Toshiaki Tamaki

Effects of a synthetic rat adrenomedullin on regional hemodynamics in rats

The effects of rat adrenomedullin, a novel vasorelaxant peptide, on systemic and regional hemodynamics were examined in conscious Sprague Dawley (SD) rats and spontaneously hypertensive rats (SHR). The intravenous infusion of adrenomedullin at rates of 1.67 and 5 micrograms/kg per min decreased the mean arterial pressure in a dose-dependent fashion in both types of rats. Adrenomedullin at a rate of 5 micrograms/kg per min increased the heart rate and cardiac output. As a result, the total peripheral resistance significantly decreased. With regards to the regional hemodynamics, adrenomedullin significantly increased the flow rates in the lungs, heart, spleen, kidneys, adrenal glands and small intestine of SHR. The flow rates in the brain and skin did not change and the flow rates in the skeletal muscle and testis were decreased. These regional hemodynamic changes were also observed in SD rats and there was no qualitative difference in the regional responses to adrenomedullin between SHR and SD rats. Thus, adrenomedullin predominantly increased the flow rates in organs in which adrenomedullin gene was highly expressed. It therefore seems that adrenomedullin may act as a local vasodilatory hormone rather than as a circulatory hormone.

Nitric oxide may participate in V2 vasopressin-receptor-mediated renal vasodilation.

Using pentobarbital-anesthetized euvolemic dogs, we investigated whether vasopressin V2-receptor stimulation induced renal vasodilation and whether nitric oxide (NO) had a role in the process. Intrarenal infusion of arginine-vasopressin (AVP) resulted in renal vasoconstriction with pressor response. After preadministration of a V1-receptor antagonist, however, intrarenal infusion of AVP caused an increase in renal blood flow (RBF) without pressor action, indicating renal vasodilation. This renal vasodilation was not observed when we infused AVP after-simultaneous pretreatment with V1- and V2-receptor antagonists. Even in the absence of the V2-receptor antagonist, this renal vasodilation was attenuated by intrarenal infusion of L-NG-nitroarginine (L-NNA). Concomitant infusion of L-arginine prevented the inhibitory effect of L-NNA on renal vasodilation induced by intrarenal infusion of AVP in the presence of the V1-antagonist. These data indicate that the renal vasodilation caused by intrarenal infusion of AVP in the presence of a V1-antagonist was mediated by V2-receptor stimulation, and the inhibitory effect of L-NNA on V2-receptor-mediated renal vasodilation was attributed to its inhibitory effect on NO synthesis, suggesting that NO may participate in V2-receptor-mediated renal vasodilation.

Effects of EXP3174, a non-peptide angiotensin II receptor antagonist, on renal hemodynamics and renal function in dogs

We examined the effects of intrarenal infusion of EXP3174, a non-peptide angiotensin II receptor antagonist, in order to evaluate the physiological role of endogenous angiotensin II in regulating renal hemodynamics and urine formation and to assess the possibility of a tubular site(s) of action of endogenous angiotensin II in anesthetized dogs. Intrarenal infusion of EXP3174 at 15 micrograms/kg per min caused increases in renal blood flow (RBF), glomerular filtration rate (GFR), urine, flow and urinary electrolyte excretion. The lower dose of EXP3174 (0.5 micrograms/kg per min) did not change mean arterial pressure, RBF and GFR, but did increase urine flow. The fractional excretion of sodium, the fractional proximal excretion of sodium and the fractional distal excretion of sodium increased with lower doses of EXP3174 infusion. EXP3174 did not affect the linear relationship between the free water reabsorption rate and osmolar clearance. These data suggest that endogenous angiotensin II plays a significant role in regulating renal hemodynamics and urine formation and endogenous angiotensin II stimulates sodium reabsorption in the proximal and the distal portions of the tubules, with the exception of the medullary portion of the ascending limb of Henle.

Lack of vasodilatory response in skeletal muscle blood vessels of aged spontaneously hypertensive rats

SummaryRegional hemodynamic responses to the vasodilators, hydralazine (1mg/kg, i.v.) and verapamil (0.1 mg/kg/min, i.v.), were examined in conscious Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), 15 and 50 weeks of age, using the radioactive microsphere method. The flow rates of heart and skeletal muscle in SHR were higher than those in WKY, and the flow rates of liver, kidney, intestines, and skin in SHR were lower than those in WKY. These differences between the regional blood flow in WKY and SHR were observed in both aged and young rats. The changes in organ blood flow induced by hydralazine and verapamil were similar for WKY and SHR in most organs. Both drugs increased the skeletal muscle blood flow in WKY and young SHR, but not in aged SHR, that is, the skeletal muscle blood vessels in aged SHR lost their vasodilatory response. These results suggest that, although a lack of vasodilatory responses in the skeletal muscle vasculature of aged SHR may be triggered by persistent hypertension, the vital organ vasculature maintains its normal vasodilating capacity.