Different Effects of Various Vasodilators on Autoregulation of Renal Blood Flow in Anesthetized Dogs
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Different Effects of Various Vasodilators on Autoregulation of Renal Blood Flow in Anesthetized Dogs Nobuyuki OGAWA and Hiroshi ONO Department of Pharmacology and Toxicology, Hatano Research Institute, Food and Drug Safety Center, 729-5 Ochiai, Hadano, Kanagawa 257, Japan Accepted March 24, 1986 Abstract-In order to examine whether the autoregulation of renal blood flow is equally influenced by all kinds of vasodilators, kidney perfusion experiments were performed in anesthetized dogs. The perfused kidney usually showed excellent autoregulation of blood flow over the perfusion pressure between 120 and 200 mmHg. Renal blood flow was increased by the renal arterial infusion of diltiazem (100 /cg/min), papaverine (10 mg/min) or nicorandil (300 ig/min) (at the basal perfusion pressure of 100 mmHg) and was maintained at an increased level while the infusion was continued. On the other hand, renal blood flow was increased only transiently by the infusion of nitroglycerin (50 ,ug/min), and the blood flow gradually decreased to the basal level in spite of the continuous infusion. Infusions of diltiazem and papaverine abolished the autoregulation of renal blood flow besides the vasodilator effect, but infusions of nitroglycerin and nicorandil have no effect on the autoregulation. Furthermore, sodium nitroprusside (30 /~g/min) and sodium nitrite (5 mg/min), which are assumed to produce vasodilation through cyclic GMP, also have no effect on the autoregulation of renal blood flow. In conclusion, all the vasodilators do not influence the renal blood flow autoregulation , and vasodilation caused by cyclic GMP is unconnected with the myogenic mechanism regulating the renal blood flow. The autoregulation of renal blood flow is renal blood flow. In other words, some the maintenance of a stable blood flow level substances produce vasodilation without in spite of fluctuation in the renal perfusion affecting the myogenic response of the renal pressure. The presently accepted mechanism vascu lature. of the autoregulation is the myogenic The present study is to examine whether response of the vascular smooth muscle or not there exists a common mechanism adjusting the vascular tone to the change of among vasodilators which do not impair the perfusion pressure. This myogenic theory is autoregulation of renal blood flow. supported by the evidence that the auto regulation is effectively abolished by Materials and Methods vasodilators, such as papaverine, amino Twenty-seven mongrel dogs of either sex, phylline, verapamil and nifedipine (1-3). weighing 11-17 kg, fed on a pellet dog food Kiil et al. (4) reported that infusion of (CD-5, Clea Japan Co.) were anesthetized acetylcholine into the renal artery produced with a-chloralose (40 mg/kg) and urethane potent vasodilation on canine kidney, but (400 mg/kg) intravenously, preceded by failed to impair the autoregulation. We have sedation with morphine hydrochloride (2 mg/ obtained similar results with acetylcholine kg, s.c.). Pressure-controlled perfusion experi (N. Ogawa and H. Ono, unpublished results) ments were performed with the left kidney. and also with prostaglandin E2 and bradykinin Details of the procedure have been described (5). Thus, there are vasodilators devoid of previously (5). The left renal artery was potency to abolish the autoregulation of cannulated and perfused with blood con ducted from the carotid artery. An initial dose values of the control and during a drug of 500 U/kg of sodium heparin was given as treatment was done according to the paired anticoagulant. When necessary, smaller doses t-test, and those between groups was done of a-chloralose and urethane were supple according to Student's t-test (P<0.05). mented, and sodium heparin was supple mented constantly by 100 U/kg/hr. Perfusion Results pressure was controlled by the use of a Systemic blood pressure and renal blood Starling's pneumatic resistance. Perfusion flow: Table 1 shows the mean values for mean pressure and systemic blood pressure in the systemic blood pressure and renal blood flow femoral artery was measured with electric at the perfusion pressure of 100 mmHg, manometers (transducers: Statham P23Db before and during infusion of drugs. Renal and carrier amplifiers: San-ei 1206B). Renal blood flow was increased by the intra blood flow was measured by an electro arterial infusion of diltiazem (100 ttg/min), magnetic flowmeter (Narco RT-500). A test papaverine (10 mg/min), nicorandil (300 drug solution was infused into a rubber tube /-,g/min), sodium nitroprusside (30 fig/min) connected close to the shank of the renal and sodium nitrite (5 mg/min). The increase arterial cannula by the aid of an infusion of blood flow reached a maximum within pump (Harvard Apparatus 901). 3 min after the onset of the infusion and was Renal blood flow was allowed to stabilize sustained at an increased level during the for 30 min at the basal perfusion pressure of infusion. Mean systemic blood pressure was 100 mmHg; then perfusion pressure was significantly decreased by the infusion of changed stepwise between 60 and 200 each one of these drugs. The infusion of mmHg. After the control observation of the nitroglycerin (50 ,ag/min), however, produced blood flow responses to the stepwise changes only a transient vasodilation, and the initial of perfusion pressure between 60 and 200 vasodilation was nullified in spite of con mmHg, the infusion of a drug was started at tinuous infusion, though a decrease in the the basal perfusion pressure of 100 mmHg, systemic blood pressure was obvious and and pressure-flow relation was examined sustained. Then, the effect of nitroglycerin on again. the renal autoregulation was examined at the Following drugs were studied: diltiazem infusion rate of 50 iig/min. The infusion of hydrochloride (Tanabe), papaverine hydro 100 ,ug/min of diltiazem did not cause a chloride (Nakarai), nitroglycerin (NGA significant increase of blood flow below the 800128, 0.5 mg/ml aqueous solution, perfusion pressure of 80 mmHg. The infusion Nippon Kayaku), nicorandil (Chugai), of papaverine and nitro-compounds except sodium nitroprusside (Wako) and sodium nitroglycerin caused vasodilation at all nitrite (Wako). All drugs were dissolved in ranges of perfusion pressure. or diluted with saline. The dose of the drug is Autoregulation of renal blood flow: expressed as the weight of the base. Control observation usually confirmed The efficiency index of autoregulation excellent autoregulation of the renal blood (ARI) was calculated as follows (6): flow between 120 and 200 mmHg of the perfusion pressure and partial autoregulation between 100 and 120 mmHg. The blood flow changed pressure-dependently below where the renal blood flow changes to 100 mmHg. RBF2 from the initial value of RBF1 when Figure 1 illustrates the effects of diltiazem renal arterial (perfusion) pressure is altered (30 and 100 /tg/min) and papaverine (10 to PRA2 from the initial value of PRA,. mg/min) on autoregulation of renal blood Efficiency of the autoregulation was con flow. Autoregulation of renal blood flow was sidered as follows: ARI<0.3: excellently clearly abolished by diltiazem and papaverine. effective, ARI=0.3-0.7: partially effective, Simultaneous infusion of CaCI2 (30 mg/min) and ARI>0.7: virtually absent. restored the autoregulation impaired by 30 Statistical analysis of differences between zcg/min of diltiazem, but it was not effective Table 1. Mean systemic blood pressure and renal blood flow before and during the infusion of a drug at basal perfusion pressure of 100 mmHg Fig. 1. Effects of (A) diltiazem (0Q: control, ~ -A: 30 ug/min, A----A: 100 ,ug/min, 17------V: simultaneous infusion of 30 mg/min of CaC12 and 30 pg/min of diltiazem, n=5) and (B) papaverine (0O: control, A---0: 10 mg/ min, n=5) on the pressure-flow curves in perfused dog kidney. Symbols and vertical bars represent means and S.E., respectively. *shows a significant difference from the corresponding value of the control (P<0.05). on restoring the autoregulation impaired by the vasodilators are shown in Table 2. The papaverine (not shown in the figure). Figures control ARI is in all experiments were less 2 and 3 illustrate the effects of nitroglycerin, than 0.5 between 100 and 120 mmHg and nicorandil, sodium nitroprusside and sodium less than 0.3 between 120 and 200 mmHg, nitrite on the autoregulation of renal blood indicating an effective autoregulation. ARI's flow. The infusion of nicorandil (300 /cg/ during infusion of nitroglycerin, nicorandil, min), sodium nitroprusside (30 /cg/min) or sodium nitroprusside and sodium nitrite sodium nitrite (5 mg/min) caused an increase were also less than 0.3 between 120 and in renal blood flow at all ranges of perfusion 200 mmHg, showing that the autoregulation pressure, but did not impair the auto was not influenced. On the other hand, the regulation, shifting the pressure-flow curve ARI's during infusion of diltiazem were upward. Nitroglycerin (50 /Lg/min) also increased at any perfusion pressure range. could not abolish the autoregulation in This effect was dose-related and ARI became addition to the lack of sustained vasodilation nearly 1.0 with the infusion of 100 /Lg/min as stated above, though the change in the of diltiazem, showing a complete abolition systemic blood pressure obviously showed of the autoregulation. ARI's during simul the effectiveness of the drug. Pressure-flow taneous infusion of CaCl2 (30 mg/min) curves before and during infusion of nitro with diltiazem (30 /ig/min) recovered to the glycerin overlapped each other. control value for 140-200 mmHg of perfusion ARI's before and during the infusion of pressure. ARI's were also increased by 10 Fig. 2. Effects of (A) nitroglycerin (Q Q: Fig. 3. Effects of (A) sodium nitroprusside control, z---0: 50 ,ug/min, n=4) and (B) (0-0: control, 0-- \: 30 yg/min, n=5) and nicorandil (0-0.