Coronary Vasodilator Effects Research Articles

Viscum album aqueous extract induces NOS-2 and NOS-3 overexpression in Guinea pig hearts

Viscum album L. aqueous extract, on the Langendorff isolated and perfused heart model, decreases coronary vascular resistance, when compared to control group (36.00 ± 2.00 vs. 15.80 ± 1.96 dyn s cm−5). Our data support the fact that this mechanism involves NOS-2 and NOS-3 overexpression (4.65 and 7.89 times over control, respectively), which is correlated with increases in NO (6.24 ± 2.49 vs. 147.95 ± 2.79 pmol) and cGMP production (43.94 ± 2.00 vs. 74.81 ± 1.96 pmol mg−1 of tissue), compared to control values. Such an effect is antagonized by gadolinium(III) chloride, L-NAME and ODQ. Therefore, coronary vasodilator effect elicited by V. album L. aqueous extract is mediated by the NO/sGC pathway.

Nesiritide for treatment of perioperative low cardiac output syndromes in cardiac surgical patients: an initial experience

The physiologic properties of the b-type natriuretic peptide nesiritide include pulmonary, coronary, and renal arterial vasodilation and lusitropic effects on ventricular myocardium. These effects may be useful during cardiac surgery, particularly when myocardial function and cardiac output (CO) are compromised. Intraoperative hemodynamic data were collected retrospectively before and 5-15 min following completion of a nesiritide loading dose in 15 adult cardiac surgical patients with low CO associated with pulmonary hypertension, low left ventricular ejection fraction, diastolic dysfunction, or left ventricular assist device placement. In seven patients, prior alternative pharmacologic interventions had failed to improve CO, and fluid challenges were ineffective in six patients with diastolic dysfunction. Perioperative nesiritide administration (2 microg.kg(-1) load, followed by 0.01 microg.kg(-1).min(-1) for a maximum of 24 h) resulted in a statistically significant median increase in CO of 35% (P = 0.0006). In conclusion, nesiritide was associated with increased CO in patients with low CO syndromes undergoing cardiac surgery, when other measures failed. This novel agent may offer an additional option to inotropes and fluid challenges for these patients perioperatively. Randomized clinical trials are desirable to determine the risks and benefits of nesiritides and to elucidate its role for the cardiac anesthesiologist.

Attenuated cardioprotective response to bradykinin, but not classical ischaemic preconditioning, in DOCA-salt hypertensive left ventricular hypertrophy

Hypertensive left ventricular hypertrophy (LVH) co-exists frequently with ischaemic heart disease. While ischaemic preconditioning (IPC) is known to protect against ischaemia-reperfusion injury in LVH, it is not known if other cardioprotective manoeuvres are effective. Bradykinin, a key autacoid mediator in IPC, is protective in normal hearts but its ability to protect against ischaemia-reperfusion injury in LVH is unknown. Hypertensive LVH was induced in male rats by 4 weeks treatment with deoxycorticosterone acetate (DOCA) and salt drinking fluid. Hearts were Langendorff perfused, subjected to 35 min coronary artery occlusion and 120 min reperfusion, and infarct size (AN/RZ %) was determined by tetrazolium staining. The effects of IPC with 2 × 5 min cycles of global ischaemia or 10 min pretreatment with bradykinin were assessed. DOCA-salt rats were markedly hypertensive and left ventricle/body weight ratio was 26% greater than in normotensive controls. Baseline coronary flow and risk zone/LV ratio were similar in normotensive hearts and DOCA-salt hearts, and infarct size was similar (AN/RZ 50.6 ± 3.2% and 47.0 ± 3.1%, respectively). IPC was equally protective in normotensive and DOCA-salt hearts (AN/RZ 18.6 ± 3.3% and 18.4 ± 2.3%, respectively, P < 0.01 versus corresponding control). Bradykinin 0.1, 0.2 or 0.5 μM pretreatment produced concentration-dependent infarct limitation in normotensive hearts (bradykinin 0.5 μM AN/RZ, 9.5 ± 3.6%, P < 0.01 versus normotensive control), but the effect in DOCA-salt hearts was attenuated (bradykinin 0.5 μM AN/RZ, 23.4 ± 3.8%). Further, the pre-ischaemic coronary vasodilator response to bradykinin was abrogated in DOCA-salt hypertensive hearts. We conclude that the cardioprotective action of bradykinin is markedly attenuated in moderate LVH and coronary vasodilator effect is lost. The reasons for reduced sensitivity to bradykinin in the hypertensive heart are unknown but these findings may have implications for the application of preconditioning-mimetic interventions in LVH.

The dietary flavonoid quercetin activates BKCa currents in coronary arteries via production of H2O2. Role in vasodilatation

Large conductance Ca(2+)-activated K(+) channels (BKCa) regulate coronary artery tone in vivo, play a key role in blood pressure regulation, and have been suggested as novel potential drug targets in hypertension. Quercetin exerts systemic and coronary vasodilator effects in vitro and reduces blood pressure in several rat models of hypertension, and its consumption is associated with a lower mortality rate from coronary heart disease in epidemiological studies. We hypothesized that quercetin might activate BKCa channel in isolated myocytes from rat coronary arteries and that this mechanism might be involved in its coronary artery relaxant effects. Membrane currents were measured using the whole-cell configuration of the patch-clamp technique. Contractile tension was recorded in rat coronary artery rings mounted in a myograph. Quercetin (>0.1 muM) increased the outward currents in the whole range of test potentials, hyperpolarized cell membranes, and increased the frequency of spontaneous transient outward currents (STOCs) carried by BKCa channels. These effects were abolished by the selective BKCa blocker iberiotoxin and by catalase. Quercetin increased dichlorofluorescein fluorescence in coronary arteries in a polyethylenglycol-catalase-sensitive manner, indicating that it increased cytosolic H(2)O(2). The membrane-permeable analogue of H(2)O(2)t-butylhydroperoxide mimicked the effects of quercetin on outward currents. The vasodilator effect of quercetin in isolated rat coronary arteries was partially inhibited by iberiotoxin. Quercetin increased BKCa currents via production of intracellular H(2)O(2). This effect is involved, at least partly, in the coronary vasodilator effects of quercetin.

A Comparison of Three Phosphodiesterase Type III Inhibitors on Mechanical and Metabolic Function in Guinea Pig Isolated Hearts

Little is known about of the comparative cardiac lusitropic and coronary vasoactive effects of type III phosphodiesterase inhibitors independent of their systemic circulatory effects. We hypothesized that phosphodiesterase inhibitors have dissimilar concentration-dependent effects on cardiac function and metabolism and that their coronary vasodilatory effects are solely dependent on flow autoregulation secondary to positive inotropic effects. Our aim was to compare the dose-response electrophysiologic, mechanical, vasodilatory, and metabolic properties of three clinically available phosphodiesterase inhibitors in isolated Langendorff perfused guinea pig hearts. We found that, over a range from 10(-7) to 10(-4) M, amrinone, enoximone, and milrinone each produced maximal concentration-dependent positive chronotropic (12%, 18%, 26%), inotropic (16%, 26%, 26%), and lusitropic (14%, 21%, 19%) effects. At clinical concentrations, all phosphodiesterase inhibitors increased heart rate, but only milrinone significantly enhanced contractility and relaxation (11%). Each phosphodiesterase inhibitor similarly increased contractility at its highest concentration; this was accompanied by an increase in oxygen consumption, which was matched by comparable increases in coronary flow and oxygen delivery. Coronary flow reserve was preserved at the highest concentration of each drug, indicating that an increased metabolic rate was responsible for the increase in coronary flow by each drug at each concentration. Over the concentrations examined, we conclude that each of the phosphodiesterase inhibitors does not directly promote coronary vasodilation and that milrinone has the most prominent effects on contractility and relaxation at clinically relevant concentrations.

Receptors involved in moxonidine-stimulated atrial natriuretic peptide release from isolated normotensive rat hearts

Imidazoline I 1-receptors are present in the heart and may be involved in atrial natriuretic peptide (ANP) release. The following studies investigated whether moxonidine (an antihypertensive imidazoline I 1-receptor and α 2-adrenoceptor agonist) acts directly on the heart to stimulate ANP release, and to characterize the receptor type involved in this action. Perfusion of rat (200–225 g) isolated hearts with moxonidine (10 − 6 and 10 − 5 M), for 30 min, resulted in ANP release (83 ± 29 and 277 ± 70 ng/30 min, above basal, respectively), significantly ( P < 0.01) different from perfusion with buffer (− 6 ± 31 ng/30 min). ANP release stimulated by moxonidine (10 − 6 M) was inhibited by co-perfusion with the antagonists, AGN192403 (imidazoline I 1-receptor), phenoxybenzamine (α 2 > α 1-adrenoceptors), and prazosin (α 1 > α 2-adrenoceptors), but increased by rauwolscine (α 2-adrenoceptors). Perfusion with 10 − 5 M brimonidine (full α 2-adrenoceptor agonist) inhibited moxonidine-stimulated ANP release. Similarly, moxonidine (10 − 6 M) tended to reduce coronary flow, but significantly increased coronary flow in the presence of brimonidine, which was vasoconstrictive when perfused alone. Coronary flow was reduced by 10 − 5 M each, brimonidine > clonidine > moxonidine; while similar bradycardia was observed with clonidine and moxonidine, but not with brimonidine. In conclusion, these results argue in favor of moxonidine acting primarily on imidazoline I 1-receptors to release ANP, with both α 2-adrenoceptor and imidazoline I 1-receptors exerting inhibitory inter-relation. In contrast, the coronary vasodilatory effect of moxonidine requires full activation of α 2-adrenoceptor. The sympatholytic and ANP-releasing effects of moxonidine appear to be mediated by cardiac imidazoline receptors that may be differentially localized. Most importantly, moxonidine can stimulate ANP release from the heart without contribution of the central nervous system.

ACUTE DILATORY AND NEGATIVE INOTROPIC EFFECTS OF HOMOCYSTEINE ARE INHIBITED BY AN ADENOSINE BLOCKER

1. Previous studies have shown that homocysteine elicits acute negative inotropic and coronary vasodilatory effects in rat hearts. In addition, this earlier work suggested that the inotropic action is mediated via an endothelium-derived agent that is neither nitric oxide (NO) nor a cyclooxygenase product, while the coronary actions were found to be antagonized by the NOS inhibitor l-NNA. Current experiments, which utilized coronary-perfused rat hearts, were designed to determine if muscarinic or adenosine receptors are involved in these acute actions of homocysteine. 2. Left ventricular developed pressure was used as a measure of systolic function in electrically paced, Langendorff-perfused heart with coronary pressure being used to monitor coronary vascular tone. Acute effects of homocysteine (10-300 micromol/L) were examined in the presence and absence of 1 yen 10(-6) mol atropine or 7 yen 10(-5) mol 8-(p-sulfophenyl) theophylline (SPT), a non-selective adenosine receptor antagonist. 3. Atropine had no effect on either the inotropic or vascular actions of homocysteine. In contrast, SPT partially antagonized both actions of the amino acid with the antagonism of the vasodilation being much greater than its inhibition of the negative inotropic effect. Experiments with adenosine demonstrated that the selected dose of SPT elicited marked rightward shifts in the dose-response curves for both the inotropic and vascular actions. 4. Current results suggest that adenosine plays a role in both the negative inotropic and vasodilatory actions of homocysteine. However, the relatively minor antagonistic action of SPT on the inotropic effect of homocysteine suggests that additional endothelium-derived mediators underlie its effects on contractility.

ACTION Study: Efficacy of Nifedipine in Preventing Cardiovascular Disease in Patients with Coronary Artery Disease

Recent reports show that nifedipine not only causes vasodilation but also exerts beneficial effects on the endothelium of blood vessels. Some clinical trials evaluated nifedipine GITS (gastrointestinal therapeutic system) in patients with coronary artery disease. The investigators found that the treatment with nifedipine improved acetylcholine reactivity in coronary arteries and inhibited increases in coronary plaque volume. Furthermore, the large randomised, double-blind, placebo-controlled ACTION (A Coronary Disease Trial Investigating Outcome with Nifedipine GITS) study in patients with stable angina pectoris revealed that the treatment with nifedipine GITS led to significant reductions in the onset of overt heart failure and in the need for coronary angiography or coronary artery bypass graft surgery. These data indicate that a direct action on blood vessels, rather than coronary vasodilating or antihypertensive effects, might be responsible for improved prognosis with nifedipine.

Insulina: efeitos cardiovasculares e aplicações terapêuticas

Several studies have suggested a beneficial role of insulin and glucose infusions after myocardial infarction and in critically ill diabetic and non-diabetic patients. However, the insulin-glucose infusions are not routinely given to these patients, since no large randomized control trial was carried out, mechanisms involved in the benefits obtained are poorly understood, infusion protocols are complex and finally, health professionals need to change their cultural premises to apply them in their practice. Insulin has beneficial cardiovascular effects, such as the optimization of substrate use by cardiomyocites, coronary vasodilation, anti-inflammatory action and direct anti-apoptotic effects on myocardial cells. In this context, clinical studies of glucose and insulin infusions after myocardial infarction and cardiovascular surgery are reviewed, as well as possible pathophysiologic mechanisms leading to these benefits, and finally, a practical algorithm is proposed for use in intensive care and cardiovascular postoperative care units.

Acute effects of endothelins on endogenous adrenomedullin system in the rat heart: Immunocytochemical and autoradiographic studies

Many lines of evidence indicate that adrenomedullin (AM) through its coronary vasodilatory and inotropic effects, exerts a major cardiac protective action. Conversely, endothelins (ETs) exert a cardiac detrimental action, which seems to be mainly mediated by the ETA receptor, whose activation promotes coronary constriction and decreases cardiac blood flow. Hence, we have investigated by immunocytochemistry (ICC) and autoradiography the acute effects of ET-1 on endogenous AM system of adult rat heart. Isolated hearts were perfused for 20 min, according to the Langendorff technique, with 2x10(-9) M ET-1[1-21] or ET-1[1-31], which are mixed ETA/ETB and selective ETA receptor agonists, respectively. ICC demonstrated AM-immunoreactivity (IR) in cardiomyocytes, endocardium and especially in the wall of coronary vessels. Quantitative densitometry showed that ET-1[1-31], but not ET1[1-21], significantly decreased AM-IR in coronary vessels, thereby suggesting that ET-1 elicits AM release in the heart through the activation of ETA receptors. Autoradiography demonstrated [125I]AM-binding sites in cardiomyocytes and especially in the wall of coronary venules, and treatment with both ET-1s did not apparently affect them. This location af AM receptors suggests that AM raises cardiac blood flow by evoking coronary artery dilation indirectly, probably via its stimulating effect on NO production, and by decreasing postcapillary resistance via cardiac vein dilation. Collectively, our findings indicate that important functional interrelationships occur between ET and AM systems in the rat heart, where ETs may at least partly hamper their own ETA receptor-mediated decrease in blood flow by increasing the local release of endogenous AM.

The interaction of MCI-154, a calcium sensitizer, and isoflurane on systemic and coronary hemodynamics in chronically instrumented dogs.

We conducted this study to determine the interaction of MCI-154, 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a calcium sensitizer, and isoflurane on myocardial contractility as well as systemic and coronary hemodynamics in chronically instrumented dogs after pharmacological autonomic nervous system activity blockade. MCI-154 increased heart rate and left ventricular function with no change in rate pressure product, pressure work index, and coronary blood flow, with a decrease in coronary vascular resistance (CVR) in the conscious state. Isoflurane decreased heart rate and left ventricular function, with a decrease in rate pressure product and pressure work index. Isoflurane also decreased CVR, but not coronary blood flow. The cardiovascular actions of MCI-154 during isoflurane anesthesia were qualitatively similar to those observed in the conscious state. In contrast to the finding in the conscious state, MCI-154 reversed the decrease in cardiac output and preload recruitable stroke work caused by isoflurane, but these are not significantly different from the effects of isoflurane alone. These results indicate that MCI-154 increases myocardial contractility and decreases CVR without changing calculated myocardial oxygen consumption during both the conscious state and isoflurane anesthesia. MCI-154, a calcium sensitizer, restores the myocardial contractility depressed by isoflurane and enhances the coronary vasodilating effect of isoflurane in chronically instrumented dogs.

The Multiple Combined Oral Platelet Aggregation Inhibitors of Aspirin, Ticlopidine and Cilostazol after PCI

Background and Objectives:Along with intracoronary stenting, medications, such as Ca channel blocker, nitric oxide and some platelet aggregation inhibitors, have contributed to the reduction of coronary restenosis. However, restenosis still remains as a challenging dilemma, with a frequency of 20-50%. Aspirin and ticlopidine are known as a standard anti-platelet regimen following PCI, but cilostazol is a comparably effective drug, which has a different mechanism to that of ticlopidine. It is unknown if the triple combination of aspirin, ticlopidine and cilostazol could further reduce adverse events and restenosis. Subjects and Methods: The clinical and angiographic data, which had been collected after PCIs at Wallace Memorial Baptist Hospital, between Jan. 2000 and Dec. 2001, were retrospectively analyzed. The patients had taken either aspirin+ ticlopidine or aspirin+ticlopidine+cilostazol, and the clinical observation and follow-up angiography was completed for 6 months. There were 111 (66 males) and 87 (male:57) in the aspirin+ticlopidine and aspirin+ ticlopidine+cilostazol groups, respectively. The rates of major adverse cardiovascular events (MACE) and restenosis were compared during the follow-up period. Results:The frequency of MACE was similar, without a significant increase in the side effects during the follow-up period. The restenosis and target lesion revascularization (TLR) rates were significantly decreased in the triple combination therapy group (37.2% vs. 21.9%, p=0.006, 29.8% vs. 14.1%, p=0.008). Conclusion:This study showed that this triple combination of platelet aggregation inhibitors is a good combination therapy for the reduction of restenosis. It is suggested that these effects were probably due to more potent platelet inhibition by the multi-directional mechanism in addition to coronary vasodilation effect. (Korean Circulation J 2004;34(5):443-450)

Coronary vasodilation by noninvasive transcutaneous ultrasound: An in vivo canine study

ObjectivesWe evaluated the coronary vasodilatory effects of transcutaneous low-frequency (27-kHz) ultrasound (USD). BackgroundUltrasound has been shown to affect vascular function. MethodsUltrasound energy was administered transcutaneously to 12 dogs. Coronary arterial dimensions were assessed using intravascular coronary ultrasound (IVUS) and quantitative coronary angiography (QCA). ResultsThe IVUS mid-left anterior descending (LAD) luminal area was 6.77 ± 1.27 mm2at baseline. After 30 s of ultrasound, this area increased by 9% (7.40 ± 1.44 mm2, p < 0.05), after 3 min by 19% (8.05 ± 1.72 mm2, p < 0.05) and after 5 min increased by 21% (8.16 ± 1.29 mm2, p < 0.05). The mean coronary diameter (2.69 ± 0.33 mm) at baseline (QCA of three segments of LAD and three segments of left circumflex coronary artery) increased by 19.3% (3.21 ± 0.28 mm) after 5 min of USD exposure. After a 90-min observation period there was a return to baseline values (p = NS). Intracoronary nitroglycerin (NTG) administered to five dogs revealed a similar magnitude of vasodilation as USD. ConclusionsNoninvasive, transthoracic low-frequency USD energy results in coronary artery vasodilation within seconds of exposure. The vasodilation is reversible and is similar in magnitude to that induced by NTG. Further evaluation is needed to assess its potential applications in humans.

Testosterone and coronary vascular tone: implications in coronary artery disease.

The greater incidence of coronary artery disease in men compared to women has often suggested possible harmful effects of male sex steroids that could promote coronary atherogenesis and vasoconstriction. However, antiatherogenic and coronary vasodilator effects of testosterone have also been suggested. The interaction of testosterone (T) with its specific receptors may trigger not only long-term genomic effects, but also acute non-genomic vasodilator responses. Testosterone may activate the endothelium and stimulate the nitric oxide-cGMP and/or the hyperpolarization-mediated vascular relaxation pathway. T may also inhibit the signaling mechanisms of smooth muscle contraction such as [Ca2+]i and protein kinases. The T-induced stimulation of endothelium-dependent mechanisms of vascular relaxation and inhibition of the mechanisms of coronary smooth muscle contraction represent potential beneficial effects of T against coronary artery disease.

Effects of adenosine receptor agonists on guinea-pig isolated working hearts and the role of endothelium and NO.

The hypothesis that the coronary vasodilator effects of adenosine receptor agonists are independent of the vascular endothelium or mediators derived therefrom was examined in guinea-pig isolated working hearts. Adenosine receptor agonists, 5'-(N-ethylcarboxamido)-adenosine (NECA; two-fold selective for A2 over A1 receptors), 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680; A2A selective), N6-cyclopentyl-adenosine (CPA; A1 selective) and N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA; A3 selective), were infused (3 x 10(-7) M) after endothelium removal by passing oxygen through the coronary circulation. In spontaneously beating hearts, CGS21680 and NECA increased, while CPA decreased, coronary flow. NECA and CPA reduced heart rate, left ventricular pressure and aortic output. The nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine (L-NOARG; 3 x 10(-5) M) abolished the vasodilatation by NECA but not CGS21680, indicating that nitric oxide (NO) of a non-endothelial source mediated the NECA response. Coronary vasodilatation by CGS21680 was inhibited bythe A2A receptor antagonist, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo [2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385). Indometacin (10(-6) M) attenuated the coronary vasodilatation to CGS21680, suggesting a partial role for cyclooxygenase products. IB-MECA had no effect, indicating no A3 receptor involvement. In paced working hearts, the responses were similar except CPA had no effect on coronary flow or aortic output and CGS21680 increased left ventricular pressure and the maximum rate of ventricular pressure rise. This study has demonstrated functionally effective removal of the endothelium by a novel method of passing oxygen through the coronary vasculature. A coronary vasodilator action of adenosine receptor agonists mediated via A2A receptors is endothelium- and NO-independent, but partially involves cyclooxygenase products.

Reduced coronary vasodilator responses to amlodipine in pacing-induced heart failure in conscious dogs: role of nitric oxide.

1. This study examined whether NO is involved in the in-vivo coronary vasodilator effects of amlodipine (a calcium channel blocker) and whether heart failure (HF) alters the coronary responses to amlodipine. 2. Nine conscious dogs were chronically instrumented to measure circumflex coronary blood flow (CBF) and coronary diameter (CD). Drugs were administered directly into the circumflex artery through an indwelling catheter to avoid systemic changes. HF was induced by right ventricular pacing (240 b.p.m., 3 weeks). 3. Compared with control (C), in HF, coronary responses to acetylcholine (1 - 10 ng kg(-1)) were reduced while responses to nitroglycerin (0.1 - 0.5 microg kg(-1)) were unchanged. In C, amlodipine (30 - 150 microg kg(-1)), increased dose-dependently CBF and CD. After LNA (a NO synthase inhibitor, 2 mg kg(-1)), amlodipine produced less increases in CBF and CD (+121+/-26 ml min(-1) and +76+/-35 microm versus +196+/-40 ml min(-1) and +153+/-39 microm respectively for 150 microg kg(-1) amlodipine alone, both P<0.05). In HF, the coronary responses to amlodipine were reduced (150 microg kg(-1) of amlodipine increased CBF and CD +121+/-23 ml min(-1) and +77+/-21 microm respectively, both P<0.05). After LNA, the CBF responses to amlodipine tended to be reduced (+94+/-19 ml min(-1) at 150 microg kg(-1)) but CD responses were significantly reduced (+41+/-16 microm, P<0.05). The supplementation with L-arginine did not enhance the coronary responses to amlodipine. 4. These results indicate that, in conscious dogs, NO participates in the coronary responses to amlodipine and in HF, the coronary responses to amlodipine are reduced, which is related to a reduced NO production.

Cardiovascular Effects of Isorhamnetin and Quercetin in Isolated Rat and Porcine Vascular Smooth Muscle and Isolated Rat Atria

Isorhamnetin and quercetin produced endothelium-independent vasodilator effects in rat aorta, rat mesenteric arteries, rat portal vein and porcine coronary arteries. The effects of the two flavonoids were similar in arteries stimulated by noradrenaline, KCl, U46619 or phorbol esters but the two flavonoids were more potent in the coronary arteries than in the aorta. At high concentrations, they also induced a positive inotropic effect in isolated rat atria. Therefore, at least part of the in vivo effects of quercetin may result from its conversion to isorhamnetin which is the main metabolite of quercetin found in plasma. The arterial, venous and coronary vasodilator effects may contribute to the protective effects of flavonoids in ischaemic heart disease observed in epidemiological studies.

AH-1058: a novel cardioselective Ca2+ channel blocker.

The pharmacologic profile of a cyproheptadine-related compound, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]piperidine hydrochloride (AH-1058), was assessed in various in vivo and in vitro models. In guinea pig cardiomyocytes, AH-1058 effectively suppressed L-type Ca2+ channel currents without affecting other ion channel or ion exchange currents. In rat cerebral cortical membranes AH-1058 appears to bind preferentially to L-type Ca2+ channels at phenylalkylamine- and benzothiazepine-binding sites. In canine isolated, blood-perfused heart preparations, AH-1058 exerted negative inotropic, dromotropic, and chronotropic and weak coronary vasodilator effects. In halothane-anesthetized dogs, AH-1058 suppressed ventricular contractility and decreased blood pressure and cardiac output. Total peripheral vascular resistance was hardly affected by the drug, suggesting that in vivo AH-1058 can selectively suppress cardiac, as compared to peripheral vascular, function. In conscious dogs, by intravenous administration AH-1058 reduced systolic blood pressure and maximal upstroke velocity of the left ventricular pressure, while it increased heart rate in a dose-dependent manner. The drug did not affect diastolic blood pressure, which is quite different from cardiovascular properties of well-known Ca2+ channel blockers, verapamil and diltiazem. This unique cardiovascular profile of AH-1058 is expected to be useful in the treatment of certain pathological processes such as the obstructive hypertrophic cardiomyopathy, vasovagal syncope, dissecting aortic aneurysm, and ventricular arrhythmias, in which selective inhibition of the ventricular Ca2+ channels is essential for drug therapy.

Cardiovascular and diuretic activity of kaurene derivatives of Xylopia aethiopica and Alepidea amatymbica

The extractives, crude and pure, of Alepidea amatymbica (AA) and Xylopia aethiopica (XA) were subjected to bioassay-directed phytochemical examination for potential cardiovascular and diuretic activity. All extractives and derivatives (XA/O, AA/1, xylopic acid, AA/3, AA/4, AA/5, AA/6, XA/1, XA/2, XA/3) displayed low toxicity, with LC 50 0.5–5.0 ng/ml. For the first time, diterpene kaurenoids were reported to have significant systemic hypotensive and coronary vasodilatory effect accompanied with bradycardia. These effects were attributed to calcium antagonistic mechanism. The diuretic and natriuretic effects found were similar to the effects of chlorothiazide, suggesting inhibition of Na + and K + reabsorption in the early portion of the distal tubule. Further experiments are needed to elaborate the exact mechanisms of the hypotensive and diuretic effects of diterpene kaurenoids.

Coronary vasodilation and positive inotropism by urocortin in the isolated rat heart

Corticotropin-releasing factor (CRF) has a coronary vasodilator effect and a positive inotropic effect on the isolated rat heart. Recently, expression of CRF receptor type 2 (CRF-R2) has been demonstrated in the heart. In addition, urocortin (Ucn), a new member of the CRF family, has been reported to have much greater affinity for CRF-R2 than CRF. It is suggested that the cardiac effects of Ucn may be more potent than those of CRF. We compared the effect of Ucn with that of CRF on isolated rat heart. The effects of Ucn were then analyzed to determine whether these effects were mediated by CRF receptors and/or any other mediators under the following conditions: perfusion buffer containing (1) alpha-helical CRF 9-41, (2) indomethacin, (3) N(G)-nitro-l -arginine methylester and (4) propranolol. Ucn exhibited a greater effect with a longer duration of action than CRF. Indomethacin significantly attenuated the vasodilator effects of Ucn (P<0.05). CRF receptor antagonist diminished both coronary vasodilation and the positive inotropic effects of Ucn (P<0.05). These results suggest that the cardiac effects of Ucn may be mediated by a CRF receptor, and prostaglandins may be involved in the vasodilator effect.