The use of a compound of formula (I) wherein R1 is H; C?1?-C3 alkyl; C1-C3 perfluoroalkyl; or C3-C5 cycloalkyl; R?2? is H; optionally substituted C?1?-C6 alkyl; C1-C3 perfluoroalkyl; or C3-C6 cycloalkyl; R?3? is optionally substituted C?1?-C6 alkyl; C1-C6 perfluoroalkyl; C3-C5 cycloalkyl; C3-C6 alkenyl; or C3-C6 alkynyl; R?4? is optionally substituted C?1?-C4 alkyl, C2-C4 alkenyl, C2-C4 alkanoyl, (hydroxy)C2-C4 alkyl or (C2-C3 alkoxy)C1-C2 alkyl; CONR?5R6; CO?2R7; halo; NR5R6; NHSO?2NR?5R6; NHSO?2R?8; SO2NR9R10; or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl; R?5 and R6? are each independently H or C?1?-C4 alkyl, or together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl, piperidino, morpholino, 4-N(R?11?)-piperazinyl or imidazolyl group; R7 is H or C?1?-C4 alkyl; R?8? is optionally substituted C?1?-C3 alkyl; R?9 and R10? together with the nitrogen atom to which they are attached form an optionally substituted pyrrolidinyl, piperidino, morpholino or 4-N(R12)-piperazinyl group; R11 is H; optionally substituted C?1?-C3 alkyl; (hydroxy)C2-C3 alkyl; or C1-C4 alkanoyl; R?12? is H; optionally substituted C?1?-C6 alkyl; CONR?13R14; CSNR13R14?; or C(NH)NR?13R14; and R13? and R?14? are each independently H; C?1?-C4 alkyl; or substituted C2-C4 alkyl; or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man; a pharmaceutical composition for said treatment; and a method of said treatment of said male animal with said pharmaceutical composition or with said either entity.

Pyrazolopyrimidinones for the treatment of impotence

Received March 15, 2006; accepted August 30, 2006. 

Overload of neonatal and adult cardiomyocytes and multicellular myocardial preparations, which include whole hearts, are accompanied by an enhanced activity of the Na+/H+ exchanger 1 (NHE-1). Exogenous administration of prohypertrophic agents such as angiotensin II (Ang II), endothelin-1 (ET-1), and α1-adrenergic agonists also stimulates NHE-1 activity, which leads to an increased concentration of intracellular Na+ ([Na+]i). Moreover, inhibition of NHE-1 activity prevents the increase in [Na+]i, induces the regression of cardiac hypertrophy, and exerts beneficial effects in experimental heart failure.

The present review summarizes the current knowledge of the causative factors and pathophysiological correlation of cardiac overload and NHE-1 activity.

NHE is an integral membrane glycoprotein expressed ubiquitously in mammalian cells, and it electroneutrally exchanges intracellular H+ for extracellular Na+ (1:1) to regulate intracellular pH (pHi) and the concentration of [Na+]i. Nine isoforms of this exchanger have been described: NHE-1 to NHE-9. NHE-1, the first isoform to be cloned, is expressed ubiquitously in the plasma membrane and is considered to be the cardiac-specific isoform.1 The inward gradient of Na+, produced mainly by the Na+/K+ ATPase, provides a constant driving force for H+ extrusion and Na+ influx through the NHE.

NHE-1 (Figure 1) is a protein of 815 amino acid residues with a predicted molecular mass of 85 kDa that can be separated into an N-terminal membrane-associated domain (≈500 amino acid residues) and a long C-terminal cytoplasmic tail. The membrane domain, composed of 12 transmembrane regions, is associated with ionic transport, and it contains the allosteric H+ sensor site that determines the exquisite sensitivity of the exchanger to intracellular H+. The cytoplasmic …

http://sedici.unlp.edu.ar/bitstream/handle/10915/83235/Documento_completo.pdf?sequence=1

Sodium-Hydrogen Exchanger, Cardiac Overload, and Myocardial Hypertrophy

Myocardial stretch elicits a rapid increase in developed force, which is mainly caused by an increase in myofilament calcium sensitivity (Frank-Starling mechanism). Over the ensuing 10–15 min, a se...

The Anrep effect: 100 years later.

I n 1976, one of the authors (D.M.A.) proposed a classification of drugs for the treatment of intermittent claudication.’ The five categories are as follows: (1) musculotropic vasodilators to increase blood flow; (2) alpha-adrenergic blockers to improve blood flow; (3) beta-adrenergic activators to augment blood flow; (4) nonadrenergic drugs to retard blood clotting and antagonize serotonin, bradykinin, and calcium ions; and (5) drugs with multiple actions involving vascular and nonvascular areas. At that time, the drugs that were available in the United States belonging to categories 1, 2, and 3 were judged by the Food and Drug Administration (FDA) to be ineffective or possibly effective because of lack of evidence of clinical efficacy and safety.2 Drugs belonging to categories 4 and 5 were already available in Europe and were undergoing clinical investigation in the United States for review by the FDA. Presently, the situation in the United States is essentially unchanged in that no vasodilator,

Clinical pharmacology of pentoxifylline with special reference to its hemorrheologic effect for the treatment of intermittent claudication.

The stretch-induced increase in force production of ventricular muscle is biphasic. An abrupt increase in force coincides with the stretch, which is then followed by a slower response that develops over minutes (the slow force response or SFR). The SFR is accompanied by a slow increase in the magnitude of the intracellular Ca2+ transient, but the stretch-dependent mechanisms that give rise to this remain controversial. We characterized the SFR using right ventricular trabeculae from mouse hearts. Application of three different blockers of stretch-activated non-selective cation channels (SAC NSC) reduced the magnitude of the SFR 60s after stretch (400 microM streptomycin: from 86+/-25% to 38+/-14%, P<0.01, n=9; 10 microM GdCl3: from 65+/-21%, to 12+/-7%, P<0.01, n=7; 10 microM GsMTx-4 from 122+/-40% to 15+/-8%, P<0.05, n=6). Streptomycin also decreased the increase in Ca2+ transient amplitude 60s after the stretch from 43.5+/-12.7% to 5.7+/-3.5% (P<0.05, n=4), and reduced the stretch-dependent increase in intracellular Ca2+ in quiescent muscles when stretched. The transient receptor potential, canonical channels TRPC1 and TRPC6 are mechano-sensitive, non-selective cation channels. They are expressed in mouse ventricular muscle, and could therefore be responsible for stretch-dependent influx of Na+ and/or Ca2+ during the SFR. Expression of TRPC1 was investigated in the mdx heart, a mouse model of Duchenne's muscular dystrophy. Resting Ca2+ was raised in isolated myocytes from old mdx animals, which was blocked by application of SAC blockers. Expression of TRPC1 was increased in the older mdx animals, which have developed a dilated cardiomyopathy, and might therefore contribute to the dilated cardiomyopathy.

Stretch-activated channels in the heart: contributions to length-dependence and to cardiomyopathy

Previous work demonstrated that the slow force response (SFR) to stretch is due to the increase in calcium transients (Ca2+T) produced by an autocrine-paracrine mechanism of locally produced angiotensin II/endothelin activating Na+-H+ exchange. Although a rise in pHi is presumed to follow stretch, it was observed only in the absence of extracellular bicarbonate, suggesting pHi compensation through the Na+-independent Cl--HCO3- exchange (AE) mechanism. Because available AE inhibitors do not distinguish between different bicarbonate-dependent mechanisms or even between AE isoforms, we developed a functional inhibitory antibody against both the AE3c and AE3fl isoforms (anti-AE3Loop III) that was used to explore if pHi would rise in stretched cat papillary muscles superfused with bicarbonate after AE3 inhibition. In addition, the influence of this potential increase in pHi on the SFR was analyzed. In this study, we present evidence that cancellation of AE3 isoforms activity (either by superfusion with bicarbonate-free buffer or with anti-AE3Loop III) results in pHi increase after stretch and the magnitude of the SFR was larger than when AE was operative, despite of similar increases in [Na+]i and Ca2+T under both conditions. Inhibition of reverse mode Na+-Ca2+ exchange reduced the SFR to the half when the AE was inactive and totally suppressed it when AE3 was active. The difference in the SFR magnitude and response to inhibition of reverse mode Na+-Ca2+ exchange can be ascribed to a pHi-induced increase in myofilament Ca2+ responsiveness.

/pdf/influence-of-na-independent-cl-hco3-exchange-on-the-slow-2ukjbmh4p9.pdf

Influence of Na+-Independent Cl--HCO3- Exchange on the Slow Force Response to Myocardial Stretch

Effect of phosphodiesterase inhibitors on heart contractile behaviour, protein kinase activity and cyclic nucleotide levels

Perfusion of the isolated rat heart at constant heart rate and coronary flow with the inhibitor of cyclic nucleotide phosphodiesterase, pentoxifylline (10(-4) moles/l), produced no significant effect on the maximum rate and the peak of contraction, but increased the maximum rate of relaxation. cAMP level and cAMP-dependent protein kinase activity were increased in the absence of changes in cGMP. The results were identical in hearts of reserpinized rats.

The mechanical and biochemical effects of pentoxifylline on the perfused rat heart

The effects of isoproterenol and insulin on phospholipid methyltransferase (PLMT) activity were investigated in adipocytes from control and streptozotocin-diabetic rats. PLMT activity was assayed by measuring the rate of incorporation of 3H-methyl groups from S-adenosyl-L-[methyl-3H] methionine into phospholipids. Basal PLMT activity was higher in adipocytes from diabetic animals. Treatment of adipocytes with isoproterenol induced a concentration-dependent stimulation of PLMT activity. In control adipocytes, the maximal effect was obtained at 100 nM isoproterenol with 2.3 fold increase in PLMT activity and a half maximal effect at 25 nM. In adipocytes from diabetic rats, a lower dose of isoproterenol (10 nM), caused 1.2 fold increase with a half maximal effect at 4 nM. Addition of 100 nM insulin inhibited basal PLMT activity and the stimulatory effect of isoproterenol in both types of adipocytes. The β-adrenergic blocking agent propranolol inhibited the stimulatory effect of isoproterenol on PLMT activity in control and diabetic adipocytes. Intracellular concentration of cAMP was higher in diabetic adipocytes but decreased to normal values after incubation in the presence of insulin.

Gladys E. Chiappe

Papers

Influence of Na+-Independent Cl--HCO3- Exchange on the Slow Force Response to Myocardial Stretch

Effect of phosphodiesterase inhibitors on heart contractile behaviour, protein kinase activity and cyclic nucleotide levels

The mechanical and biochemical effects of pentoxifylline on the perfused rat heart

Phospholipid methyltransferase activity in diabetic rat fat cells: effect of isoproterenol and insulin.