Treatment of hypertension has reduced the incidence of stroke, heart failure and renal failure. However, the incidence of coronary heart disease is not reduced to the same degree. Many of the drugs advocated as first-line drugs in the step-wise therapy have been shown to cause carbohydrate intolerance and it is an independent risk factor in the development of coronary heart disease. It is thus important to identify the antihypertensive drugs that may cause deterioration in glucose tolerance. Cicletanine, the first derivative of the furopyridines, is a new class of antihypertensive agents. It acts directly on vascular endothelium cells by increasing prostacyclin synthesis. It also decreases intracytosolic calcium levels in smooth muscles. The purpose of this study is to evaluate the effects of Cicletanine on insulin release in rat isolated pancreas by the perfusion technique adapted from Loubatieres and co-workers (1972). Doses used were based on therapeutic peak plasma concentration. Diazoxide was used as a positive control ie a known insulin suppressant. Cicletanine at 1/10 and equivalent therapeutic concentrations (0.5 microgram/mL and 5.0 micrograms/mL) did not suppress insulin release. However, at concentration exceeding 10X its therapeutic levels (50 micrograms/mL) it begins to suppress insulin release. In conclusion, Cicletanine did not inhibit insulin release at concentrations within the therapeutic range.
Intravenous injection of the aspidofractinine alkaloid, kopsingine (1, 0.2-10.0 mg/kg) from Kopsia teoi, produced dose-related decreases in the mean arterial blood pressure and heart rate in anesthetized spontaneously hypertensive rats, which were similar to those seen in normotensive controls. Minor modifications in the molecular structure of kopsingine, as in kopsaporine (2, the 12-demethoxy derivative of kopsingine) and 14,15-dihydrokopsingine (4), did not significantly alter the hypotensive responses, whereas a more drastic change in the structure, as in the heptacyclic kopsidine A (3) and the 3-to-17 oxo-bridged compound 5, resulted in an increase in blood pressure. The antihypertensive effects of kopsingine (1) and its congeners (2 and 4) along with the pressor effects produced by the heptacyclic oxo-bridged compounds (5 and 3) could be ascribed to central as well as peripheral actions.
14-deoxyandrographolide (DA) and 14-deoxy-11,12-didehydroandrographolide (DDA) are two diterpenoids isolated from A. paniculata, a popular folk medicine used as an antihypertensive drug in Malaysia. We have previously reported that DDA exhibited a greater hypotensive effect in anaesthetized rats and a vasorelaxant activity in isolated rat aorta, compared with DA. Their vasorelaxant activities were mediated through the activation of the enzymes, nitric oxide synthase (NOS) and guanylyl cyclase. The present study demonstrated that both DA and DDA stimulated nitric oxide (NO) release from human endothelial cells. DDA compared with DA caused a greater production of NO; this is in line with the finding of the earlier study that the vasorelaxant effect of DDA was more dependent on endothelium than DA.
The objective of this study was to examine the effect of angiotensin II (Ang II) and angiotensin II type 1 (AT(1)) receptor blockade on pulse wave velocity (PWV) in healthy humans. We studied nine young male volunteers in a double-blind randomised crossover design. Carotid-femoral PWV (an index of arterial stiffness) was measured by using a Complior machine. Subjects were previously treated for 3 days with once-daily dose of either a placebo or valsartan 80 mg. On the third day, they were infused with either placebo or 5 ng/kg/min of Ang II over 30 min. Subjects thus received placebo capsule + placebo infusion (P), valsartan + placebo infusion (V), placebo + Ang II infusion (A), and valsartan + Ang II infusion (VA) combinations. Heart rate (HR), blood pressure and PWV were recorded at baseline and then every 10 min during infusion and once after the end of infusion. There were significant increases in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) with A compared with P (P = 0.002, P = 0.002, P = 0.001 respectively). These rises in blood pressure were completely blocked by valsartan. A significant rise in PWV by A was seen compared with P (8.38 +/- 0.24 vs 7.48 +/- 0.24 m/sec, P = 0.013) and was completely blocked by valsartan; VA compared with P (7.27 +/- 0.24 vs 7.48 +/- 0.24 m/sec, P = NS). Multiple linear regression analysis showed that blockade of Ang II induced increase in blood pressure by valsartan contributed to only 30% of the total reduction in Ang II induced rise in PWV (R(2) = 0.306). The conclusions were that valsartan completely blocks the effect of Ang II on PWV. The effect of Ang II on PWV is mediated through AT(1)receptors. Reduction in PWV by Ang II antagonist is not fully explained by its pressure lowering effect of Ang II and may be partially independent of its effect on blood pressure.
We investigated the total urinary kallikrein levels, left-ventricular wall thickness and mean arterial blood pressure of nontreated and captopril-treated diabetic and nondiabetic spontaneously hypertensive rats. The mean arterial blood pressure was significantly elevated in diabetic spontaneously hypertensive rats as compared to nondiabetic spontaneously hypertensive rats. Captopril treatment caused a significant reduction in the arterial blood pressure of both nondiabetic and diabetic spontaneously hypertensive rats. The left-ventricular wall thickness was also significantly reduced in diabetic and nondiabetic spontaneously hypertensive treated with captopril as compared to nontreated diabetic and nondiabetic spontaneously hypertensive rats. The total urinary kallikrein levels were significantly raised in captopril-treated diabetic and nondiabetic spontaneously hypertensive rats against the values obtained from nontreated diabetic and nondiabetic spontaneously hypertensive rats. These results indicate that blood pressure reduction and left ventricular wall regression with captopril treatment might be due to enhanced renal kallikrein formation. The significance of these findings is discussed.
Physiological and pharmacological responses may be influenced by ethnicity as a result of genetic factors, environmental factors and/or their interaction. This review is divided into 2 parts. Firstly, there will be overview of ethnicity as a determinant of drug metabolism and response with reference to antihypertensive agents. The concept of ethnicity has been applied extensively to the study of hypertension especially in American blacks in whom the hypertension is more common and more aggressive. Thus, the second part of this review will then focus on examining the black-white differences in physiological responses to pharmacological challenge that may provide a link between these models and known ethnic differences in drug responses. We will discuss the hypertension studies that have examined the relative effectiveness of different classes of antihypertensive agents including several recent cardiovascular outcome trials that either have a high proportion of blacks or were conducted entirely in black subjects.
Stroke is one of the leading causes of death worldwide, and spontaneous bleeding into the brain parenchyma, intracerebral haemorrhage (ICH), is a stroke subtype associated with high morbidity and mortality. Overall, it comprises about 15% of all stroke in Caucasians, this figure being much higher in Asians and black people. Blood pressure (BP) appears to play an important role in this disease. We have reviewed available literature on the relationship of BP to the occurrence of primary and secondary ICH, the association of BP levels measured early after stroke with prognosis and complications, and evidence about the effects of early BP lowering treatments on post-stroke outcomes. BP appears to be an important risk factor for primary and secondary ICH. In addition, high BP early after ICH may be detrimental to outcome, possibly contributing to complications such as rebleeding and haematoma enlargement. Few data are available about the effects of early lowering of BP on outcome after ICH with no reliable trial yet conducted. Proper randomised trials are required to establish the effect of early lowering of BP on outcome after ICH.
Previous studies have demonstrated the anti-hypertensive effects of Hibiscus sabdariffa L. (HS) in both humans and experimental animals. To explore the mechanisms of the anti-hypertensive effect of the HS, we examined the effects of a crude methanolic extract of the calyces of HS (HSE) on vascular reactivity in isolated aortas from spontaneously hypertensive rats. HSE relaxed, concentration-dependently, KCl (high K(+), 80 mM)- and phenylephrine (PE, 1 microM)-pre-contracted aortic rings, with a greater potency against the alpha(1)-adrenergic receptor agonist. The relaxant effect of HSE was partly dependent on the presence of a functional endothelium as the action was significantly reduced in endothelium-denuded aortic rings. Pretreatment with atropine (1 microM), L-NAME (10 microM) or methylene blue (10 microM), but not indomethacin (10 microM), significantly blocked the relaxant effects of HSE. Endothelium-dependent and -independent relaxations induced by acetylcholine and sodium nitroprusside, respectively, were significantly enhanced in aortic rings pretreated with HSE when compared to those observed in control aortic rings. The present results demonstrated that HSE has a vasodilator effect in the isolated aortic rings of hypertensive rats. These effects are probably mediated through the endothelium-derived nitric oxide-cGMP-relaxant pathway and inhibition of calcium (Ca(2+))-influx into vascular smooth muscle cells. The present data further supports previous in vivo findings and the traditional use of HS as an anti-hypertensive agent.
Angiotensin 1-7, a heptapeptide derived from metabolism of either angiotensin I or angiotensin II, is a biologically active peptide of the renin-angiotensin system. The present study investigated the effect of angiotensin 1-7 on the vasopressor action of angiotensin II in the renal and mesenteric vasculature of Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and streptozotocin-induced diabetic rats. Angiotensin II-induced dose-dependent vasoconstrictions in the renal vasculature. The pressor response was enhanced in the SHR and reduced in the streptozotocin-diabetic rat compared to WKY rats. Angiotensin 1-7 attenuated the angiotensin II pressor responses in the renal vasculature of WKY and SHR rats. However, the ability to reduce angiotensin II response was diminished in diabetic-induced rat kidneys. The effect of angiotensin 1-7 was not inhibited by 1-[(4-(Dimethylamino)-3-methylphenyl] methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate (PD123319), an angiotensin AT(2) receptor antagonist. (D-ALA(7))-Angiotensin I/II (1-7) (D-ALA) (an angiotensin 1-7 receptor antagonist), indomethacin (a cyclo-oxygenase inhibitor), and N(omega)-Nitro-L-Arginine Methyl Ester (L-NAME)(a nitric oxide synthetase inhibitor) abolished the attenuation by angiotensin 1-7 in both WKY rats and SHR, indicating that its action is mediated by angiotensin 1-7 receptor that is either coupled to the release of prostaglandins and/or nitric oxide. The vasopressor responses to angiotensin II in mesenteric vasculature bed was also dose-dependent but smaller in magnitude compared to the renal vasculature. The responses to angiotensin II were relatively smaller in SHR but no significant difference was observed between WKY and streptozotocin-induced diabetic rats. Angiotensin 1-7 attenuated the angiotensin II pressor responses in WKY, SHR and diabetic-induced mesenteric bed. The attenuation was observed at the lower concentrations of angiotensin II in WKY and diabetic-induced rats but at higher concentrations in SHR. Similar observation as in the renal vasculature was seen with PD123319, D-ALA, and L-NAME. Indomethacin reversed the attenuation by angiotensin 1-7 only in the SHR mesenteric vascular bed. The present findings support the regulatory role of angiotensin 1-7 in the renal and mesenteric vasculature, which is differentially altered in hypertension and diabetes.
To investigate the hypotensive and angiotensin-converting enzyme (ACE) inhibitory activities of a partially purified fraction (FA-I) of the leaves of Gynura procumbens and to qualitatively analyse the putative compounds present in the fraction.
This study examined the sympathoinhibitory effects of clonidine and a novel clonidine analog, AL-12, in rat models of genetic hypertension and a combined state of genetic hypertension and diabetes. Rats in the treatment groups were given either clonidine or AL-12 while the respective control groups received either saline or Tween 80 for 6 days. Physiological data were collected during this period, which was followed by acute studies on day 7 when bolus administrations (i.v.) of graded doses of noradrenaline, phenylephrine and methoxamine were carried out. It was observed that in AL-12-treated nondiabetic spontaneously hypertensive rats (SHR), the pressure responses to all adrenergic agonists were greater (p < 0.05) in the treated group, while in the diabetic SHR rats a larger pressure response was observed only to noradrenaline (p < 0.05). In nondiabetic SHR rats treated with clonidine, a greater (p < 0.05) pressure response was observed only in the case of phenylephrine. In the diabetic SHR rats treated with clonidine, the pressure responses to the adrenergic agonists were similar (p > 0.05) in the treated and its control animals except that methoxamine caused a greater (p < 0.05) pressure response in the control group. The data obtained suggest that clonidine and AL-12 act possibly via vascular alpha1 and alpha2 adrenoceptors present at both pre- and postsynaptic locations.
This study set out to investigate the impact of chronic cumulative blockade of angiotensin II and adrenoceptors in WKY and SHR and to explore how the renovascular responses to adrenergic and angiotensin II receptor agonists may be interdependent. Rats were treated with either losartan, carvedilol or losartan+carvedilol for 7 days and on day eight, animals were pentobarbitone anaesthetized and prepared for renal haemodynamic study. Dose-response relationships were determined in terms of reduction/elevation in the magnitude of renal blood flow in response to intrarenal arterial injection of dopamine, phenylephrine and isoprenaline. Renal vascular responses were blunted in WKY and SHR treated with either losartan or carvedilol as compared to their untreated counterparts (P<0.05). In the combined treated rats, the vascular responses to isoprenaline and phenylephrine were restored to levels observed in the untreated rats, but the renal vasoconstrictor responses to dopamine decreased (P<0.05) in both WKY and SHR. There was a reduction of (P<0.05) in the magnitude of the isoprenaline induced renal vasodilation in all SHR as compared to WKY groups. The data obtained showed that the renal vascular action of dopamine, phenylephrine and isoprenaline depended on an intact renin-angiotensin system (RAS) in WKY and SHR. Treatment with losartan or carvedilol blunted the renal vasoconstrictor/vasodilator responses to sympathomimetics which was attenuated with the combined treatment. These observations using chronic blockade of adrenergic and angiotensin receptors demonstrated that there was a long standing interdependency between the RAS and sympathetic nervous system (SNS) in determining the responsiveness of the renal vasculature of normal and hypertensive rats.
In the present study, L. ferrugineus methanol extract (LFME) was evaluated for its blood pressure lowering effect in anesthetized normotensive Sprague Dawley (SD) rats and its spasmogenic effect in isolated guinea pig ileum. The possible mechanism(s) of action were also investigated. LFME was obtained by Soxhlet extraction. The rats were fasted overnight and anesthetized with sodium pentobarbitone (60 mg/kg i.p.). LFME was administered in i.v. boluses in the concentrations of 25, 50, 100 and 200 mg/kg respectively, with concomitant monitoring of mean arterial pressure (MAP). It was found that LFME dose-dependently reduced MAP. An i.v. bolus injection of atropine significantly decreased the blood pressure lowering effect of LFME. Similarly, L-NAME (Nomega-nitro-L-arginine methyl ester) significantly lowered both the MAP and the action duration. Conversely, no significant change in MAP was seen following i.v. injections of neostigmine, hexamethonium, prazosin and propranolol. LFME also produced a dose-dependent contractile effect in guinea pig ileum. This contraction was significantly reduced in atropine pre-incubated tissue segments, yet it was significantly enhanced in the presence of neostigmine. No appreciable change in the ability of LFME to contract guinea pig ileum was seen in the presence of hexamethonium. Accordingly, it can be postulated that LFME possesses a marked hypotensive effect that can be attributed to stimulation of muscarinic receptors and/or stimulation of nitric oxide (NO) release. Moreover, LFME retains a considerable spasmogenic action due to its cholinergic properties. The hypotensive and spasmogenic effects of LFME justify its traditional uses.
Lactobacillus sp. FTDC 2113, L. acidophilus FTDC 8033, L. acidophilus ATCC 4356, L. casei ATCC 393, Bifidobacterium FTDC 8943 and B. longum FTDC 8643 were incorporated into soymilk supplemented with fructooligosaccharides (FOS), inulin, mannitol, maltodextrin and pectin. The objective of the present study was to evaluate the effects of prebiotics on the bioactivity of probiotic-fermented soymilk. Proteolytic activity was increased in the presence of FOS, while the supplementation of inulin and pectin increased the angiotensin I-converting enzyme inhibitory activity accompanied by lower IC(50) values. The beta-glucosidase activity was also enhanced in the presence of pectin. This led to higher bioconversion of glucosides to aglycones by probiotics, especially genistin and malonyl genistin to genistein. Results from this study indicated that the supplementation of prebiotics enhanced the in-vitro antihypertensive effect and production of bioactive aglycones in probiotic-fermented soymilk. Therefore, this soymilk could potentially be used as a dietary therapy to reduce the risks of hypertension and hormone-dependent diseases such as breast cancer, prostate cancer and osteoporosis.
To investigate the antihypertensive activity of aqueous extracts obtained from Malaysian coastal seaweeds and to determine the pharmacological mechanisms of the extracts on rat aorta in vitro.
Glaucoma, a leading cause of irreversible blindness, is often associated with increased resistance to aqueous outflow in trabecular tissue. Increased outflow resistance has been attributed to increased extracellular matrix (ECM) deposition in trabecular tissue. A critical balance between the synthesis and breakdown of the components of extracellular tissue is important in keeping the intraocular pressure within the normal range. Multiple mechanisms have been shown to affect ECM turnover in trabecular tissue. In this review, we examine the related literature to understand the role of TGF-beta in ECM turnover, in the development and progression of glaucoma, and in possible therapeutic strategies that can be devised by targeting the TGF-beta signaling pathways.
The leaves extract of Apocynum venetum (AVLE), also known as "luobuma", have long been used in traditional Chinese medicine to treat hypertension and depression in parts of China and it has been shown to possess anti-oxidant and anti-lipid peroxidation effects. AVLE (10 μg/ml) has been reported to have a long-lasting endothelium-dependent relaxant effect and this effect has been proposed to be due to its nitric oxide(NO)-releasing and superoxide anion(SOA)-scavenging properties.
Gentiana floribunda was investigated for the possible hypotensive and vasodilator activities in an attempt to rationalize its traditional use in hypertension.
Hypertension is a widespread and frequently progressive ailment that imparts a foremost threat for cardiovascular and renal disorders. Mammoth efforts are needed for the synthesis of innovative antihypertensive agents to combat this lethal disease. Chalcones have shown antihypertensive activity through inhibition of Angiotensin Converting Enzyme (ACE). Hence, a series of chalcone analogues is synthesized and used as precursor for the synthesis of novel series of pyrimidines. Precursor chalcones were prepared by reacting aldehydes and ketones in presence of sodium hydroxide followed by synthesis of corresponding pyrimidines by reaction with urea in presence of potassium hydroxide. Both groups were then evaluated for their effects on ACE. The results depicted that pyrimidines were more active than chalcones with methoxy (C5 and P5) substitution showing best results to inhibit ACE. Given that chalcone analogues and pyrimidines show a potential as the angiotensin converting enzyme inhibitors.