Alfonso J. Tobia

Positive inotropic and hemodynamic properties of flosequinan, a new vasodilator, and a sulfone metabolite.

Flosequinan, a new orally active vasodilator, and its sulfone metabolite were evaluated for inotropic activity in isolated ferret papillary muscles and pentobarbital anesthetized open-chest dogs. In vitro, flosequinan and its sulfone derivative increased tension development in a concentration-dependent manner (1–50 μM) in electrically stimulated papillary muscles pretreated with the β-adrenergic blocking agent atenolol (2 μM). Peak increases in tension of 75 ± 17%, and 111 ± 46% with potencies (ECso) of 15 and 10 μM were observed for flosequinan and its metabolite, respectively. In vivo, flosequinan increased left ventricular dP/dtmax (74 ± 12%) and right ventricular contractile force (CF) (104 ± 10%) after administration of 1.875 mg/kg, i.v. Inotropic activity was dose-dependent and remained elevated for at least 60 min postinfusion. Flosequinan also increased heart rate (HR) (14 ± 2%) and reduced mean arterial pressure (−9 ± 3%). The i.v. potency of flosequinan (ED50 = 0.45 mg/kg) and its metabolite (ED50 = 0.38 mg/kg) were similar to that of the inotropic vasodilator amrinone (ED50 = 0.38 mg/kg). Inotropic activity was not significantly altered by pretreatment with propranolol (0.5 mg/kg) and atropine (1.0 mg/kg), further supporting the in vitro data indicating that flosequinan can directly stimulate myocardial contractility independent of β-adrenergic receptor activation. Additional hemodynamic studies were conducted in an acute heart failure model produced by an overdose of propranolol. Flosequinan (2 mg/kg, i.v.) increased cardiac output (CO) (50 ± 9%) and stroke volume (SV) (29 ± 8%) while reducing total peripheral vascular resistance (TPR) (−36 ± 4%), right atrial pressure (−62 ± 5%), and left ventricular end-diastolic pressure (LVEDP) (−41 ± 2%). Myocardial contractility was markedly elevated (dP/dtmax 82 ± 9%, CF 627 ± 150%) with minor changes in blood pressure (BP) and HR. These results show that flosequinan exerts a direct cardiostimulatory effect on the myocardium in addition to reducing preload and afterload through systemic vasodilation and suggest an additional heretofore unrecognized mechanism for the reported clinical efficacy of flosequinan in congestive heart failure (CHF).

Hemodynamic alterations in the young spontaneously hypertensive rat: elevated total systemic and hindquarter vascular resistance.

Summary Abdominal aortic blood flow and hindquarter vascular resistance were determined in young (2-3 mo) spontaneously hypertensive rats (SHR) and in age-matched Wistar Kyoto (WKY) normo-tensives. Abdominal aortic blood flow was similar in the 2 groups, whereas hindquarter vascular resistance was elevated in the SHR compared to WKY. Additionally, in the open-chest preparation there was no significant difference in ascending aortic blood flow between hypertensives and normoten-sives, while total peripheral resistance was increased in the SHR relative to WKY. These data suggest that early in the development of hypertension in the SHR the hemodynamic pattern of normal blood flow and elevated resistance exists in the hindquarter vasculature and the total systemic circulation.

Normal cardiac output in the conscious young spontaneously hypertensive rat: Evidence for higher oxygen utilization

Summary Cardiac output was determined using the Fick Principle in conscious young female (9–12 weeks of age) spontaneously hypertensive rats (SHR) and in age- and sex-matched normotensive Wistar Kyoto (WKY) controls. Oxygen consumption was measured by the closed circuit method using a spirometer and arterio-venous oxygen content was determined by the method of Van Slyke. Mean aortic blood pressure (P

Unaltered Distribution of Cardiac Output in the Conscious Young Spontaneously Hypertensive Rat: Evidence for Uniform Elevation of Regional Vascular Resistances

Radioactive microspheres (50 µ mdiameter) were injected into the left ventricle of conscious rats fasted for 12 h, and the percent distribution of cardiac output to major organs was

Bemoradan—a novel inhibitor of the rolipram-insensitive cyclic AMP phosphodiesterase from canine heart tissue

Canine cardiac muscle contains a type IV cyclic AMP (cAMP) phosphodiesterase (PDE) that is composed of two subtypes. One subtype is sensitive to rolipram inhibition (RSPDE), whereas the other is not inhibited significantly by rolipram (RIPDE). The RIPDE is inhibited by several cardiotonic agents operating by a PDE-inhibitory mechanism. Bemoradan [RWJ-22867; 7-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-2H-1,4-benzoxazin -3(4H)-one], a novel, potent positive inotropic agent, demonstrated biphasic inhibition of the fraction III enzyme from canine cardiac muscle. Inhibition by rolipram of the RSPDE converted the IC50 curves of bemoradan, indolidan, pimobendan, and imazodan to sigmoidal, monophasic curves. Lineweaver-Burk analysis yielded competitive inhibition KI values of 0.023, 0.09, 0.065 and 0.60 microM, respectively, for these compounds. The cardiotonic compounds, however, were not potent inhibitors of the Type I and Type II cAMP PDEs found in canine ventricular muscle. The order of potency for inhibiting the RIPDE cAMP PDE subtype was bemoradan greater than pimobendan greater than indolidan greater than imazodan. Bemoradan is, therefore, a potent inhibitor of the cardiac muscle cAMP PDE which could, in part, be responsible for its cardiotonic activity.

Increased Vasodilator Responsiveness to BRL 34915 in Spontaneously Hypertensive versus Normotensive Rats: Contrast with Nifedipine

Abstract The blood pressure-lowering potency and activity of BRL 34915, a new vasodilator and putative stimulator of potassium efflux from vascular smooth muscle, was investigated in conscious spontaneously hypertensive rats (SHR) and normotensive rats (NTR) after intravenous administration and compared with that of the calcium channel blocker, nifedipine. In SHR, BRL 34915 (3–100 μg/kg) or nifedipine (10–3000 μg/kg) produced similar reductions in mean arterial pressure of 58 ± 3% and 55 ± 3%, respectively. BRL 34915 (ED30% = 13.8 μg/kg) was 15.3 times more potent than nifedipine (ED30% = 207 μg/kg) in SHR. In contrast, only a 1.7-fold difference in potency was observed in NTR between BRL 34915 (ED30% = 123 μg/kg) and nifedipine (ED30% = 182 μg/kg). The potency ratio (ED30% NTR/ED30% SHR) for BRL 34915 was 8.83 whereas nifedipine had a ratio of 0.88, reflecting the greater responsiveness of the SHR to BRL 34915. Systemic hemodynamics were monitored in anesthetized SHR and NTR to determine the basis for the reductions in blood pressure. BRL 34915 (3–100 μg/kg iv) lowered mean arterial pressure in both groups solely by decreasing total peripheral vascular resistance, since no changes in cardiac output were observed. Relaxation responses were also obtained in phenylephrine-contracted isolated aortic strips from both strains of rat to ascertain whether differences in responsiveness existed at this level of the vasculature. No significant difference in the potency of BRL 34915 (3–10 μM) as a vasodilator was found in aortas from SHR or NTR. These results indicate that, unlike nifedipine, BRL 34915 is a more potent vasodepressor agent in SHR than in NTR and suggests that the potassium efflux stimulator may preferentially relax resistance vessels in the hypertensive rat.

Intact hindquarter vascular responses of young spontaneously hypertensive rats to norepinephrine and tyramine

Abstract Intact hindquarter vascular responses to abdominal aortic injections of subpressor doses of norepinephrine (0.01, 0.02, 0.03 μg) or tyramine (5, 10, 15 μg) were examined in young ( 2 1 2 –3 months ) spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) normotensives to ascertain whether altered vascular response to catecholamines in SHR could be detected in the presence of relatively constant systemic arterial perfusion pressure. Increases in vascular resistance (Δ mmHg. min/ml) and total decreases in blood flow volume (Δ ml) were determined by using electromagnetic flowmetry and blood flow integration techniques. Under a resting condition the abdominal aortic flow rate (ml/min) was similar between the SHR (8.7 ± 0.5) and WKY control (9.1 ± 0.5), whereas hindquarter vascular resistance was greater (73.8%) in SHR than in WKY normotensives (P

Renal vasodilator responses to captopril in dogs pretreated with indomethacin.

Abstract Renal vasodilator responses to captopril administered intravenously were evaluated in pentobarbital anesthetized dogs pretreated with indomethacin to determine whether synthesis and release of vasodilator prostaglandins are involved in the response. Renal artery blood flow was measured using electromagnetic flowmetry and renal vascular resistance was calculated from the ratio of mean arterial blood pressure/renal artery blood flow. In control dogs, captopril caused significant dose-related increases (ranging from 9 ± 2 to 37 ± 6 ml/min) in renal artery blood flow and decreases in renal vascular resistance. The drug also decreased mean arterial blood pressure by 22 ± 3 mm Hg, whereas, heart rate was not significantly altered from precaptopril control values. In indomethacin pretreated dogs, the renal vasodilator and systemic hypotensive responses of captopril were not attenuated. The data suggest that captopril causes renal vasodilation by a mechanism independent of prostaglandins.

The Role of Demethylbetahistine in the Depressor Response to Betahistine in the Rat

Summary Betahistine and demethylbetahistine lower arterial blood pressure in the rat, and the depressor response was blocked by pretreatment with the antihistamine, tripelennamine. Rats pretreated with SKF-525-A exhibited no modification of the depressor action of betahistine. No detectable betahistine N-demethylase activity was observed in rat liver homogenates. The data do not support the contention that demethylbetahistine contributes to the overall depressor response observed after intravenous administration of betahistine, and suggest that direct deamination of betahistine may represent the major pathway of enzymatic degradation of this drug in the rat.

Altered regional vasodilator responses to glossopharyngeal nerve stimulation in spontaneously hypertensive rats.

The hindlimb and renal vasodilator responses produced by electrical stimulation of the glossopharyngeal nerve were examined in adult (six to eight months) male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) normotensive rats to ascertain whether central neurogenically activated vasodilator capacity of these regional vascular beds is altered in SHR. Changes in systemic blood pressure and regional blood flow were simultaneously measured, and vascular resistance was calculated. Glossopharyngeal nerve stimulation (3.0 volts, 0.3 ms) at the frequency of 10 Hz resulted in a significantly greater vasodilation (% decrease in resistance) in SHR than in WKY control for both the hindlimb (SHR - 13.0 +/- 1.5% versus WKY - 3.4 +/- 1.6%, P less than 0.01) and renal (SHR - 7.6 +/- 0.6% versus WKY - 1.3 +/- 0.4%, P less than 0.01) vascular beds. The linear portion of the frequency-response curves of hindlimb or renal vasodilation of SHR was shifted parallel to the left of the WKY curve. Stimulus frequencies required to produce a 20% reduction in hindlimb resistance and a 10% reduction in renal resistance were lower in SHR (hindlimb 17.0 +/- 1.8 Hz; renal 19.9 +/- 1.4 Hz) than in WKY control (hindlimb 24.6 +/- 1.1 Hz; renal 39.3 +/- 4.8 Hz; P less than 0.01). The maximal vasodilator response to glossopharyngeal nerve stimulation in the hindlimb vascular bed was similar in SHR and WKY control, but in the renal vascular bed SHR showed a greater maximal response compared to WKY normotensives (SHR - 16.3 +/- 0.9% versus WKY - 12.7 +/- 1.6%, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)