Renal Hypertensive Dogs Research Articles

Effects of the new angiotensin II type 1 receptor antagonist KRH-594 on several types of experimental hypertension.

The antihypertensive effect of dipotassium (Z)-2-[[5-ethyl-3-[2'-(1H- tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazoline-2- ylidene]aminocarbonyl]-1-cyclopentenecarboxylate (CAS 169328-25-0, KRH-594), a new angiotensin II type 1 (AT1) receptor antagonist, was studied in several experimental hypertensive models. The effects of KRH-594 on the circulating reninangiotensin system and on renal function were also investigated. Oral administration of KRH-594 (0.3 or 1 mg/kg) dose-dependently inhibited the angiotensin II-induced pressor response in common marmosets. KRH-594 (1, 3, or 10 mg/kg p.o.) dose-dependently exerted a long-lasting antihypertensive effect in spontaneously hypertensive rats (SHRs) and in 2-kidney 1-clip renal hypertensive rats (RHRs). Furthermore, repeated oral administration of KRH-594 (3 or 10 mg/kg/d) reduced blood pressure dose-dependently in SHRs, RHRs, and renal hypertensive dogs without tachycardia and with no evidence of a rebound phenomenon following drug withdrawal. On the other hand, in deoxycorticosterone acetate salt rats and normotensive rats, KRH-594 (10 or 30 mg/kg p.o.) did not have significant effects on systolic blood pressure. In SHRs, KRH-594 (3 or 10 mg/kg/d p.o. for 2 weeks) dose-dependently increased both plasma renin activity and the plasma angiotensin I concentration, but had no effect on the urinary excretion of sodium, potassium, and chloride or on creatinine clearance. These results suggest that KRH-594 should be effective in patients with essential or renal hypertension.

Antihypertensive, insulin-sensitising and renoprotective effects of a novel, potent and long-acting angiotensin II type 1 receptor blocker, azilsartan medoxomil, in rat and dog models

The pharmacological profile of a novel angiotensin II type 1 receptor blocker, azilsartan medoxomil, was compared with that of the potent angiotensin II receptor blocker olmesartan medoxomil. Azilsartan, the active metabolite of azilsartan medoxomil, inhibited the binding of [(125)I]-Sar(1)-I1e(8)-angiotensin II to angiotensin II type 1 receptors. Azilsartan medoxomil inhibited angiotensin II-induced pressor responses in rats, and its inhibitory effects lasted 24h after oral administration. The inhibitory effects of olmesartan medoxomil disappeared within 24h. ID(50) values were 0.12 and 0.55 mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In conscious spontaneously hypertensive rats (SHRs), oral administration of 0.1-1mg/kg azilsartan medoxomil significantly reduced blood pressure at all doses even 24h after dosing. Oral administration of 0.1-3mg/kg olmesartan medoxomil also reduced blood pressure; however, only the two highest doses significantly reduced blood pressure 24h after dosing. ED(25) values were 0.41 and 1.3mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In renal hypertensive dogs, oral administration of 0.1-1mg/kg azilsartan medoxomil reduced blood pressure more potently and persistently than that of 0.3-3mg/kg olmesartan medoxomil. In a 2-week study in SHRs, azilsartan medoxomil showed more stable antihypertensive effects than olmesartan medoxomil and improved the glucose infusion rate, an indicator of insulin sensitivity, more potently (≥ 10 times) than olmesartan medoxomil. Azilsartan medoxomil also exerted more potent antiproteinuric effects than olmesartan medoxomil in Wistar fatty rats. These results suggest that azilsartan medoxomil is a potent angiotensin II receptor blocker that has an attractive pharmacological profile as an antihypertensive agent.

Nitroprusside and the Treatment of Hypertension

…2. Intravenously injected nitroprusside is strongly hypotensive without producing tachyphylaxis. Adrenergic blocking agents and surgical ablation of portions of the central nervous system failed to abolish its action…. Dogs with experimental neurogenic hypertension are more sensitive than renal hypertensive or normotensive dogs to the depressor effect of intravenous nitroprusside. 3. Nitroprusside is moderately vasodilator in perfused kidneys of dogs and strongly dilator in perfused hind legs. In normal, conscious dogs it caused slight increase in renal blood flow and decrease in vascular resistance with no effect on the maximal tubular excretory capacity for para-aminohippurate (TmPAH) OR the maximal tubular capacity for reabsorption of glucose (TmG), when infused intravenously. A dog with neurogenic hypertension, in contrast with those with renal hypertension, exhibited large decreases in both arterial pressure and renal resistance…. 4. Moderately depressor doses induce renal vasodilatation in hypertensive patients which is roughly equivalent to the decrease of pressure. It does not increase renal blood flow appreciably nor decrease glomerular filtration conspicuously…. 7. Hypertensive patients are more sensitive to the hypotensive action of intravenously administered nitroprusside than normotensive subjects. Chronic treatment with hydralazine or hexamethonium or single doses seems to increase this sensitivity. 8. Constant infusion of nitroprusside into patients with hypertensive encephalopathy has kept the arterial pressure at normal levels as long as 14 days with complete disappearance of the signs and symptoms. No deleterious effects from such prolonged administration have been noted and the rapidity of its therapeutic effects has been striking. 1

Study on the Mechanism of Compound Mistletoe Fluidextract in Relieving Hypertension

To observe the effect of fufang jisheng liujin gao (Compound Mistletoe Fluidextract) on blood pressure in the spontaneous hypertensive rats (SHR) and the renal hypertensive dogs (RHD). The blood pressure-decreasing effects of single administration and 14-day consecutive administration of Compound Mistletoe Fluidextract (CMF) in SHR and RHD were investigated and compared with that of niuhuang jiangya wan (Bezoar Hypertension-relieving Pills). Both single administration and 14-day consecutive administration of CMF had significant hypotensive effects in SHR and RHD. The hypotensive action of CMF is gradual, but lasts for a longer period, with a dose-effect relationship in a range of doses.

Development of Hypertension and Effects of Benazepril Hydrochloride in a Canine Remnant Kidney Model of Chronic Renal Failure

In order to determine whether hypertension would develop in dogs with chronic renal failure, we performed 7/8 renal ablation in 6 healthy dogs and compared pre- and post-ablation blood pressures determined by telemetry. One month after the renal ablation, blood urea nitrogen and creatinine were significantly increased (p<0.05), creatinine clearance was decreased (p<0.05), and blood pressure was increased significantly (p<0.05). Simultaneously, plasma renin activity, angiotensin I and II, and aldosterone were elevated significantly (p<0.05) compared with the values obtained from 11 healthy dogs with intact renal function. The dogs with induced renal failure and hypertension were administered an angiotensin-converting enzyme inhibitor, benazepril hydrochloride, once daily for 2 weeks at 2 mg/kg body weight, and changes in blood pressure and the renin-angiotensin-aldosterone (RAA) system were determined. During the administration of benazepril hydrochloride, blood pressure, angiotensin II and aldosterone decreased significantly (p<0.05) and, upon discontinuation of administration, increased to the pre-administration levels (p<0.05). Plasma renin activity and angiotensin I showed no significant changes throughout the administration study. These results provide experimental evidence that hypertension develops in dogs with chronic renal failure through mechanisms involving the RAA system and demonstrate that benazepril hydrochloride improves renal hypertension in dogs.

Total peripheral resistance responsiveness during the development of secondary renal hypertension in dogs

To determine whether the responses of total peripheral resistance and arterial pressure to vasoconstrictor agents are amplified as renovascular hypertension develops in dogs. After baseline measurements, the effects of renal artery stenosis (1K, 1C hypertension) were studied in groups of untreated and enalapril-treated dogs early (1-3 weeks) and later (4-6 weeks) as the hypertension developed. Both resting and open-loop haemodynamic measurements were made and the effects of acute intravenous infusions of vasopressin (0.25, 0.5 and 1.25 ng/kg per min) and phenylephrine (0.125, 0.25 and 0.50 microg/kg per min on arterial pressure, cardiac output and calculated total peripheral resistance responses were measured. Renal artery stenosis induced an increase in arterial blood pressure in both groups of dogs, with similar changes in haemodynamics also observed in open-loop conditions. The slopes of arterial pressure and peripheral resistance responses to vasopressin and phenylephrine were not significantly changed in early or late hypertension, in either the untreated or enalapril-treated groups. Hypertension from renal artery stenosis in dogs was due to nonautonomic, nonangiotensin II mechanisms. There was no evidence of vascular amplification of the effects of vasoconstrictor agents, indicating that this did not play a role in the development of hypertension.

Pharmacokinetic and Pharmacodynamic Interaction Between Irbesartan and Hydrochlorothiazide in Renal Hypertensive Dogs

Combined irbesartan/hydrochlorothiazide (HCTZ) formulations are often used clinically. Pharmacokinetic-pharmacodynamic (PK/PD) modeling was applied to investigate the pharmacokinetic and pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs at non-steady-state and steady-state. The renal hypertensive dogs were treated with oral irbesartan alone, or HCTZ alone, or the combination of irbesartan and HCTZ for 8 days. Blood pressure and plasma concentrations were measured and pharmacokinetic-pharmacodynamic parameters were analyzed. Irbesartan showed a two-compartment model pharmacokinetic profile. The concentration-time course of irbesartan was not changed by HCTZ, but irbesartan increased the peak plasma concentration and area under the curve of HCTZ at steady-state. HCTZ had no blood pressure lowering effect at non-steady-state. Irbesartan plus HCTZ had greater blood pressure lowering action than irbesartan alone. HCTZ increased actions of irbesartan. Hysteresis loops were found between effect and plasma concentrations of irbesartan after a single dose. However, hysteresis loops disappeared at steady state with more rapid realization of maximum concentration and effects. The relationship between effects and effect-compartment concentrations of the drugs was represented by a sigmoid Emax model. The results suggest synergistic pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs and some differences of pharmacokinetic-pharmacodynamic properties between irbesartan and irbesartan/HCTZ combinations at non-steady-state and steady state.

Targeting Small Arteries of Hypertensive Status with Novel ATP-Sensitive Potassium Channel Openers&amp;#

The excessive contraction of small arteries under high blood pressure is the main contributor to the pathological change of hypertension. Current anti-hypertensive drugs, which lack a selective effect on small arteries in a hypertensive state, may cause many adverse effects. We have developed a novel opener of ATP-sensitive potassium channels, iptakalim, the vasorelaxing action of which is determined by the hypertensive status of small arteries. In conscious stroke-prone, spontaneously hypertensive rats and "two-kidneys, one-clip" renal hypertensive dogs, this compound produced long-lasting hypotensive effects, with no tolerance. Furthermore, it exerted a protective effect against hypertensive damage to target organs. Given its potency and fewer side effects, iptakalim hydrochloride is a promising drug for the treatment of hypertension.

Pharmacokinetic and pharmacodynamic of irbesartan in renal hypertensive dogs under non-steady-state and steady-state conditions

The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of irbesartan in renal hypertensive dogs under non-steady-state and steady-state conditions using pharmacokinetic-pharmacodynamic (PK/PD) modeling. Drugs were administered intragastrically to renal hypertensive dogs, plasma drug concentration was determined by HPLC method and Pharmacologic effects, including SBP, DBP, dp/dtmax and LVSP, were measured simultaneously. AT II, Aldosterone (ALD) and Endothelin (ET) were also used as measurement of effect. The PK and PD data were quantitatively analyzed according to the PK/PD model theory. The pharmacokinetic profiles of irbesartan conformed to a two-compartment open model. There was hysteresis loops between effects and plasma concentrations under non-steady-state condition. The relationship between effects and effect compartment concentrations (Ce) could be represented by the Sigmoid-Emax model. The Hysteresis loops disappeared under steady-state condition with more rapidly attainment of maximum concentration and effect. There were certain difference of pharmacokinetic and pharmacodynamic properties between non-steady-state and steady-state condition.

A New ATP-Sensitive Potassium Channel Opener Reduces Blood Pressure and Reverses Cardiovascular Remodeling in Experimental Hypertension

Some potassium channel openers (KCOs) are potent vasodilators that mainly target the ATP-sensitive potassium channels in vascular smooth muscle cells. Their lack of tissue selectivity limits their clinical use in hypertension therapy. Iptakalim [2,3-dimethyl-n-(1-methylethyl)-2-butylamine], which belongs to a novel chemical type of KCO, possesses unique pharmacological characteristics. In vitro experiments have shown that iptakalim could limit its vasorelaxing actions to resistance vessels. In this study, we investigate the antihypertensive effects of iptakalim on two different experimental hypertensive models: stroke-prone, spontaneously hypertensive rats (SHRsps) and two-kidney with one-clip renal hypertensive dogs (2K1C RHD). In acute hypotensive tests, iptakalim showed stable, long-lasting antihypertensive effects in SHRsps and 2K1C RHDs. Mean-while, it had little effect on heart rate when compared with pinacidil, nifedipine, captopril, or bisoprolol. In experimental therapeutic tests, repeated doses in SHRsps for 30 days or in 2K1C RHDs for 14 days produced consistent antihypertensive effects without causing tolerance. In separate experiments, chronic administration of iptakalim resulted in reversing hypertensive vascular remodeling in spontaneously hypertensive rats and hypertensive cardiac remodeling in SHRsps. These results suggest that iptakalim is a promising antihypertensive drug.

Pharmacological characteristics of the novel antihypertensive drug, iptakalim hydrochloride, and its molecular mechanisms

AbstractThe purpose of the present study was to evaluate the pharmacological characteristics of the novel antihypertensive drug iptakalim hydrochloride and to investigate the molecular mechanisms underlying its antihypertensive action. In conscious hypertensive animals, oral administration of iptakalim hydrochloride at doses of 0.75, 1.5, 3.0, and 6.0 mg/kg in spontaneously hypertensive rats, or at doses of 0.125, 0.25, 0.5, and 1.0 mg/kg in renal hypertensive dogs (two‐kidney with one‐clip), decreased the blood pressure in a dose‐dependent manner. In conscious normotensive dogs blood pressure was not changed when iptakalim hydrochloride was given at doses of 0.8–3.2 mg/kg, but was decreased by 20 mmHg at the high dose of 12.8 mg/kg. Repeated administration of iptakalim hydrochloride decreased blood pressure in a dose‐dependent manner and also reversed the hypertensive cardiovascular remodeling. The molecular mechanisms underlying its antihypertensive action include ATP‐sensitive potassium channel activation and endothelin antagonism. Drug. Dev. Res. 58:65–68, 2003. © 2003 Wiley‐Liss, Inc.

Pharmacologic characterization of FR172516: a new combined calcium channel-blocking and beta-adrenoceptor-blocking agent.

The pharmacologic characterization of FR172516, a new combined calcium channel-blocking and beta-adrenoceptor-blocking agent, was studied and compared with amlodipine in receptor-binding assay and in vivo studies. In the binding assay, Ki values of FR172516 for calcium channel and beta-receptor were 29.3 nM and 44.1 nM, respectively. In the in vivo studies with pithed rats, FR172516 shifted the dose-response curves of isoproterenol in heart rate to the right, suggesting that this compound has a antiadrenoceptor effect in vivo. The hypotensive effect of FR172516, which could be mainly attributed to its calcium channel-blocking action, was compared with that of amlodipine in normotensive Wistar rats (NTRs), spontaneously hypertensive rats (SHRs), and renal hypertensive dogs (RHDs). FR172516 showed more potent hypotensive action than amlodipine when administered intravenously to NTRs, and apparent bradycardia was seen only with FR172516. In SHRs, FR172516 showed a long-lasting hypotensive action and dose-dependently decreased heart rate, whereas amlodipine scarcely affected heart rate. In RHDs, oral administration of FR172516 once daily for 5 days decreased blood pressure without reflex tachycardia or an increase of plasma renin activity. On the other hand, amlodipine, in the dose at which hypotensive effects equipotent to those of FR172516 were observed, produced apparent reflex tachycardia and concomitant increase of plasma renin. These results indicate that FR172516 has a potent long-lasting antihypertensive effect without activating sympathetic tone by calcium channel-blocking and beta-adrenoceptor-blocking actions.

Antihypertensive activity and pharmacokinetics of KD3-671, a nonpeptide AT1-receptor antagonist, in renal hypertensive dogs.

The antihypertensive activity and pharmacokinetics of KD3-671 (previously named KT3-671), a nonpeptide AT1-receptor antagonist, were investigated in renal hypertensive dogs with normal or high plasma renin activity (PRA). A single administration of KD3-671 at 3 and 10 mg/kg, p.o., to the hypertensive dogs with high PRA dose-dependently reduced mean blood pressure (MBP), which was not correlated with plasma KD3-671 concentration. Significant increases in PRA and plasma angiotensin (Ang) II occurred 2 h after KD3-671 dosing. Enalapril at 3 mg/kg, p.o., also reduced MBP. Neither KD3-671 nor enalapril affected heart rate. When given orally once a day for 29 days to the hypertensive dogs with normal PRA, KD3-671 at 3 and 10 mg/kg/day dose-dependently reduced MBP, which was smaller than that in the dogs with high PRA. This was the case for enalapril. The hypotension induced by the first dose of KD3-671 or enalapril was consistently observed after doses 8, 15, 22, and 29. After cessation of repeated dosing, no rebound phenomenon in MBP was observed. Pharmacokinetic parameters of KD3-671 were not influenced by repeated dosing. KD3-671 markedly increased both PRA and plasma Ang II concentration at 2 h after dosing. These results suggest that KD3-671 may be useful for the treatment of hypertension.

Peculiarities of the neurohumoral regulation of lymphodynamics in renal hypertensive dogs

Medicine students from the University of Medicine and Pharmacy “Grigore T. Popa” Iasi, attended the Clinical Simulation course for one semester. They had the opportunity to test their skills and acquire professional abilities in order to express their opinion on the efficiency of the medical simulation for training and professional assessment, following a series of parameters set out in a professional self-evaluation sheet included in the simulator software. Materials and methods. The method was to simulate clinical cases on Human Patient Simulator (HPS) and endoscopic investigations on GI Mentor (clinical, diagnosis, treatment scenarios). The main focus of this test was self-evaluation, as well as eye - hand coordination (indicators on time and quality of the examination) and keeping in mind the safety and comfort of the patient. Results. The information taken from records of the self evaluation reveals the following aspects:- improved quality of exploration (identification of lesions, shorter exploration) for 77% of the students after three sessions working on simulators; - the duration and quality of the exploration in the complex cases simulated on GI Mentor improved after 10 sessions for 77% of students, while progress on the HPS was recorded after 4 sessions for 89% of the students. Conclusion. The evolution of a registered clinical simulation is useful, but we consider that it should have more time granted. Given the results, clinical simulation is important for the development of medical skills of the students, but we consider that more time should be awarded for training.

Antihypertensive activity of a nonpeptide angiotensin II receptor antagonist, YM358, in rats and dogs

The antihypertensive activity of YM358, 2,7-diethyl-5-[[2-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo-[1,5-b] [1,2,4]triazole potassium salt monohydrate, a new nonpeptide angiotensin II receptor antagonist, was characterized in rats and dogs. In conscious rats, YM358 after a single oral administration (1–30 mg/kg) lowered blood pressure. The rank order of hypotensive potency of YM358 in conscious rats was 2-kidney, 1-clip renal hypertensive rats>spontaneously hypertensive rats>normotensive rats on the basis of maximum hypotension. YM358 also caused decreases in blood pressure in 2-kidney, 1-clip renal hypertensive dogs and furosemide-treated dogs. Repeated administration of YM358 to 2-kidney, 1-clip renal hypertensive rats for 28 d produced a stable and long-lasting antihypertensive effect without influencing circadian blood pressure and heart rate rhythms. No reflex tachycardia was observed in any animals of either species treated with YM358. Therefore, the pharmacological profile of this compound indicates that YM358 has potential as a useful antihypertensive agent.

KRN4884, a novel K channel opener: antihypertensive effects in conscious renal hypertensive dogs.

We examined the antihypertensive effects of KRN4884, 5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarbocamidine+ ++, in normotensive dogs, a high-renin model acute renal hypertensive dog (RHD), and a low-renin model chronic RHD in the conscious state, compared with levcromakalim and nilvadipine. KRN4884 decreased mean blood pressure (MBP) at a dose of 0.1 mg/kg p.o. in normotensive dogs and both RHDs. The decrease in MBP was greater in both RHDs than in normotensive dogs, and there were no significant differences between the two RHDs. A transient increase in heart rate (HR) accompanied the increase in MBP in all three types of dogs. In the chronic RHD, KRN4884 at doses of 0.05, 0.1, and 0.2 mg/kg produced a dose-dependent decrease in MBP. The antihypertensive effect of KRN4884 (0.1 mg/kg) was similar to those of levcromakalim (0.05 mg/kg) and nilvadipine (1.0 mg/kg) in magnitude and more prolonged than those of the compounds. The tachycardia induced by KRN4884 was similar to that induced by levcromakalim and was stronger than that induced by nilvadipine. In the 15-day repeated oral-administration study, KRN4884 (0.1 mg/kg) induced sustained hypotensive effects and transient increases in HR and plasma renin activity. No tolerance to the antihypertensive effect of KRN4884 was observed during a 15-day repeated dosing period. After withdrawal of KRN4884, no rebound phenomena in MBP and HR were observed. Neither the maximal concentration nor area under the curve (AUC) of KRN4884 in plasma were changed at days 1, 8, and 15. These data indicate that KRN4884 produces a strong and persistent antihypertensive response in both low-renin and high-renin models of RHD in a conscious state, which suggests that KRN4884 may be useful as an antihypertensive agent.

Pharmacological Studies on a New Antihypertensive Agent, S-2150, a Benzothiazepine Derivative: 3. Hypotensive and Antimyocardial-Stunning Effects in Dogs

The hypotensive and antimyocardial-stunning effects of a new 1,5-benzothiazepine antihypertensive agent, S-2150, were investigated in dogs. S-2150 (30 mg/kg, p.o.) decreased the blood pressure in conscious renal hypertensive dogs. Although the maximal hypotensive effect of S-2150 was observed at 5-9 h after administration, the effect of diltiazem was seen at 2.0 h. Arrhythmia was not observed as a hypotensive effects of S-2150 but was markedly induced by diltiazem. In anesthetized open-chest dogs, S-2150 (20 micrograms/kg/min, i.v.) caused by hypotensive effect similar to that of diltiazem but decreased myocardial work (double product) by much less than did diltiazem. S-2150 more promptly improved the local myocardial stunning caused by occlusion of the left anterior descending coronary artery and its reperfusion. This effect did not accompany the energy-sparing action in ischemic/reperfused myocardium, which was different from the case of diltiazem. In isolated dog mesenteric arteries, S-2150 relaxed KCl and phenylephrine contracture. These results suggest that S-2150 is a favorable hypotensive agent for hypertensive patients with ischemic heart disease. Blockage of both Ca2+ channels and alpha 1-adrenoceptors by S-2150 seems to lead to cardiovascular effects different from those of diltiazem.

Antihypertensive effects of long-term treatment with AE0047, a novel long-lasting calcium antagonist, in hypertensive models of rats and dogs

The antihypertensive effects of AE0047, a novel 1,4-dihydropyridine-type calcium antagonist, were investigated in spontaneously hypertensive rats (SHR/crj) and two kidney-one clip renal hypertensive dogs (RHD). AE0047, which was orally administered at the dose of 0.3, 1 or 3 mg/kg once daily for 8 consecutive weeks to SHR/crj, exhibited a dose-related decrease in systolic blood pressure. The antihypertensive action was reinforced during the drug treatment at 0.3 and 1 mg/kg. At each dose, the trough-to-peak (T/P) ratio was above 0.50 two weeks later. Although the reflex tachycardia was observed at 1 or 3 mg/kg on the 1st day, it gradually weakened within 8 weeks. Long-term treatment with AE0047 led to the regression of left ventricular hypertrophy. Furthermore, AE0047 had no influences on lipid and glucose metabolism. In RHD, and AE0047 capsule (GJ-0956) containing 2 or 8 mg of the drug was administered for 2 weeks. GJ-0956 produced no reduction in blood pressure at 2 mg, but enhanced the antihypertensive effect starting at 8 mg. The T/P ratios were 0.52 and 0.67 for the systolic and diastolic pressure, respectively, on the 14th day. These results indicate that AE0047 may be expected to exhibit beneficial effects for the clinical treatment of hypertension.

Hypotensive effects of YM430, a 1,4-dihydropyridine derivative, in spontaneously hypertensive rats and renal hypertensive dogs.

The hypotensive effects of YM430 (4(((S)-2-hydroxy-3-phenoxypropyl)amino)butyl methyl 2,6-dimethyl-((S)-4-(m-nitrophenyl))-1,4-dihydropyridine-3,5-dicarboxyla te) were evaluated in hypertensive animals. In conscious spontaneously hypertensive rats (SHR), single oral administration of YM430 (10-100 mg/kg) produced a dose-dependent decrease in mean blood pressure (MBP) with slight reflex tachycardia. The hypotensive effect of YM430 reached its maximum about 2 hr after dosing and lasted for over 10 hr. Importantly, the beta 1-adrenoceptor blocking activity of YM430 had a similar time course to that of its calcium entry blocking activity. In conscious normotensive dogs (NTD: 1-10 mg/kg, p.o.), YM430 decreased MBP without reflex tachycardia, and inhibited isoproterenol (ISO)-induced tachycardia in a dose-dependent manner. In conscious renal hypertensive dogs (RHD: 0.3-3 mg/kg, p.o.), YM430 also produced a sustained hypotensive effect. Furthermore, on repeated oral administration to conscious SHR and NTD, YM430 caused a long-lasting hypotensive effect. This hypotensive activity and inhibition of ISO-induced tachycardia showed neither tolerance, augmentation nor rebound. In conclusion, YM430 has a long-lasting hypotensive effect and behaves as a hybrid compound, combining calcium entry blocking and beta 1-adrenoceptor blocking activities in vivo. In addition, the degree of the blocking activities of YM430 remains nearly constant in the long-term after oral administration.

Hypotensive Effects of YM430, a 1,4-Dihydropyridine Derivative, in Spontaneously Hypertensive Rats and Renal Hypertensive Dogs

The hypotensive effects of YM430 (4(((S)-2-hydroxy-3-phenoxypropyl)amino)butyl methyl 2,6-dimethyl-((S)-4-(m-nitrophenyl))-l,4-dihydropyridine-3,5-dicarboxylate) were evaluated in hypertensive animals. In conscious spontaneously hypertensive rats (SHR), single oral administration of YM430 (10-100 mg/kg) produced a dose-dependent decrease in mean blood pressure (MBP) with slight reflex tachycardia. The hypotensive effect of YM430 reached its maximum about 2 hr after dosing and lasted for over 10 hr. Importantly, the β1-adrenoceptor blocking activity of YM430 had a similar time course to that of its calcium entry blocking activity. In conscious normotensive dogs (NTD: 1-10mg/kg, p.o.), YM430 decreased MBP without reflex tachycardia, and inhibited isoproterenol (ISO)-induced tachycardia in a dose-dependent manner. In conscious renal hypertensive dogs (RHD: 0.3-3 mg/kg, p.o.), YM430 also produced a sustained hypotensive effect. Furthermore, on repeated oral administration to conscious SHR and NTD, YM430 caused a long-lasting hypotensive effect. This hypotensive activity and inhibition of ISO-induced tachycardia showed neither tolerance, augmentation nor rebound. In conclusion, YM430 has a long-lasting hypotensive effect and behaves as a hybrid compound, combining calcium entry blocking and β1-adrenoceptor blocking activities in vivo. In addition, the degree of the blocking activities of YM430 remains nearly constant in the long-term after oral administration.