograms/25 g IP. This dose produces an abrupt and significant elevation of BP and shear, which return to baseline levels in less than 30 minutes. Laser/dye damage of endothelium and resultant adhesion/aggregation of platelets were not induced until after BP and shear returned to basal levels. The effect of topical Ang II on damage-induced adhesion/aggregation was also tested. In addition, mice injected with Ang II were treated with either topical indomethacin 40 micrograms/mL or topical Ng-monomethyl L-arginine (L-NMMA; 10(-6) mol/L) in an effort to prevent the preceding increase in shear from inhibiting subsequent adhesion/aggregation. Finally, norepinephrine instead of Ang II was used to transiently raise BP (and shear) in an effort to delay subsequently induced adhesion/aggregation. Platelet adhesion/aggregation at the injured site was significantly delayed by a prior transient rise in shear produced by either Ang II or norepinephrine. Locally applied Ang II failed to influence adhesion/aggregation, although a previous study showed that such Ang II reaches the endothelium. Locally applied indomethacin had no effect on inhibition of platelet adhesion/aggregation, but locally applied L-NMMA prevented the prior transient elevation of shear from inhibiting adhesion/aggregation at a subsequently injured site. Elevation of BP with consequent elevation of shear inhibits local platelet adhesion/aggregation even when the latter is initiated by endothelial damage produced after return of shear to basal levels. The direct action of Ang II on endothelium is not responsible for the effect on adhesion/aggregation, and indeed the effect is independent of the pressor agent. The pharmacological data, together with the literature, support the hypothesis that increased shear causes an increased release of EDRFACh, which may continue for at least some minutes after return of shear to normal levels.

Hypertensive rats produced by in vivo introduction of the human renin gene.

We established an efficient and nontoxic in vivo gene transfer method mediated by the Sendai virus (hemagglutinating virus of Japan [HVJ]), liposomes, and nuclear protein. In this study, to produce a hypertensive model rat that is dependent on human renin, the human renin gene was introduced into adult rat liver by our efficient in vivo gene transfer method using HVJ and liposomes (HVJ-liposomes). The rats treated with HVJ-liposomes containing the human renin gene showed a significant elevation of blood pressure for 6 days compared with control rats, which received injections of HVJ-liposomes without the human renin gene. On day 5 after the transfer, human active renin as well as angiotensin II were found in the plasma of rats in which the human renin gene was introduced. Moreover, the blood pressure of these rats was significantly correlated with the plasma levels of human active renin and angiotensin II. To confirm that the elevated blood pressure was due to the expression of the human renin gene, we administered a newly developed specific human renin inhibitor, FK 906. The elevated blood pressure was normalized by the intravenous administration of this drug. These data indicate that this hypertensive rat was produced by the in vivo transfer of the human renin gene into rat liver and that the expressed human renin cleaved rat substrate (angiotensinogen). This hypertensive rat produced by in vivo gene transfer should be useful in further studies on hypertension.

Angiotensin II increases glucose utilization during acute hyperinsulinemia via a hemodynamic mechanism.

To determine whether hemodynamic changes can modulate insulin action in vivo, we administered angiotensin II (AII) to normal men under three separate, euglycemic conditions. First, in the presence of physiological hyperinsulinemia (approximately 115 microU/ml), infusion of AII at rates of 2, 10, and 20 ng/min per kg caused significant elevations of blood pressure, whole-body glucose clearance, and plasma insulin concentrations in an AII dose-dependent manner. Second, in the presence of plasma insulin concentrations that stimulate glucose transport maximally (approximately 5,000 microU/ml), AII infusions increased whole-body glucose clearance without enhancing glucose extraction across the leg. Third, in the presence of basal insulin concentrations (approximately 13 microU/ml), AII infusions had no effect on whole-body glucose turnover or leg glucose extraction. Thus, AII enhanced whole-body glucose utilization without directly stimulating glucose transport in a major skeletal muscle bed. To evaluate a possible hemodynamic mechanism for the effects of AII on glucose utilization, we measured blood flow to two areas that differ in their sensitivity to insulin: the kidneys and the leg. We found that AII redistributed blood flow away from the predominantly insulin-independent tissues of the kidney and toward the insulin-sensitive tissues of the leg during both sham and hyperinsulinemic glucose clamps. The redistribution of flow had no effect on whole-body glucose turnover when leg glucose uptake was unstimulated (sham clamps). However, when leg glucose uptake was activated by insulin, the redistribution of flow caused a net increase in whole-body glucose utilization. Our findings indicate that hemodynamic factors can modulate insulin action in vivo. Furthermore, our results suggest that variable activity of the renin-angiotensin system may contribute to inconsistencies in the association between insulin resistance and hypertension.

Effect of chronic lung disease on blood pressure levels at follow up.

Thirteen preterm infants (median gestational age 28 weeks) who had developed neonatal chronic lung disease (CLD) and 13 gender- and gestational age-matched controls (without CLD) were prospectively followed. The infants were seen at monthly intervals for 6 months. At each attendance the infants were examined and their blood pressure (BP) measured using a noninvasive Doppler technique. No infant developed symptoms related to hypertension and there were no significant differences in their BP levels at follow up. Our results suggests significant BP elevation is uncommon following neonatal CLD.