Search

Na

The Na+/Ca2+ exchanger (NCX) is an ion transporter that exchanges Na+ and Ca2+ in either Ca2+ efflux or Ca2+ influx mode, depending on the ion gradients across the plasma membrane and the membrane potential. In heart, smooth muscle cells, neurons, and nephron cells, this exchanger is thought to play an important role in the regulation of intracellular Ca2+ concentration. We aim at clarifying the function and pathologic state of the exchanger by developing NCX inhibitors and NCX-engineered mice as experimental tools, and finally establishing a novel therapeutic method using the exchanger as a molecular target. First, we present the pharmacological profiles and the molecular mechanism of NCX inhibitors (KB-R7943, SEA0400, SN-6) recently developed. Our results suggest that these NCX inhibitors preferentially block the Ca2+ influx mode rather than the Ca2+ efflux mode. Further mutational analysis reveals that these NCX inhibitors have different interaction domains in the exchanger molecule. Secondly, we present that heterozygous NCX1-knockout mice are useful as a low NCX1-expressing animal model. From comparative experiments with heterozygous and wild-type mice and pharmacological experiments of the NCX inhibitors, we provided an evidence that NCX1 functionally contributes to maintaining the vascular tension.

The antihypertensive effect of naftopidil (KT-611) following single oral administration was investigated in normotensive Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), DOCA-Salt hypertensive rats (DHR), 2-kidney 1-clip renal hypertensive rats (RHR) and Grollman type renal hypertensive dogs with 1-kidney (RHD); and it was compared with that of the selective alpha 1-adrenoceptor antagonist prazosin. The blood pressure and heart rate were measured under the unanesthetized, unrestrained state through an arterial catheter that was chronically implanted into the abdominal aorta. In SHR and WKY, both KT-611 (10 and 30 mg/kg, p.o.) and prazosin (1 and 3 mg/kg, p.o.) markedly inhibited the pressor response to the alpha 1-adrenoceptor agonist phenylephrine (3 micrograms/kg, i.v.). KT-611 (10 to 100 mg/kg, p.o.) showed a dose-dependent hypotensive effect in SHR, DHR and RHR but not in WKY. The hypotensive effect of KT-611 reached maximum at 0.5-1 hr, lasted for 4-6 hr and was more potent in DHR and RHR than in SHR. The potency of KT-611 was 1/10-1/30 weaker than that of prazosin. In RHD, single oral administration of KT-611 (1 to 10 mg/kg) caused a dose-dependent and long-lasting hypotensive effect. These results suggest that KT-611 has a long-lasting hypotensive effect in experimental hypertensive animal models.