Central alpha-2 adrenoceptor-mediated hypertensive response to clonidine in conscious, normotensive rats

Possible involvement of central alpha-2 adrenoceptors in the hypertensive response to i.c.v. injected clonidine was investigated in free-moving, normotensive rats. Clonidine (2-50 micrograms) injected i.c.v. produced a dose-dependent and long-lasting pressor response associated with bradycardia in conscious rats, but a long-lasting depressor response in anesthetized rats. The pressor response to clonidine (20 micrograms i.c.v.) was antagonized in a dose-dependent manner by central (i.c.v.) pretreatment with yohimbine (20-100 micrograms) and was abolished by a high dose (100 micrograms), whereas the same dose of yohimbine injected i.v. had less effect on the response. Central pretreatment with prazosin (10 and 20 micrograms) inhibited, but did not abolish, the pressor response to clonidine. However, systemic (i.v.) pretreatment with the same dose of prazosin (10 and 20 mu) was more effective in reducing the clonidine-induced pressor response than central pretreatment with the drug. The pressor response to clonidine (20 micrograms i.c.v.) was not significantly modified by central pretreatment with pyrilamine (50 and 100 micrograms), cimetidine (50 and 100 micrograms), ketanserin (50 and 100 micrograms) or procaine (100 micrograms). The selective alpha-2 adrenoceptor agonist, BHT-920, injected i.c.v. (5-50 micrograms) also produced a dose-dependent pressor response which was abolished by either anesthesia or central pretreatment with yohimbine, but not with prazosin, whereas the selective alpha-1 adrenoceptor agonist, methoxamine (10-100 micrograms i.c.v.), caused a slight increase in mean blood pressure only at higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endothelin binding in brain of normotensive and spontaneously hypertensive rats.

The endothelins (ETs) are a recently discovered family of peptides which appear to be involved in hemodynamic regulation; they have potent vasoconstrictor properties and dose-related effects on blood pressure when administered peripherally. Little is known about the role of ET in the brain. The purpose of this study was to characterize the binding properties of various ETs in the brain of normotensive (Wistar-Kyoto) and hypertensive (spontaneously hypertensive) rats. [125I]ET 1 was prepared using the enzymobead lactoperoxidase method and purified by high-pressure liquid chromatography. Membrane fractions were prepared from homogenates of various brain regions. A differential distribution of ET binding was found among the 14 brain regions studied. The cerebellum, brainstem and area postrema/nucleus tractus solitarius had the highest binding, whereas the cortex, pituitary and septum had the least binding. Competition experiments performed with hypothalamus, brainstem and cerebellum demonstrated different Ki values for the ET studied. ET 2 had the highest affinity with a Ki of 4 x 10(-1) M, whereas the ET analog, Ala3,11-ET 1, had the lowest affinity with a Ki of 3 x 10(-10) M. Saturation experiments indicated a single class of high-affinity receptors in cerebellar (Kd = 2.5 x 10(-11) M, maximal binding Bmax = 1.25 x 10(-12) mol/mg) and hypothalamic membranes (Kd = 1.9 x 10(-11) M, Bmax = 0.93 x 10(-12) mol/mg). No differences in Kd or Bmax were detected between Wistar-Kyoto and spontaneously hypertensive rats hypothalamic and cerebellar tissues. The results of this study suggest a role for ET in the brain, but revealed no differences between normotensive and hypertensive strains.     

Central 5HT1A-receptor binding in normotensive and spontaneously hypertensive rats

Central 5HT1A-receptors have been found with a high density in brainstem and are involved in cardiovascular control. The high-affinity binding of [3H]-8-OH-DPAT, a specific 5HT1A-receptor ligand, was measured in medulla oblongata of normotensive and spontaneously hypertensive rats (SHR). The maximal number of [3H]-8-OH-DPAT binding site (Bmax) was significantly increased in SHR when compared to normotensive rats. Whether central 5HT1A-receptors are involved in the etiology of hypertension or are influenced by other neurochemical events remains to be investigated.     

Fibrinolytic system in normotensive subjects and hypertensive patients

The aim of this study was to evaluate the fibrinolytic system by measurement of fibrinogen, plasminogen, tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) in healthy normotensive subjects and in patients with essential hypertension. A group of 21 healthy normotensive subjects [age, 39.2 +/- 1.8 years; 8 males, 13 females; body mass index (BMI) = 27.9 kg/m] and 42 patients with untreated essential hypertension (age, 47.6 +/- 1.7 years; 19 males, 23 females; BMI = 28.3 kg/m) were studied. Blood samples and clinical measurement were taken between 7 am and 9 am by an observer in a blind fashion. The systolic/diastolic blood pressure of normotensive subjects was 121.3 +/- 2.5/78.4 +/- 1.3 mm Hg and that of hypertensive patients was 166.4 +/- 4.3/102.9 +/- 1.83 mm Hg, measured in the sitting position. Plasma fibrinogen levels in the normotensive and hypertensive individuals were 295.7 +/- 9.4 mg/dL and 305.67 +/- 10.9 mg/dL, respectively (P = 0.456). The corresponding values for plasminogen were 71.4 +/- 3.8% and 89.5 +/- 2.5%, (P = 0.0031), for t-PA were 6.3 +/- 0.5 ng/mL and 7.6 +/- 0.4 ng/mL (P = 0.0487), and for PAI-1 were 46.9 +/- 5.1 ng/mL and 63.0 +/- 5.6 ng/mL (P = 0.0324), respectively. In conclusion, patients with essential hypertension have disequilibrium in the fibrinolytic system with a tendency toward a hypercoagulability state when compared with normotensive subjects. This state could explain, in part, the thrombotic complications that occur with a higher frequency in hypertensive patients as compared with normotensive subjects.     

5-Hydroxytryptamine lowers blood pressure in normotensive and hypertensive rats

Arterial hyper-responsiveness to 5-hydroxytryptamine (5-HT) is a hallmark of hypertension, and plasma levels of free 5-HT are elevated in hypertension. We hypothesized that chronic administration of 5-HT would cause blood pressure to 1) rise in normotensive rats and 2) rise significantly more in hypertensive rats. The deoxycorticosterone acetate (DOCA)-salt hypertensive and sham normotensive rat were used. Animals were implanted with minipumps that delivered 5-HT (or vehicle) at a rate of 25 microg/kg/min for 7 days. Free plasma 5-HT was elevated significantly by this protocol. Within 48 h, mean arterial blood pressure measured telemetrically decreased in sham (106 +/- 2 to 83 +/- 2 mm Hg) and in DOCA-salt hypertensive (166 +/- 9 to 112 +/- 3 mm Hg) rats; vehicle did not change blood pressure in either group. Ganglionic blockade (hexamethonium) reduced blood pressure to a greater magnitude in DOCA vehicle-administered rats (peak fall arterial pressure, 91 +/- 14 mm Hg) compared with DOCA 5-HT-administered rats (40 +/- 6 mm Hg). Maximal acetylcholine-induced (NO-dependent) relaxation in phenylephrine-contracted aortic strips was greater in 5-HT-administered (69.2 +/- 9.1% relaxation) versus vehicle-administered (39.7 +/- 14.2%) DOCA rats; aortic endothelial cell nitric oxide synthase expression was higher in the 5-HT- versus vehicle-administered DOCA-salt rats. In normotensive and DOCA-salt hypertensive rats, the nitric oxide synthase (NOS) inhibitor N(omega)-nitro-l-arginine (0.5 g/l in water) prevented the fall in blood pressure to 5-HT. We conclude that chronic exogenous 5-HT reduces blood pressure in normotensive and hypertensive rats through mechanisms critically dependent on NOS.     

Differences in ouabain-induced natriuresis between isolated kidneys of Milan hypertensive and normotensive rats.

1. Several observations support the hypothesis that in rats of the Milan hypertensive strain elevated levels of a circulating ouabain-like factor might normalize the elevated Na+ reabsorption, but, on the other hand, might contribute to the development of hypertension. 2. As the receptor occupancy of this endogenous factor seems to be reversible, the aim of our study was to test, in vitro, the hypothesis of its presence in isolated kidneys from Milan hypertensive rats by studying the response to exogenous ouabain before and after prolonged washing. 3. The kidneys were isolated from adult Milan hypertensive rats and from age-matched normotensive controls and ouabain was given at two different experimental time intervals: shortly (15 min) after washout or after a further 60 min of washout (75 min in total). Comparative experiments with the diuretic hydrochlorothiazide were performed using the same protocol. 4. Ouabain given after 15 min of perfusion caused an increase in renal vascular resistance, diuresis and natriuresis; these haemodynamic and tubular responses were similar in kidneys from both Milan hypertensive and Milan normotensive rats. If given after the washout period, ouabain caused a comparable increase in renal vascular resistance, but a significantly greater natriuresis in kidneys from Milan hypertensive rats as compared with kidneys from Milan normotensive rats. On the other hand, hydrochlorothiazide caused similar natriuresis in kidneys from both strains after washout. 5. These results support the hypothesis that a factor, capable of interacting with the ouabain receptor on the Na+/K(+)-ATPase of tubular cells, is present in the kidney of adult Milan hypertensive rats and that it can be removed by prolonged washout.     

Effects of L-tryptophan on blood pressure in normotensive and hypertensive rats

The effects of L-tryptophan on blood pressure and brain serotonin have been investigated in normotensive and spontaneously hypertensive rats. Doses of L-tryptophan from 25 to 100 mg/kg increased the blood pressure of normotensive rats by 10 to 15 mm Hg. The lower doses of L-tryptophan also increased blood pressure in hypertensive rats but, in contrast, the highest dose (100 mg/kg) lowered blood pressure by 30 to 35 mm Hg. Blood pressure effects of L-tryptophan were evident within 30 min of treatment and reached maximal response by 60 min. L-Tryptophan-induced changes in serotonin neurochemistry were correlated on a temporal basis with changes in blood pressure. However, the dose-response relationship between blood pressure changes and increases in brain serotonin and 5-hydroxyindoleacetic acid content produced by L-tryptophan was not related. The effects of L-tryptophan on blood pressure in normotensive and spontaneously hypertensive rats cannot be explained entirely by its effects on brain serotonin.     

Vascular areas where clonidine induces vasodilation in hypertensive and normotensive rats

The aim of this study was to find vascular areas where clonidine decreases the regional vascular resistance when this drug lowers arterial pressure in conscious spontaneously hypertensive rats and normotensive control rats. Arterial pressure was observed with an indwelling catheter at a carotid. Blood flow was measured with an electromagnetic flow probe implanted around the renal artery or the superior mesenteric artery. Regional vascular resistance was calculated as arterial pressure divided by blood flow. Intravenous bolus injection of clonidine at a dose to decrease arterial pressure decreased renal resistance and superior mesenteric resistance. Quantitatively, the combined effect of the decrease in these two resistances was enough to account for the decrease in arterial pressure. Although clonidine is thought to inhibit sympathetic nerve activity centrally, the above vasodilator effect is not ascribable to this inhibitory mechanism: Sympathetic activity to be inhibited does not seem to be present in the superior mesenteric area and clonidine similarly decreased renal vascular resistance even after renal denervation.     

Pharmacodynamics and pharmacokinetics of intravenously administered morphine in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

The analgesic and hyperthermic effects of i.v. administered morphine were determined in age-matched male spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Two doses of morphine (5 and 10 mg/kg) were used. In the doses used, morphine produced analgesia in WKY rats as measured by the tail-flick test and expressed as area under the time-response curve. The intensity and duration of the analgesic area under the time-response curve was significantly greater in SHR rats in comparison to WKY rats. For example, whereas the effect of a 10-mg/kg dose lasted for 4 hr in WKY rats; in SHR rats the effect lasted for 10 hr. Similarly, the intensity and duration of morphine-induced hyperthermic response was greater in SHR rats in comparison to WKY rats. In order to determine if the differences in responses to morphine in SHR and WKY were related to its kinetics, the pharmacokinetic parameters of morphine in serum were determined. The area under the serum morphine concentration-time curve, serum levels of morphine extrapolated to zero time, T1/2, apparent volume of distribution at steady state, terminal elimination rate constant and total body clearance values for morphine in SHR and WKY rats did not differ. Previous studies from this laboratory indicate that the density of mu opiate receptors labeled with [3H]D-Ala2.MePhe4,Gly-ol5-enkephalin and [3H]naltrexone and of kappa-opiate receptors labeled with [3H]ethylketocyclazocine in the brain of SHR rats is higher than in WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of clentiazem on arterial pressure and renal function in normotensive and hypertensive rats.

The present study evaluated the effects of a new benzothiazepine calcium channel antagonist, clentiazem, on arterial pressure and renal function in spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto (WKY) and Munich-Wistar rats (MWR). Administration of clentiazem in doses from 1 to 20 micrograms/kg/min produced dose-dependent increases in sodium and water excretion in MWR, reaching maximum values of 292 and 376% of control, respectively, at the 20-micrograms/kg/min dose. Clentiazem (10 micrograms/kg/min) lowered arterial pressure by 16% and doubled glomerular filtration rate (GFR) in MWR. The rise in GFR was associated with an increase in glomerular capillary pressure of 16 mm Hg, produced by a combination of preglomerular vasodilation and efferent arteriolar vasoconstriction. In SHR, administration of clentiazem (10 micrograms/kg/min) lowered arterial pressure by 30 mm Hg and increased urine flow and sodium excretion by 137 and 200%, respectively. In WKY rats, the same dose of clentiazem decreased arterial pressure by only 10 mm Hg, whereas urine flow and sodium excretion increased 62 and 38%, respectively. A high dose of clentiazem (1 mg/kg bolus plus 1 mg/kg/hr infusion i.v.) lowered arterial pressure by 63 mm Hg in SHR. Renal vascular resistance fell by 39% and there was a 5-fold increase in sodium excretion. In WKY rats, the same dose of clentiazem reduced arterial pressure by 20 mm Hg, but it had no significant effect on sodium excretion. These results indicate that clentiazem increases sodium excretion and GFR in normotensive rats in part by preferentially dilating the renal preglomerular vasculature. This compound is also an antihypertensive agent that lowers arterial pressure and promotes sodium excretion in SHR.     

Influence of dietary protein on glomerular angiotensin II-receptor binding in normotensive and spontaneously hypertensive rats.

1. The binding of angiotensin II to glomerular receptors was studied in spontaneously hypertensive and normotensive Wistar-Kyoto rats in response to 7, 16 and 32% isocaloric, isonatraemic protein diets. 2. Increased dietary protein elevated the systemic angiotensin II levels of both spontaneously hypertensive and Wistar-Kyoto rats [F0.05(2,26) = 4.758, P less than 0.05; n = 36], and this was not associated with changes in either systemic blood pressure or cortical renin activity. 3. Furthermore, no significant changes in the affinity or density of angiotensin II receptors were associated with changes of dietary protein intake in either strain. 4. These results indicate a dissociation between the system renin-angiotensin system and the tissue renin-angiotensin system in response to protein intake.     

Effect of angiotensin-converting enzyme inhibitors on glomerular eicosanoid production in normotensive and spontaneously hypertensive rats.

1. This study was designed to examine the production of certain eicosanoids (prostaglandin E2), prostacyclin (as 6-keto-prostaglandin F1 alpha) and thromboxane A2 (as thromboxane B2) by glomeruli isolated from normotensive Wistar-Kyoto and spontaneously hypertensive rats both before and after the administration of one of three angiotensin-converting enzyme inhibitors, captopril, enalapril or fosinopril, for 10 days. 2. Measurements of glomerular eicosanoid production were made under basal conditions and in the presence of excess exogenous arachidonic acid. 3. The production of prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2 was greater by glomeruli from untreated spontaneous hypertensive rats (prostaglandin E2 2.24 +/- 0.41, 6-keto-prostaglandin F1 alpha 1.20 +/- 0.13 and thromboxane B2 2.75 +/- 0.43 ng 10 min-1 mg-1 of protein) than by those from Wistar-Kyoto rats (prostaglandin E2 1.41 +/- 0.28, 6-keto-prostaglandin F1 alpha 0.98 +/- 0.11 and thromboxane B2 1.29 +/- 0.24 ng 10 min-1 mg-1 of protein) under basal conditions. However, these differences only achieved statistical significance for thromboxane B2 (P less than 0.01). Similar strain-related differences were noted in the presence of arachidonic acid. 4. The ratio of glomerular (prostaglandin E2 + prostacyclin)/thromboxane A2 production was significantly lower in spontaneously hypertensive rats than in their normotensive counterparts under basal conditions with values of 1.3 +/- 0.18 and 2.2 +/- 0.20, respectively (P less than 0.01). 5. Angiotensin-converting enzyme inhibitors induced significant changes in the glomerular production of some eicosanoids, which differed both between strains and with the nature of the inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differences in glomerular binding and response to angiotensin II between normotensive and spontaneously hypertensive rats

1. Angiotensin II (ANG II) binding and the physiological response to exogenous ANG II have been studied in isolated glomerular preparations from normotensive (NTR) and spontaneously hypertensive (SHR) rats. 2. The binding of 125I-labelled ANG II by glomeruli from SHR was significantly greater than that by glomeruli from NTR, whereas the binding affinity constant (Ka) showed that the SHR ANG II glomerular receptor had a lower affinity for the hormone than the NTR glomerular receptor. 3. Glomeruli from SHR were significantly less responsive to exogenous ANG II than those from NTR. 4. Sodium loading resulted in a significant increase in ANG II binding by glomeruli from NTR, whereas a decrease in binding occurred in glomeruli from SHR. 5. Although a high sodium intake caused a reduction in the response of glomeruli from both NTR and SHR to exogenous ANG II, these changes were not statistically significant. In NTR this was associated with a decrease in the concentration of agonist required to cause half-maximal response (EC50), whereas an increase in EC50 was shown by glomeruli from SHR.     

Differential effects of dopaminergic drugs on open-field behavior of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats

Brain catecholamines may play a role in the development of hypertension in the spontaneously hypertensive rat (SHR). To investigate central dopaminergic function in this strain, the effect of various dopaminergic drugs on open-field activity was assessed. In general, basal levels of ambulation were similar in SHRs and their controls, the Wistar-Kyoto rats (WKY). Exploratory rearing activity was increased in SHRs, however. Haloperidol inhibited open-field ambulation in SHRs and WKY, but higher doses were needed in the SHR. Apomorphine inhibited ambulatory activity in WKY but had virtually no effect in SHRs. Amphetamine and the dopamine uptake inhibitor GBR-12909 increased ambulation in SHRs and WKY to a similar extent. Central administration of haloperidol or sulpiride decreased ambulatory activity in WKY, but had no effect in SHRs at the doses used. SCH-23390 decreased ambulation scores both in SHRs and WKY, with the effect being slightly greater in the latter strain. In all cases exploratory rearing was affected as well by the drugs used. The large difference in base-line scores has to be taken into account when interpreting these data, however. Also, for comparison the noradrenergic drugs clonidine and desipramine were tested. Both elicited decreases in activity which were identical in SHRs and WKY. These results show that a number of dopaminergic drugs have differential effects on open-field activity of SHRs as compared to WKY. Ambulatory activity appeared more resistant to inhibition in SHRs than in WKY. The possibility that these results could reflect altered dopaminergic function in SHR involved in the development of hypertension in this strain is discussed.     

Thyroid function and blood pressure in two new strains of spontaneously hypertensive and normotensive rats

1. The influence of thryoid function on the development of hypertension was studied in strains of spontaneously hypertensive (SH) and normotensive rats. 2. Surgical thyroidectomy decreased systolic blood pressure more markedly in SH rats than in normotensive rats. The effects of oral administration of 5 and 100 micrograms of thyroxine 24 h-1 100 g-1 were studied in the thyroidectomized animals. In the two strains the blood pressure returned to control levels only after administration of the larger dose. 3. The evolution of body weight, total plasma tri-iodothyronine (T3) and tetraiodothyronine (T4) concentrations were followed as a function of age in SH rats and normotensive rats from 5 to 21 weeks. At each age, SH rats showed significantly larger body weight and decreased T4 concentrations. Plasma T3 in SH rats was lower than in normotensive rats until 15 weeks of age, after which the difference was not significant. At 11 weeks, plasms free T3 and T4 concentrations were slightly lower in SH rats than in normotensive rats. 4. The more marked hypotensive effects of surgical thyroidectomy in SH rats cannot be related to increased thyroid function.     

Transdermal HRT and Doppler findings in normotensive and hypertensive postmenopausal patients.

OBJECTIVE: To evaluate the effects of transdermal hormone replacement therapy (HRT) on plasma viscosity, serum levels of thromboxane B2 (TXB2) and vascular impedance in the uterine, bladder wall, internal carotid and ophthalmic arteries in normotensive and hypertensive postmenopausal patients. METHODS: Thirty postmenopausal patients underwent continuous estradiol transdermal supplementation at a dose of 50 microg/day and 12-day courses of medroxyprogesterone acetate 10 mg/day every 2 months. The women were divided into two groups according to their blood pressure: normotensive women (Group 1, n=14) and hypertensive subjects (Group 2, n=16). Before starting HRT and after 6 months of therapy, the patients underwent: transvaginal ultrasonographic examination of the pelvic organs; Doppler examination of the blood flow velocities in the uterine, bladder wall, internal carotid and ophthalmic arteries; and analysis of plasma viscosity and plasma TXB2. RESULTS: After 6 months of HRT plasma viscosity had decreased in both groups (mean reduction in Group 1, (14+/-1)%, P=0.005; mean reduction in Group 2, (10+/-1)%, P=0.005) as had the TXB2 levels (mean reduction in Group 1, (93+/-2)%, P<0.001; mean reduction in Group 2, (92+/-3)%, P<0.001). The mean percentage reduction in plasma viscosity was smaller in hypertensive women than in normotensive women (P<0.05). There was also a significant reduction in vascular impedance in the uterine artery (mean reduction in Group 1, (16+/-1)%, P=0.005; mean reduction in Group 2, (19+/-1)%, P=0.005), the bladder wall arteries (mean reduction in Group 1, (23+/-2)%, P=0.005; mean reduction in Group 2, (18+/-1)%, P=0.005), the internal carotid artery (mean reduction in Group 1, (25+/-1)%, P=0.005; mean reduction in Group 2, (26+/-1)%, P=0.005) and the ophthalmic artery (mean reduction in Group 1, (24+/-2)%, P=0.005; mean reduction in Group 2, (16+/-1)%, P=0.005). The percentage reduction in vascular impedance did not differ significantly between the two groups. CONCLUSIONS: Our results show that transdermal HRT is effective in reducing plasma viscosity, TXB2 levels and vascular impedance in the peripheral and central vessels both in normotensive and hypertensive postmenopausal patients.