Responses In Normotensive Rats Research Articles

Differential blood pressure response in normotensive rats and rats with angiotensin II‐dependent hypertension following systemic cannabinoid CB1 receptor blockade (1140.11)

Evidence for interactions between the endocannabinoid (ECS) and the renin‐angiotensin (RAS) systems in brain and vasculature is emerging. In transgenic (mRen2)27 rats, an angiotensin (Ang) II‐dependent model of hypertension involving excess sympathetic nervous system activity (SNS), acute systemic blockade of CB1 cannabinoid receptors by the CB1‐selective antagonist SR141716A (SR; 10 mg/kg orally; n = 5) significantly reduced systolic blood pressure (SBP) from 176 ± 3 mmHg baseline to 134 ± 3 mmHg after 90 min (P < 0.001). SBP showed evidence of recovery after 24 h but remained significantly reduced at 146 ± 5 mmHg (P < 0.01) compared to baseline. Plasma collected at 24 h showed no differences in levels of Ang II and Ang‐(1‐7) in the SR‐treated group compared to the vehicle (0.1% Tween‐80 in dH2O) group. Interestingly, oral SR treatment in normotensive Sprague‐Dawley control rats (n = 2) modestly increased SBP from a baseline of 120 ± 3 mmHg to 135 ± 2 mmHg after 90 min, suggesting blockade of the known vasodilator actions of the CB1 receptor. After 24 h, SBP recovered to 126 ± 4 mmHg. There was no effect of vehicle on SBP in either strain. These results indicate that CB1 receptor blockade in (mRen2)27 rats may disrupt the hypertension by interfering with the upregulated RAS‐dependent excess SNS activity in these animals, overcoming the blockade of the beneficial ECS effects in the vasculature.Grant Funding Source: Supported by NIH: P01‐HL051952 and R01‐DA03690

Pressor and Renal Hemodynamic Effects of the Novel Angiotensin A Peptide Are Angiotensin II Type 1A Receptor Dependent

Recently, a new derivative of angiotensin (Ang) II, called "Ang A," has been discovered to be present in plasma of healthy humans and, in increased concentrations, in end-stage renal failure patients. The objectives of the study were to investigate the blood pressure and renal hemodynamic responses to Ang A in normotensive and hypertensive rats and in genetically modified mice and the binding properties of Ang A to Ang II type 1 (AT(1)) or Ang II type 2 (AT(2)) receptors. Intravenous and intrarenal administration of Ang A induced dose-dependent pressor and renal vasoconstrictor responses in normotensive rats, which were blocked by the AT(1) receptor antagonist candesartan but were not altered by the AT(2) receptor ligands PD123319, CGP42112A, or compound 21. Similar responses were observed after intravenous administration in spontaneously hypertensive rats. Deletion of AT(1a) receptors in mice almost completely abolished the pressor and renal vasoconstrictor responses to Ang A, indicating that its effects are mediated via AT(1a) receptors. Ang A was less potent than Ang II in vivo. The in vitro study demonstrated that Ang A is a full agonist for AT(1) receptors, with similar affinity for AT(1) and AT(2) receptors as Ang II. Overall, the responses to Ang A and Ang II were similar. Ang A has no physiological role to modulate the pressor and renal hemodynamic effects of Ang II.

Angiotensin II AT1 blockade reduces the lipopolysaccharide-induced innate immune response in rat spleen

ANG II AT(1) receptor blockade reduces inflammation in hypertension. To determine whether ANG II AT(1) receptor blockers (ARBs) influence the innate immune inflammatory response in normotensive rats, we studied rat plasma and spleen after a 3-day subcutaneous pretreatment with the ARB candesartan followed by a single dose of the bacterial endotoxin LPS (50 microg/kg ip). Peripheral administration of LPS to rodents produced a generalized inflammatory response with increased release of TNF-alpha, IL-1beta, and IL-6 into the circulation. Candesartan pretreatment reduced the LPS-induced release of TNF-alpha, IL-1beta, and IL-6 into the circulation. The red pulp of rat spleen expressed large numbers of AT(1) receptors and the LPS receptors Toll-like receptor 4 and CD14. Candesartan administration significantly blocked AT(1) receptors. The ARB reduced the LPS-induced upregulation of CD14 gene expression; expression of TNF-alpha and IL-6 mRNA and protein; expression of IL-1beta and IkappaB-alpha mRNA; COX-2 mRNA and protein expression and PGE(2) concentration; inducible nitric oxide synthase (iNOS) gene and protein expression and iNOS activity; and Nox2 gene expression and 8-isoprostane levels. In addition, candesartan reduced the CD14 protein expression in saline- and LPS-treated rats. Our results suggest that AT(1) receptors are essential for the development of the full innate immune response to bacterial endotoxin. The ARB decreased the general peripheral inflammatory reaction to LPS and partially decreased the inflammatory response in the spleen. An unrestricted innate immune response to the bacterial endotoxin may have deleterious effects for the organism and may lead to development of chronic inflammatory disease. We postulate that ARBs may have therapeutic effects on inflammatory conditions.

Restoration of Female Genital Vasocongestive Arousal Responses in Young and Aged Rats

Treatments of aged, male hypertensive rats that induce vascular remodeling or that normalize endothelial function are known to produce sustained improvements in erectile function. Whether the treatments targeting these processes benefit female genital vasocongestive arousal (GVA) responses is currently not known. To determine whether the actions of nitric oxide (NO) are critical to the apomorphine (APO)-generated GVA responses in both intact and ovariectomized OVX young adult female rats (before any aging-associated decreases in the responses). In addition, we also investigated whether the diminished GVA responses in aged rats could be restored, at least in part, using an antihypertensive treatment, which is known to enhance erectile responses and improve general vascular function in male rats. In female Wistar rats, APO-induced GVA responses (80 microg/kg, subcutaneously [sc], 30 minutes) were assessed by videomonitoring following various treatments. Young adult females were ovariectomized or were treated with the nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (30 mg/kg, iv), followed by an NO mimetic, sodium nitroprusside (10 microg/kg/minute, intravenous). Aged females (18 months) were treated for 2 weeks with the angiotensin converting enzyme (ACE) inhibitor, enalapril (30 mg/kg/day, orally) plus low sodium (0.04%). APO-induced GVA responses in female rats. There was an age-associated reduction in sexual responses in normotensive rats that was greatly enhanced (fourfold) by brief, aggressive antihypertensive treatment. The enhanced vasocongestive responses persisted for a 5-week off-treatment. Both OVX and NOS inhibition significantly decreased sexual responses by approximately 80% in young female rats. Systemic administration of an NO mimetic recovered vasocongestive responses in the NOS-blocked rats, but not in OVX animals. Although mechanisms were not established, the major findings were that brief aggressive ACE inhibitor treatment markedly improved sexual responses in aged female rats, and systemic delivery of an NO mimetic recovered sexual responses in globally NOS-blocked animals.

T01-O-16 Restoration of female genital vasocongestive arousal responses in young and aged rats

Objectives To examine whether the actions of nitric oxide (NO) were critical to the apomorphine-generated genital vasocongestive arousal (GVA) responses in both intact and ovariectomized (OVX) young adult female rats. We also investigated whether the diminished GVA responses in aged rats could be restored using an antihypertensive treatment. Design and Methods In female Wistar rats (n=8), apomorphine- induced GVA responses were assessed following various treatments. Young adult females were ovariectomized or treated with the NO synthase (NOS) inhibitor Nnitro-L-arginine methyl ester (30mg/kg, i.v.) followed by an NO-mimetic, sodium nitroprusside (10mg/kg/min, i.v.). Aged females (18 months-old; n=8) were treated for 2 weeks with the angiotensin converting enzyme inhibitor (ACEI) enalapril (30mg/kg per day, p.o.) + low sodium (0.04%). Results Age-associated reduction in sexual responses in normotensive rats was greatly enhanced by brief, aggressive antihypertensive treatment. The enhanced vasocongestive responses persisted for 5 weeks off-treatment. Both OVX and NOS inhibition significantly decreased sexual responses in the young female rats. Systemic administration of an NO-mimetic recovered vasocongestive responses in the NOS blocked rats, but not in OVX animals. Conclusions Brief aggressive ACEI treatment markedly improved sexual responses in aged female rats, and systemic delivery of a NO-mimetic recovered sexual responses in globally NOS blocked animals.

Losartan Reduces the Increased Participation of Cyclooxygenase-2-Derived Products in Vascular Responses of Hypertensive Rats

This study analyzes the role of angiotensin II (Ang II), via AT1) receptors, in the involvement of cyclooxygenase (COX)-2-derived prostanoids in phenylephrine responses in normotensive rats (Wistar Kyoto; WKY) and spontaneously hypertensive rats (SHR). Aorta from rats untreated or treated for 12 weeks with losartan (15 mg/kg . day) or hydralazine plus hydrochlorothiazide (44 and 9.4 mg/kg . day, respectively) and vascular smooth muscle cells (VSMC) from SHR were used. Vascular reactivity was analyzed by isometric recording; COX-2 expression by Western blot and reverse transcription-polymerase chain reaction; prostaglandin (PG)I2, PGF(2alpha), 8-isoprostane, and total antioxidant status (TAS) by commercial kits; superoxide anion (O2*-) by lucigenin chemiluminescence; and plasmatic malondialdehyde (MDA) by thiobarbituric acid assay. The COX-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398) at 1 microM reduced phenylephrine responses more in SHR than in WKY rats. COX-2 protein and mRNA expressions, PGF(2alpha), PGI2, 8-isoprostane, and O2*- production, and MDA levels were higher in SHR, but TAS was similar in both strains. Losartan, but not hydralazine-hydrochlorothiazide treatment, reduced COX-2 expression and the effect of NS-398 on phenylephrine responses in SHR. Losartan also increased TAS and reduced PGF(2alpha), PGI2, 8-isoprostane, and O2*- production and MDA levels in SHR. Ang II (0.1 microM) induced COX-2 expression in VSMC from SHR that was reduced by 30 microM apocynin and 100 microM allopurinol, NADPH oxidase, and xanthine oxidase inhibitors, respectively. In conclusion, AT1 receptor activation by Ang II could be involved in the increased participation of COX-2-derived contractile prostanoids in vasoconstriction to phenylephrine with hypertension, probably through COX-2 expression regulation. The increased oxidative stress seems to be one of the mechanisms involved.

Effects of KMD-3213, a Uroselective α1A-Adrenoceptor Antagonist, on the Tilt-Induced Blood Pressure Response in Normotensive Rats

KMD-3213 ((-)-1-(3-hydroxypropyl)-5-((2R)-2-[[2-([2-[(2,2,2-trifluoroethyl)oxy]phenyl]oxy)ethyl]amino]propyl)-2,3-dihydro-1H-indole-7-carboxamide), an alpha(1A)-adrenoceptor antagonist with potency similar to that of tamsulosin, is under development for the treatment of bladder outlet obstruction in patients with benign prostatic hypertrophy. In the present study, we investigated the effects of KMD-3213 on the tilt-induced blood pressure response in anesthetized normotensive rats. Male normotensive Sprague-Dawley rats were placed in the supine position on a board under cocktail anesthetization (alpha-chloralose, urethane and sodium pentobarbital). The arterial blood pressure was measured from the carotid artery. The animals were given consistent 45 degrees head-up tilt from the horizontal position, following the transient decrease in the blood pressure, and then recovery of the blood pressure to the normal level. Significant orthostatic hypotension was seen with intravenous administration of both prazosin and tamsulosin at doses over 3 micro g/kg, and these drugs completely blocked the tilt-induced blood pressure responses at 30 micro g/kg. On the other hand, these responses were still retained when KMD-3213 was administered intravenously at a dose up to 75 micro g/kg of KMD-3213. Moreover, KMD-3213 showed the highest uroselectivity of the test drugs. These results indicate that KMD-3213 is not likely to induce orthostatic hypotension and would be a useful compound for the treatment of urinary outlet obstruction in patients with benign prostatic hyperplasia.

Delayed Vaccination Does Not Improve Antibody Responses in Splenectomized Rats Experiencing Hypovolemic Shock

Delayed vaccination after splenectomy has been shown to increase the antibody response in normotensive rats. The purpose of this experiment was to study the effect of timing of vaccination on antibody responses in rats undergoing splenectomy and experiencing hypovolemic shock. Sixty male Sprague-Dawley rats weighing 250 to 400 g underwent either a sham abdominal surgery or splenectomy after a 30-minute period of controlled hypovolemic shock. All rats then received pneumococcal vaccinations one day, 7 days, or 28 days postoperatively. Antibody levels were determined by enzyme-linked immunosorbent assay 3 weeks after vaccination. Results were compared by analysis of variance. Animals vaccinated one day postoperatively had similar or higher antibody responses than did rats receiving delayed vaccinations after 7 or 28 days. These results were similar for immunoglobulins G and M and more importantly were consistent for animals undergoing splenectomy and sham operations. Delayed vaccinations failed to improve antibody responses when hypovolemic shock preceded splenectomy. We propose that this is the result of complex cytokine responses to hypovolemic shock. These responses have been studied extensively in the setting of septic shock but not in the setting of hypovolemic or hemorrhagic shock.

Altered Mechanisms Underlying Hypoxic Dilation of Skeletal Muscle Resistance Arteries of Hypertensive versus Normotensive Dahl Rats

To determine mechanisms underlying hypoxic dilation of skeletal muscle resistance arteries from normotensive (NT) and hypertensive (HT) Dahl salt-sensitive (SS) rats. Isolated gracilis arteries (GA) from both rat groups were viewed via television microscopy and vascular responses to a reduction in PO2 from 145 mm Hg to 40 mm Hg were measured with a video micrometer. Responses were determined following endothelium removal and following inhibition of specific biochemical pathways regulating vascular tone. Hypoxic dilation was impaired in HT rats versus NT controls. Endothelium removal abolished hypoxic dilation in NT rats, although a significant dilation to hypoxia remained in vessels from HT animals. Inhibition of cytochrome P450 (CP450) 4A enzymes blunted hypoxic dilation in both groups, while inhibition of epoxyeicosatrienoic acid (EET) production impaired responses in NT rats only. Inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) production or blockade of membrane receptors for 20-HETE reduced hypoxic dilation in HT rats, with minimal effects in NT animals. Nitric oxide synthase inhibition had no effect on hypoxic dilation in either group, while cyclooxygenase inhibition significantly reduced this response in both groups. These results suggest that the mechanisms of hypoxic dilation in GA from NT Dahl-SS rats are altered with HT, impairing the response to reduced PO2. While hypoxia induces substantial prostanoid release in both groups, the role of CP450 4A enzymes is shifted from EET production in NT rats toward inhibition of 20-HETE production in HT rats.

Angiotensin-converting enzyme inhibitor prevents age-related endothelial dysfunction.

Vascular relaxation via endothelium-derived hyperpolarizing factor (EDHF) declines in association with aging and also with hypertension, and antihypertensive treatment improves the endothelial dysfunction connected with hypertension. We tested whether the angiotensin-converting enzyme inhibitor improves EDHF-mediated responses in normotensive rats, with special reference to the age-related process. Wistar-Kyoto rats (WKY) were treated with either 20 mg. kg(-1). d(-1) enalapril (WKY-E group) or a combination of 50 mg. kg(-1). d(-1) hydralazine and 7.5 mg. kg(-1). d(-1) hydrochlorothiazide (WKY-H group) from 9 to 12 months of age. Twelve-month-old WKY (WKY-O) and 3-month-old WKY (WKY-Y) served as controls (n=6 to 10 in each group). The 2 treatments lowered systolic blood pressure comparably. EDHF-mediated hyperpolarization to acetylcholine (ACh) in mesenteric arteries was significantly improved in WKY-E, but not in WKY-H, compared with WKY-O, and the hyperpolarization in WKY-E was comparable to that in WKY-Y (hyperpolarization to 10(-)(5) mol/L ACh in the presence of norepinephrine: WKY-O, -14+/-2 mV; WKY-E, -22+/-3 mV; WKY-H, -15+/-2 mV; and WKY-Y, -28+/-0 mV). EDHF-mediated relaxation, as assessed by relaxation to ACh in norepinephrine-precontracted rings in the presence of indomethacin and NO synthase inhibitor, was also significantly improved in WKY-E, but not in WKY-H, to a level comparable to that in WKY-Y (maximum relaxation: WKY-O, 45+/-6%; WKY-E, 63+/-8%; WKY-H, 43+/-4%; and WKY-Y, 72+/-4%). Hyperpolarization and relaxation to levcromakalim, an ATP-sensitive K(+) channel opener, were similar in all groups. These findings suggest that the angiotensin-converting enzyme inhibitor prevents the age-related decline in EDHF-mediated hyperpolarization and relaxation in normotensive rats, presumably through an inhibition of the renin-angiotensin system.

Increased neuropeptide Y pressor activity in goldblatt hypertensive rats: in vivo studies with BIBP 3226

Nanomoles of neuropeptide Y (NPY) and noradrenaline (NA), administered IV to pentobarbital-anesthetized rats, caused nearly equipotent dose-dependent pressor responses in normotensive rats. However, in renovascular Goldblatt hypertensive rats, the dose-response curves for both NPY and NA were significantly displaced to the left, approximately threefold. Intravenous administration of BIBP 3226 (30–180 μg/kg) did not consistently lower blood pressure, per se , but did evoke competitive antagonism of the NPY pressor response in both rat populations. The magnitude of the NPY antagonism evoked by BIBP 3226 was comparable in normotensive and hypertensive rats. The absence of NA antagonism demonstrates the selectivity of the BIBP 3226 blockade.

Habituation of airpuff-elicited cardiovascular responses in the spontaneously hypertensive rat

Repeated delivery of fast rise-time acoustic stimuli elicit cardiac changes in humans that reflect startle, orienting, and defense responses. To test the hypothesis that fast rise-time stimuli produce these responses in the rat, we evaluated magnitude, latency, and habituation of cardiovascular responses to brief airpuff stimuli in normotensive rats. We also evaluated airpuff-elicited cardiovascular responses in spontaneously hypertensive rats. In addition to a robust increase in blood pressure, airpuffs produced one or more of three sequential heart-rate responses in normotensive rats—first, short-latency tachycardia (latency 0.8 s), then rapidly habituating bradycardia (latency 2.2 s), then long-latency tachycardia (latency 3.5 s)—which likely reflected startle, orienting, and defense responses, respectively. Airpuffs rarely produced bradycardia in hypertensive rats, suggesting that this strain does not appropriately orient to sensory stimuli. In addition, compared to normotensive rats, hypertensive rats exhibited greater between-session habituation of long-latency tachycardia and blood pressure increases. This finding contrasts with the Folkow hypothesis, which assumes that, in subjects with a genetic predisposition to develop hypertension, sympathetic responses will remain exaggerated after repeated stimulation, thus contributing to thickening of the arterial vasculature.

Habituation of Airpuff-Elicited Cardiovascular Responses in the Spontaneously Hypertensive Rat

Repeated delivery of fast rise-time acoustic stimuli elicit cardiac changes in humans that reflect startle, orienting, and defense responses. To test the hypothesis that fast rise-time stimuli produce these responses in the rat, we evaluated magnitude, latency, and habituation of cardiovascular responses to brief airpuff stimuli in normotensive rats. We also evaluated airpuff-elicited cardiovascular responses in spontaneously hypertensive rats. In addition to a robust increase in blood pressure, airpuffs produced one or more of three sequential heart-rate responses in normotensive rats—first, short-latency tachycardia (latency 0.8 s), then rapidly habituating bradycardia (latency 2.2 s), then long-latency tachycardia (latency 3.5 s)—which likely reflected startle, orienting, and defense responses, respectively. Airpuffs rarely produced bradycardia in hypertensive rats, suggesting that this strain does not appropriately orient to sensory stimuli. In addition, compared to normotensive rats, hypertensive rats exhibited greater between-session habituation of long-latency tachycardia and blood pressure increases. This finding contrasts with the Folkow hypothesis, which assumes that, in subjects with a genetic predisposition to develop hypertension, sympathetic responses will remain exaggerated after repeated stimulation, thus contributing to thickening of the arterial vasculature.

The synthesis and biological activity of tetrahydroquinoline angiotensin II antagonists containing a substituted biphenyltetrazole group

The synthesis of analogues of tetrahydroquinoline angiotensin II antagonist, ZENECA ZD6888, bearing substituents on the biphenyl ring system is reported. Several of these compounds show comparable or superior activity to ZD6888 in an in vitro beinding assay and in inhibition of the AII-induced pressor response in normotensive rats.

Quinoline, 1,5-naphthyridine and pyridine derivatives as potent, nonpeptidic angiotensin II receptor antagonists

Quinoline-, 1,5-naphthyridine- and pyridine-based angiotensin II antagonists are reported. The more potent compounds gave IC 50 values of ca 0.01 μM in a guinea pig adrenal membrane binding assay and intravenous ED 50 values in the range 0.1–1.0 mg/kg for inhibition of the AII-induced pressor response in normotensive rats. Several of these compounds, for example 4d (ICI D6888), showed good oral activity in this animal model.

The Pharmacological Characterization of FK 739, a New Angiotensin II-Receptor Antagonist

The pharmacological properties of FK 739, a new angiotensin II-receptor antagonist, were examined. FK 739 inhibited the specific binding of [125I]-angiotensin II to rat aortic smooth muscle cell membrane with an IC50 value of 8.6 nM, but did not displace the specific binding of [125I]-angiotensin II to bovine cerebellum membrane. In isolated helical strips of rabbit aorta, FK 739 shifted the concentration-response curve of angiotensin II-induced contraction in parallel to the right, and the values of the slope and pA2 were 1.06 and 8.45, respectively. In in vivo studies, oral administration of FK 739 at 10 mg/kg significantly inhibited the angiotensin I-induced pressor response in normotensive rats and dogs, and it caused a fall of mean blood pressure in renal hypertensive rats and dogs. In spontaneously hypertensive rats, FK 739 at 32 and 100 mg/kg significantly decreased the mean blood pressure in a dose-dependent manner. Additionally, we studied whether FK 739 would cause side effects such as dry cough, like other ACE inhibitors did. Oral administration of FK 739 (10 and 32 mg/kg) did not affect the capsaicin-induced bronchial edema. On the other hand, captopril (10 mg/kg) significantly enhanced capsaicin-induced bronchial edema. These results indicate that FK 739 is a potent and competitive antagonist for AT1-type receptors, and suggest that FK 739 might be a safe and useful agent for the treatment of hypertension in clinical trials.

The pressor response to spinal cholinergic stimulation in spontaneously hypertensive rats

Several laboratories have demonstrated that central cholinergic stimulation in spontaneously hypertensive rats (SHR) results in an exaggerated pressor response as compared to normotensive (NT) controls. Recent studies in this laboratory have demonstrated a spinal cholinergic pressor system in the NT rat. The purpose of this study was to determine whether the pressor response to spinal cholinergic stimulation is enhanced in SHR. In freely moving rats, intrathecal injection of neostigmine or carbachol (1–5 μg) produced a dose-related hypertensive response in both strains of rats. While both agonists produced similar maximal increases in blood pressure in NT rats, the pressor responses to both agonists were significantly greater in SHR. The tachycardic responses to IT injection of cholinergic agonists were also significantly greater in SHR. These differences were more apparent at the lower doses where, for example, the pressor response to 1 μg of agonist in the SHR was increased by 123% and 109% of the response in NT rats for carbachol and neostigmine, respectively. Since both direct and indirect acting agonists produced greater responses in SHR, and spinal depletion of acetylcholine did not reduce blood pressure in SHR, it is most likely that spinal cholinergic systems ascend to higher centers to elicit pressor responses. In the case of the SHR, these higher centers may be supersensitive to cholinergic stimulation.

Baroreceptor reflex enhancement by chronic intracerebroventricular infusion of enalapril in normotensive rats.

Involvement of the brain renin-angiotensin system in baroreceptor reflex regulation was assessed by recording reflex heart rate and sympathetic nerve responses in normotensive rats that had been infused intracerebroventricularly with the converting enzyme inhibitor enalapril for 15 days. Reflex bradycardia and sympathetic nerve inhibition during pressor responses to phenylephrine were larger in rats with intracerebroventricularly infused enalapril than in control rats similarly infused either intracerebroventricularly with saline or intravenously with enalapril. In contrast, opposite reflex responses to sodium nitroprusside-induced hypotension were mostly unaffected. Because depressor, bradycardic, and sympathoinhibitory responses to electrical stimulation of the central cut end of the left aortic depressor nerve were also enhanced, intracerebroventricularly infused enalapril must be affecting the baroreceptor reflex arc centrally. These results are compatible with the interpretation that intracerebroventricularly infused enalapril enhanced baroreceptor reflex sensitivity by reducing endogenous angiotensin II levels in the brain through converting enzyme inhibition.

Hypotensive Action of Salvia miltiorrhiza Cell Culture Extract

Salvia miltiorrhiza cell culture extract (SCE) was shown to produce dose-dependent hypotensive response in normo-tensive rats. The mode of this hypotensive action was studied both in vivo and in vitro. This vasodepressor effect was not due to the presence of cations (potassium, calcium and magnesium) in the extract. In pharmacological antagonist studies, the hypotensive effect was shown not being mediated via the alpha-, beta-adrenoceptors, histamine receptors and autonomic ganglion; nor via direct vasodilation and diuresis. However, the vasodepressor effect was probably angiotensin- and/or bradykinin-related since captopril infusion potentiated the hypotensive effect of SCE. Furthermore, data indicated that the vasodepressor effect might be accounted for by the positive inotropic and negative chronotropic effects of SCE, the latter via its modulation of cholinergic activity.

Studies on angiotensin converting enzyme inhibitors. 4. Synthesis and angiotensin converting enzyme inhibitory activities of 3-acyl-1-alkyl-2-oxoimidazolidine-4-carboxylic acid derivatives.

(4S)-1-Alkyl-3-[[N-(carboxyalkyl)amino]acyl]-2-oxoimidazolidine-4- carboxylic acid derivatives (3) were prepared by two methods. Their angiotensin converting enzyme (ACE) inhibitory activities and antihypertensive effects were evaluated, and the structure-activity relationships were discussed. The dicarboxylic acids 3a-n possessing S,S,S configuration showed potent in vitro ACE inhibitory activities with IC50 values of 1.1 X 10(-8)-1.5 X 10(-9) M. The most potent compound in this series, monoester 3p, had an ID50 value of 0.24 mg/kg, po for inhibition of angiotensin I induced pressor response in normotensive rats and produced a dose-dependent decrease in systolic blood pressure of spontaneously hypertensive rats (SHRs) at doses of 1-10 mg/kg, po.