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To support its class III antiarrhythmic candidacy, we examined the acute cardiovascular effects of ibutilide and its R- and S-enantiomers in conscious beagle dogs. Eight dogs were given stepped i.v. doses (0.01, 0.1, and 1.0 mg/kg) of these agents while monitoring changes in mean arterial pressure (MAP), heart rate (HR), and lead II ECG QTc length (index of class III activity). None of the treatments affected MAP and only R-ibutilide slightly increased HR. The R-isomer was also slightly more potent in prolonging QTc at the lowest dose, but its mean peak QTc change (+44 msec) overlapped those achieved with racemic (+37 msec) and S-ibutilide (+41 msec). Plasma drug analyses showed that total drug levels (sum of enantiomers) were similar with each agent, averaging 1, 12, and 170 ng/ml at 30 min after the low, middle, and high doses, respectively. Nearly equal enantiomer proportions were seen after racemic ibutilide, and no chiral inversion was seen after enantiomer administration. All treatments were well tolerated without enhanced ventricular ectopy. These data demonstrate that in conscious dogs, racemic, R-, and S-ibutilide similarly prolong QTc independent of appreciable cardiovascular changes, differential pharmacokinetics, or dysrhythmias, thereby helping to establish racemic ibutilide as the optimal developmental candidate.

In support of clinical antianginal studies, the vasodilator nicorandil (NIC) was combined with the beta-adrenergic receptor antagonists propranolol (PRO) and atenolol (ATN) and with the calcium channel blocker diltiazem (DTZ) to determine their cardiovascular and pharmacokinetic interactions. Beagle dogs were chronically cannulated to record mean arterial pressure, heart rate, and the lead II electrocardiogram under conscious conditions. Oral NIC (1, 3, and 10 mg/kg) was coadministered with i.v. PRO (5.0 mg/kg) or ATN (7.5 mg/kg), both of which lessened NIC's reflex tachycardia. ECG rhythm remained normal, but both beta-blockers restricted high dose NIC's QTc prolongation and ST segment depression. Intravenous DTZ (5-23 micrograms/kg/min) did not affect i.v. NIC's hypotensive profile (10-80 micrograms/kg/min) but attenuated its tachycardia, whereas NIC-reversed DTZ's PR interval shortening and frequency of ectopic beats. Similar cardiovascular interactions were seen with chronic oral DTZ (10 mg/kg/day) + NIC (3.0 or 7.5 mg/kg). Plasma analysis confirmed that none of the adjuncts affected NIC's disposition nor its concentration-dependent hypotensive response profile. These studies establish the cardiovascular effects of NIC when combined with PRO, ATN or DTZ in dogs, and outline paradigms useful for evaluating such antianginal drug combinations.

The cardiovascular effects of the K-ATP channel blocker U-37883A and 5 related morpholinoguanidines were determined in 6 experimental preparations. In anesthetized dogs, U-37883A (0.5-8.0 mg/kg i.v.) increased mean arterial pressure (MAP; +18%) and left ventricular (LV) effective refractory period (ERP; +35%), and decreased LV contractility (-41%). Higher doses of U-37883A (16-32 mg/kg) fatally reduced MAP (-84%), heart rate (HR; -57%) and LV contractility (-72%). In anesthetized rats, U-37883A (1.0-50 mg/kg i.v.) also maximally reduced MAP, HR and LV contractility by 68, 77 and 48%, respectively. U-37883A and its analogs were diuretic in conscious rats (1.5-15 mg/kg i.v.) and blocked pinacidil in rabbit mesenteric artery (EC50 = 0.5-50 microM). In rabbit papillary muscle, 50 microM U-37883A significantly reduced force of contraction (-33%) and prolonged conduction time (+244%). Milder papillary effects were seen with the N'-OH analog U-45194A, which did not depress LV contractility in intact rats. In conscious dogs, oral U-45194A (50 mg/kg) was diuretic but reduced LV stroke volume and increased peripheral vascular resistance. These studies characterize U-37883A's systemic cardiovascular and direct myocardial effects, and identify U-45194A as a less cardiac depressant analog having U-37883A-like diuretic and functional K-ATP channel blocking activities.

Several guanidine diuretics related to the renal tubular K-ATP blocker U-37883A were compared to standard diuretics under high K+ excretion conditions. In conscious rats, oral KCl(0.28 mEq) increased K+ excretion 3-fold. This kaliuresis was further enhanced by oral diuretic doses of ethoxzolamide (1 and 2 mg/kg), hydrochlorothiazide (HCTZ; 0.3 and 0.9 mg/kg), and furosemide (18 mg/kg), but was significantly blunted by oral triamterene (1 and 10 mg/kg). By comparison, diuretic doses of U-37883A and analogs U-18177 (10 and 30 mg/kg) and U-38658A (3 and 9 mg/kg) did not affect K+ excretion. In conscious dogs, oral U-18177A (10 mg/kg) and HCTZ (1 mg/kg) were compared during 3- to 13-fold kaliuresis induced by oral isotonic saline (200 mL), oral KCl (30.8 mEq), subcutaneous deoxycorticosterone acetate (1.0 mg/kg), and oral acetazolamide (20 mg/kg). HCTZ was diuretic and further increased K+ excretion and its fractional clearance by 42 and 34%, respectively. Conversely, U-18177A was diuretic and slightly reduced these kaliuretic parameters by 11 and 20%. Thus, the guanidines U-18177 and U-37883A exert a relatively eukalemic diuresis under normal and high K+ excretion conditions, and their putative renal tubular K-ATP blocking action seems an effective means of inducing diuretics with less K+ imbalance than with standard diuretics.

U-37883A is a K+ sparing diuretic which selectively blocks openers of vascular ATP-sensitive K channels. Many N'-disubstituted morpholinoguanidine (N'-DMG) analogs of U-37883A were synthesized and tested for diuretic activity. In conscious rats, 10-100 mg/kg orally of the most active N'-DMGs increased urine volume (V) and Na+ excretion by up to 4-fold with little kaliuresis. The N'-DMGs U-37997A and U-38658A were less potent than standard diuretics, but did not induce the K+ loss seen with hydrochlorothiazide and furosemide or the K+ retention of amiloride and triamterene. In conscious dogs, 10 mg/kg i.v. of the N'-DMGs U-40389A and U-52090 increased V and Na+ excretion by over 7-fold with little kaliuresis. Despite their attractive diuresis, all of the N'-DMGs had narrow margins of safety. Reflecting their direct myocardial depressant action, in isolated rat hearts, bolus intracoronary U-37883A, U-18177A, and U-38658A (0.25-10 mumol) severely reduced the rate (-10 to -100%) and force (-9 to -100%) of contraction. These studies characterize the eukalemic diuretic activity of N'-DMG analogs of U-37883A, and demonstrate the marked cardiac depression characteristic of the morpholinoguanidine diuretic series.

The in vitro vasorelaxant and in vivo cardiovascular effects of synthetic S-nitrosothiols (RSNOs) were compared to standard nitrovasodilators. S-Nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteine (NACysNO), S-nitroso-galactopyranose (GPSNO), S-nitroso-thioglycerol (TGSNO) and S-nitroso-homocysteine (HCysNO) relaxed phenylephrine (PE) contracted rabbit aorta at 50% effective concentrations (EC50s) of 3-46 nM. While nitroglycerin (GTN) exhibited in vitro tolerance after preincubation, the RSNOs were considerably less cross tolerant to GTN. In conscious dogs, GSNO, NACysNO and GPSNO (1-20 mcg/kg/min i.v.) paralleled nitroprusside (SNP) in reducing mean arterial and central venous pressure (MAP; CVP) with mild tachycardia. GSNO, NACysNO and SNP were more hypotensive and more resistant to isosorbide dinitrate (ISDN) cross tolerance than GTN. NACysNO showed mild self tolerance with low infusion (2.5 mcg/kg/min x 4h x 3 days) and blunted GTN's hypotension. These studies demonstrate that GSNO and NACysNO are SNP-like vasodilators in conscious dogs, which exhibit less cross tolerance to ISDN than GTN. Further, RSNOs relax vascular smooth muscle seemingly independent of nitric oxide (NO) liberation, and nitrate tolerance may involve reduced RSNO formation or NO release rather than desensitized guanylate cyclase (GC).