Two endogenous receptors for the potent smooth musclestimulating peptide neuromedin U (NmU) have recently been identified and cloned. Pharmacological, binding, and expression studies were conducted in an attempt to determine the receptor(s) involved in the smooth muscle-stimulating effects of NmU. The NmU peptides caused a concentration-dependent contraction of canine isolated urinary bladder. NmU did not have this same effect in the urinary bladder from rat, guinea pig, rabbit, mouse, or ferret. Although NmU had no effect on canine uterus it did cause contraction of canine stomach, ileum, and colon. As well as causing contraction of canine bladder in vitro, NmU administered systemically resulted in a significant increase in urinary bladder pressure in vivo. High-affinity binding sites for NmU were identified in canine bladder. The four NmU peptides porcine NmU-8, rat NmU-23, human NmU-25, and porcine NmU-25 displaced 125 I-NmU-25 binding with similar K i values (0.08 -0.24 nM). A different binding profile was revealed in human embryonic kidney-293 cells transiently expressed with the canine NmU-2 receptor where porcine NmU-8 (K i ϭ 147.06 nM) was much less potent than the other NmU peptides. Using TaqMan, expression of NmU-1 was detected in human urinary bladder, small intestine, colon, and uterus. Expression of NmU-2 was much lower or absent in these human tissues and undetectable in canine bladder and stomach. The results of this study reveal significant species differences in the activity of NmU. The contractile activity in human and canine smooth muscle seems to be mediated by the recently cloned NmU-1 receptor.

1 The eect of carvedilol on renal function, structure and expression of TGFb and the matrix proteins ®bronectin, collagen I and collagen III, was evaluated in spontaneously hypertensive strokeprone (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 signi®cant reduction in heart rate. 3 Carvedilol treatment reduced renal ®brosis 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 71 ) than WKY rats (18+2 mg day 71) and this was further increased when SHR-SP rats were fed a high fat, high salt diet (251+120 mg day 71). Treatment with carvedilol resulted in signi®cantly lower urinary protein excretion (37+15 mg day 71). 5 The expression of TGFb mRNA was signi®cantly 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 TGFb expression was signi®cantly reduced by treatment with carvedilol. The expression of ®bronectin and collagen I and collagen III mRNA showed a pattern similar to that observed with TGFb mRNA expression. Collagen I mRNA expression followed a pattern similar to renal ®brosis. 6 These data indicate that carvedilol can provide signi®cant renal protection in the absence of any antihypertensive activity and that the mechanisms involved in this action may include reduced expression of pro®brotic factors such as TGFb.

1 The effect of the novel P-adrenoceptor antagonist and vasodilator, carvedilol (SK&F 105517, -70 mg kg-' daily in the food), and captopril (-38 mg kg-' daily in the drinking fluid) on the progression of chronic renal failure in rats was studied.2 Six weeks following partial renal ablation, the urinary protein excretion of the carvediol-(60 ± 21 mg day-') and captopril-treated (35 ± 9 mg day-') animals was less than 50% that of control rats (133 ± 27 mg d-').3 Serum creatinine (Scr) and urea nitrogen (SUN) concentrations of the carvedilol-(Scr, 0.63 ± 0.09 mg dl'; SUN, 11.3 ± 1.2 mg dl-') and captopril-treated (Scr, 0.82 ± 0.05 mg d1-'; SUN, 14.1 1.5 mg dl-') animals were also significantly (P<0.05) lower than that observed in control animals (Scr, 1.4 ± 0.3 mg dl-'; SUN, 19.2 ± 3.9 mg dl-'), indicating that glomerular filtration rate was improved by both drugs. Plasma renin activity was significantly (P<0.05) higher in captopril-treated rats (24.7 ± 4.6 ng angiotensin I ml-' h-') than in either carvedilol-treated (7.9 ± 1.4 ng angiotensin I ml -' h-') or control animals (7.4 ± 1.0 ng angiotensin I ml1 ' h-'). 4 Histological examination of the kidneys demonstrated a significantly reduced glomerular hypertrophy and glomerulosclerosis in those animals receiving carvedilol or captopril compared to controls. 5 Serum carvedilol concentration measured every 6 h for 24 h was variable and ranged on average from 57 ± 13 ng ml-' at 16 h 00 min to 121 ± 31 ng ml1' at 03 h 00 min. These data indicate that the rats probably had 24 h systemic exposure to carvedilol. 6 The present study indicates that carvedilol is effective in attenuating the progression of chronic renal failure in rats.

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