INHIBITION OF NO SYNTHESIS HAS AN ADDITIVE EFFECT ON HYPERTENSION INDUCED BY ACTH IN CONSCIOUS RATS

1. The haemodynamic and metabolic effects of oral intake of approximately 30 mg/kg per day N-nitro-L-arginine (NOLA) were examined in sham and adrenocorticotrophin (ACTH, 0.5 mg/kg per day) treated conscious Sprague-Dawley rats (n = 33). 2. NOLA administration produced an increase in systolic blood pressure of 24 +/- 6 mmHg (P < 0.001), but did not alter food or water intake, urine volume or electrolyte excretion in rats not treated with ACTH. 3. Compared with sham injection, ACTH-treated rats demonstrated an increase in systolic blood pressure (water + sham, 3 +/- 1 mmHg; water + ACTH, 16 +/- 3 mmHg; P < 0.001), loss of bodyweight, and increases in water intake and urine volume. 4. The magnitude of the blood pressure rise in ACTH-treated rats was greater in those receiving NOLA than in those drinking water only (water + ACTH, 16 +/- 3 mmHg; NOLA + ACTH, 37 +/- 3 mmHg; P < 0.05). Metabolic changes were similar. 5. Inhibition of nitric oxide is unlikely to be a major determinant of ACTH-induced hypertension in the rat, since NOLA increased blood pressure whether or not ACTH was administered, indicating an additive effect of ACTH and NOLA administration.     

Vasopressin V1a receptor antagonism does not reverse adrenocorticotrophin-induced hypertension in the rat

1. The role of arginine vasopressin (AVP) was examined in adrenocorticotrophin (ACTH)-induced hypertension in Sprague-Dawley rats using the non-peptide AVP V1a receptor antagonist OPC 21268. 2. In an acute study, six rats were pretreated with ACTH for 11 days and direct arterial blood pressure (4 h), plasma osmolality and electrolyte concentrations were measured after OPC 21268 gavage. In a chronic study, 40 rats were randomly divided into four groups: (i) sham injection + sham gavage; (ii) ACTH + sham gavage; (iii) sham injection + OPC 21268; or (iv) ACTH + OPC-21268 for 16 days. Systolic blood pressure (SBP), water intake, urine volume (UV), urine osmolality and electrolytes, food intake, bodyweight and plasma osmolality and electrolyte concentrations were measured. 3. In the acute study, direct mean arterial blood pressure did not change with OPC 21268 (122+/-2 and 120+/-3 mmHg at 0 and 240 min, respectively). 4. In the chronic study, OPC 21268 did not affect ACTH-induced rises in blood pressure (from 125+/-2 (control) to 145+/-5 mmHg (group 4) compared with 122+/-3 (control) to 149+/-5 mmHg (group2)). Water intake and UV increased (from 29+/-2 to 83+/-6 mL/day; and from 5+/-1 to 36+/-5 mL/day, respectively) and the change in bodyweight decreased from 0+/-2 to -107+/-7 g. 5. These results suggest that AVP (at the V1a receptor) does not play a significant role in the maintenance of ACTH-induced hypertension.     

Role of nitric oxide in adrenocorticotrophin-induced hypertension: L-arginine effects reversed by N-nitro-L-arginine

1. L-arginine prevents adrenocorticotrophin (ACTH)-induced hypertension in the rat. To confirm that this effect is mediated through the nitric oxide (NO) system, we examined whether N-nitro-L-arginine (NOLA) could reverse the L-arginine-induced blockade of ACTH-induced hypertension. 2. Blood pressure and metabolic parameters were examined in sham-, ACTH-, L-arginine + sham-, NOLA + sham-, ACTH + L-arginine- and ACTH + L-arginine + NOLA-treated Sprague-Dawley rats (n = 40). 3. Adrenocorticotrophin treatment increased systolic blood pressure (SBP), water intake and urine output and decreased bodyweight. N-Nitro-L-arginine alone increased SBP without affecting metabolic variables. L-Arginine alone did not affect blood pressure. The SBP was lower in L-arginine + ACTH- than ACTH-treated rats (P < 0.001), but was higher following ACTH + L-arginine + NOLA than ACTH + L-arginine (P < 0.05). 4. N-Nitro-L-arginine reversed the blood pressure-lowering effect of L-arginine in ACTH-induced hypertension in the rat, supporting the notion that NO plays a role in the hypertension.     

Arachidonic acid metabolism in glucocorticoid-induced hypertension

1. Products of metabolism of arachidonic acid, such as 20-hydroxyeicosatetraenoic acid (20-HETE), thromboxane A(2) (TXA(2)) and prostaglandin I(2) (PGI(2)), regulate vascular tone. Among them, 20-HETE is a potent constrictor in small arteries that also has natriuretic properties. The present study investigated changes in urinary concentrations of 20-HETE and metabolites of TXA(2) and PGI(2) in glucocorticoid-hypertension in rats, a sodium-independent model. 2. Male Sprague-Dawley rats were treated with saline, adrenocorticotrophic hormone (ACTH; 0.2 mg/kg) or dexamethasone (20 microg/kg) by daily s.c. injection for 12 days. Systolic blood pressure (SBP) was measured using the tail-cuff method. Metabolic cages were used for 24 h urine collection. Thymus weight and urinary concentrations of 20-HETE, TXA(2) and PGI(2) were determined. 3. In the present study, SBP was increased by both ACTH (from 102 +/- 2 to 134 +/- 7 mmHg; n = 10; P < 0.01) and dexamethasone (from 106 +/- 5 to 122 +/- 4 mmHg; n = 10; P < 0.01). Thymus weight, a marker for glucocorticoid activity, was significantly decreased by both ACTH and dexamethasone (56 +/- 9 and 76 +/- 5 mg/100 g bodyweight, respectively; n = 10; P' < 0.01) compared with the saline control (151 +/- 5 mg/100 g bodyweight; n = 20). Urinary 20-HETE excretion was increased by ACTH (501 +/- 115 pmol/g creatinine; n = 10; P' < 0.05) but not by dexamethasone (126 +/- 13 pmol/g creatinine; n = 10) compared with the saline control (219 +/- 54 pmol/g creatinine; n = 20). Neither ACTH nor dexamethasone affected urinary excretion of TXB(2) or PGI(2) compared with the saline control. 4. In conclusion, ACTH but not dexamethasone increased urinary 20-HETE excretion in male Sprague-Dawley rats. Urinary concentrations of the metabolites TXB(2) and PGI(2) were unchanged in both models of glucocorticoid-hypertension. The vasoconstrictor 20-HETE may play a role in the genesis of ACTH-induced hypertension.     

Role of xanthine oxidase in dexamethasone-induced hypertension in rats

1. Glucocorticoid-induced hypertension (GC-HT) in the rat is associated with nitric oxide-redox imbalance. 2. We studied the role of xanthine oxidase (XO), which is implicated in the production of reactive oxygen species, in dexamethasone-induced hypertension (dex-HT). 3. Thirty male Sprague-Dawley rats were divided randomly into four treatment groups: saline, dexamethasone (dex), allopurinol plus saline, and allopurinol plus dex. 4. Systolic blood pressures (SBP) and bodyweights were recorded each alternate day. Thymus weight was used as a marker of glucocorticoid activity, and serum urate to assess XO inhibition. 5. Dex increased SBP (110 +/- 2-126 +/- 3 mmHg; P < 0.001) and decreased thymus (P < 0.001) and bodyweights (P" < 0.01). Allopurinol decreased serum urate from 76 +/- 5 to 30 +/- 3 micromol/L (P < 0.001) in saline and from 84 +/- 13 to 28 +/- 2 micromol/L in dex-treated (P < 0.01) groups. 6. Allopurinol did not prevent dex-HT. This, together with our previous findings that allopurinol failed to prevent adrenocorticotrophic hormone induced hypertension, suggests that XO activity is not a major determinant of GC-HT in the rat.     

Telemetric monitoring of adrenocorticotrophin-induced hypertension in mice

1. The mouse is the animal of choice for studies involving genetic manipulation and transgenic and knockout mice are valuable tools for physiological studies. We have studied adrenocorticotrophin (ACTH)- and steroid-induced hypertension in both rat and humans. The aim of the present study was to develop a model of ACTH-induced hypertension in the mouse and to assess a chronically implanted telemetric device for measurement of blood pressure (BP). 2. Male Swiss Outbred and Quackenbush Swiss (QS) mice (35-45 g) were implanted with TA11PA-C20 BP devices (Data Sciences International, St Paul, MN, USA) under isoflurane anaesthesia. Seven to 10 days later, mice were monitored telemetrically for baseline BP for 4 days. Mice were then randomly allocated to: (i) sham treatment with normal saline s.c.; or (ii) ACTH at 500 microg/kg per day, s.c. Mice were monitored 24 h/day for 10 days. 3. Sham treatment (n = 7) did not affect BP (114 +/- 2/84 +/- 1 to 115 +/- 2/84 +/- 1 mmHg; P = NS). Adrenocorticotrophin treatment (n = 5) raised BP from 112 +/- 7/82 +/- 4 to 138 +/- 3/104 +/- 4 mmHg, which was significantly different from sham treatment (P = 0.0021 for systolic BP; P < 0.0001 diastolic BP). The increase in BP with ACTH was comparable with that seen in previous studies in humans, sheep and rat. Sham and ACTH-treated animals each lost 3% bodyweight. 4. Administration of ACTH (500 microg/kg per day) raises BP in two strains of mice, measured using a telemetry system. This model will allow the selective use of transgenic and/or knockout mice to further elucidate the mechanism of ACTH- and steroid-induced hypertension.     

ROLE OF THE SYMPATHETIC NERVOUS SYSTEM IN THE ONSET OF HYPERTENSION IN THE RAT: THE EFFECT OF 6-OH-DOPAMINE

1. The effect of chemical sympathectomy with 6-OH-dopamine (6-OHDA) on the onset of adrenocorticotrophin (ACTH)-induced hypertension was examined in Sprague-Dawley rats (n = 23). 2. 6-OHDA injection produced a fall in systolic blood pressure (SBP) from 100 +/- 5 mmHg control to 74 +/- 4 mmHg post-6-OHDA Treatment Day 1 (P less than 0.001), but did not alter food or water intake, urine volume or electrolyte excretion. 3. Compared with sham injection, ACTH-treated rats showed an increase in blood pressure (sham: 98 +/- 7 mmHg; ACTH: 123 +/- 9 mmHg on Treatment Day 10; P less than 0.01), loss of bodyweight, and increases in water intake and urine volume. 4. The magnitude of the blood pressure rise on ACTH was greater in 6-OHDA-treated rats than in intact control rats. Metabolic changes were similar. 5. Chemical sympathectomy with 6-OHDA did not delay or block the onset of ACTH hypertension in the rat.     

Comparison of angiotensin II-induced blood pressure and structural changes in Fischer 344 and Wistar Kyoto rats

1. The purpose of the present study was to evaluate the blood pressure (BP) response, the BP and heart rate (HR) components of the startle reaction and the structure of the carotid artery and the aorta during chronic infusion of angiotensin (Ang) II in Fischer 344 (F344) compared with Wistar Kyoto (WKY) rats, two in-bred normotensive contrasted strains. 2. Osmotic mini-pumps filled with saline vehicle or AngII (120 ng/kg per min) were implanted subcutaneously in 8-week-old normotensive rats and infused for 4 weeks in F344 rats (saline, n = 10; AngII, n = 10) and WKY rats (saline, n = 10; AngII, n = 9). Basal BP, HR and the responses to an acoustic startle stimulus (duration 0.7 s, 115 dB) were recorded in conscious rats. The structure of the carotid artery and aorta was determined in 4% formaldehyde-fixed arteries. 3. Compared with WKY rats, vehicle-treated F344 rats had lower bodyweight (BW; 266 +/- 7 vs 299 +/- 9 g; P < 0.05) and heart weight (0.80 +/- 0.02 vs 0.98 +/- 0.04 g; P < 0.05) and higher aortic systolic BP (SBP; 131 +/- 1 vs 123 +/- 5 mmHg; P < 0.001) and diastolic BP (98 +/- 3 vs 89 +/- 2 mmHg; P < 0.001). In F344 rats, compared with the WKY rats, the wall thickness/BW ratio was increased in the carotid artery (156 +/- 9 vs 131 +/- 6 nm/g; P < 0.05) and abdominal aorta (264 +/- 13 vs 217 +/- 12 nm/g; P < 0.05) and decreased in the thoracic aorta (246 +/- 13 vs 275 +/- 8 nm/g; P < 0.05). There was no difference in elastin and collagen density. Angiotensin II differentially enhanced BP in both strains: (SBP: 163 +/- 5 and 132 +/- 4 mmHg in F344 and WKY rats, respectively; P(strain x treatment) < 0.05). Circumferential wall stress was increased in the aorta of F344 rats compared with WKY rats (1176 +/- 39 vs 956 +/- 12 kPa (P < 0.001) and 1107 +/- 42 vs 813 +/- 12 kPa (P < 0.001) in thoracic and abdominal aortas, respectively). The startle response was amplified in F344 rats, with enhanced increases in SBP and pulse pressure (PP) and bradycardia compared with responses of WKY rats (+44 +/- 9 mmHg, +10 +/- 2 mmHg and -40 +/- 17 b.p.m., respectively, in F344 rats vs+28 +/- 4 mmHg, + 4 +/- 2 mmHg and -19 +/- 10 b.p.m. in WKY rats, respectively; P(strain) < 0.05 for BP and PP). The startle response was not affected by AngII. 4. These results indicate a higher BP producing an increase in wall thickness in F344 rats compared with WKY rats. We propose that an increase in sympathetic nervous activity causes these haemodynamic differences, as suggested by the excessive increase in BP during an acoustic startle stimulus. Angiotensin II increased BP in F344 rats, but did not exaggerate the increase in BP during the startle reaction.     

N-Acetylcysteine prevents but does not reverse dexamethasone-induced hypertension

1. We have shown previously that N-acetylcysteine (NAC) prevents the increase in blood pressure induced by adrenocorticotropin treatment. The present study investigated the effect of NAC on dexamethasone (Dex)-induced hypertension. 2. Male Sprague-Dawley rats were randomly divided into six groups (n = 10 in each). In a prevention study, NAC (10 g/L in the drinking water) was given for 4 days prior to and 11 days during concurrent treatment with saline (0.1 mL/rat per day) or with Dex (10 mg/rat per day). In a reversal study, daily injections of Dex or saline began 8 days before NAC and cotreatment continued for 5 days. Systolic blood pressure (SBP) was measured on alternate days using a tail-cuff system. 3. Dexamethasone significantly increased SBP from 113 +/- 4 to 139 +/- 6 mmHg (n = 10; P < 0.01). N-Acetylcysteine alone had no effect on SBP. In NAC + Dex-treated rats, SBP was significantly lower than that of Dex-treated rats (P cent < 0.01). In fully established Dex-hypertension NAC was ineffective and SBP remained high. 4. Both Dex and NAC treatments decreased bodyweight gain. N-Acetylcysteine reduced food and water consumption. Dexamethasone reduced thymus weight (P cent < 0.01) but NAC treatment did not alter this marker of glucocorticoid activity. 5. Dexamethasone tended to decrease plasma NO(x), whereas NAC restored plasma NO(x) concentrations to control levels. N-Acetylcysteine had no effect on Dex-induced increased plasma F(2)-isoprostane concentrations. 6. In conclusion, NAC partially prevented, but did not reverse, Dex-induced hypertension.     

Comparison of telemetric and tail-cuff blood pressure monitoring in adrenocorticotrophic hormone-treated rats

1. The aim of the present study was to validate a telemetric blood pressure (BP) monitoring system against tail-cuff blood pressure in both adrenocorticotrophic hormone (ACTH)- and sham-treated rats. In the statistical analyses, we first tested whether there was a detectable effect on systolic blood pressure (SBP) of 10 days treatment with ACTH compared with saline. Second, we compared results of telemetered and tail-cuff measurements and, third, we developed a novel method for estimating the relative power of the two techniques. 2. Twenty-three male Sprague-Dawley rats were randomly divided into two groups: (i) ACTH (100 microg/kg per day, s.c; n = 12) treated; or (ii) sham treated (0.9% saline, s.c; n = 11). Systolic BP was measured by the telemetric system (sampled for 10 s every 2 min) continuously for 4 h (n = 16) or for 30 min (n = 23) and also by the indirect tail-cuff method daily (n = 23). Data were compared within and between groups; ordinary least products (OLP) regression analysis was then performed to test for bias between the two methods. Sample size/power estimations were also performed. 3. Adrenocorticotrophic hormone treatment raised telemetered SBP by 11 mmHg (P < 0.001) compared with 14 mmHg (P < 0.001) using the tail-cuff method. There was no fixed or proportional bias between the two methods of measurement, as shown by regression analysis. Power calculations indicate that a minimum sample size of six gives a power of telemetered to tail-cuff of 0.84/0.86 = 0.98. The power of 4 h versus 30 min BP measurements was 0.99/0.82 = 1.2. 4. Telemetry gave very similar results to the tail-cuff method. Telemetry allows for a longer period of measurement, giving greater power to the study so that fewer animals are needed.     

DEHYDROEPIANDROSTERONE DOES NOT PREVENT ADRENOCORTICOTROPHIN-INDUCED HYPERTENSION IN CONSCIOUS RATS

1. We tested the hypothesis that dehydroepiandrosterone (DHEA), which prevents dexamethasone-induced hypertension in rats, may block adrenocorticotrophin (ACTH) hypertension, which has been presumed due to corticosterone excess. The blood pressure and metabolic effects of DHEA (18 mg/kg per day) were examined in sham and ACTH-treated (0.5 mg/kg per day) conscious Sprague-Dawley rats (n= 20). 2. ACTH but not sham injection increased blood pressure, water intake and urine output and decreased bodyweight. 3. DHEA administration for 10 days did not alter blood pressure or metabolic effects in either sham or ACTH-treated rats. 4. DHEA, which is known to block dexamethasone-induced hypertension, did not modify ACTH-induced hypertension in the rat. This suggests either that ACTH-induced hypertension is not simply a consequence of glucocorticoid activity or that the action of DHEA in dexamethasone hypertension is not through blocking the glucocorticoid receptor.     

INFLUENCE OF SOMATOSTATIN ANALOGUE (SMS 201–995, OCTREOTIDE) ON BLOOD PRESSURE IN ADRENOCORTICOTROPHIN (ACTH) TREATED RATS: ROLE OF HYPERINSULINAEMIA IN ACTH HYPERTENSION

1. The hypothesis that adrenocorticotrophin (ACTH)-induced hypertension is a consequence of steroid-induced hyperinsulinaemia was tested using the somatostatin analogue (sandostatin, octreotide) to inhibit insulin release in Sprague-Dawley (SD) rats (n= 41). 2. Octreotide (20 μg, twice daily) did not modify blood pressure, plasma glucose, bodyweight, water and electrolyte balance, or organ weights but inhibited insulin secretion in the SD rat. 3. Compared with sham injection, ACTH-treated (0.5 mg/kg per day) SD rats showed an increase in blood pressure (sham 111 ± 4 mmHg; ACTH 140 ± 5 mmHg on treatment day 10 (P≤ 0.01), organ weights, water intake, urine volume, plasma glucose, insulin and sodium concentrations, and decrease of bodyweight and plasma potassium concentration. 4. Systolic blood pressure in rats treated with combined octreotide and ACTH was similar to that in rats on ACTH alone. Plasma insulin concentration was lower in octreotide + ACTH treated rats than with ACTH treatment alone. There were no differences in body or organ weights, plasma glucose, water or electrolyte balance. 5. Octreotide lowered plasma insulin concentration to the normal range but did not modify ACTH-induced hypertension in SD rats. These data do not support the notion that insulin-mediated alterations in blood pressure are a major mechanism for ACTH-induced hypertension in the rat.     

ADRENOCORTICOTROPHIC HORMONE-INDUCED HYPERTENSION IN THE RAT: EFFECTS OF THE ENDOTHELIN ANTAGONIST BOSENTAN

1. The effects of the endothelin antagonist bosentan on adrenocorticotrophic hormone (ACTH)-induced hypertension were examined in the conscious male Sprague-Dawley rat. 2. In order to confirm endothelin antagonism, 18 rats were randomly divided into two groups: receiving either (i) endothelin-1 (0.125, 0.25, 0.5 and 1 nmol/kg, i.v.); or (ii) endothelin-1 at these doses following bosentan (100 mg/kg gavage) and mean arterial pressure recorded (study A). Subsequently, 40 male rats (320 +/- 5 g) were randomly divided into four groups (n = 10): (i) Sham (0.9% saline, s.c.) + 5% acacia gum gavage; (ii) ACTH (500 micrograms/kg per day, s.c.) + 5% acacia gum gavage; (iii) Sham injection + bosentan (100 mg/kg per day) gavage; or (iv) ACTH + bosentan. Six control days (C1-C6) were followed by 11 treatment days (T0-T10). Systolic blood pressure, water intake, urine volume, food intake and bodyweight were measured every second day (study B). 3. Bosentan significantly attenuated the endothelin-1-induced blood pressure rise at 0.125 nmol/kg (P < 0.05), but not at higher doses. 4. Bosentan at a dose which attenuated endothelin-1-induced blood pressure increase had no effect on either blood pressure or metabolic parameters in ACTH-treated rats. 5. These results suggest that endothelin does not play a major role in ACTH-induced hypertension.     

Nitric oxide inhibition accelerates hypertension and induces perivascular inflammation in rats

1. Inflammatory changes in peripheral arteries have been reported in animal models of hypertension. Whether they occur in cerebral arteries (CA) with hypertension induced by deprivation of endogenous nitric oxide (NO) remains unknown. 2. In the present study, we compared the arteriolar injury score (AIS) and perivascular inflammation in CA between hypertensive and normotensive rats following NO deprivation with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). Five-week-old male spontaneously hypertensive rats (SHR) and Wistar -Kyoto (WKY) rats were fed with L-NAME (1 mg/mL) for 4 weeks. 3. Nitric oxide deprivation resulted in time-dependent elevations in tail-cuff pressure (representing systolic blood pressure (SBP)) in both SHR and WKY rats. The magnitude of increase in SBP was larger in SHR (+81.0 +/- 3.2 vs+25.0 +/- 2.2 mmHg; P < 0.01). Arteriolar hyalinosis and AIS in various segments of the CA were assessed with periodic acid-Schiff staining and inflammatory cells were immunostained with the antibody against macrophage/monocyte marker (ED1). The ED1+ cells appeared in the middle CA of L-NAME-treated SHR as early as 2 weeks after treatment. These cells were not observed in L-NAME-treated WKY rats and untreated SHR. More ED1+ cells were found in L-NAME-treated SHR than L-NAME-treated WKY rats after 4 weeks treatment. 4. The AIS and number of ED1+ cells around the perivascular area of the internal carotid artery were significantly higher in L-NAME-treated compared with untreated rats (AIS: 137 +/- 28 vs 46 +/- 10 for WKY rats, respectively; 169 +/- 18 vs 53 +/- 6 for SHR, respectively (P < 0.01); ED1+ cells: 7.9 +/- 0.6 vs 1.3 +/- 0.9 for WKY rats, respectively; 13.6 +/- 2.7 vs 2.1 +/- 0.9 for SHR, respectively (P < 0.01)), although SBP was higher in untreated SHR than in L-NAME-treated WKY rats (170 +/- 4 vs 137 +/- 4 mmHg, respectively; P < 0.05). 5. These findings suggest that ED1+ cells appeared in the middle CA of L-NAME-SHR as early as 2 weeks after treatment. Chronic inhibition of NO accelerates hypertension and induces perivascular inflammation.     

Sex-differences in circadian blood pressure variations in response to chronic angiotensin II infusion in rats

1. The aim of this study was to investigate the effect of chronic angiotensin II (AngII) infusion on the circadian rhythms of arterial blood pressure, heart rate (HR) and locomotor activity (ACT) in male and female rats. 2. Radiotelemetry probes were implanted into the aorta in male and female rats and allowed 10 days for recovery. Control levels for mean arterial pressure (MAP), HR and ACT were recorded for 3 days, then AngII (400 ng/kg per min s.c. via osmotic minipump) or vehicle (saline) was infused for 10 days (n = 6 per group). Further recordings of MAP, HR and ACT were made during days 8, 9 and 10 of the infusion period. 3. In response to AngII infusion, night and day-time MAP increased significantly in female (18 +/- 2 mmHg; 28 +/- 7 mmHg) and male (27 +/- 4 mmHg; 30 +/- 3 mmHg) rats, respectively. The degree of elevation in MAP in response to AngII was attenuated in the females during the night period (P(sex) < 0.05) but not the day (P(sex) = 0.2). Control night-day differences in MAP, HR and ACT averaged 7 +/- 1 mmHg, 58 +/- 5 b.p.m. and 30 +/- 4 units in the female and 6 +/- 1 mmHg, 43 +/- 3 b.p.m. (P(sex) < 0.05) and 14 +/- 2 units (P(sex) < 0.05) in male rats, respectively. AngII infusion disrupted MAP circadian rhythm in female (-4 +/- 2 mmHg) and male rats (1 +/- 2 mmHg; P(treat) < 0.01), but did not affect heart rate or locomotor activity. 4. In conclusion, sex differences in the circadian rhythm of heart rate and locomotor activity, but not arterial pressure exist under basal conditions. Circulating AngII modulated the circadian rhythm of MAP in female and male rats but not heart rate or locomotor activity. These findings have important implications for our understanding of circadian blood pressure rhythms in states of activation of the renin angiotensin system.     

PROGESTERONE ANTAGONIZES DEVELOPMENT BUT NOT MAINTENANCE OF ACTH-INDUCED HYPERTENSION IN SHEEP

1. This study investigated the effect of progesterone, which, under certain circumstances, can antagonize both the mineralocorticoid and glucocorticoid activities of steroid hormones, on the development and maintenance of adrenocorticotrophic hormone (ACTH)-induced hypertension in conscious sheep. 2. Progesterone (500 mg/day) alone, for 5 days, had no effect on blood pressure, but increased urinary Na excretion by 38 +/- 10 mmol/day (P less than 0.05) during the first 24 h. 3. Infusion of ACTH (5 micrograms/kg per day), alone, for 3 days, increased arterial pressure by 21 +/- 2 mmHg (P less than 0.001) associated with hypernatraemia, hypokalaemia, urinary Na retention, and increased fasting plasma glucose concentration. 4. Progesterone (500 mg/day) concurrently with ACTH blocked the rise in mean arterial pressure and the mineralocorticoid (urinary Na retention) but not the glucocorticoid (increase in plasma glucose concentration) effects associated with ACTH administration. 5. Progesterone (500 and 1000 mg/day) failed to reverse the hypertension and hypokalaemia in sheep pretreated for 3 days with ACTH. 6. Thus, progesterone blocked the onset but did not affect established ACTH hypertension. The mechanism by which progesterone blocked the development of ACTH hypertension appears to be related to the ability of progesterone to block the essential mineralocorticoid component of the adrenocortical steroids involved in the development of ACTH hypertension.     

Contribution of the renin-angiotensin system to short-term blood pressure variability during blockade of nitric oxide synthesis in the rat.

1. The aim of this study was to investigate, by use of spectral analysis, (1) the blood pressure (BP) variability changes in the conscious rat during blockade of nitric oxide (NO) synthesis by the L-arginine analogue NG-nitro-L-arginine methyl ester (L-NAME); (2) the involvement of the renin-angiotensin system in these modifications, by use of the angiotensin II AT1-receptor antagonist losartan. 2. Blockade of NO synthesis was achieved by infusion for 1 h of a low-dose (10 micrograms kg-1 min-1, i.v., n = 10) and high-dose (100 micrograms kg-1 min-1, i.v., n = 10) of L-NAME. The same treatment was applied in two further groups (2 x n = 10) after a bolus dose of losartan (10 mg kg-1, i.v.). 3. Thirty minutes after the start of the infusion of low-dose L-NAME, systolic BP (SBP) increased (+10 +/- 3 mmHg, P < 0.01), with the effect being more pronounced 5 min after the end of L-NAME administration (+20 +/- 4 mmHg, P < 0.001). With high-dose L-NAME, SBP increased immediately (5 min: +8 +/- 2 mmHg, P < 0.05) and reached a maximum after 40 min (+53 +/- 4 mmHg, P < 0.001); a bradycardia was observed (60 min: -44 +/- 13 beats min-1, P < 0.01). 4. Low-dose L-NAME increased the low-frequency component (LF: 0.02-0.2 Hz) of SBP variability (50 min: 6.7 +/- 1.7 mmHg2 vs 3.4 +/- 0.5 mmHg2, P < 0.05), whereas the high dose of L-NAME not only increased the LF component (40 min: 11.7 +/- 2 mmHg2 vs 2.7 +/- 0.5 mmHg2, P < 0.001) but also decreased the mind frequency (MF: 0.2-0.6 Hz) component (60 min: 1.14 +/- 0.3 mmHg2 vs 1.7 +/- 0.1 mmHg2, P < 0.05) of SBP. 5. Losartan did not modify BP levels but had a tachycardic effect (+45 beats min-1). Moreover, losartan increased MF oscillations of SBP (4.26 +/- 0.49 mmHg2 vs 2.43 +/- 0.25 mmHg2, P < 0.001), prevented the BP rise provoked by the low-dose of L-NAME and delayed the BP rise provoked by the high-dose of L-NAME. Losartan also prevented the amplification of the LF oscillations of SBP induced by L-NAME; the decrease of the MF oscillations of SBP induced by L-NAME was reinforced after losartan. 6. We conclude that the renin-angiotensin system is involved in the increase in variability of SBP in the LF range which resulted from the withdrawal of the vasodilating influence of NO. We propose that NO may counterbalance LF oscillations provoked by the activity of the renin-angiotensin system.     

Enhanced blood pressure sensitivity to DOCA-salt treatment in endothelin ET(B) receptor-deficient rats

The role of endothelin ET(B) receptor-mediated action in the development and maintenance of deoxycorticosterone acetate (DOCA)-salt-induced hypertension was evaluated using the spotting-lethal (sl) rat which carries a naturally occurring deletion in the ET(B) receptor gene. Homozygous (sl/sl) rats treated with DOCA-salt for 1 week exhibited an earlier onset of hypertension than heterozygous (sl/+) and wild-type (+/+) rats (systolic blood pressure, SBP; 156.7+/-3.4 versus 128.8+/-5.3 and 132.9+/-3.7 mmHg, respectively). Four weeks after the start of DOCA-salt treatment, homozygous rats developed marked hypertension, with a SBP of 206. 0+/-4.5 mmHg, compared with 184.8+/-10.7 mmHg in heterozygous and 164.3+/-4.8 mmHg in wild-type rats. Cardiovascular hypertrophy and renal dysfunction observed after 4-weeks treatment with DOCA-salt were more severe in homozygous rats, compared to wild-type and heterozygous animals. These evidences support strongly the view that ET(B) receptor-mediated actions are a protective factor in the pathogenesis of DOCA-salt-induced hypertension.     

RENAL AND MYOCARDIAL ADRENOCEPTORS IN STEROID CONTRACEPTIVE-INDUCED HYPERTENSION IN RATS

1. Systolic blood pressure (SBP), bodyweight, organ weight, renal beta-adrenoceptor and myocardial beta- and myocardial alpha 1-adrenoceptor characteristics were investigated in female Sprague-Dawley rats after chronic subcutaneous (s.c.) administration of ethynyloestradiol (EE2, 0.2 microgram/day), levonorgestrel (NG, 2.0 micrograms/day) separately and in combination (EE2/NG). 2. EE2 caused a sustained increase in SBP from 6 weeks (maximum at 14 weeks, +22 mmHg compared to control) which was accompanied by increased kidney and ventricle weight after 12 weeks. EE2/NG-treated rats also demonstrated a gradual rise in SBP (maximum at 9 weeks, +18 mmHg compared with control) with renal and ventricular hypertrophy, but were normotensive by week 17 of treatment. In contrast, NG induced only transient SBP increases (maxima at 5 and 10 weeks, +14 mmHg compared with control), unaccompanied by organ hypertrophy. Norethisterone (2 micrograms/day) also produced transient increases (weeks 6-8, +13 mmHg) in SBP. 3. alpha 1- and beta-adrenoceptors were investigated using [3H]-prazosin and (-)-[125I]-iodocyanopindolol (ICYP), respectively. Myocardial alpha 1- and beta-adrenoceptors were unaffected by steroid contraceptive administration for up to 12 weeks. Renal beta-adrenoceptor affinity was markedly reduced in 12 week EE2-treated rats (equilibrium dissociation constant, KD, 53 +/- 7 pmol/L) compared with controls (KD, 31 +/- 4 pmol/L), an effect which was prevented by co-administration of NG (KD, 34 +/- 8 pmol/L). Renal beta-adrenoceptor number was not altered by any treatment. 4. The relatively late onset of organ hypertrophy and beta-adrenoceptor changes appear to result from, rather than cause, EE2-induced hypertension.