Haptoglobin genotype 2-2 associated with atherosclerosis in patients with ischemic stroke.

AIM: Ischemic stroke (IS) is multifactorial disease and therefore different genes and proteins play a role in its development. Haptoglobin (Hp) removes free hemoglobin and protects from iron-induced oxidative damage, inflammatory response, atherosclerosis and cerebrovascular diseases. The aim of this study was to investigate Hp genetic variants in patients with carotid atherosclerotic lesions and IS. MATERIAL AND METHODS: A total of 121 subjects with IS participated in the study, 81 male and 40 female. RESULTS: Among 121 patients with IS, 79 had diffuse atherosclerotic plaques and stenosis. Hp genotype was statistically significantly associated with CDFI neck carotid artery stenosis findings (p = 0.006). Patients with Hp1-2 genotype had statistically significantly larger odds for atherosclerotic changes compared to those with Hp1-1 genotype, as well as those with Hp2-2 genotype. CONCLUSION: This study has shown an association of the Hp2-2 genotype and atherosclerosis in patients with IS, indicating Hp2-2 genotype as a genetic biomarker for precision medicine and personalized healthcare.

Use of the H3 receptor antagonist radioligand [3H]-A-349821 to reveal in vivo receptor occupancy of cognition enhancing H3 receptor antagonists.

BACKGROUND AND PURPOSE: The histamine H3 receptor antagonist radioligand [3H]-A-349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H3 receptor antagonists that affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H3 receptor occupancy to blood levels and efficacy in preclinical models. EXPERIMENTAL APPROACH: In vivo cerebral cortical H3 receptor occupancy by [3H]-A-349821 was determined in rats from differences in [3H]-A-349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H3 receptors. Comparisons were made to relate antagonist H3 receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five-trial inhibitory avoidance response in rat pups. KEY RESULTS: In adult rats, [3H]-A-349821, 1.5 microg x kg(-1), penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, [3H]-A-349821 levels were twofold higher in the latter. With increasing [3H]-A-349821 doses, cortical H3 receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer [3H]-A-349821 doses, ABT-239 and other H3 receptor antagonists inhibited H3 receptor occupancy by [3H]-A-349821 in a dose-dependent manner. Blood levels of the antagonists corresponding to H3 receptor occupancy were consistent with blood levels associated with efficacy in the five-trial inhibitory avoidance response. CONCLUSIONS AND IMPLICATIONS: When employed as an occupancy radiotracer, [3H]-A-349821 provided valid measurements of in vivo H3 receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H3 receptor antagonists.

A-272651, a nonpeptidic blocker of large-conductance Ca2+-activated K+ channels, modulates bladder smooth muscle contractility and neuronal action potentials.

BACKGROUND AND PURPOSE: The large-conductance Ca(2+)-activated K(+) channel (BK(Ca), K(Ca)1.1) links membrane excitability with intracellular Ca(2+) signaling and plays important roles in smooth muscle contraction, neuronal firing, and neuroendocrine secretion. This study reports the characterization of a novel BK(Ca) channel blocker, 2,4-dimethoxy-N-naphthalen-2-yl-benzamide (A-272651). EXPERIMENTAL APPROACH: (86)Rb(+) efflux in HEK-293 cells expressing BK(Ca) was measured. Effects of A-272651 on BK(Ca) alpha- and BK(Ca) alphabeta1-mediated currents were evaluated by patch-clamp. Effects on contractility were assessed using low-frequency electrical field stimulated pig detrusor and spontaneously contracting guinea pig detrusor. Effects of A-272651 on neuronal activity were determined in rat small diameter dorsal root ganglia (DRG). KEY RESULTS: A-272651 (10 microM) inhibited (86)Rb(+) efflux evoked by NS-1608 in HEK-293 cells expressing BK(Ca) currents. A-272651 concentration-dependently inhibited BK(Ca) currents with IC(50) values of 4.59 microM (Hill coefficient 1.04, measured at +40 mV), and 2.82 microM (Hill coefficient 0.89), respectively, for BK(Ca) alpha and BK(Ca) alphabeta1-mediated currents. Like iberiotoxin, A-272651 enhanced field stimulated twitch responses in pig detrusor and spontaneous contractions in guinea pig detrusor with EC(50) values of 4.05+/-0.05 and 37.95+/-0.12 microM, respectively. In capsaicin-sensitive DRG neurons, application of A-272651 increased action potential firing and prolonged action potential duration. CONCLUSIONS AND IMPLICATIONS: These data demonstrate that A-272651 modulates smooth muscle contractility and neuronal firing properties. Unlike previously reported peptide BK(Ca) blockers, A-272651 represents one of the first small molecule BK(Ca) channel blockers that could serve as a useful tool for further characterization of BK(Ca) channels in physiological and pathological states.

Characterization of a novel ATP-sensitive K+ channel opener, A-251179, on urinary bladder relaxation and cystometric parameters.

BACKGROUND AND PURPOSE: ATP-sensitive K(+) channels (K(ATP)) play a pivotal role in contractility of urinary bladder smooth muscle. This study reports the characterization of 4-methyl-N-(2,2,2-trichloro-1-(3-pyridin-3-ylthioureido)ethyl)benzamide (A-251179) as a K(ATP) channel opener. EXPERIMENTAL APPROACH: Glyburide-sensitive membrane potential, patch clamp and tension assays were employed to study the effect of A-251179 in vitro. The in vivo efficacy of A-251179 was characterized by suppression of spontaneous contractions in obstructed rat bladder and by measuring urodynamic function of urethane-anesthetized rat models. KEY RESULTS: A-251179 was about 4-fold more selective in activating SUR2B-Kir6.2 derived K(ATP) channels compared to those derived from SUR2A-Kir6.2. In pig bladder smooth muscle strips, A-251179 suppressed spontaneous contractions, about 27- and 71-fold more potently compared to suppression of contractions evoked by low-frequency electrical stimulation and carbachol, respectively. In vivo, A-251179 suppressed spontaneous non-voiding bladder contractions from partial outlet-obstructed rats. Interestingly, in the neurogenic model where isovolumetric contractions were measured by continuous transvesical cystometry, A-251179 at a dose of 0.3 micromol kg(-1), but not higher, was found to increase bladder capacity without affecting either the voiding efficiency or changes in mean arterial blood pressure. CONCLUSIONS AND IMPLICATIONS: The thioureabenzamide analog, A-251179 is a potent novel K(ATP) channel opener with selectivity for SUR2B/Kir6.2 containing K(ATP) channels relative to pinacidil. The pharmacological profile of A-251179 is to increase bladder capacity and to prolong the time between voids without affecting voiding efficiency and represents an interesting characteristic to be explored for further investigations of K(ATP) channel openers for the treatment of overactive bladder.

A-315456: a selective alpha(1D)-adrenoceptor antagonist with minimal dopamine D(2) and 5-HT(1A) receptor affinity.

In functional assays, A-315456, N-[3-(cyclohexylidene-(1H-imidazol-4-ylmethyl))phenyl]ethanesulfonamide, behaved as an alpha(1D)-adrenoceptor subtype selective antagonist (pA(2)=8.34) in the rat aorta. It was 83-fold less potent at the alpha(1B)-adrenoceptor subtype expressed in the rat spleen, and was inactive at the alpha(1A)-adrenoceptor subtype expressed in the rat vas deferens. Radioligand binding assays also revealed high affinity (pK(i)=8.71) for the alpha(1D)-adrenoceptor subtype and weaker affinities at the alpha(1A)-adrenoceptor (pK(i)=6.23) and alpha(1B)-adrenoceptor (pK(i)=7.86). In comparison to its potent affinity at the alpha(1D)-adrenoceptor subtype, A-315456 was 3020-, 794- and 38-fold weaker at the dopamine D(2)-, 5-HT(1A)-, and alpha(2a)-adrenoceptors, respectively. These studies indicate that A-315456 is a potent and selective alpha(1D)-antagonist that may serve as a useful pharmacological ligand to probe the physiological role of the alpha(1D)-adrenoceptor subtype in normal and disease states.

Pharmacological properties of A-204176, a novel and selective alpha1A adrenergic agonist, in in vitro and in vivo models of urethral function.

A-204176 (N-[5-(1H-imidazol-4-y1)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide) is a potent and selective alpha1A adrenoceptor agonist that binds with 17-fold and 9-fold greater affinity to the alpha1A (Ki=176 nM) than the alpha1b and alpha1d subtypes, respectively. In functional studies A-204176 is potent (pD2=6.4) and efficacious (83% of maximum control phenylephrine response) at rabbit urethra alpha1A receptors, with weaker potency and greatly reduced efficacy at rat spleen alpha1B (pD2=5.3, 11%) and rat aorta alpha1D (pD2=4.4, 10%) subtypes. In anesthetized female dogs, A-204176 is more potent than the non-selective alpha1 adrenoceptor agonist phenylpropanolamine (PPA) to increase measures of urethral tone and is more efficacious to increase pressure in the proximal region of the urethra. Significant increases on parameters of the urethral pressure profilometry were induced at 100 and 300 nmol/kg, i.v., by A-204176 and PPA, respectively. A-204176 was more potent than PPA to increase the abdominal pressure required to produce leakage. In the simultaneous measurement of intraurethral pressure and mean arterial blood pressure, A-204176 displays enhanced urethral selectivity relative to PPA. However, despite its selectivity for alpha1A versus alpha1B and alpha1D adrenoceptors in vitro, A-204176 did not display the degree of urethral selectivity in vivo that would have been expected. The observed effect of A-204176 on blood pressure may be due to the presence of extra-synaptic alpha1A adrenoceptors in the vasculature or to activation of spinal and supraspinal alpha1A adrenoceptors. These data indicate that A-204176 may represent a useful pharmacological tool to investigate the functional role of the alpha1A adrenoceptor in the urethra and to elucidate the lack of uroselectivity observed in vivo.

Pharmacological and molecular analysis of ATP-sensitive K(+) channels in the pig and human detrusor.

The pharmacological and molecular properties of ATP-sensitive K(+) channels present in pig detrusor smooth muscle were investigated. In isolated pig detrusor strips, ATP-sensitive K(+) channel openers inhibited contractions elicited by low frequency field-stimulation in a concentration-dependent manner. The inhibitory effects of P1075 [N-cyano-N'-(1,1-dimethylpropyl)-N"-3-pyridylguanidine] were attenuated by glyburide with a pA(2) value of 7.38 (slope=1.08). The potency of the inhibitory effects of the K(+) channel openers on the field-stimulated contractions correlated well with those evoked by the muscarinic receptor agonist, carbachol (r=0.93) and furthermore, to relaxation of the pre-contracted (25 mM potassium chloride, KCl) human detrusor (r=0.95). Reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed the presence of mRNA for sulfonylurea receptors SUR1 and SUR2B in both pig and human detrusor. Considering the similarities in the molecular and pharmacological profile of ATP-sensitive K(+) channels between the pig and the human detrusor, it is concluded that the pig detrusor may serve as a suitable in vitro model for the evaluation of novel K(+) channel openers with potential use in urological disorders in humans.

Characterization of the ATP-sensitive potassium channels (KATP) expressed in guinea pig bladder smooth muscle cells.

ATP-sensitive K+ (KATP) channels play an important role in the regulation of smooth muscle membrane potential. To investigate the properties of KATP channels in guinea pig urinary bladder smooth muscle cells, fluorescence-based assays were carried out with the membrane potential-sensitive probe bis-(1,3-dibutylbarbituric acid)trimethine oxonol [DiBAC4(3)]. The prototypical channel openers, including pinacidil, (-)-cromakalim, and diazoxide, elicited concentration-dependent decreases in membrane potential that were attenuated by glyburide. Similar responses were evoked by a reduction in intracellular ATP levels by metabolic inhibition. The observed rank order potency (EC50) for evoking membrane potential changes by potassium channel openers, P1075 (53 nM) approximately Bay X 9228 > (-)-cromakalim approximately ZD6169 approximately pinacidil > Bay X 9227 approximately ZM244085 > diazoxide (59 microM), showed a good correlation with that of bladder smooth muscle relaxation, as assessed by isolated tissue bath studies. The maximal efficacies of (-)-cromakalim, pinacidil, Bay X 9228, and ZD6169 were comparable with the response achieved by the reference activator P1075. Whole cell currents in bladder smooth muscle cells were increased in both inward and outward directions by P1075 and were reversed by glyburide to control levels. The molecular composition assessed by reverse transcriptase-polymerase chain reaction analysis using subunit-specific primers revealed the presence of mRNA for inward rectifying potassium channel (KIR6.2) and sulfonylurea receptors (SUR)2B and SUR1. The subunit profile together with pharmacological properties suggests that the KATP channel in bladder smooth muscle cells could be composed of SUR2B associated with a single inward rectifier, KIR6.2. In summary, these studies have characterized the pharmacological profile using fluorescent imaging plate reader-based membrane potential techniques and provide evidence for the molecular identity of KATP channels expressed in guinea pig bladder smooth muscle cells.

Actions of A-131701, a novel, selective antagonist for alpha-1A compared with alpha-1B adrenoceptors on intraurethral and blood pressure responses in conscious dogs and a pharmacodynamic assessment of in vivo prostatic selectivity.

A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b, hexahydro-[1H]-benz[e]isoindol-2-yl)ethyl]pyrido [3',4': 4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione) is a novel compound previously shown to be selective for alpha-1a sites compared with alpha-1b adrenoceptors in radioligand binding studies and isolated tissue bioassays and to block canine urethral pressure (IUP) responses to exogenous alpha-1 adrenergic agonists to a greater extent than blood pressure responses. In conscious dogs in which IUP and mean arterial blood pressure (MABP) responses were measured periodically up to 24 hr, A-131701 blocked phenylephrine (PHE)-induced increases in IUP to a greater extent than MABP responses, and the blockade of the IUP effects of PHE was significantly different from control for up to 12 hr after doses greater than 0.3 mg/kg p.o., whereas blood pressure effects were of a lesser extent and duration. In addition to the weak antagonism of PHE-induced blood pressure responses, A-131701 also exhibited minimal effects on basal blood pressure in the dog, unlike terazosin, doxazosin or tamsulosin. Pharmacokinetic analysis of plasma samples from dogs indicated that A-131701 had a half-life of 0.4 to 0.8 hr and a bioavailability of 30 to 50% in dogs. Somewhat longer half-lives were observed in rat and monkey, with bioavailability values in the 25 to 30% range. Evidence of nonlinearity of pharmacokinetics was obtained in dogs and monkeys. Pharmacodynamic analysis revealed differences between A-131701 and nonselective alpha-1 adrenoceptor antagonists in selectivity for prostatic versus vascular alpha-1 adrenoceptors based on either extent or duration of blockade, which were either similar to or superior to compounds such as tamsulosin or REC 15/2739. These data demonstrate that A-131701 selectively blocks canine prostatic alpha-1 adrenoceptors for prolonged periods compared with MABP responses in vivo. Therefore, A-131701 should have clinical utility in the pharmacotherapy of benign prostatic hyperplasia.

Relationships between pharmacokinetics and blockade of agonist-induced prostatic intraurethral pressure and mean arterial pressure in the conscious dog after single and repeated daily oral administration of terazosin.

The purpose of this study was to determine the potency and selectivity of the alpha-1 adrenergic receptor antagonist terazosin based on relationships between plasma concentrations and blockade of intraurethral pressure (IUP) and mean arterial pressure (MAP) responses after single dosing and to determine cumulative effects after repeated dosing. To this end, the relationships between plasma concentrations and blockade effects of terazosin on phenylephrine (PE)-induced IUP and MAP were evaluated in conscious male beagle dogs after single (0.1, 0.3 and 1 mg/kg) and repeated (0.3 and 1 mg/kg) daily oral dosing of terazosin. Blockade effects and plasma concentrations were evaluated at selected times for periods of < or = 24 hr. Terazosin produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against terazosin plasma concentration, direct relationships were observed that were well described by the sigmoidal maximal effect model and resulted in IUP and MAP IC50 values of 48.6 and 12.2 ng/ml, respectively. Repeated daily dosing resulted in little accumulation of terazosin in plasma and demonstrated consistent blockade responses over 7 days. MAP blockade was observed up to 23 hr after terazosin administration, whereas IUP blockade returned to control levels before 23 hr. Combined pharmacokinetic/pharmacodynamic analysis showed no selective antagonism of IUP by terazosin but may provide a useful way to show uroselectivity of novel agents.

Effects of selective and nonselective alpha-1-adrenoceptor antagonists on intraurethral and arterial pressures in intact conscious dogs.

In this study, we used a novel conscious dog model to evaluate the uroselectivity of selected alpha 1-antagonists either approved for human use or in clinical development for the treatment of symptomatic benign prostatic hyperplasia (BPH) and compared those results to their in vitro binding and functional affinities at alpha 1A, alpha 1B and alpha 1D receptor subtypes. Conscious dogs were instrumented acutely with a balloon catheter for the measurement of changes in prostatic intraurethral pressure (IUP) and chronically with implantable telemetry devices for the measurement of arterial pressure. The pressor effects of the alpha 1-agonist phenylephrine (PE) on IUP and mean arterial pressure (MAP) were compared before and at various time points after oral doses of either terazosin, doxazosin, tamsulosin or Rec 15/2739 (SB 216469). At submaximal doses, terazosin and doxazosin blocked PE-induced increases in MAP to a greater extent than increases in IUP. Tamsulosin blocked both parameters equally at the lowest and highest doses; however, at the intermediate dose, IUP was blocked more than MAP. Rec 15/2739 at each dose always blocked IUP to a greater extent than MAP. While the in vivo uroselectivity of these agents was predicted by radioligand binding and in vitro functional selectivity for the alpha 1A subtype over alpha 1B and alpha 1D subtypes, results from conscious dog experiments indicate that estimates of in vivo uroselectivity also depend upon dose and the time after administration. Our conscious canine model provides the basis for frequent and repeated evaluation of uroselectivity parameters over many hours, thus providing a pharmacological profile of compound effects perhaps more relevant to clinical practice.

Pharmacologic characterization of CHIR 2279, an N-substituted glycine peptoid with high-affinity binding for alpha 1-adrenoceptors.

We characterize the in vitro and in vivo pharmacology of CHIR 2279, an N-substituted glycine peptoid previously identified from a combinatorial library as a novel ligand to alpha 1-adrenoceptors. Competitive receptor-binding assays with [3H]prazosin showed that CHIR 2279 was similar to prazosin in binding to alpha 1A (rat submaxillary), alpha 1a, alpha 1b, and alpha 1 d (cDNA expressed in LTK- cells) with high and approximately equipotent affinity. Ki values for CHIR 2279 ranged from 0.7 to 3 nM, and were 10-fold weaker than with prazosin. Functional assays for postsynaptic alpha 1-adrenoceptors showed CHIR 2279 was approximately equipotent in antagonizing agonist-induced contractile responses with rat was deferens (alpha 1A), canine prostate (alpha 1A), rat spleen (alpha 1B) and rat aorta (alpha 1D). The pA2 for CHIR 2279 averaged 7.07 in these assays, indicating a 10- to 100-fold lower in vitro potency than prazosin. In dogs, CHIR 2279 antagonized the epinephrine-induced increase in intraurethal pressure (pseudo pA2, 6.86) and in rats antagonized the phenylephrine-induced increase in mean arterial blood pressure. In rats and guinea pigs, CHIR 2279 induced a dose-dependent decrease in mean arterial blood pressure without eliciting the tachycardia commonly observed with other alpha 1-blockers. Pharmacokinetic/pharmacodynamic modeling showed the i.v. system clearance rate of CHIR 2279 was 60 and 104 ml/min/kg in rats and guinea pigs, respectively, and the in vivo potency for mean arterial blood pressure reduction was twice as great in guinea pigs (EC50, 520 ng/ml) than rats (EC50, 1170 ng/ml).

In vivo characterization of a phosphoramidon-sensitive endothelin-converting enzyme in the rat.

Experiments were conducted to characterize the nature of a phosphoramidon-sensitive endothelin-converting enzyme in vivo by evaluating the pressor response to a bolus intravenous (i.v.) injection of endothelin family peptides following administration of phosphoramidon in anesthetized Sprague-Dawley rats. Phosphoramidon given i.v. at 10 mg/kg completely prevented the pressor response to human big endothelin-1-(1-38) (big ET-1). The EC50 for phosphoramidon was determined to be in the range of 1 to 3 mg/kg. The pressor response to big ET-1 60 min after phosphoramidon injection was attenuated by roughly 60% indicating a long inhibitory half-life. Very high doses of big ET-1 (> 20 mg/kg) were capable of over-riding the effect of phosphoramidon and produced characteristic pressor responses suggesting that the inhibition by phosphoramidon can be considered competitive in nature. Human big endothelin-3-(1-41) (big ET-3) produced significant increases in arterial pressure although with less potency and efficacy compared to big ET-1. The pressor response to big ET-3 was also inhibited by phosphoramidon. Phosphoramidon does not act indirectly by interfering with ET-1 receptor-mediated actions since the inhibitor has no effect on the in vivo pressor response to ET-1 and does not antagonize [125I]ET-1 receptor binding or constrictor responses in vitro. These results are consistent with the idea that a phosphoramidon-sensitive endothelin-converting enzyme is capable of cleaving both big ET-1 and big ET-3 to the active peptides in the rat.

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.

Normalization of pressure-natriuresis by nisoldipine in spontaneously hypertensive rats.

This study examined whether the calcium antagonist nisoldipine can shift the relations between sodium excretion, papillary blood flow, renal interstitial pressure, and renal perfusion pressure toward lower pressures in spontaneously hypertensive rats. Mean arterial pressure decreased similarly by 9% and 12% in Wistar-Kyoto and spontaneously hypertensive rats after nisoldipine (0.5 microgram/kg bolus + 0.017 microgram/kg/min). Urine flow and sodium excretion increased by 35% and 24% in Wistar-Kyoto rats after nisoldipine. In contrast, urine flow and sodium excretion rose by 121% and 132% in spontaneously hypertensive rats, and fractional sodium excretion rose from 1.9 +/- 0.3 to 4.2 +/- 0.4%. Control sodium excretion, papillary blood flow, and renal interstitial pressure were significantly lower in spontaneously hypertensive rats than in Wistar-Kyoto rats when compared at similar renal perfusion pressures. Sodium excretion, papillary blood flow, and renal interstitial pressure all increased in spontaneously hypertensive rats after nisoldipine, whereas it had no effect on papillary blood flow or renal interstitial pressure in Wistar-Kyoto rats. The relations among sodium excretion, papillary blood flow, renal interstitial pressure, and renal perfusion pressure were shifted toward lower pressures in spontaneously hypertensive rats given nisoldipine and became similar to those seen in Wistar-Kyoto rats. These results indicate that nisoldipine normalizes the relations among sodium excretion, renal interstitial pressure, papillary blood flow, and renal perfusion pressure in spontaneously hypertensive rats perhaps by correcting the defect in renal medullary perfusion associated with resetting of pressure natriuresis in this model of hypertension.

Effects of DuP 753 on renal function of normotensive and spontaneously hypertensive rats.

This study examined the effects of a new, orally-active, nonpeptide angiotensin II (AII) receptor antagonist, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biph eny l-4- yl)methyl] imidazole, DuP 753, on renal function of anesthetized, volume-expanded Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), and in a group of euvolemic Munich-Wistar (MW) rats. Plasma renin activities were similar and averaged 4.4 +/- 0.7 and 4.3 +/- 1.4 ng AI/mL.h, respectively, in the SHR and WKY rats. In WKY rats (n = 15), DuP 753 (2 or 10 mg/kg, intravenously) had no effect on urine flow, sodium excretion, renal blood flow (RBF), or glomerular filtration rate (GFR). Fractional excretion of lithium (FELi) rose from 32 +/- 5 to 40 +/- 4% of the filtered load and arterial pressure decreased slightly from 129 +/- 2 to 122 +/- 2 mm Hg. In SHR (n = 9), urine flow fell 24%, and FELi and RBF increased by 27% and 30%, respectively, after 2 mg/kg DuP 753, but sodium excretion, GFR, and arterial pressure were not significantly altered. A higher dose of DuP 753 (10 mg/kg; n = 8) reduced arterial pressure, urine flow, and sodium excretion in the SHR. RBF increased 34%, while GFR and FELi were not significantly altered. Similar effects were seen in SHR (n = 11), given an equivalent antihypertensive dose of captopril (20 mg/kg). In euvolemic MW rats in which plasma renin activity was elevated to 18.8 +/- 3.3 ng AI/mL.h, DuP 753 (2 mg/kg, n = 7) increased RBF, urine flow, and sodium excretion, while mean arterial pressure and GFR were unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)