Revascularization in the rabbit hindlimb: dissociation between capillary sprouting and arteriogenesis.

OBJECTIVE: Animal models of hindlimb ischemia are critical to our understanding of peripheral vascular disease and allow us to evaluate therapeutic strategies aimed to improve peripheral collateral circulation. To further elucidate the processes involved in revascularization following ischemia, we evaluated the temporal association between tissue ischemia, vascular endothelial cell growth factor (VEGF) release, angiogenesis (capillary sprouting), arteriogenesis (growth of the larger muscular arteries), and reserve blood flow (functional collateral flow). METHODS: New Zealand White rabbits (male 3-4 kg) were evaluated at specific days (0, 5, 10, 20 or 40) following femoral artery removal for measurement of hindlimb blood flow, skeletal muscle lactate production and VEGF content, capillary density (a marker of angiogenesis), and angiographic score (a marker of arteriogenesis). RESULTS: Maximal capillary sprouting occurred within 5 days of femoral artery removal and was temporally associated with reduced resting hindlimb blood flow, increased lactate release and detectable levels of skeletal muscle VEGF. The growth of larger angiographically visible collateral vessels occurred after 10 days and was not temporally associated with ischemia or skeletal muscle VEGF content, but did coincide with a large functional improvement in the reserve blood flow capacity of the limb. CONCLUSIONS: Following femoral artery removal in the rabbit, the time course of angiogenesis and arteriogenesis were clearly distinct. Tissue ischemia and/or VEGF may stimulate capillary sprouting, but this response does not translate to a significant improvement in collateral flow. The growth and development of the larger collateral vessels was correlated with a large functional improvement in collateral flow, and occurred at a time when VEGF levels were undetectable.

Decreased endothelium-dependent relaxation in New Zealand genetic hypertensive rats.

The relaxation response to endothelium-dependent (acetylcholine and the calcium ionophore A23187) and independent (sodium nitroprusside) vasodilators was examined in isolated aortic ring segments from age-matched genetically hypertensive (GH) and normotensive (N) rats (New Zealand strain). Tissues were initially contracted with methoxamine to achieve similar levels of contractile force. The IC20, IC40 and IC50 values for acetylcholine, A23187 and sodium nitroprusside were shifted significantly to the right (P less than 0.05) in aortic rings from GH rats compared to the corresponding values in N rats. The maximal relaxation achieved by acetylcholine and A23187 was significantly depressed in aortas from GH rats (P less than 0.05). Sodium nitroprusside elicited the maximal relaxation in both groups of tissues. These results demonstrate that there exists a generalized defect in the relaxant ability of vascular smooth muscle from GH rats. In addition, our findings suggest that this defect is coupled with a decreased responsiveness to endothelium-dependent vasodilators in this particular animal model of hypertension.

Potent noncovalent thrombin inhibitors that utilize the unique amino acid D-dicyclohexylalanine in the P3 position. Implications on oral bioavailability and antithrombotic efficacy.

In an effort to prepare orally bioavailable analogs of our previously reported thrombin inhibitor 1, we have synthesized a series of compounds that utilize the unique amino acid D-dicyclohexylalanine as a P3 ligand. The resulting compounds are extremely potent and selective thrombin inhibitors, and the N-terminal Boc derivative 8 exhibited excellent oral bioavailability and pharmacokinetics in both rats and dogs. The des-Boc analog 6 was not orally bioavailable in rats. The high level of oral bioavailability observed with 8 appears to be a direct function of its increased lipophilicity versus other close analogs. Although increased lipophilicity may serve to increase the oral absorption of tripeptide thrombin inhibitors, it also appears to have detrimental effects on the antithrombotic properties observed with the compounds. Compound 6 performed extremely well in our in vivo antithrombotic assay, while the much more lipophilic but essentially equipotent analog 8 performed poorly. We have found that in general with this series of thrombin inhibitors as well as with other unreported series, increased lipophilicity and the associated increases in plasma protein binding have detrimental effects on 2X APTT values and subsequent performance in in vivo antithrombotic models.

Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position.

A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b,c,e and 14d) showed nanomolar potency (Ki 0.8-12 nM), 300-1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (F = 40-76%) in rats or dogs. The neutral P1 was expected to increase metabolic stability and oral absorption. Identification of this novel aminopyridyl group at P1 was a key step in our search for a clinical candidate.

Synthesis of a series of potent and orally bioavailable thrombin inhibitors that utilize 3,3-disubstituted propionic acid derivatives in the P3 position.

As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a, b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl3-induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a.

Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position.

As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

Effects of atriopeptins on relaxation and cyclic GMP levels in rat and rabbit aortas.

The effects of atriopeptins I and II on relaxation and cyclic GMP levels were studied on rat and rabbit aortas. Atriopeptin I was 2- and 100-fold less potent than atriopeptin II in causing relaxation of rat and rabbit aortas, respectively. The atriopeptin-elevated cyclic GMP levels generally correlated with the amount of relaxation. These results demonstrate that the vasodilator profile and, presumably, the receptor for atrial natriuretic factor, varies among different blood vessels and species.

Characterization of synthetic atrial natriuretic factor: vasodilator profile and decreased vascular sensitivity in hypertensive rats.

Synthetic atrial natriuretic factor (ANF) relaxed agonist-induced tone in rabbit aortic rings as well as intrinsic, myogenic contractions in the isolated rabbit facial vein (IC50s = 0.1 to 5 nM). Tissues depolarized by high levels of K+ were refractory to ANF. A similar profile was obtained with extracts of rat atria and with sodium nitroprusside (NaNP) but not other vasodilators. Aortas from spontaneously hypertensive rats (SHR) were significantly less sensitive to the relaxant effects of ANF (and NaNP) than were aortas from Wistar-Kyoto (WKY) rats. However, atrial extracts from SHR were more effective than WKY rat atrial extracts in relaxing normotensive aortic rings. Radioimmunoassay analysis confirmed a small increase in ANF immunoreactive material in SHR compared with WKY rat atria. The similar vascular profile for both ANF and NaNP suggests that these agents share a common mechanism of action. A reduced end organ responsiveness in SHR may lead to an increased atrial content of ANF in these animals.

Differential atrial versus ventricular activities of class III potassium channel blockers.

The atrial versus ventricular activities of Class III agents with differing K+ channel blocking profiles were assessed in vitro in ferret atrial and right ventricular papillary muscles. In concentration-effective refractory period (ERP) response studies at 2 Hz and 32 degreesC, the selective IKr blockers dofetilide, E-4031 and d-sotalol, as well as ibutilide, an IKr blocker also reported to enhance inward Na+ current, displayed markedly greater efficacies in increasing atrial ERP (+90-110%) versus ventricular ERP (+10-20%). RP58866, a blocker of IK1 and IKr, and tedisamil, primarily a blocker of Ito and IKr, increased atrial ERP with approximately 10-fold greater potencies than ventricular ERP, but with similar efficacies for both tissues (+60-80% with RP58866; +150-160% with tedisamil). Azimilide, a blocker of IKr and IKs, and indapamide, a blocker of IKs, displayed essentially "balanced" activities, increasing atrial and ventricular ERP with equivalent potencies and efficacies (+40-60% increases for both tissues). Frequency-dependence profiles at 32 degrees C varied between atrial and ventricular tissues, and there was no general correspondence between atrial versus ventricular selectivity and frequency-dependence profiles. In the papillary muscle preparation, increasing temperature from 32 degrees C to 37 degrees C altered both magnitude and frequency dependence of response to K+ channel blockers. These findings support the potential to selectively modulate atrial versus ventricular refractoriness with the targeting of appropriate K+ channel subtypes, and further demonstrate the differential frequency and temperature dependence of varying K+ channel subtype blockade. Ultimately, the identification and targeting of an appropriate K+ channel subtype or mix of subtypes may result in the achievement of optimal atrial-selective activity for the treatment of supraventricular arrhythmias.

Calcium channels resistant to organic calcium entry blockers in a rabbit vein.

We compared the effects of calcium entry blockers on myogenic tone with the effects of these compounds on agonist- and depolarization-induced mechanical responses in isolated rings of the rabbit facial vein. The development of intrinsic tone in response to distension of the vessel wall and its potentiation by increasing the ambient temperature were antagonized by MnCl2 (0.5 mM) but not verapamil, diltiazem, or nifedipine. Similarly, the contractile response to histamine was blocked by MnCl2 but was unaffected by moderate concentrations of the organic calcium entry blockers. The histamine contractile response elicited at 34 degrees C (a condition which abolishes intrinsic tone) was also refractory to verapamil (10(-6) M). Verapamil, diltiazem, and nifedipine antagonized the contractile response to calcium in depolarized facial vein rings. Thus both extrinsic and intrinsic contractile responses in the rabbit facial vein depend on an extracellular source of calcium. The distension-operated channels are unique in exhibiting a marked temperature sensitivity. However, receptor- and distension-operated calcium channels can be distinguished from the voltage-operated channels in their insensitivity to the organic calcium entry blockers.

Comparative effects of increased extracellular potassium and pacing frequency on the class III activities of methanesulfonanilide IKr blockers dofetilide, D-sotalol, E-4031, and MK-499.

The methanesulfonanilide-containing Class III agents dofetilide, D-sotalol, E-4031, and MK-499 have been characterized as selective blockers of a rapidly activating component of the cardiac delayed rectifier (IK) K+ current, IKr. In the present studies, the effects of dofetilide (3-30 nM), D-sotalol (10-100 microM), E-4031 (30-300 nM), and MK-499 (30-300 nM) on myocardial effective refractory period (ERP) were assessed in ferret right ventricular papillary muscles in conditions of altered extracellular K+ concentration ([K+]e[normal (4 mM) versus increased (10 mM)] concentrations, and of altered pacing frequency (1-3 Hz). With 4 mM [K+]e, all four agents elicited significant, concentration-dependent ERP increases in the frequency range of 1-3 Hz, and all four agents displayed reverse frequency-dependent activity. Reverse frequency-dependent profiles also were demonstrable in 10 mM [K+]e at the higher test agent concentrations; dofetilide (10 and 30 nM), D-sotalol (100 microM), E-4031 (100 and 300 nM) and MK-499 (100 and 300 nM). All four agents displayed diminished ERP increases in increased versus normal [K+]e. Among individual test agents, however, there were differences in magnitudes of diminution of ERP increases observed in increased [K+]e: The activities of D-sotalol and MK-499 were better maintained in increased [K+]e than were those of dofetilide and E-4031. As a result of this differential sensitivity increased [K+]e, significant ERP increases were not demonstrable for dofetilide and E-4031 in simultaneous conditions of increased [K+]e and rapid pacing, whereas significant activities were maintained with D-sotalol and MK-499 in increased [K+]e throughout the 1-3 Hz range of pacing frequencies. However, the inherent tendency of myocardial refractoriness to increase in increased [K+]e, particularly at faster pacing frequencies, played a dominant role in determining the relationship between increased versus normal [K+]e posttreatment ERP in all Class III treatment groups. This frequency-dependent increment in refractoriness in increased [K+]e reflected in baseline ERP determined in 10 versus 4 mM [K+]e, respectively, at frequencies of 1 Hz (163 +/- 3 vs. 157 +/- 2 ms, p = 0.06), 2 Hz (146 +/- 3 vs. 134 +/- 2 ms, p < 0.01), and 3 Hz (134 +/- 2 vs. 112 +/- 2 ms, p < 0.01) tended to offset as well as minimize differences among the IKr blockers in diminution of activity observed in increased [K+]e.(ABSTRACT TRUNCATED AT 400 WORDS)

Synthetic tumor-derived human hypercalcemic factor exhibits parathyroid hormone-like vasorelaxation in renal arteries.

Synthetic human tumor hypercalcemic factor (1-34, hHF) was compared with parathyroid hormone (human sequence, 1-34; hPTH) for vasorelaxant activity in isolated rabbit renal artery segments. The hHF exhibited a potent (IC50 = 1.3 x 10(-9) M) and profound (98%) relaxation which was significantly greater in magnitude than that obtained for hPTH (IC50 = 4.5 x 10(-9) M; maximal relaxation = 78%). The relaxations to both peptides were concentration-dependent and not associated with changes in cyclic AMP levels. These results demonstrate a parathyroid hormone-like response, independent of adenylate cyclase activation, in isolated renal arteries. Renal vasodilation may be important for the effects on renal function shared by these two peptides.

Calcium entry blocker activity of cyproheptadine in isolated cardiovascular preparations.

Cyproheptadine was compared with nifedipine, verapamil and diltiazem for calcium entry blocker activity in isolated cardiovascular preparations. Using rat aortic strips, all compounds (10(-7) M) inhibited both the contraction caused by the readdition of calcium (1.0 mM) into regular buffer or buffer containing potassium (130 mM) or norepinephrine (10(-5) M) and the potassium-stimulated uptake of 45Ca. The rank order of potency for these experiments was in general nifedipine greater than cyproheptadine greater than or equal to verapamil greater than diltiazem. The same order of potency also was found for the four compounds in relaxing potassium (40 mM)-contracted aortic strips (IC50 values: nifedipine, 2.6 X 10(-9) M; cyproheptadine, 6.3 X 10(-8) M; verapamil, 7.6 X 10(-8) M; and diltiazem, 2.1 X 10(-7) M), but cyproheptadine was the least potent agent in antagonizing the spontaneous contractions of the rat portal vein (IC50 values: nifedipine, 6.6 X 10(-9) M; verapamil 7.7 X 10(-8) M; diltiazem 9.6 X 10(-8) M; and cyproheptadine 3.9 X 10(-7)M). None of the compounds (10(-7) M) inhibited the contraction to norepinephrine (10(-5) M) in rabbit aortic strips bathed in calcium-free buffer (1 mM ethylene glycol bis(beta-aminoethyl ether)-N, N'-tetraacetic acid). Nifedipine, verapamil and diltiazem were more potent in inhibiting the restoration of contractility by isoproterenol in potassium-depolarized rabbit papillary muscles than decreasing force in normally polarized muscles; cyproheptadine was equipotent when tested in these two preparations. Cyproheptadine was the least potent of the four compounds in lowering perfusion pressure in the perfused canine hindlimb.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial contractile behavior of a new sotalol derivative.

The effects of E4031, a new class III antiarrhythmic agent similar to sotalol, were tested in isometrically contracting rabbit papillary muscles and in anesthetized, open-chest dogs. In papillary muscles, E4031 caused a modest dose-dependent increase of 26 +/- 8% in developed tension and 38 +/- 8% in its maximal rate of rise. Since there was no significant change in the maximal rate of relaxation, the ratio between both maximal velocities increased from 0.92 +/- 0.03 to 1.19 +/- 0.10. Time to peak tension did not change significantly, whereas time to half relaxation increased from 72 +/- 3 to 85 +/- 4 ms. The effective refractory period in the rabbit papillary muscles increased from 179 +/- 10 to 414 +/- 45 ms. In the open-chest dog, the i.v. administration of E4031 did not induce significant changes in heart rate, mean arterial pressure, or left ventricular end diastolic pressure. +dP/dt increased from 1,839 +/- 162 to 2,470 +/- 247 mm Hg/s with no significant change in -dP/dt after 100 micrograms/kg of E4031. Consequently, (+dP/dt)/(-dP/dt) increased from 0.97 +/- 0.07 to 1.18 +/- 0.08. To further evaluate the effects of E4031 on myocardial relaxation, the time constant of isovolumic left ventricular pressure decay was measured by two different methods (tau 1 and tau 2) before and after administering 10 micrograms/kg E4031. Tau 1 increased from 27 +/- 1.8 to 33 +/- 1.6 ms and tau 2 increased from 30 +/- 2.3 to 41 +/- 3.3 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

Glyburide blocks the relaxation response to BRL 34915 (cromakalim), minoxidil sulfate and diazoxide in vascular smooth muscle.

BRL 34915 [6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl) 2H-benzo(b) pyran-3-ol], minoxidil sulfate and diazoxide may relax vascular smooth muscle via hyperpolarization due to an opening of membrane potassium channels. We therefore examined the effects of several potassium channel antagonists on the relaxation response to these vasodilators in isolated rat portal venous strips which were mounted in vitro for detecting changes in isometric force. BRL 34915 (IC50 = 4.7 X 10(-8) M), minoxidil sulfate (IC50 = 1.4 X 10(-7) M) and diazoxide (IC50 = 5 X 10(-6) M) elicited concentration-dependent relaxations of the spontaneous, myogenic contractions in venous strips. The relatively nonselective potassium channel antagonists tetraethylammonium ion (0.3-10 X 10(-3) M) and 4-aminopyridine (1-10 X 10(-3) M) caused concentration-dependent shifts (5- to 50-fold) in the relaxation responses to each vasodilator. Charybdotoxin (up to 10(-7) M) and apamin (up to 10(-7) M), known to be antagonists of high and low conductance calcium-activated potassium channels, respectively, had no inhibitory effect on the relaxation-response curves to BRL 34915, minoxidil sulfate or diazoxide. Glyburide (10(-7) to 3 X 10(-5) M), a sulfonylurea which has been shown to block the ATP-modulated potassium channel in insulin-secreting cells, caused concentration-dependent shifts to the right (up to 100-fold) of the IC50 value for BRL 34915 and diazoxide, and at 10(-6) M, abolished the relaxation response to minoxidil sulfate.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of binding to rapidly activating delayed rectifier K+ channel, IKr, and effects on myocardial refractoriness for class III antiarrhythmic agents.

Saturation binding studies in guinea pig ventricular myocytes with 3H-dofetilide, a radioligand for the cardiac rapidly activating delayed rectifier K+ IKr channel, indicated specific high-affinity binding with a Kd of 83 nM and a Bmax of 0.18 pmol/mg cellular protein (1.36 x 10(6) sites/cell). Using displacement of high-affinity 3H-dofetilide binding as a measure of interaction with the IKr channel, potencies (Ki values) for binding to the IKr channel in guinea pig myocytes for six class III antiarrhythmic agents were characterized and compared to indices of functional electrophysiologic activity in isolated guinea pig papillary muscles [EC25 values, concentration required to increase effective refractory period (ERP) 25% above baseline]. Dofetilide, E-4031, sematilide, and d-sotalol, which have been characterized previously as selective IKr blockers, displayed good agreement between Ki values for displacement of 3H-dofetilide binding (47 +/- 7 nM, 38 +/- 8 nM, 12 +/- 5 microM, and approximately 100 microM, respectively) and EC25 values for increasing ERP in papillary muscles (45.0 nM, 76.9 nM, 20.2 microM and 63.5 microM, respectively). Ibutilide and RP58866, which have been reported to act via mechanisms other than IKr block, had Ki values for displacement of 3H-dofetilide binding (16 +/- 7 nM and 17 +/- 2 nM, respectively) that were approximately 10-fold lower than EC25 values for increasing ERP in papillary muscles (185.8 nM and 223.5 nM, respectively). The potent displacement of high-affinity 3H-dofetilide binding by ibutilide and RP58866 strongly suggest a role for interaction with IKr in their actions.(ABSTRACT TRUNCATED AT 250 WORDS)

Use-dependent effects of the class III antiarrhythmic agent NE-10064 (azimilide) on cardiac repolarization: block of delayed rectifier potassium and L-type calcium currents.

We studied the effects of NE-10064 (azimilide), a new antiarrhythmic agent reported to be a selective blocker of the slowly activating component of the delayed rectifier, IKs. In ferret papillary muscles, NE-10064 increased effective refractory period (ERP) and decreased isometric twitch tension in a concentration-dependent manner (0.3-30 microM). Increases in ERP showed reverse use-dependence, and were greater at 1 than at 3 Hz. In contrast, changes in tension were use dependent, with larger decreases observed at 3 than at 1 Hz. In guinea pig ventricular myocytes, NE-10064 (0.3-3 microM) significantly prolonged action potential duration (APD) at 1 Hz. At 3 Hz, NE-10064 (0.3-1 microM) increased APD only slightly, and at 10 microM decreased APD and the plateau potential. NE-10064 potently blocked the rapidly activating component of the delayed rectifier, IKr (IC50 0.4 microM), and inhibited IKs (IC50 3 microM) with nearly 10-fold less potency. NE-10064 (10 microM) did not block the inward rectifier potassium current (IKl). NE-10064 (10 microM) blocked the L-type calcium current (ICa) in a use-dependent manner; block was greater at 3 than at 1 Hz. We conclude that (a) NE-10064's block of potassium currents is relatively selective for IKr over IKs, (b) NE-10064 inhibits ICa in a use-dependent fashion, and (c) NE-10064's effects on ERP and tension in papillary muscle as well as APD and action potential plateau level in myocytes may be explained by its potassium and calcium channel blocking properties.

Pharmacology and receptor binding of atrial natriuretic factor in vascular smooth muscle.

Characterization of the vascular pharmacology and receptor binding of atrial natriuretic factor (ANF) has been achieved utilizing a synthetic peptide which contains the sequence and biological activity of ANF. The synthetic ANF (sANF) relaxes aortic segments contracted by agonists or by low (15 to 20 mM) but not high (greater than or equal to 40 mM) concentrations of K+. The relaxation to sANF is well maintained, reversible, independent of the vascular endothelium and correlated with increases in cyclic GMP (with no change in cyclic AMP). Plasma membranes prepared from rabbit aorta and kidney possess high affinity (Kd = 100 pM) specific binding sites for sANF. An excellent correlation exists between the receptor binding and pharmacology for several synthetic analogs of ANF. The presence of these receptors appears consistent with the activation of particulate (but not soluble) guanylate cyclase by sANF. sANF does exhibit a profound regional vasodilator selectivity which can be explained, in part, by changes in receptor density.

Effects of new and potent methanesulfonanilide class III antiarrhythmic agents on myocardial refractoriness and contractility in isolated cardiac muscle.

The effects of the new and potent methanesulfonanilide class III antiarrhythmic agents (E-4031, UK-66,914, and UK-68,798) on myocardial refractoriness and contractility were compared to those of d-sotalol in ferret isometrically contracting right ventricular papillary muscle preparations. During 1 Hz pacing at 37 degrees C, the four class III agents elicited concentration-dependent increases in ventricular effective refractory period (ERP), with a relative order of potency of UK-68,798 greater than E-4031 greater than UK-66,914 much greater than d-sotalol. EC25 values (effective concentration required to increase ERP 25% above baseline) were (in microM) UK-68,798, 0.018; E-4031, 0.058; UK-66,914, 0.501; and d-sotalol, 43.76. Maximal increases in ERP relative to baseline (% of baseline value) for the class III agents at 37 degrees C (range of 44.5 +/- 4.5 to 63.0 +/- 3.1%) were greater than the maximal increases observed at 27 degrees C (range of 15.0 +/- 3.3 to 31.2 +/- 4.8%), whereas the maximal absolute (ms) increases in ERP above baseline were comparable for the class III agents at both temperatures. Increases in ERP produced by the four class III agents at 37 degrees C were significantly greater at a pacing frequency of 1 Hz (range of 70.0 +/- 7.6 to 102.0 +/- 2.3 ms) than at 3 Hz (range of 18.3 +/- 4.4 to 31.BBB/- 4.8 ms). During a temporary period of hypoxic perfusion at 37 degrees C, increases in ERP produced by the four class III agents were reversed, such that "hypoxic" ERP values approximated pretreatment, baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac electrophysiologic and antiarrhythmic actions of tedisamil.

The Class III electrophysiologic and antiarrhythmic actions of the bradycardic agent tedisamil were assessed in vitro and in vivo. In ferret isolated right ventricular papillary muscles, tedisamil increased effective refractory period (ERP) in a concentration-dependent manner, with a 25% ERP increase achieved with 3.0 microM tedisamil, and a 133.4% +/- 28.8% increase in ERP achieved at the high 100 microM concentration tested. In anesthetized dogs, the cumulative i.v. administration of tedisamil significantly increased ventricular relative refractory period (VRRP) and ventricular effective refractory period (VERP) as well as electrocardiographic QTc intervals (100-1000 micrograms/kg i.v.). A 20msec increase in VRRP was achieved with 45.0 micrograms/kg i.v. tedisamil, and a 56.1 +/- 9.8 msec (40.1% +/- 8.1%) increase in VRRP was achieved at the highest dose tested (1000 micrograms/kg i.v.). In the same dosage range in anesthetized dogs, tedisamil produced significant hemodynamic effects, including reduction in HR (100-1000 micrograms/kg i.v.) and elevations in mean arterial pressure (1000 micrograms/kg i.v.), left ventricular developed pressure (1000 micrograms/kg i.v.) and the maximum rate of LV pressure development (100-1000 micrograms/kg i.v.). In anesthetized dogs studied chronically (8.2 +/- 0.6 days) after anterior myocardial infarction, tedisamil suppressed programmed stimulation-induced ventricular tachyarrhythmias (8/10, 80% suppression at 100-1000 micrograms/kg i.v.) and reduced the incidence of lethal ischemic arrhythmias developing in response to acute posterolateral myocardial ischemia (arrhythmic mortality 5/10, 50% tedisamil vs. 34/40, 85% vehicle control cohort; P = .027). The latter findings suggest that tedisamil might be useful in the prevention of malignant ventricular arrhythmias in the setting of myocardial ischemic injury.(ABSTRACT TRUNCATED AT 250 WORDS)