Development of GPIIb/IIIa antagonists as antithrombotic drugs.

Thrombosis represents a major target for development of drugs to prevent and treat a variety of cardiovascular and cerebrovascular diseases, which are the leading cause of morbidity and mortality in the Western world. This review by Andy Nichols and colleagues focuses on a central process in thrombosis, namely platelet aggregation, and how it can be inhibited by antagonists of the adhesion molecule GPIIb/IIIa. Successful and future therapeutic applications of GPIIb/IIIa antagonists, and their pharmacology, are considered in detail.

Alpha-adrenoceptors.

Major advances have been made in our understanding of the molecular structure and function of the alpha-adrenoceptors. Many new subtypes of the alpha-adrenoceptor have been identified recently through biochemical and pharmacological techniques and several of these receptors have been cloned and expressed in a variety of vector systems. Currently, at least seven subtypes of the alpha-adrenoceptor have been identified and the molecular structure and biochemical functions of these subtypes are beginning to be understood. The alpha-adrenoceptors belong to the super family of receptors that are coupled to guanine nucleotide regulatory proteins (G-proteins). A variety of G-proteins are involved in the coupling of the various alpha-adrenoceptor subtypes to intracellular second messenger systems, which ultimately produce the end-organ response. The mechanisms by which the alpha-adrenoceptor subtypes recognize different G-proteins, as well as the molecular interactions between receptors and G-proteins, are the topics of current research. Furthermore, the physiological and pathophysiological role that alpha-adrenoceptors play in homeostasis and in a variety of disease states is also being elucidated. These major advances made in alpha-adrenoceptor classification, molecular structure, physiologic function, second messenger systems and therapeutic relevance are the subject of this review.

Apoptosis: a potential target for discovering novel therapies for cardiovascular diseases.

The realization that apoptosis is genetically programmed raises the exciting prospect that modulating apoptosis may provide novel approaches for treatment of cardiovascular diseases in which apoptosis has been demonstrated. Low molecular weight inhibitors of caspases and mitogen-activated protein kinases have been evaluated, with promising results in a variety of cardiovascular apoptotic models.

Apoptosis and congestive heart failure.

Congestive heart failure (CHF) is the final clinical manifestation of a variety of cardiac (myopathies), coronary (atherosclerosis), and systemic diseases (diabetes, hypertension). Regardless of the origin of the cardiac insult, left ventricular dysfunction resulting in decreased cardiac output elicits a series of adaptational processes that attempt to compensate for some of the decrement in myocardial function. One of the key manifestations of these compensatory processes is cardiac hypertrophy, which is characterized by a marked increase in myocyte size and an increase in contractile proteins. The benefits resulting from these compensatory adaptational mechanisms, however, are only transient, and within a period of months to years, the changes induced in the myocardium fail to sustain cardiac output at a level that is sufficient to meet the demands of the body; subsequently, physical performance is impaired. Typically, progressive dilation and thinning of the left ventricle occur along with progression of CHF. The mechanisms responsible for the thinning of ventricular tissue and loss of left ventricular mass are poorly understood; traditionally, such loss has been attributed to tissue necrosis based on the morphologic observation of dead cardiac myocytes. Very recently, there have been data suggesting that apoptosis, a form of programmed cell death (PCD), occurs in the heart and may be responsible, at least in part, for the progression of CHF and the chronic loss of left ventricular function and mass. Evidence for a role of apoptosis/PCD in the progression of heart failure has been obtained from a variety of observations, including in vitro studies of cardiac myocytes in culture, experimental animal models of cardiac injury, and cardiac tissue obtained from patients with CHF. Thus, apoptosis/PCD may be a critical mechanism involved in the progressive loss of cardiac myocytes, which ultimately results in end-stage heart failure. In this brief review, the evidence for apoptosis/PCD in cardiac myocytes is presented and its potential role in the progression of CHF is analyzed. In particular, the genomic basis for apoptosis in cardiac myocytes is explored, and its relevance to the identification of novel targets for future pharmacological interventions is discussed. (Trends Cardiovasc Med 1997;7:249-255). © 1997, Elsevier Science Inc.

Cardioprotective effects of carvedilol, a novel beta adrenoceptor antagonist with vasodilating properties, in anaesthetised minipigs: comparison with propranolol.

OBJECTIVE: The aim was to evaluate in a minipig model of acute myocardial infarction the cardioprotection provided by the beta adrenoceptor blocking and vasodilating activities present in carvedilol; comparison was made to the pure beta adrenoceptor antagonist, propranolol. METHODS: Experiments were performed in 25 Yucatan minipigs (9-12 kg), randomly assigned to receive vehicle (n = 7), carvedilol 0.3 mg.kg-1 (n = 6), carvedilol 1 mg.kg-1 (n = 6), or propranolol 1 mg.kg-1 (n = 6). Myocardial infarction was produced by occlusion of the left anterior descending coronary artery for 45 min followed by 4 h of reperfusion. Vehicle, carvedilol (0.3 and 1 mg.kg-1) or propranolol (1 mg.kg-1) were given intravenously 15 min before the coronary artery occlusion. At the end of the reperfusion period, infarct size was determined using Evans blue dye and triphenyltetrazolium chloride staining. Infarct volumes were visualised using computer assisted three dimensional image analysis of the stained myocardial tissue sections. Myeloperoxidase activity was measured in tissue samples removed from normal, infarcted, and at risk areas. RESULTS: Carvedilol (1 mg.kg-1) reduced infarct size by over 90% without producing pronounced changes in systemic haemodynamic variables. The ability of carvedilol to reduce infarct size was clearly dose dependent. Thus infarct size, which represented 27.5(SEM 2.3)% of the area at risk in the vehicle treated group, was only 13.1(4.0)% (p < 0.05) and 2.4(1.5)% (p < 0.01) in pigs treated with carvedilol at 0.3 and 1 mg.kg-1, respectively. In animals treated with propranolol (1 mg.kg-1), infarct size represented 10.9(2.4)% of the area at risk (p < 0.05). The 60% and 91% reductions in infarct size produced by propranolol (1 mg.kg-1) and carvedilol (1 mg.kg-1), respectively, were clearly evident upon three dimensional image analysis. The reduction in infarct size was significantly greater for carvedilol (1 mg.kg-1) compared to propranolol (1 mg.kg-1) at equivalent beta adrenoceptor blocking doses. Pretreatment with propranolol did not reduce the increases in myeloperoxidase activity observed in the area at risk or in the infarcted area. In contrast, carvedilol produced a dose dependent reduction in myeloperoxidase activity in these areas. CONCLUSIONS: Carvedilol limits myocardial necrosis resulting from coronary artery occlusion and reperfusion in a more pronounced manner than the pure beta adrenoceptor antagonist, propranolol. The cardioprotective effect of carvedilol, which reduced infarct size by 91%, may result from the combined effects of beta adrenoceptor blockade and vasodilatation, and possibly also from inhibition of intracellular calcium overload in cardiac cells resulting from antagonism of myocardial alpha 1 adrenoceptors and/or calcium channel blockade. The cardioprotection provided by carvedilol may ultimately be of benefit in hypertensive patients who are at risk for acute myocardial infarction.

Effects of eprosartan on renal function and cardiac hypertrophy in rats with experimental heart failure.

Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac function in congestive heart failure. The present study evaluated the effects of eprosartan, a selective angiotensin II receptor antagonist, on renal hemodynamic and excretory parameters and on the development of cardiac hypertrophy in rats with aortocaval fistula, an experimental model of congestive heart failure. Infusion of eprosartan (1.0 mg/kg) in rats with aortocaval fistula produced a significant increase (+34%) in total renal blood flow and a sustained decrease (-33%) in the calculated renal vascular resistance. These effects on renal hemodynamics were more pronounced than those observed in sham-operated control rats and occurred despite a significant fall (-12%) in mean arterial blood pressure. Moreover, eprosartan caused a preferential increase in renal cortical blood perfusion and significantly increased glomerular filtration in rats with congestive heart failure. Chronic administration of eprosartan (5.0 mg/kg per day for 7 days through osmotic minipumps inserted intraperitoneally on the day of operation) resulted in a significant enhancement of urinary sodium excretion compared with nontreated rats with heart failure. Moreover, administration of eprosartan to salt-retaining rats with congestive heart failure resulted in a progressive increase and ultimate recovery in urinary sodium excretion. Finally, early treatment with eprosartan blocked the development of cardiac hypertrophy in rats with aortocaval fistula to a larger extent than the angiotensin-converting enzyme inhibitor enalapril. These findings emphasize the importance of angiotensin II in mediating the impairment in renal function and induction of cardiac hypertrophy in heart failure and further suggest that angiotensin II receptor blockade may be a useful treatment of these consequences in severe cardiac failure.

Carvedilol, a new antihypertensive agent, prevents lipid peroxidation and oxidative injury to endothelial cells.

The protective effects of carvedilol, a new beta-adrenergic receptor blocker and vasodilating antihypertensive agent, against oxygen free radical-mediated injury were studied in cultured bovine endothelial cells and compared with five other beta-blockers. Carvedilol dose-dependently inhibited oxygen radical-induced lipid peroxidation (50% inhibition at 2.6 mumol/L) and glutathione depletion (50% inhibition at 1.8 mumol/L) in the cells. Under the same conditions, other beta-blockers--propranolol, labetalol, pindolol, atenolol, and celiprolol--had only mild or no effect. Moreover, carvedilol protected against oxygen radical--mediated cell damage, as assessed by cellular lactate dehydrogenase release, with a 50% inhibition at 4.1 mumol/L and increased the cell survival in a dose-dependent manner, whereas other beta-blockers had mild or no effects. Pretreatment of the cells with carvedilol for 7 days significantly enhanced the protective effects of carvedilol. Using 2-methyl-2-nitrosopropane as a trapping agent, the spin adduct in cell lipids was monitored by electron paramagnetic resonance. Carvedilol dose-dependently decreased the intensity of the free radical signals, indicating its free radical-scavenging ability. The prevention of oxidative injury to endothelial cells might potentially contribute to the clinical beneficial effects of carvedilol as an antihypertensive agent.

Carvedilol, a new antihypertensive, prevents oxidation of human low density lipoprotein by macrophages and copper.

Growing evidence indicates that oxidized low-density lipoprotein (LDL) may promote atherogenesis. Therefore, inhibition of LDL oxidation may impede this process. Carvedilol is a vasodilating, beta-adrenoceptor blocking agent. As a new antihypertensive drug, carvedilol is unique by virtue of its potent antioxidant activity. Therefore, we tested the ability of carvedilol to inhibit the oxidation of LDL by either macrophages or Cu2+. Carvedilol inhibited LDL oxidation by macrophages in a dose-dependent manner, with an IC50 value of 3.8 microM, as assessed by a thiobarbituric acid reactive substance (TBARS) assay. Under the same conditions, propranolol showed only a mild inhibitory effect (IC50 > 100 microM), while pindolol, atenolol and labetalol had almost no effect. Carvedilol, at 10 microM, almost completely inhibited the macrophage-induced increase in electrophoretic mobility of LDL, while other beta-blockers at 50-300 microM had no significant effect. Carvedilol inhibited superoxide release from mouse macrophages, which correlated well with its inhibition of LDL oxidation. Carvedilol also inhibited Cu(2+)-induced LDL oxidation with an IC50 value of 17 microM, while all other beta-blockers were inactive up to 300 microM. These observations suggest that carvedilol might not only be an effective antihypertensive drug, but might also be effective in prevention of atherosclerosis.

Importance of receptor regulation in the pathophysiology and therapy of congestive heart failure.

The available data indicate that the beta-adrenergic receptors that mediate positive inotropic responses undergo "down-regulation," a cellularly mediated decrease in surface receptor number, in congestive heart failure. This decrease in beta-adrenergic receptor number is proportional to the degree of myocardial dysfunction and the loss of contractility that occurs in congestive heart failure. It appears to be chamber-specific, occurring to the greatest degree in the most severely affected ventricular chamber, and is specific to the beta 1-adrenergic receptor subtype. Beta-adrenergic receptor down-regulation may be the result of the excessively high levels of plasma catecholamines seen in congestive heart failure, inasmuch as a similar phenomenon of beta-adrenergic receptor down-regulation is seen in animals treated with high doses of catecholamines. The specific down-regulation in cardiac beta receptors may be, in part, the cause of the decrease in myocardial function observed during long-term beta-adrenergic receptor stimulation, and an actual decrease in beta-adrenergic receptor number has been observed in myocardial tissue from patients with congestive heart failure. Down-regulation of beta receptors in congestive heart failure results in a decrease or loss of efficacy of beta-adrenergic receptor agonists on long-term administration. This is especially evident for partial agonists, which are more dependent on receptor number for their positive inotropic effects than full agonists. Although beta receptors are down-regulated in congestive heart failure, myocardial alpha 1-adrenergic receptors and histamine H2 receptors do not appear to be subject to this same regulatory process. Inasmuch as stimulation of both of these receptors results in a positive inotropic effect, further study should be given to the potential therapeutic utility of selective stimulation of myocardial alpha 1-adrenergic receptors and histamine H2 receptors in congestive heart failure. It is evident that the status of specific receptor subtypes in pathophysiologic states such as congestive heart failure must be considered when assessing the likelihood of success in treating patients with beta-adrenergic receptor agonists.

Stereochemical studies of adrenergic drugs. Optically active derivatives of imidazolines.

The synthesis of (R)-(+)-4-methyl-2-(1-naphthylmethyl)imidazoline hydrochloride (2) and (S)-(-)-4-methyl-2-(1-naphthylmethyl)imidazoline hydrochloride (3) is presented. The synthesis involves the preparation of (R)-(+)- and (S)-(-)-1,2-diaminopropane dihydrochloride and then allowing the appropriate diaminopropane to react with ethyl 1-naphthyliminoacetate hydrochloride in the presence of triethylamine. The parent compound, naphazoline, is a potent alpha-adrenoreceptor agonist (-log ED50 = 7.22), whereas the methylated derivatives, 2 and 3, were moderately potent antagonists (pA2 = 5.6 and 5.8, respectively) of the alpha-adrenoreceptor. Compounds 2 and 3 also produced blockade of the response to histamine on the rabbit aorta, but at concentrations approximately 20 times higher than necessary to produce equal blockade of the alpha-adrenoreceptor.

The 3,4-catechol derivative of propranolol, a minor dihydroxylated metabolite.

The O,O-dibenzyl ether of the 3,4-catechol derivative of propranolol (11) was prepared to determine whether the catechol is a product of metabolic hydroxylation. 4-(Allyloxy)-1,2-naphthoquinone (5) was reduced with sodium dithionite and alkylated with benzyl chloride to produce ether 7. Osmium tetroxide oxidation of 7 afforded glycol 8. Subsequent monotosylation, oxirane formation with KOH, and opening with isopropylamine afforded benzyl ether 11. Although hydrogenolysis was successful, catechol 3 was rapidly oxidized to the corresponding o-quinone (12). Reduction of 12 with sodium bisulfite afforded 3, which was derivatized with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) to serve as a standard for the metabolic experiments. Gas chromatography-mass spectrometry of the Me3Si ethers of the products of metabolism of pseudoracemic propranolol (made up of equal molar (2R)-propranolol-d0/(2S)-propranolol-3',3'-d2) in the presence of the rat liver 9000g supernatant fraction showed four dihydroxylated metabolites, of which catechol 3 was in smallest amount, approximately 9% of the sum of dihydroxylated metabolites. Each of the four dihydroxylated propranolols arises stereoselectively from the 2R enantiomer of propranolol (by 1.15- to 2-fold), as determined by parent ion intensities at m/z 507 vs. 509. Quinone 12 was a nonselective competitive beta-adrenoceptor antagonist, being about 16-fold less potent than propranolol in both beta 1 and beta 2 assays.

N-substituted imidazolines and ethylenediamines and their action on alpha- and beta-adrenergic receptors.

A series of N-substituted imidazolines and ethylenediamines were synthesized and examined for their activity in alpha- and beta-adrenergic systems. The length of the intermediate side chain between the catechol and imidazoline ring or the amine of the ethylenediamine segment was shown to affect the adrenergic activity. N-[2-(3,4-Dihydroxyphenyl)ethyl]imidazoline hydrochloride (2) and N-[2-(3,4-dihydroxyphenyl)ethyl]ethylenediamine dihydrochloride (4), both with two methylene groups between the catechol and amine segment, were found to be somewhat selective for alpha 2-adrenergic receptors while 1-(3,4-dihydroxybenzyl)imidazoline hydrochloride (1) and N-2-(3,4-dihydroxybenzyl)ethylenediamine dihydrochloride (3), both with one methylene group between the catechol and amine segment, were more selective for alpha1-adrenergic receptors in a pithed rat model. Of the four compounds examined, only compound 2 showed significant direct activity on beta1- and beta2-adrenergic receptors.

Protective effects of carvedilol in the myocardium.

Beta blockers have long been used in the treatment of systemic hypertension, where they effectively lower blood pressure and, in so doing, they decrease left ventricular hypertrophy. The sympathetic nervous system is activated in patients with congestive heart failure, and therefore it is logical that beta blockers may also provide benefit in these patients. As such, beta blockers are currently being evaluated in several large clinical trials in congestive heart failure. One particular drug, carvedilol, is a third-generation vasodilating beta blocker that is marketed for the treatment of hypertension. The drug lowers systemic arterial blood pressure without producing reflex tachycardia and preserves renal function. Carvedilol decreases mortality by 65% and decreases hospitalization by 29% in patients with congestive heart failure. The effects of carvedilol in heart failure may result, at least in part, from beta blockade as well as vasodilation, the latter resulting from alpha(1)-adrenoceptor blockade. Interestingly, carvedilol has a number of additional properties that may also provide benefit in these patients. Carvedilol and several of its metabolites are potent antioxidants that may inhibit catecholamine toxicity resulting from the oxidation of norepinephrine and the subsequent formation of toxic intermediates, including the generation of reactive oxygen free radicals in the myocardium. As a result of its antioxidant activity, carvedilol also blocks the expression of several genes involved in myocardial damage and cardiac remodeling, and the drug inhibits free radical-induced activation of transcription factors and programmed cell death (apoptosis). Carvedilol is a novel beta blocker that is highly effective in the treatment of hypertension and congestive heart failure, and combines in one molecule a number of important pharmacologic properties.

Receptor interactions of imidazolines: alpha-adrenoceptors of rat and rabbit aortae differentiated by relative potencies, affinities and efficacies of imidazoline agonists.

1 Noradrenaline and a series of imidazolines were used to characterized and differentiate the postsynaptic alpha-adrenoceptors of rat and rabbit aortae. 2 Dose-response curves in each tissue revealed marked differences in the profile of agonist activity among the compounds. Based on the ED50 values for each compound, a rank order of potency of oxymetazoline greater than noradrenaline greater than tramazoline greater than tetrahydrozoline greater than clonidine was obtained in rabbit aorta and an order of noradrenaline greater than clonidine greater than tramazoline greater than oxymetazoline was obtained in rat aorta. Tetrahydrozoline had no agonist activity in rat aorta. 3 Dissociation constants were determined for each agonist in rat and rabbit aortae. Again, differences between the tissues were observed to the extent that the rank order of affinities for the imidazolines were exactly opposite for the two tissues. In rabbit aorta the order was, oxymetazoline greater than tramazoline greater than tetrahydrozoline greater than clonidine, whereas in rat aorta it was, clonidine greater than tetrahydrozoline greater then tramazoline greater than oxymetazoline. The extremes in tissue selectivity were observed with clonidine, which had approximately 125 fold higher affinity in rat aorta, and oxymetazoline, which had approximately 4 times higher affinity in rabbit aorta. 4 The absolute values of relative efficacies of the imidazolines studied, and their rank order, also differed between the two tissues. The relative efficacies of oxymetazoline and tramazoline were more than 15 fold greater in rabbit aorta than in rat aorta. Furthermore, tetrahydrozoline had a greater relative efficacy than clonidine in rabbit aorta while the converse was true in rat aorta. 5 Differences in the rank order of potency, affinity and relative efficacy of noradrenaline and a series of imidazolines in rat and rabbit aortae indicate that the postsynaptic alpha-adrenoceptors in these tissues are different. While the postsynaptic alpha-adrenoceptor of rabbit aorta is clearly of the alpha 1-subtype, the exact nature of the postsynaptic alpha-receptor of rat aorta is not clear. The unique alpha-receptor of rat aorta has properties of both alpha 1- and alpha 2-adrenoceptors.

Comparison between carvedilol and captopril in rats with partial ablation-induced chronic renal failure.

1. The effect of the novel beta-adrenoceptor antagonist and vasodilator, carvedilol (SK&F 105517, approximately 70 mg kg-1 daily in the food), and captopril (approximately 38 mg kg-1 daily in the drinking fluid) on the progression of chronic renal failure in rats was studied. 2. Six weeks following partial renal ablation, the urinary protein excretion of the carvediol- (60 +/- 21 mg day-1) and captopril-treated (35 +/- 9 mg day-1) animals was less than 50% that of control rats (133 +/- 27 mg d-1). 3. Serum creatinine (Scr) and urea nitrogen (SUN) concentrations of the carvedilol-(Scr, 0.63 +/- 0.09 mg dl-1; SUN, 11.3 +/- 1.2 mg dl-1) and captopril-treated (Scr, 0.82 +/- 0.05 mg dl-1; SUN, 14.1 +/- 1.5 mg dl-1) animals were also significantly (P < 0.05) lower than that observed in control animals (Scr, 1.4 +/- 0.3 mg dl-1; SUN, 19.2 +/- 3.9 mg dl-1), indicating that glomerular filtration rate was improved by both drugs. Plasma renin activity was significantly (P < 0.05) higher in captopril-treated rats (24.7 +/- 4.6 ng angiotensin I ml-1 h-1) than in either carvedilol-treated (7.9 +/- 1.4 ng angiotensin I ml-1 h-1) or control animals (7.4 +/- 1.0 ng angiotensin I ml-1 h-1). 4. Histological examination of the kidneys demonstrated a significantly reduced glomerular hypertrophy and glomerulosclerosis in those animals receiving carvedilol or captopril compared to controls. 5. Serum carvedilol concentration measured every 6 h for 24 h was variable and ranged on average from 57 +/- 13 ng ml-1 at 16 h 00 min to 121 +/- 31 ng ml-1 at 03 h 00 min. These data indicate that the rats probably had 24 h systemic exposure to carvedilol.6. The present study indicates that carvedilol is effective in attenuating the progression of chronic renal failure in rats.

Cardiovascular actions of a new selective postjunctional alpha-adrenoceptor antagonist, SK&F 104856, in normotensive and hypertensive dogs.

1. SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4- methylthieno[4,3,2ef][3]benzazepine) is a novel postjunctional alpha 1- and alpha 2-adrenoceptor antagonist. 2. SK&F 104856 as well as prazosin and SK&F 86466 reduced blood pressure in the anaesthetized normotensive dog. 3. SK&F 86466 and rauwolscine but not SK&F 104856 or prazosin, produced a marked increase in myocardial contractility which corresponds with their ability to block prejunctional alpha 2-adrenoceptors. 4. Intravenous or oral administration of SK&F 104856 resulted in dose-dependent antihypertensive responses in 1-kidney, 1-clip (1-K, 1-C) Goldblatt hypertensive dogs with baseline blood pressure of approximately 140 mmHg. At 0.1 and 1 mg kg-1, i.v., mean arterial blood pressure fell by 11 +/- 5 and 23 +/- 5 mmHg, respectively. At 3 and 10 mg kg-1, p.o., blood pressure fell by 9 +/- 3 and 22 +/- 5 mmHg, respectively. At 10 mg kg-1, p.o., the antihypertensive effect of SK&F 104856 was still evident at 4 h. 5. The data indicate that SK&F 104856 shows selectivity in vivo for postjunctional versus prejunctional alpha-adrenoceptors and is a potent and long-acting antihypertensive agent in 1-K, 1-C Goldblatt hypertensive dogs.

Effects of a hydroxylated metabolite of the beta-andrenoreceptor antagonist, carvedilol, on post-ischaemic splachnic tissue injury.

1 Reactive oxygen species have been demonstrated to play a critical role in post-ischaemic tissue injury. The present experiment was designed to evaluate the effects of SB 211475, a hydroxylated metabolite of the new beta-adrenoceptor antagonist, carvedilol, on rat splanchnic ischaemia (SI, 60 min) and reperfusion(R)-induced shock and tissue injury. 2 Administration of SB 211475 two min before R attenuated SI/R injury in a dose-dependent manner. At doses of 0.5 mg kg(-1) and 1.0 mg kg(-1), SB 211475 exerted significant anti-shock and endothelial protective effects, characterized by prolonged survival times, increased survival rates, attenuated increases in tissue myeloperoxidase activity and haematocrits, and preserved endothelium-dependent vasorelaxation. 3 Administration of 1 mg kg(-1) carvedilol attenuated shock-induced tissue injury and endothelial dysfunction. However, administration of 0.5 mg kg(-1) carvedilol had no protective effects on post-ischaemic tissue injury. 4 Previous studies have shown that SB 211475 has virtually no beta-blocking activity but possesses more potent antioxidant activity than carvedilol. In the present study, SB 211475 exerted more potent protective effects than the parent compound, suggesting that this metabolite of carvedilol is superior to carvedilol with regard to its protection against post-ischaemia tissue injury.

Recent observations with beta-adrenoceptor blockade. Beneficial effects in hypertension and heart failure.

Carvedilol is a third-generation vasodilating beta-blocker initially approved for the treatment of hypertension. It lowers systemic arterial blood pressure without causing reflex tachycardia and preserves renal function. More recently, carvedilol has been shown to reduce morbidity and mortality in patients with congestive heart failure. This reduction may occur in part via beta-blockade and alpha 1-adrenoceptor blockade, the latter resulting in vasodilation. Importantly, carvedilol and several of its metabolites are potent antioxidants that may inhibit the oxidation of norepinephrine and the subsequent formation of toxic intermediates, such as reactive free radicals in the myocardium. As a result, carvedilol inhibits the expression of certain genes involved in myocardial damage, such as intracellular adhesion molecule-1, free-radical-induced activation of transcription factors, and programmed cell death or apoptosis. In this respect, carvedilol represents a new therapy for the treatment of hypertension and congestive heart failure and combines, in one molecule, a number of potentially beneficial properties.

The pharmacology of fenoldopam.

Fenoldopam is a selective dopamine1 (DA1) receptor agonist. Most of the DA1 receptor agonist activity of fenoldopam resides in the R-enantiomer, which also shows weaker alpha 2-adrenoceptor antagonist activity Fenoldopam produces vasodilation in vascular beds that are rich in vascular DA1 receptors, eg, renal and mesenteric receptors, and produces an increase in renal blood flow at doses that do not affect blood pressure. At higher doses, fenoldopam lowers blood pressure but still maintains renal perfusion. In addition to its renal vasodilator activity, fenoldopam is natriuretic, possibly resulting from a direct effect of DA1 receptors on the proximal convoluted tubule. In animals with spontaneous or drug-induced renal failure, fenoldopam improves renal function.

Possible structural and functional relationships between imidazoline receptors and alpha 2-adrenoceptors.

Although it is now well established that imidazoline receptors and alpha 2-adrenoceptors are discrete entities with distinct endogenous ligands, the two receptor classes apparently have several common features. While the catecholamines stimulate alpha 2-adrenoceptors but not imidazoline receptors, agmatine, a guanidine analog that may be an endogenous imidazoline receptor ligand, can interact with both I1 and I2 imidazoline receptors as well as alpha 2-adrenoceptors, although, interestingly, other guanidines such as guanabenz are highly selective for alpha 2-adrenoceptors versus I1 receptors. Most I1 receptor agonists such as moxonidine, rilmenidine, and clonidine can also stimulate alpha 2-adrenoceptors, and the same physiological response is produced by activation of central I1 receptors and alpha 2-adrenoceptors, but their anatomical locations differ. The imidazoline idazoxan is an antagonist at I1, I2, and alpha 2-receptors, but minor structural alterations of idazoxan can result in molecules with selectivity for either alpha 2-adrenoceptors or imidazoline receptors. The precise mode of interaction of imidazoline agonists and antagonists with the alpha 2-adrenoceptor is not yet understood, and structures of the imidazoline receptors are still unknown. Nevertheless, the fact that many agents can stimulate or block both receptor classes, combined with the fact that alpha 2-adrenoceptors and I1 receptors can mediate identical physiological responses, suggests that many common structural features may be present.