Hypertensive end-organ damage and premature mortality are p38 mitogen-activated protein kinase-dependent in a rat model of cardiac hypertrophy and dysfunction.

BACKGROUND: Numerous pathological mediators of cardiac hypertrophy (eg, neurohormones, cytokines, and stretch) have been shown to activate p38 MAPK. The purpose of the present study was to examine p38 MAPK activation and the effects of its long-term inhibition in a model of hypertensive cardiac hypertrophy/dysfunction and end-organ damage. METHODS AND RESULTS: In spontaneously hypertensive stroke-prone (SP) rats receiving a high-salt/high-fat diet (SFD), myocardial p38 MAPK was activated persistently during the development of cardiac hypertrophy and inactivated during decompensation. Long-term oral treatment of SFD-SP rats with a selective p38 MAPK inhibitor (SB239063) significantly enhanced survival over an 18-week period compared with the untreated group (100% versus 50%). Periodic echocardiographic analysis revealed a significant reduction in LV hypertrophy and dysfunction in the SB239063-treatment groups. Little or no difference in blood pressure was noted in the treatment or vehicle groups. Basal and stimulated (lipopolysaccharide) plasma tumor necrosis factor-alpha concentrations were reduced in the SB239063-treatment groups. In vitro vasoreactivity studies demonstrated a significant preservation of endothelium-dependent relaxation in animals treated with the p38 MAPK inhibitor without effects on contraction or NO-mediated vasorelaxation. Proteinuria and the incidence of stroke (53% versus 7%) were also reduced significantly in the SB239063-treated groups. CONCLUSIONS: These results demonstrate a crucial role for p38 MAPK in hypertensive cardiac hypertrophy and end-organ damage. Interrupting its function with a specific p38 MAPK inhibitor halts clinical deterioration.

Vasopressin in rats with genetic and streptozocin-induced diabetes.

Rats were administered streptozocin (STZ; 50 or 75 mg/kg i.v., tail vein) or vehicle. Approximately 2 wk later, venous and arterial catheters was implanted for subsequent (24 h later) vasopressin, electrolyte, and hemodynamic measurements. STZ-induced diabetic (STZ-D) rats demonstrated a dose-dependent increase in the plasma glucose concentration, plasma osmolality, and plasma vasopressin concentration. Mean arterial blood pressure (MABP) was unchanged, but heart rate was reduced. Diabetes-prone BB rats, maintained on or withdrawn from insulin treatment for 24-48 h, and diabetes-resistant rats were instrumented and studied as above. Spontaneous-diabetes-prone rats demonstrated increase in plasma glucose concentration and plasma osmolality similar to STZ-D rats but had significantly greater plasma vasopressin concentrations. The significant decrease in MABP observed in these animals probably contributed to the enhanced vasopressin response. We conclude that both osmotic and cardiovascular parameters play important roles in vasopressin secretion in diabetic rats.

Female, but not male, serotonin reuptake transporter (5-HTT) knockout mice exhibit bladder instability.

Correlations exist between the incidence of depression, irritable bowel syndrome (IBS) and overactive bladder [Masand, P.S., Kaplan, D.S., Gupta, S., Bhandary, A.N., Nasra, G.S., Kline, M.D., Margo, K.L., 1995. Major depression and irritable bowel syndrome: is there a relationship? J. Clin. Psychiatry 56, 363-367.; Cukier, J.M., Cortina-Borja, M., Brading, A.F., 1997. A case-control study to examine any association between idiopathic detrusor instability and gastrointestinal tract disorder, and between irritable bowel syndrome and urinary tract disorder. Br. J. Urol. 79, 865-878.; Monga, A.K., Marrero, J.M., Stanton, S.L., Lemieux, M.C., Maxwell, J.D., 1997. Is there an irritable bladder in the irritable bowel syndrome? Br. J. Obstet. Gynaecol. 104, 1409-1412.; Zorn, B.H., Montgomery, H., Pieper, K., Gray, M., Steers, W.D., 1999. Urinary incontinence and depression. J. Urol. 162, 82-84.]. Furthermore, alterations in serotonergic neurotransmission may play a common role in the etiology of these disorders. Serotonin reuptake transporter knockout mice (5-HTT(-/-)) display phenotypes consistent with clinical features of mood and bowel disorders including anxiety and abnormal gastrointestinal motility [Holmes, A., Murphy, D.L., Crawley, J.N., 2003. Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol. Psychiatry 54, 953-959.]. In the present study, we evaluated bladder function in 5-HTT(-/-) mice. We have found that female 5-HTT(-/-) mice exhibit bladder dysfunction, characterized by significant increases in the frequency of spontaneous non-voiding bladder contractions and decreases in void volume compared to control female mice. These differences were not observed in male knockout mice. These studies provide significant supporting data for a mechanistic link between alterations in 5-HT, depression, IBS and overactive bladder in women.

Eprosartan reduces cardiac hypertrophy, protects heart and kidney, and prevents early mortality in severely hypertensive stroke-prone rats.

OBJECTIVE: Eprosartan is a selective angiotensin II type I receptor antagonist approved for the treatment of hypertension. In the present studies, eprosartan's ability to provide end-organ protection was evaluated in a model of cardiomyopathy and renal failure in stroke-prone rats (SP). METHODS: SP were fed a high fat (24.5% in food) and high salt (1% in water) diet (SFD). Eprosartan (60 mg/kg/day) or vehicle (saline control) (n = 25/group) was administered by intraperitoneally-implanted minipumps to these SP on the SFD for 12 weeks. Normal diet fed SP and WKY rats (n = 25/group) were also included for comparison (i.e. served as normal controls). Mortality, hemodynamics, and both renal and cardiac function and histopathology were monitored in all treatment groups. RESULTS: Eprosartan decreased the severely elevated arterial pressure (-12%; P < 0.05) produced by SFD but did not affect heart rate. Vehicle-treated SP-SFD control rats exhibited significant weight loss (-13%; P < 0.05) and marked mortality (50% by week 6 and 95% by week 9; P < 0.01). Eprosartan-treated SP-SFD rats maintained normal weight, and exhibited zero mortality at week 12 and beyond. Eprosartan prevented the increased urinary protein excretion (P < 0.05) that was observed in vehicle-treated SP-SFD rats. Echocardiographic (i.e. 2-D guided M-mode) evaluation indicated that SP-SFD vehicle control rats exhibited increased septal (+22.2%) and posterior left ventricular wall (+30.0%) thickness, and decreased left ventricular chamber diameter (-15.9%), chamber volume (-32.7%), stroke volume (-48.7%) and ejection fraction (-22.3%), and a remarkable decrease in cardiac output (-59.3%) compared to controls (all P < 0.05). These same parameters in eprosartan-treated SP-SFD rats were normal and differed markedly and consistently from vehicle-treated SP-SFD rats (i.e. treatment prevented pathology; all P < 0.05). Cardiac-gated MRI data confirmed the ability of eprosartan to prevent cardiac pathology/remodeling (P < 0.05). Histopathological analysis of hearts and kidneys indicated that eprosartan treatment significantly reduced end-organ damage (P < 0.01) and provided corroborative evidence that eprosartan reduced remodeling of these organs. Vehicle-treated SP-SFD rats exhibited a 40% increase in the plasma level of pro-atrial natiuretic factor that was reduced to normal by eprosartan (P < 0.05). CONCLUSION: These data demonstrate that eprosartan, at a clinically relevant dose, provides significant end-organ protection in the severely hypertensive stroke-prone rat. It preserves cardiac and renal structural integrity, reduces cardiac hypertrophy and indices of heart failure, maintains normal function of the heart and kidneys, and eliminates premature mortality due to hypertension-induced end-organ failure.

Gene expression in rats with renal disease treated with the angiotensin II receptor antagonist, eprosartan.

The role of ANG II on renal and cardiac gene expression of matrix proteins was studied in rats with progressive renal disease. Induction of renal failure by five-sixths nephrectomy of Sprague-Dawley rats resulted in hypertension (163 +/- 19 vs. control pressures of 108 +/- 6 mmHg), proteinuria (83 +/- 47 vs. 14 +/- 2 mg/day), and increased renal expression of fibronectin, thrombospondin, collagen I and III, transforming growth factor-beta (TGF-beta), and plasminogen activator inhibitor-1 (PAI-1) mRNA. Treatment with the ANG II receptor antagonist, eprosartan (60 mg. kg(-1).day(-1)), lowered blood pressure (95 +/- 5 mmHg) and proteinuria (19 +/- 8 mg/d) and abrogated the increased TGF-beta, fibronectin, thrombospondin, collagens I and III, and PAI-1 mRNA expression. An increase in left ventricular weight was observed in five-sixths nephrectomized rats (0.13 +/- 0.01 vs. 0.08 +/- 0.01 g/100 g body wt), a response that was inhibited by eprosartan treatment (0.10 +/- 0.01 g/100 g). Left ventricular expression of TGF-beta and fibronectin was also increased in rats with renal disease; however, the small decreases in expression observed in eprosartan-treated rats did not reach statistical significance. These data suggest that eprosartan may be beneficial in progressive renal disease and that the mechanism of action includes inhibition of cytokine production in addition to antihypertensive activity.

Role of brain prostaglandins in the control of vasopressin secretion in the conscious rat.

Administration of 10 micrograms prostaglandin D2 (PGD2), the primary PG identified in the rat brain, into the lateral cerebral ventricle of conscious rats resulted in a significant elevation in the plasma vasopressin (AVP) concentration, without a change in mean arterial blood pressure or heart rate. The central administration of indomethacin (100 micrograms) resulted in a significant attenuation of the AVP response to a peripheral osmotic stimulus (iv 2.5 M NaCl; 100 microliters/kg X min for 30 min), but had little effect on the AVP response to hemorrhage (two successive 10% reductions in the estimated blood volume). Administration of another PG synthetase inhibitor, meclofenamate (100 micrograms, into the lateral cerebral ventricle), resulted in a significant attenuation of the AVP response to both the osmotic stimulus and hemorrhage. It is concluded that brain PGs play a central role in the control of AVP secretion.

Effects of nonhypotensive hemorrhage on renal organ and urinary clearances of vasopressin in the dog.

A study was undertaken to investigate the effects of moderate nonhypotensive hemorrhage on the renal organ and urinary clearances of vasopressin in anesthetized dogs. A nonhypotensive hemorrhage was conducted in nine dogs by withdrawal of 12 ml/kg arterial blood over 10 min. This reduction in blood volume increased the plasma vasopressin concentration from a prehemorrhage value of 4.3 +/- 0.5 to 12.5 +/- 3.4 microU/ml (P less than 0.01) in the 15-min period immediately after hemorrhage and to 8.1 +/- 1.4 microU/ml (P less than 0.01) in the 45- to 60-min period after hemorrhage. The increased plasma vasopressin concentration was not associated with changes in either plasma osmolality or mean arterial blood pressure. The urinary excretion of vasopressin increased significantly after hemorrhage (P less than 0.01, 0-15 min after hemorrhage; P less than 0.05, 45-60 min after hemorrhage) and correlated significantly with the plasma vasopressin concentration (r = 0.92; P less than 0.001). However, this moderate nonhypotensive hemorrhage did not change the renal vasopressin extraction ratio or the renal organ and urinary clearances of vasopressin from their prehemorrhage values of 0.27 +/- 0.02, 2.00 +/- 0.20 ml/min X kg, and 1.43 +/- 0.13 ml/min X kg, respectively. At no time were these values different from those in nine time control dogs. Thus, changes in the renal handling of vasopressin do not contribute to the increase in the plasma vasopressin concentration after moderate nonhypotensive hemorrhage.

Vasopressin release in male and female rats: effects of gonadectomy and treatment with gonadal steroid hormones.

We have found, in normal Wistar rats 10-11 weeks old, that the plasma vasopressin concentration (PADH) and the 24-h urinary excretion of vasopressin (UADHV) were higher in males than in females (P less than 0.01). In rats that were gonadectomized when they were 3 weeks old and studied when they were 10-11 weeks old, PADH and UADHV were reduced in males (P less than 0.01) and increased in females (P less than 0.01 for UADHV; PADH not significant) compared to those in intact males and females, respectively. Treatment of castrated male rats with testosterone tended to increase PADH, but estradiol, progesterone, or a combination of estradiol and progesterone were without effect; UADHV was increased by testosterone (P less than 0.01) and lowered by estradiol plus progesterone (P less than 0.01). In ovariectomized rats, PADH was unaffected by either testosterone or estradiol, but was decreased by progesterone alone (P less than 0.05) or in combination with estradiol (P less than 0.05). In these ovariectomized rats, UADHV was unaffected by testosterone and was decreased by estradiol and progesterone individually or in combination (P less than 0.01). These findings suggest that the gonadal steroid hormones can act either centrally to affect ADH release or peripherally to affect ADH metabolism. Compared to intact male rats, the lower PADH in intact female rats was accompanied by lower urine osmolality and greater urine volume, but further study will be required to appreciate fully the physiological significance of the differing PADH in males and females.

The metabolic clearance rate of and pressor responses to vasopressin in male and female rats.

Recent evidence indicates that the plasma vasopressin concentration is higher in males than in females and that this may be due to sexually dimorphic effects of the gonadal steroids. However, whether this difference in plasma vasopressin levels reflects differences in secretion or metabolism of the hormone could not be determined from the available data. Therefore, we measured the MCR of vasopressin in conscious male and female rats over a broad range of plasma concentrations of the hormone. No differences were observed in MCR either within a sex or between the sexes over the ranges of plasma concentrations of vasopressin tested. This indicates that the differences in basal plasma vasopressin concentration that were previously reported between male and female rats reflect differences in secretion. In addition, the pressor responses to infused vasopressin were 2 to 3 times greater (P less than 0.01) in male than in female rats, even though the plasma vasopressin concentrations achieved in the two groups were identical. Although the basal heart rate was higher (P less than 0.01) in female than in male rats, the decreases in heart rate observed in response to the vasopressin infusions were similar between the sexes. The mechanisms responsible for the differences in basal vasopressin secretion and pressor responsiveness between males and females are uncertain, but could involve actions of the gonadal steroids on the central nervous system and the peripheral vasculature.

Central atrial natriuretic factor reduces vasopressin secretion in the rat.

Atrial natriuretic factor (ANF, Arg 101-Tyr 126; 0.5 and 2.5 micrograms) administered into the lateral cerebral ventricle of conscious euhydrated and dehydrated rats resulted in a significant reduction in the plasma vasopressin concentration. The effect of ANF on vasopressin secretion was greater in the water-deprived animal. Central ANF was without effect on mean arterial blood pressure in both euhydrated and dehydrated rats. The data suggest that ANF occurring in the central nervous system may be important in the control of vasopressin secretion.

Effects of changes in steady state plasma vasopressin levels on renal and urinary vasopressin clearances in the dog.

A study was made of the effects of changes in the plasma vasopressin concentration on the extraction ratio and the renal organ and urinary clearances of vasopressin. Plasma vasopressin levels were increased in a stepwise fashion in anesthetized dogs by the iv infusion of vasopressin at rates of 100, 400, and 800 microU/min . kg. A steady state was achieved by infusing vasopressin for 60 min at each dose. Before the infusion of vasopressin, the extraction ratio and the renal and urinary clearances of vasopressin (one kidney) were 0.30 +/- 0.04, 1.8 +/- 0.2, and 1.4 +/- 0.1 ml/min . kg, respectively. The urinary clearance of vasopressin did not differ significantly from the inulin clearance (1.5 +/- 0.1 ml/min . kg). The infusion of vasopressin, which increased the plasma vasopressin concentration from an initial value of 4.3 +/- 1.3 to 54.6 +/- 2.4 microU/ml at the highest rate of infusion, was without effect on the vasopressin extraction ratio and the renal and urinary clearances of vasopressin. The MCR of vasopressin was estimated to be approximately 16 ml/min . kg. The renal clearance of vasopressin, calculated for both kidneys in all periods of all experiments, accounted for approximately 27% of the total clearance of vasopressin from the plasma. Thus, over a broad range of plasma vasopressin concentrations, a constant fraction of the vasopressin delivered to the kidney was removed from the blood perfusing the kidney, and the mechanisms for the renal extraction of vasopressin were not saturated.

Sex difference in the development of deoxycorticosterone-salt hypertension in the rat.

To investigate a possible sex difference in the development of deoxycorticosterone (DOC)-salt hypertension in rats, systolic blood pressure was measured over 6 weeks in unilaterally nephrectomized male and female rats with or without DOC-salt treatment. Throughout the treatment, systolic blood pressure was significantly lower in female than in male DOC-salt rats (at the end of the sixth week: 190 +/- 8 vs 163 +/- 7 mm Hg, p less than 0.05). The difference in blood pressure was also confirmed by the direct measurement of mean arterial pressure at the end of the experiment. The 24-hour urinary excretion of vasopressin was significantly higher in male control rats than in female control rats; however, no difference was observed between male and female DOC-salt rats, in which the urinary excretion of vasopressin was four to five times higher than in control rats. The plasma vasopressin concentration was higher in DOC-salt rats, but there were no differences between sexes. There were no differences in the metabolic clearance rate of vasopressin among the four groups of rats. This indicates that the elevated plasma vasopressin concentration in DOC-salt hypertensive rats is due to increased release of the hormone, rather than to impaired metabolism. Thus, although vasopressin plays a pivotal role in the pathogenesis of DOC-salt hypertension, the sexual dimorphism in this form of hypertension cannot be attributed to differences in the secretion, metabolism, or plasma concentration of vasopressin.

Osmotic stimulation in DOC-salt hypertension: vasopressin and blood pressure.

To determine whether there is a change in the sensitivity of the osmotic control of vasopressin release in deoxycorticosterone (DOC)-salt hypertension, experiments were performed in unilaterally nephrectomized rats that were either normotensive or were made hypertensive with DOC and given 1% saline to drink. After 3 weeks of treatment, 2.5 mol/l NaCl was infused i.v. into conscious normotensive and hypertensive rats. Increases in both plasma osmolality and plasma vasopressin concentration were similar throughout the course of this infusion in the two groups of rats. Hypertonic saline infusion increased the mean arterial blood pressure in the two groups of rats, but this increase was partially attenuated by the i.v. injection of a vasopressin pressor antagonist. In conclusion, vasopressin release in response to osmotic stimulation was similar in normotensive and hypertensive rats. The pressor response to hypertonic saline in both groups of rats could be partially attributed to the increased plasma vasopressin concentration.

Sex difference in pressor responsiveness to vasopressin and baroreflex function in DOC-salt hypertensive rats.

This study was undertaken to investigate further the possible role of vasopressin in the sexual dimorphism of deoxycorticosterone (DOC)-salt hypertension. The study was carried out 3 weeks after initiating treatment with DOC and salt in uninephrectomized male and female rats. Mean arterial pressure (MAP) was lower in female than in male DOC-salt hypertensive rats (177 +/- 7 versus 198 +/- 4 mmHg; P less than 0.01). Mean arterial pressure did not differ between male and female normotensive control rats. Increases in MAP in response to graded i.v. infusions of vasopressin were markedly attenuated in female normotensive and hypertensive rats, but there was no sex difference in pressor responses to i.v. phenylephrine. Baroreflex sensitivity was reduced in both male and female DOC-salt rats, but to a greater extent in males (P less than 0.01). Diminished pressor responsiveness to vasopressin and a smaller impairment of baroreflex sensitivity may contribute to the reduced development of DOC-salt hypertension in female rats.

Increased endothelin excretion in rats with renal failure induced by partial nephrectomy.

1. Six weeks following partial nephrectomy in rats, significant increases in serum urea nitrogen and serum creatinine concentration and a significant decrease in creatinine clearance were observed. 2. Measurement of systolic blood pressure by tail plethysmography indicated that animals that had undergone partial nephrectomy were hypertensive. 3. Compared to sham-operated animals, there were 4 fold increases in both urinary protein excretion and urinary endothelin excretion. 4. There was a significant correlation between urinary protein and urinary endothelin excretion (r = 0.77). There was also a correlation (r = 0.65) between urinary endothelin excretion and systolic blood pressure. 5. Plasma endothelin concentrations were not different in sham-operated and partially nephrectomized rats. 6. The data indicate that there is an increased renal endothelin production in rats with chronic renal failure.

Vasopressin and the pathogenesis of chronic renal failure.

1. Partial (5/6) renal ablation was performed in Long Evans rats treated with vehicle or a vasopressin V1-receptor antagonist, in control Long Evans rats, and in homozygous Brattleboro rats which lack endogenous vasopressin. 2. In control and vasopressin-blocked Long Evans rats, 3 weeks following partial renal ablation, systolic blood pressure was 215 +/- 5 and 199 +/- 9 mmHg and, urinary protein excretion was 54 +/- 4 and 50 +/- 3 mg day-1, respectively. 3. The pressor response to exogenous vasopressin was significantly (P less than 0.05) reduced in rats treated with the V1-receptor antagonist (ED50 mmHg 5.0 +/- 1.6 vs. 0.09 +/- 0.01 micrograms kg-1). 4. In control Long Evans and in Brattleboro rats, 3 weeks following renal ablation, systolic blood pressure was 204 +/- 10 and 191 +/- 7 mmHg, and urinary protein excretion was 97 +/- 27 and 71 +/- 5 mg day-1, respectively. 5. Histological examination of the remaining kidney tissue demonstrated significant glomerular hyalinization following renal ablation but no differences between any of the groups. 6. The data indicate that neither vasopressin nor the urinary concentrating mechanism is likely to be involved in the hypertension and proteinuria associated with partial renal ablation.

Effect of cyclo-oxygenase blockade on the renal actions of vasopressin and SK&F 105494 in the rhesus monkey.

1. Vasopressin administration to pentobarbitone-anaesthetized, hydrated female rhesus monkeys resulted in dose-dependent increases in urine osmolality and decreases in urine flow. Treatment with indomethacin at a dose (5 mg kg-1, i.v.) that reduced urinary prostaglandin E2 (PGE2) excretion by at least 70% did not alter these responses. 2. The vasopressin antagonist, SK&F 105494 (Pas1,6D-Tyr(Et)2Val4Arg7D-Arg8desGly9 arginine vasopressin; 10 micrograms kg-1), caused significant rightward shifts (P less than 0.05) of both the vasopressin-urine osmolality and the vasopressin-urine flow dose-response curves. Treatment with indomethacin did not alter these responses. 3. SK&F 105494 alone or after indomethacin treatment had minimal effects on urine osmolality and urine flow. 4. The data indicate that indomethacin does not alter the antidiuretic activity of vasopressin in the rhesus monkey and that SK&F 105494 is a potent antagonist of exogenous vasopressin with minimal agonist activity.

Flushing and haemodynamic responses to vasopressin peptides in the rhesus monkey.

1. The mechanism of the flushing, hypotension and tachycardia associated with i.v. administration of desGlyd(CH2)5D-Tyr(Et)VAVP (SK&F 101926; 25 micrograms kg-1) and the selective V2 antidiuretic agonist, desamino-8-D-arginine vasopressin (dDAVP; 3 micrograms kg-1) was studied in ketamine-anaesthetized rhesus monkeys. 2. The flushing associated with SK&F 101926 was reduced by pretreatment with a mast cell stabilizer and by repeated administration of peptide (within 2-4 weeks). A similar desensitization to dDAVP-associated flushing was observed on repeated administration. 3. Treatment with dDAVP also resulted in reduced SK&F 101926-associated flushing. 4. The hypotension associated with SK&F 101926 was not affected by pretreatment with a mast cell stabilizer. A similar degree of hypotension was observed with repeated administration of either SK&F 101926 or dDAVP. 5. The tachycardia associated with SK&F 101926 was reduced by pretreatment with a mast cell stabilizer or repeated administration of SK&F 101926. Repeated administration of dDAVP, however, resulted in an enhanced tachycardia. 6. Indomethacin (5 mg kg-1 i.v.) did not alter the flushing or the hypotension associated with the administration of either SK&F 101926 or dDAVP, but resulted in an enhanced tachycardia to SK&F 101926. 7. Administration of a selective V1 vasopressor antagonist did not result in flushing, hypotension or tachycardia. 8. It was concluded that the flushing response to vasopressin-like peptides in rhesus monkeys may be due to an action on mast cells, whereas the haemodynamic responses are not, but probably involve direct vasodilator actions.

Cardiovascular actions of a new selective postjunctional alpha-adrenoceptor antagonist, SK&F 104856, in normotensive and hypertensive dogs.

1. SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4- methylthieno[4,3,2ef][3]benzazepine) is a novel postjunctional alpha 1- and alpha 2-adrenoceptor antagonist. 2. SK&F 104856 as well as prazosin and SK&F 86466 reduced blood pressure in the anaesthetized normotensive dog. 3. SK&F 86466 and rauwolscine but not SK&F 104856 or prazosin, produced a marked increase in myocardial contractility which corresponds with their ability to block prejunctional alpha 2-adrenoceptors. 4. Intravenous or oral administration of SK&F 104856 resulted in dose-dependent antihypertensive responses in 1-kidney, 1-clip (1-K, 1-C) Goldblatt hypertensive dogs with baseline blood pressure of approximately 140 mmHg. At 0.1 and 1 mg kg-1, i.v., mean arterial blood pressure fell by 11 +/- 5 and 23 +/- 5 mmHg, respectively. At 3 and 10 mg kg-1, p.o., blood pressure fell by 9 +/- 3 and 22 +/- 5 mmHg, respectively. At 10 mg kg-1, p.o., the antihypertensive effect of SK&F 104856 was still evident at 4 h. 5. The data indicate that SK&F 104856 shows selectivity in vivo for postjunctional versus prejunctional alpha-adrenoceptors and is a potent and long-acting antihypertensive agent in 1-K, 1-C Goldblatt hypertensive dogs.

Renoprotective effects of carvedilol in hypertensive-stroke prone rats may involve inhibition of TGF beta expression.

1. The effect of carvedilol on renal function, structure and expression of TGF beta and the matrix proteins fibronectin, collagen I and collagen III, was evaluated in spontaneously hypertensive stroke-prone (SHR-SP) rats fed a high fat, high salt diet. 2. Carvedilol treatment for 11 to 18 weeks did not alter systolic blood pressure in SHR-SP rats, however, it resulted in a significant reduction in heart rate. 3. Carvedilol treatment reduced renal fibrosis and total, active and chronic renal damage to levels approaching those of WKY rats on a normal diet. 4. Urinary protein excretion was higher in SHR-SP rats (51+/-10 mg day(-1)) than WKY rats (18+/-2 mg day(-1)) and this was further increased when SHR-SP rats were fed a high fat, high salt diet (251+/-120 mg day(-1)). Treatment with carvedilol resulted in significantly lower urinary protein excretion (37+/-15 mg day(-1)). 5. The expression of TGF beta mRNA was significantly higher in SHR-SP rats compared to WKY rats and a further increase was observed when rats were fed a high fat, high salt diet. Renal TGF beta expression was significantly reduced by treatment with carvedilol. The expression of fibronectin and collagen I and collagen III mRNA showed a pattern similar to that observed with TGF beta mRNA expression. Collagen I mRNA expression followed a pattern similar to renal fibrosis. 6. These data indicate that carvedilol can provide significant renal protection in the absence of any antihypertensive activity and that the mechanisms involved in this action may include reduced expression of profibrotic factors such as TGF beta.