Additional effects of endothelin receptor blockade and angiotensin converting enzyme inhibition in rats with chronic heart failure.

AIM: To evaluate the acute effects of tezosentan, a new dual parenteral endothelin receptor antagonist, on hemodynamics in a rat model of chronic heart failure (CHF), and further investigated if the combination of tezosentan with the angiotensin converting enzyme (ACE) inhibitor, enalapril, had additive hemodynamic effect. METHODS: Hemodynamics was measured in rats with CHF, induced by ligation of the left coronary artery. RESULTS: At 3 to 5 weeks after myocardial infarction, rats developed CHF. This was evidenced by a marked increase in left ventricular end-diastolic pressure (LVEDP) with mean values of 23 to 26 mmHg, by a 30 % to 40 % reduction in left ventricular dp/dt(max) and by a more than 10 % decrease in mean arterial pressure (MAP) as compared to sham-operated rats. In CHF rats, acute intravenous administration of either tezosentan (10 mg . kg) or enalapril (1 mg . kg) markedly decreased MAP and LVEDP, without affecting heart rate or dp/dtmax. Tezosentan had additive effects on MAP and LVEDP when given with enalapril compared with tezosentan (P < 0.05) or enalapril (P < 0.05) alone. There were no significant changes in heart rate and dp/dtmax with the combination treatment compared with tezosentan- or enalapril-treated CHF rats. CONCLUSION: Acute intravenous tezosentan improves cardiac hemodynamics and decreases LVEDP and afterload (MAP) without changes in heart rate and cardiac contractility dp/dtmax) in CHF rats. These favorable effects of tezosentan are similar to those of enalapril. Furthermore, the benefits of tezosentan are apparent in addition to ACE inhibition. Thus, tezosentan could be a useful therapeutic agent in the acute treatment of heart failure.

Endothelin mediates the altered renal hemodynamics associated with experimental congestive heart failure.

Congestive heart failure (CHF) is commonly associated with renal dysfunction. The goal of the current study was to evaluate the role of endothelin in the renal dysfunction of experimental CHF by using tezosentan, a potent dual endothelin receptor antagonist. Rats were subjected to coronary artery ligation. Cardiac and renal hemodynamics were assessed after 3-5 weeks, when CHF had developed. Compared with control rats, CHF rats had significantly higher left ventricular end-diastolic pressure (LVEDP), lower mean arterial pressure, and reduced dP/dt(max). CHF rats had severe renal vasoconstriction, as assessed by increased renal vascular resistance (RVR, p < 0.001), decreased renal plasma flow (RPF, p < 0.001), and glomerular filtration rate (GFR, p < 0.001). Filtration fraction rose (p < 0.001). Urine flow rate and sodium excretion were markedly lower. Acute administration of tezosentan induced a marked decrease in LVEDP without change of dP/dt(max) and heart rate. Tezosentan decreased RVR (-43%, p < 0.001) and increased RPF and GFR. Filtration fraction decreased slightly. Tezosentan also increased urine flow rate and sodium excretion. These findings demonstrate that endothelin at least partly mediates the altered renal hemodynamics associated with experimental CHF. Dual endothelin receptor blockade could be useful for the improvement of both cardiac and renal function in CHF.

Piperidine renin inhibitors: from leads to drug candidates.

Non-peptidomimetic renin inhibitors of the piperidine type represent a novel structural class of compounds potentially free of the drawbacks seen with peptidomimetic compounds so far. Synthetic optimization in two structural series focusing on improvement of potency, as well as on physicochemical properties and metabolic stability, has led to the identification of two candidate compounds 14 and 23. Both display potent and long-lasting blood pressure lowering effects in conscious sodium-depleted marmoset monkeys and double transgenic rats harboring both the human angiotensinogen and the human renin genes. In addition, 14 normalizes albuminuria and kidney tissue damage in these rats when given over a period of 4 weeks. These data suggest that treatment of chronic renal failure patients with a renin inhibitor might result in a significant improvement of the disease status.

A new model of chronic cardiac ischemia in rabbits.

Chronic cardiac ischemia has mainly been studied in large species such as pigs or dogs. Little research has been performed using small species such as rabbits. In the present study, 1-3 wk after implantation of a novel device (ameroid) on the circumflex coronary artery of New Zealand White rabbits, vessel patency was evaluated by coronary angiography, corrosion cast, and radiolabeled microspheres. Coronary angiograms showed, after 21 days, either total occlusion or severe stenosis in seven of eight arteries, which was confirmed by corrosion casts. The ameroid group had less blood flow in the epicardial (-62%) and endocardial (-54%) layers of the ischemic area compared with sham-operated rabbits (P < 0.05). Blood flow increased in the ischemic area compared with day 0 during acute occlusion, suggesting that progressive coronary occlusion initiated the growth of de novo collateral vessels. Thus we have developed a new model of chronic cardiac ischemia in rabbits with documented progressive coronary stenosis and occlusion that is suitable to test various therapeutic angiogenesis strategies.

Nonlinear kinetics and pharmacologic response to mibefradil.

BACKGROUND: Increasing oral doses of mibefradil (10 to 320 mg) decrease its apparent oral clearance; however, intravenous doses up to 80 mg do not reduce its systemic clearance. This study aimed to understand the mechanisms underlying the zero-order kinetics of mibefradil. METHODS: A group of 10 normotensive volunteers received 50 mg/day oral mibefradil for 8 days and, on days 1 and 8, 5 mg deuterated mibefradil by infusion. Ten additional volunteers observed the same protocol with a daily oral dose of 100 mg mibefradil. Serial blood samples were withdrawn, and mibefradil plasma concentrations were assayed by liquid chromatography-mass spectrometry. Blood pressure and heart rate were measured for 4 hours, and an ECG was performed 2 hours after drug administration. RESULTS: Repeated oral administration of 50 mg mibefradil generated zero-order kinetics secondary to a decrease in mibefradil systemic clearance. Compared with the 50-mg dose, single and repeated oral doses of 100 mg further decreased mibefradil clearance. Mibefradil bioavailability was not affected by increasing mibefradil doses. Mean diastolic blood pressure was decreased by single and repeated doses of 100 mg to the same extent. Repeated doses of 100 mg reduced heart rate and prolonged the PR and QTc, changes that were associated with mibefradil plasma concentrations. CONCLUSIONS: Repeated doses of 50 mg or doses of 100 mg mibefradil generated zero-order kinetics secondary to a decrease in hepatic extraction of the drug. Zero-order kinetics did not affect the response-concentration relationship of mibefradil.

Combination of non-hypotensive doses of valsartan and enalapril improves survival of spontaneously hypertensive rats with endothelial dysfunction.

There is increasing evidence to suggest endothelial dysfunction as a critical factor in vascular diseases. Genetically predisposed spontaneously hypertensive rats (SHR) treated with inhibitors of nitric oxide (NO) synthase, develop a severe hypertensive nephrosclerosis without the necessity for surgical reduction in renal mass, nephrectomy, renal infarction or nephrotoxic drugs. In these animals, endothelial dysfunction is considered a valid model for assessment of the efficacy of cardiovascular therapy. SHR were treated with either the angiotensin-converting enzyme inhibitor enalapril or the angiotensin II (Ang II) AT(1)-receptor antagonist (AIIA) valsartan at sub-hypotensive doses and the effects on survival rates, cardiac and renal changes were monitored. Rats treated with valsartan, alone or in combination with enalapril, showed markedly higher survival rates (67-85%, respectively) than untreated animals (37%) or those treated with enalapril alone (55%). Valsartan at a dose which attenuated blood pressure increase led to even greater survival rates (95%). Despite these improved survival rates, at non-hypotensive doses the drugs had no effect on histological appearance, nor was kidney function improved. Plasma creatinine levels were reduced by valsartan, alone or in combination with enalapril, but proteinuria persisted with all treatments over the 12 weeks of the study. Aldosterone levels were significantly reduced by all treatments. The results suggest a beneficial role for endothelium in hypertension. Reduced renal perfusion pressure probably underlies the beneficial renal effects of high-dose valsartan.

Renal vascular and biochemical responses to systemic renin inhibition in dogs at low renal perfusion pressure.

Renin is produced by the kidney and secreted into the systemic circulation. However, its biochemical and physiological role of regulating renal blood flow with changing renal perfusion pressure (RPP) is not fully understood. In this study, the function of the intrarenal renin for production of angiotensin (Ang) I and maintenance of vascular tone was evaluated in dogs under normal conditions and when the kidney was perfused at low RPP. The dog left kidney was perfused first at normal (100 mm Hg) and then at low (30 mm Hg) RPP in the presence or absence of the renin inhibitor ciprokiren (3 mg/kg, i.v.). Both hemodynamic and biochemical parameters were measured. Lowering RPP markedly reduced left renal blood flow and elevated left renal vascular resistance. These effects were prevented by ciprokiren, which blocked the intrarenal production of Ang I. Lowering RPP increased the renal venous/ arterial ratio from 1.4+/-0.1 to 3.6+/-0.3 for plasma renin activity and from 2.4+/-0.2 to 9.8+/-1.1 for Ang I, but did not change the venous/arterial ratio for Ang II. The net renal venous conversion rate of Ang I to Ang II decreased from 0.22 to 0.09 after RPP was lowered, whereas the conversion rate in arterial blood was 1.35 and did not decrease significantly. Our results demonstrated the importance of intrarenal renin-angiotensin system for Ang I production and for the maintenance of the vascular tone, especially at low RPP. Our study also shows the limited capacity for Ang I conversion in the renal vasculature in vivo.

Voltage-gated T-type Ca2+ channels and heart failure.

In the cardiovascular system, two types of voltage-gated Ca2+ channels are present: the L-type and the T-type. Under normal conditions, T-type Ca2+ channels are involved in the maintenance of vascular tone and cardiac automaticity but, since they are not present in contractile myocardial cells, they do not contribute significantly to myocardial contraction. In experimental models of cardiac hypertrophy, myocardial T-type Ca2+ channels are upregulated, which could contribute to the increased incidence of ventricular arrhythmia. In addition, T-type Ca2+ channels participate in the regulation of cell proliferation and neurohormonal secretion; through these pathways, T-type Ca2+ channels might participate in myocardial remodeling. The pathophysiological role of T-type Ca2+ channels in heart failure has been investigated using mibefradil, a Ca2+ antagonist that is 10-50 times more potent at blocking T-type than L-type Ca2+ channels. In contrast with classic L-type Ca2+ channel antagonists, miberfradil appears beneficial in many animal models of heart failure; in particular, it does not exert negative inotropic effects nor does it stimulate the neurohormonal system. Furthermore, in the Pfeffer rat model, blockade of T-type Ca2+ channels with mibefradil is associated with an improved survival rate. In humans, however, major metabolic drug interactions independent of T-type Ca2+ channel blockade made it impossible to determine the efficacy of mibefradil in treating heart failure; indeed, these interactions led to the withdrawal of the drug from the market.

Contrasting effects of selective T- and L-type calcium channel blockade on glomerular damage in DOCA hypertensive rats.

Mibefradil and amlodipine are calcium antagonists with different channel selectivities. Mibefradil blocks both L- and T-type calcium channels; although in the usual pharmacological doses, it predominantly blocks the T-type channels. In contrast, amlodipine selectively blocks L-type channels. The goal of the present study was to assess whether this differential selectivity would result in different effects on end-organ damage in experimental hypertension. For this purpose, deoxycorticosterone acetate (DOCA)-salt hypertensive rats were treated either with equipotent doses of mibefradil or amlodipine (30 mg. kg(-1). d(-1) as food admix). Despite the fact that both drugs decreased systolic arterial pressure to the same extent (140+/-5 mm Hg in the mibefradil group and 144+/-3 mm Hg in the amlodipine group versus 225+/-5 mm Hg in the untreated-DOCA group), only mibefradil decreased proteinuria (35. 5+/-6.5 versus 103.3+/-14.1 mg/24 h in untreated DOCA-salt animals) and prevented glomerular lesions. Both drugs, however, prevented the occurrence of vascular renal lesions. To elucidate the mechanism responsible for this difference, we evaluated in an additional series of experiments the effects of mibefradil and amlodipine on plasma and renal renin concentrations, as well as the effects of the addition of enalapril, an ACE inhibitor, given on top of both drugs on proteinuria. Amlodipine, in contrast to mibefradil, markedly stimulated the plasma (17.8+/-2.6 ng Ang I. mL(-1). h(-1) in the amlodipine group versus 3.9+/-0.4 ng Ang I. mL(-1). h(-1) in the mibefradil group and 3.2+/-0.3 ng Ang I. mL(-1). h(-1) in the untreated-DOCA group) and renal (2.42+/-0.37 ng Ang I. mL(-1). h(-1) in the amlodipine group versus 0.36+/-0.04 ng Ang I. mL(-1). h(-1) in the mibefradil group and 0.26+/-0.08 ng Ang I. mL(-1). h(-1) in the untreated-DOCA group) renin concentrations. Stimulation of the renin-angiotensin system could explain the absence of a renal protective effect of amlodipine. This was also suggested by the fact that enalapril given in addition to amlodipine could decrease proteinuria. In conclusion, T-type channel blockade by mibefradil decreases blood pressure without stimulation of the renin-angiotensin system and therefore prevents most of the glomerular damage in DOCA hypertensive rats.

Protective effects of endothelin receptor antagonists in dogs with aortic cross-clamping.

Endothelin (ET) may play an important role in the pathogenesis of vasoconstriction and acute renal failure after aortic cross-clamping (ACC). However, the relative contribution of the ET(A) and ET(B) receptors to the physiopathology of ischemic acute renal failure is poorly understood. This study was carried out to evaluate the potential protective effect of a selective ET(A) antagonist versus combined ET(A)/ET(B) antagonist on altered systemic, pulmonary, and renal hemodynamics induced by cross-clamping the suprarenal aorta for 1 h, followed by 2-h reperfusion. Studies were performed in three groups of anesthetized mongrel dogs. After baseline measurements, treatment (3 mg/kg i.v. bolus + 3 mg/kg/h infusion) with either a selective ET(A) antagonist, Ro 61-1790 (n = 5), or a combined ET(A)/ET(B) antagonist, bosentan (n = 5) or vehicle (n = 8) was initiated 5 min before ACC. There were marked increases in total peripheral (TPR), pulmonary (PVR), and renal (RVR) vascular resistances, and significant decreases in cardiac output (CO) and glomerular filtration rate (GFR) and tubular sodium reabsorption after ACC in the vehicle group. Both Ro 61-1790 and bosentan prevented the marked increases in TPR, PRV, and RVR, and attenuated the declines in CO, GFR, and tubular sodium reabsorption. We concluded that the profound systemic, pulmonary, and renal vasoconstriction, as well as the impairments in glomerular and tubular functions associated with ACC, is mostly ET mediated and that the ET(A) receptor activation makes a major contribution to the ET-mediated impairments of hemodynamics and renal function after ACC.

Pharmacology of tezosentan, new endothelin receptor antagonist designed for parenteral use.

Tezosentan (Ro 61-0612) [5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-+ ++pyri din-4-yl)-pyrimidin-4-ylamide] is a new endothelin (ET) receptor antagonist specifically designed for parenteral use. Tezosentan competitively antagonizes the specific binding of (125)I-labeled ET-1 and of the selective ET(B) receptor ligands (125)I-labeled ET-3 and (125)I-labeled sarafotoxin S6c on cells and tissues carrying ET(A) and ET(B) receptors, with inhibitory constants in the nanomolar range, and has high water solubility. Tezosentan exhibits high functional inhibitory potency for inhibiting contraction induced by ET-1 on isolated rat aorta (ET(A) receptors; pA(2) = 9.5) and by sarafotoxin S6c on rat trachea (ET(B) receptors; pA(2) = 7.7). In vivo, tezosentan inhibits the pressor effect of big ET-1 in pithed rats and increases ET-1 plasma concentrations in conscious rats in a dose-dependent fashion. In spontaneously hypertensive rats, i.v. injection of tezosentan has acute hemodynamic effects and decreases blood pressure. Tezosentan is also able to prevent the acute renal failure that complicates rhabdomyolysis in a rat model of myoglobinuric nephropathy. Finally, tezosentan exhibits an apparent elimination half-life of less than 1 h in rabbits and primates and of 2 h in rats. In conclusion, tezosentan, a potent mixed ET receptor antagonist with a short half-life, may offer a novel medical approach for the i.v. treatment of acute pathological conditions.

Effects of nonpeptide endothelin receptor antagonists in rats with reduced renal mass.

This study was set up to evaluate the long-term effects of nonpeptide endothelin (ET) antagonists in rats with renal mass reduction (RMR). In the first series of experiments, rats were administered bosentan (100 mg/kg/day) or the angiotensin-converting enzyme inhibitor cilazapril (10 mg/kg/day) for 14 weeks beginning 24 h after RMR. As expected, cilazapril completely prevented the development of hypertension, proteinuria, and renal structural damage. In contrast, bosentan had no influence on the development of proteinuria and renal structural damage, although it had a moderate antihypertensive effect and improved creatinine clearance. A second set of experiments was performed to assess whether Ro 48-5695, a very potent ET antagonist optimized from bosentan, could prevent the development of renal damage and reverse established renal damage. Rats received Ro 48-5695 (30 mg/kg/day) beginning either 24 h (prevention) before for 8 weeks, or 4 weeks (reversal) after RMR. Ro 48-5695 attenuated the hypertension and the decline of creatinine clearance when treatment was started at 24 h, but not when started at 4 weeks. Ro 48-5695 had no effect on proteinuria. These observations suggest that ET-receptor activation does not play a major role in the progression of glomerular sclerosis in this model of chronic renal failure.

Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases?

BACKGROUND: The aspartic proteinase renin catalyses the first and rate-limiting step in the conversion of angiotensinogen to the hormone angiotensin II, and therefore plays an important physiological role in the regulation of blood pressure. Numerous potent peptidomimetic inhibitors of this important drug target have been developed, but none of these compounds have progressed past clinical phase II trials. Limited oral bioavailability or excessive production costs have prevented these inhibitors from becoming new antihypertensive drugs. We were interested in developing new nonpeptidomimetic renin inhibitors. RESULTS: High-throughput screening of the Roche compound library identified a simple 3, 4-disubstituted piperidine lead compound. We determined the crystal structures of recombinant human renin complexed with two representatives of this new class. Binding of these substituted piperidine derivatives is accompanied by major induced-fit adaptations around the enzyme's active site. CONCLUSIONS: The efficient optimisation of the piperidine inhibitors was facilitated by structural analysis of the renin active site in two renin-inhibitor complexes (some of the piperidine derivatives have picomolar affinities for renin). These structural changes provide the basis for a novel paradigm for inhibition of monomeric aspartic proteinases.

Angiotensin I-converting enzyme inhibition but not angiotensin II suppression alters angiotensin I-converting enzyme gene expression in vessels and epithelia.

The concentration of angiotensin-converting enzyme (ACE) increases during chronic treatment with ACE inhibitors for unknown reasons. We investigated whether alterations in ACE mRNA and ACE concentration occur in the different tissues during ACE inhibition and the role of angiotensins in these regulations by comparing ACE inhibitors with other blockers of the renin-angiotensin system. Enalapril, an ACE inhibitor, in the range of 0.3 to 10 mg/kg/day in rats induced dose- and time-dependant increases in plasma ACE up to two to three times control values. There were significant increases in the steady state ACE mRNA in the lung (32%), duodenum (64%) and aorta (324%) and 40% to 140% increases in membrane-bound enzyme concentration in these tissues and in the heart and kidney. The ACE content of purified duodenal brush border was increased by 80%, but the enzyme and its mRNA in the testis were not altered. The angiotensin II receptor antagonist losartan at several regimens of up to 30 mg/kg twice a day for 14 days produced no change in plasma ACE level or lung ACE mRNA. The human renin inhibitor ciprokiren was tested in guinea pigs, a species sensitive to this compound. Both enalapril and cilazapril induced 2-fold increases in plasma ACE, but ciprokiren (24 mg/kg/day for 12 days) had no effect. Enalapril treatment of BN/Kat rats (lacking circulating kininogens) caused a similar increase in ACE as in other rats. This study documents a general increase in ACE gene expression and enzyme concentration in tissues during ACE inhibition, with the exception of the testis, most probably reflecting an activation of the 5', so-called somatic promoter of the ACE gene. Angiotensins are not involved in this regulation and do not seem to control ACE gene expression in normal rodents.

Local angiotensin II generation in the rat heart: role of renin uptake.

To elucidate the local effects of renin in the coronary circulation, we examined local angiotensin (Ang) I and II formation, as well as coronary vasoconstriction in response to renin administration, and compared the effects with exogenous infused Ang I. We perfused isolated hearts from rats overexpressing the human angiotensinogen gene in a Langendorff preparation and measured the hemodynamic effects and the released products. We also investigated cardiac Ang I conversion, including the contribution of non-angiotensin-converting enzyme-dependent Ang II-generating pathways. Finally, we studied Ang I conversion in vitro in heart homogenates. Renin and Ang I infusion both generated Ang II. Ang II release and vasoconstriction continued after renin infusion was stopped, even though renin disappeared immediately from the perfusate. In contrast, after Ang I infusion, Ang II release and coronary flow returned to basal levels. Ang I conversion (Ang II/Ang I ratio) was higher after renin infusion (0.109+/-0.027 versus 0.026+/-0.003, 15 minutes, P<.02) compared with infused Ang I. Remikiren added to the renin infusion abolished Ang I and II; captopril suppressed only Ang II, whereas an AT1 receptor blocker did not affect Ang I and II formation. All the drugs prevented renin-induced coronary flow changes. Total cardiac Ang II-forming activity was only partially inhibited by cilazaprilat (4.1+/-0.1 fmol x min(-1) x mg[-1]) and on a larger extent by chymostatin (2.6+/-0.3 fmol x min(-1) x mg[-1]) compared with control values (5.6+/-0.4 fmol x min(-1) x mg[-1]). We conclude that renin can be taken up by cardiac or coronary vascular tissue and induces long-lasting local Ang II generation and vasoconstriction. Locally formed Ang I was converted more effectively than infused Ang I. Furthermore, the comparison of in vivo and in vitro Ang I conversion suggests that in vitro assays may underestimate the functional contribution of angiotensin-converting enzyme to intracardiac Ang II formation.

Additional hypotensive effect of endothelin-1 receptor antagonism in hypertensive dogs under angiotensin-converting enzyme inhibition.

BACKGROUND: Endothelin-1 (ET-1) may play a role in hypertension. ET-1 receptor antagonism by bosentan lowers blood pressure in hypertension. We evaluated whether the effect of bosentan is still observed under ACE inhibitors (ACEI). METHODS AND RESULTS: Thirty anesthetized and 18 conscious hypertensive dogs were studied randomly. Anesthetized dogs were divided into 4 groups: group 1 received cumulative doses of bosentan (bolus+30-minute infusion: 0.1 mg/kg+/-0.23 mg/kg per hour to 3 mg/kg+/-7 mg/kg per hour); group 2, the same dose-responses after 1 mg/kg enalaprilat; group 3, the vehicle after enalaprilat; and group 4, the dose responses to bosentan followed by enalaprilat. The conscious dogs were divided into 3 groups: group 5 received 2 cumulative doses of bosentan; group 6, the vehicle; and group 7, enalaprilat alone. In groups 1 and 2, bosentan produced dose-related decreases (P=.0001) in left ventricular systolic pressure and mean aortic pressure (AOP). In group 1, bosentan decreased mean AOP by 22%. In group 2, enalaprilat decreased mean AOP by 25% (from 173+/-26 to 130+/-25 mm Hg; P<.005); an additional 18% decrease was obtained with bosentan, the mean AOP reaching 98+/-21 mm Hg (P<.01). In group 3, the effect of enalaprilat alone was a 22% decrease in mean AOP (P<.005). The additive effect of the bosentan-ACEI association was also observed in group 4. In group 5, bosentan reduced mean AOP by 20% (P<.005), whereas mean AOP remained unchanged in group 6. The effect of ACEI alone (group 7) was similar to that of bosentan. CONCLUSIONS: Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.

Mibefradil (Ro 40-5967): the first selective T-type Ca2+ channel blocker.

Mibefradil is a novel Ca2+ antagonist acting on both L- and T-type Ca2+ channels, with a ten-fold selectivity for T-type Ca2+ channels. It belongs to a chemical class different from other Ca2+ antagonists (tetralol derivative), and binds to a new receptor site on the L-type Ca2+ channel, where it does not affect dihydropyridine (DHP) binding but appears to overlap the verapamil and fantofarone sites. In vitro and in vivo studies indicate that mibefradil has a high selectivity for the coronary vasculature over the peripheral vasculature and the myocardium. It has no relevant negative inotropic effects in various animal models, in normotensive patients, and patients with hypertension or angina pectoris. Instead, treatment with mibefradil slightly decreases heart rate and improves cardiac function. Clinical studies confirm that mibefradil is an effective antihypertensive and anti-ischaemic drug, which may be beneficial in the treatment of heart failure. Its excellent pharmacological and safety profile combined with high bioavailability makes it a promising new drug. Many of the unique pharmacological properties of mibefradil may derive from its selective block of T-type Ca2+ channels.

Cardiovascular alterations in rat fetuses exposed to calcium channel blockers.

Preclinical toxicologic investigation suggested that a new calcium channel blocker, Ro 40-5967, induced cardiovascular alterations in rat fetuses exposed to this agent during organogenesis. The present study was designed to investigate the hypothesis that calcium channel blockers in general induce cardiovascular malformations indicating a pharmacologic class effect. We studied three calcium channel blockers of different structure, nifedipine, diltiazem, and verapamil, along with the new agent. Pregnant rats were administered one of these calcium channel blockers during the period of cardiac morphogenesis and the offspring examined on day 20 of gestation for cardiovascular malformations. A low incidence of cardiovascular malformations was observed after exposure to each of the four calcium channel blockers, but this incidence was statistically significant only for verapamil and nifedipine. All four agents were associated with aortic arch branching variants, although significantly increased only for Ro 40-5967 and verapamil.

Functional and biochemical analysis of angiotensin II-forming pathways in the human heart.

Blockade of the renin-angiotensin system by inhibition of angiotensin-converting enzyme (ACE) is beneficial for the treatment of hypertension and congestive heart failure. However, it is unclear how complete the blockade by ACE inhibitors is and if there is continuing angiotensin II (Ang II) formation during chronic treatment with ACE inhibitors. Indeed chymase, a serine protease, which is able to form angiotensin II from angiotensin I (Ang I) and cannot be blocked by ACE inhibitors, has been shown to be present in human heart. The goal of the present study was to evaluate the extent of renin-angiotensin system blockade and the Ang II-forming pathways in cardiac tissue of patients chronically treated with ACE inhibitors or in patients without ACE inhibition therapy. Our studies indicate an incomplete ACE inhibition in human heart tissue after chronic ACE inhibitor therapy. Moreover, ACE contributes only a small portion to the total Ang I conversion, as shown in biochemical studies in ventricular and coronary homogenates or functionally as Ang I contractions in isolated rings of coronary arteries. A serine protease was responsible for the majority of Ang II production in both the membrane preparation and Ang I-induced contractions of isolated coronary arteries. In humans, the serine protease pathway is likely to play an important role in cardiac Ang II formation. Thus, drugs such as renin inhibitors and Ang II receptor blockers might be able to induce a more complete blockade of the renin-angiotensin system, providing a more efficacious therapy.

Increased survival after long-term treatment with mibefradil, a selective T-channel calcium antagonist, in heart failure.

OBJECTIVES: We sought to investigate the effects of mibefradil on survival, hemodynamic variables and cardiac remodeling in a rat model of chronic heart failure (HF) and to compare these effects with those of the angiotensin-converting enzyme (ACE) inhibitor cilazapril. BACKGROUND: The use of calcium channel blocking agents in chronic HF has been disappointing. Most studies have shown that these drugs have either no or even detrimental effects due in part to the negative inotropic effects they induce. Mibefradil is a calcium channel blocker that selectively blocks T channels and displays moderately negative inotropic properties only at high doses. Because T channels are upregulated in the hypertrophied heart and could mediate hypertrophic signals and increase arrhythmogenicity, blockade of these channels might be beneficial in chronic HF. METHODS: Rats were subjected to coronary artery ligation and 9 months of treatment with mibefradil (15 mg/kg body weight per day) or cilazapril (10 mg/kg per day) or no treatment. Survival and systolic blood pressure were assessed over the 9-month treatment period, after which cardiac hemodynamic variables and structure were determined. RESULTS: Mibefradil increased survival rate to the same extent as cilazapril (71% for mibefradil vs. 75% for cilazapril and 44% for no treatment). Mibefradil decreased systolic blood pressure, although to a lesser extent than cilazapril. Both treatments decreased left ventricular (LV) end-diastolic and central venous pressures, without any change in the first derivative of LV pressure over time or heart rate. Mibefradil decreased LV weight (although less than cilazapril) without affecting right ventricular weight. Finally, both drugs normalized LV collagen density. CONCLUSIONS: Mibefradil in a rat model improved survival to the same extent as an ACE inhibitor, without impairing LV function, and was associated with a reduction in LV weight and fibrosis. Thus, mibefradil might be beneficial in the treatment of chronic HF.