For an appropriate extrapolation to patients with peripheral arterial obstructive disease, we tested the efficacy of monocyte chemoattractant protein 1 (MCP-1) treatment in a porcine hindlimb ligation model. In 40 minipigs, a femoral artery ligation was performed. Control animals were examined immediately after ligation (n = 4) or after 2 wk of intra-arterial infusion of PBS (n = 11). A second group of animals was evaluated after intra-arterial infusion of 2.0 microg/h of MCP-1 for 48 h (followed by 12 days of PBS; n = 13) or 2 wk continuously (n = 12). In the terminal experiment after 2 wk, resting flow to the leg and peripheral arterial pressures were assessed without vasodilatation. Subsequently, vascular conductance was determined by using a pump-driven extracorporal circulation during maximal vasodilatation. The results showed that resting blood flow to the hindlimb was 53% of the normal after 2 wk of infusion of PBS, compared with 81% in both MCP-1 treatment groups (P < 0.05). Collateral conductance was 645 +/- 346 ml x min(-1) x mmHg(-1) after 2 wk of infusion with PBS, compared with 1,070 +/- 530 and 1,158 +/- 535 ml x min(-1) x mmHg(-1) after 48 h and 2 wk treatment with MCP-1, respectively (P < 0.05). Modulation of the process of arteriogenesis is feasible in this large animal model via intra-arterial infusion of the Cys-Cys-chemokine MCP-1.

Abstract-Cardiac hypertrophy is often associated with an increased sympathetic drive, and both in vitro and in vivo studies have demonstrated the development of cardiomyocyte hypertrophy in response to either ␣-or ␤-adrenergic stimulation. Because an association between the Na ϩ /H ϩ exchanger and cellular growth has been proposed, this study aimed to analyze the possible role of the antiporter in isoproterenol-induced cardiac hypertrophy. Isoproterenol alone (5 mg/kg IP once daily) or combined with a selective inhibitor of the Na ϩ /H ϩ exchanger activity (3 mg · kg) was given to male Wistar rats for 30 days. Sex-and age-matched rats that received 0.9% saline IP daily served as controls. Echocardiographic follow-up showed a 33% increase in left ventricular mass in the isoproterenol-treated group, whereas it did not increase in the isoproterenolϩBIIB723-treated group. Heart weight-to-body weight ratio at necropsy was 2.44Ϯ0.11 in controls and increased to 3.35Ϯ0.10 (PϽ0.05) with isoproterenol, an effect that was markedly attenuated by BIIB723 (2.82Ϯ0.07). Intense cardiomyocyte enlargement and severe subendocardial fibrosis were found in isoproterenol-treated rats, and both effects were attenuated by BIIB723. Myocardial Na ϩ /H ϩ exchanger activity and protein expression significantly increased in isoproterenol-treated rats compared with the control group (1.45Ϯ0.11 vs 0.91Ϯ0.05 arbitrary units, PϽ0.05). This effect was significantly reduced by BIIB723 (1.17Ϯ0.02, PϽ0.05). In conclusion, our results show that Na ϩ /H ϩ exchanger inhibition prevented the development of isoproterenolinduced hypertrophy and fibrosis, providing strong evidence in favor of a key role played by the antiporter in this model of cardiac hypertrophy. Key Words: hypertrophy, cardiac Ⅲ signal transduction Ⅲ antiporters Ⅲ fibrosis Ⅲ adrenergic receptor agonists I ncreased sympathetic activity is often implicated in the development of cardiac hypertrophy (CH). A correlation between cardiac mass and sympathetic activity was found in young hypertensive humans, 1 and long-term infusion of subpressor doses of norepinephrine leads to CH in dogs and rats. 2,3 This cardiotrophic effect of catecholamines involves both ␣-or ␤-adrenergic receptors. 4 It is well recognized that repeated or continuous injections of the ␤-adrenoceptor agonist isoproterenol (Iso) causes, within days, clear CH, 5 and therefore it represents a useful experimental model.Although several mechanisms have been imputed to underlie the cardiotrophic action of Iso, 5-7 the exact nature is still under debate. Because cumulative evidence supports a cause-effect link between the activity of the Na ϩ /H ϩ exchanger (NHE) and cardiac cell growth (Cingolani and Camilión de Hurtado 8 ), we sought to analyze the possible role of NHE activity in Iso-induced CH by taking advantage of the specific, orally active inhibitor against NHE isoform 1 (NHE-1). This study provides evidence indicating a key role for NHE-1 activity as a mechanism underlying the development of CH and fibrosis induced by I...

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The purpose of the present study was to investigate the renoprotective effect of telmisartan, an angiotensin II receptor antagonist, on the early stages of diabetic nephropathy in obese Zucker rats, which is a type 2-related diabetes mellitus model. Telmisartan 1, 3 or 10 mg/kg/day was orally administered to 7-week-old rats that demonstrated glucose tolerance without albuminuria or proteinuria, for 24 consecutive weeks (Experiment A). In another experiment (Experiment B), oral administration of telmisartan 10 mg/kg/day was initiated at the age of 16 weeks after the rats demonstrated marked proteinuria, and continued for 24 weeks. Telmisartan inhibited the increase in proteinuria and albuminuria in a dose-dependent manner, and the inhibition for all telmisartan groups was statistically significant by the completion of administration (Experiment A). Telmisartan also displayed similar inhibitory effects on proteinuria and albuminuria in Experiment B. Histologically, telmisartan [3 and 10 mg/kg/day] was associated with a significant decrease in the progression of glomerulosclerosis, and significantly improved interstitial cell infiltration, interstitial fibrosis and dilation and atrophy of renal tubules. Furthermore, telmisartan treatment was associated with a tendency towards normalized plasma lipids (total cholesterol and triglyceride). Our results suggest that telmisartan has a definite renoprotective effect against renal injury in type II diabetic nephropathy.

Severe blood loss is a major cause of death occurring within hours of traumatic injury. Na+/H+ exchange (NHE-1) activity is an important determinant of the extent of ischemic myocardial injury. The goal of the present study was to test the hypothesis that NHE-1 inhibition delays the onset of hypovolemic circulatory shock, thereby preventing early death due to severe hemorrhage in pigs. Severe hypovolemia was studied in 16 (25.2 kg) anesthetized male pigs in steps of 10-, 20-, 30-, 40-, and 50-mL kg(-1) blood loss, each in 30-min intervals. Shed blood resuscitation was started 30 min after 50 mL kg(-1) blood loss. The experiment was terminated after 3 h of resuscitation. Eight pigs were used as seline control. Eight pigs received 3 mg kg(-1) benzamide, N-(aminoiminomethyl)-4-[4-(2-furanylcarbonyl)-1-piperazinyl]-3-(methylsulfonyl), methanesulfonate (NHE-1 inhibitor) 15 min before hemorrhage. Seven control pigs died at 40- to 50-mL kg(-1) blood loss. One control pig survived initial resuscitation but died soon after. In contrast, all animals treated with NHE-1 inhibitor survived the entire protocol. In control animals, cardiac output and MAP gradually decreased at each step of blood loss with marked increase in heart rate. Cardiovascular decompensation occurred at 40 mL kg(-1) blood loss. Na+/H+ exchange inhibition increased oxygen delivery, attenuated cardiovascular decompensation, delayed the onset of irreversible hypovolemic circulatory shock, and enabled resuscitation to survival. Echocardiography analysis showed that myocardial hypercontracture gradually developed with each step of blood loss in control animals, but this hypercontracture was attenuated in the animals receiving the NHE-1 inhibitor. We conclude that NHE-1 inhibition attenuates ischemic myocardial hypercontracture, cardiovascular decompensation, delays the onset of hypovolemic circulatory shock, and prevents early death in severe hemorrhage.