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J F Smits

Publications and source records attributed to J F Smits.

At least 127 records · Page 7Linked to original sources
PubMed1985

Pharmacological evidence for rapid destruction of efferent renal nerves in rats by intrarenal infusion of 6-hydroxydopamine.

In a previous study we reported that intrarenal (i.r.) infusion of 1 mg 6-hydroxydopamine (6-OHDA) in rats resulted in selective efferent denervation of the infused kidney. Although the vasoconstrictor response to electrical stimulation of the posterior hypothalamus (PH) was already abolished 24 h after infusion, norepinephrine (NE) content of the kidney was reduced by only approximately 50% at that time. In the present study, the status of renal nerves 45 min after infusion of 6-OHDA by i.r. application of scorpion venom (SV), a NE releasing agent, was investigated. In saline pretreated rats, 10 micrograms SV i.r. caused a rapid increase (+355 +/- 80%) in vascular resistance in the injected kidney, whereas only minor changes were observed in resistances of the non-injected kidney, mesentery and hindquarters. Pretreatment of animals with phentolamine (1 mg/kg i.v.) largely abolished the vasoconstrictor response (+57 +/- 20%), confirming dependence of the effect of SV on release of NE from nerve terminals. Finally, pretreatment with 1 mg 6-OHDA i.r. also resulted in abolition of renal vasoconstriction following SV (+7 +/- 6%). The results indicate that as early as 45 min after i.r. infusion of 1 mg 6-OHDA in rats, efferent renal nerve endings are no longer functional.

Animals↗
PubMed1985

Antihypertensive and haemodynamic properties of the renal vasodilator CGP 22 979A in conscious spontaneously hypertensive rats.

The acute haemodynamic and long-term antihypertensive properties of the renal vasodilator pro-drug CGP 22 979A (N-acetyl-L-glutamic acid-N-[N2-(5-n-butyl-2- pyridyl)-hydrazide]) were studied in conscious, chronically instrumented spontaneously hypertensive rats (SHR). Its effects were compared with those of its parent substance CGP 18 137A (2-hydrazino-5-n-butyl-pyridine) which is a general arteriolar dilator. CGP 18 137A (0.3-1 mg/kg) caused an immediate reduction in mean arterial pressure (MAP) and total peripheral resistance index (TPRI). These effects were paralleled by reflex increases in heart rate (HR) and cardiac index (CI). In high doses CGP 22 979A (30 mg/kg) caused similar effects. In contrast, lower doses of CGP 22 979A (3-10 mg/kg) did not reduce MAP or TPRI acutely. However, these doses caused a more gradual reduction in MAP without reflex increase in HR or CI. In long-term experiments a 7-day continuous infusion of CGP 18 137A (0.1-1 mg/kg per day) or a high rate of CGP 22 979A (30 mg/kg per day) reduced MAP with parallel reflex rises in HR. Ten mg/kg per day CGP 22 979A caused a gradual reduction in MAP without reflex tachycardia.

Animals↗
PubMed1985

Preferential renal vasodilator effects of CGP 22979A in conscious spontaneously hypertensive rats.

CGP 18137A (2-hydrazino-5-n-butyl-pyridine) and its prodrug CGP 22979A [N-acetyl-L-glutamic acid-N-[N2-(5-n-butyl-2-pyridyl)hydrazide]] were evaluated for their blood pressure-lowering potency and regional hemodynamic actions in conscious spontaneously hypertensive rats. The effects were compared to those of hydralazine. Animals were instrumented with miniaturized pulsed Doppler flowprobes to allow continuous simultaneous measurement of renal, mesenteric and hindquarter blood flow. From changes in mean arterial pressure and the respective flows, changes in renal, mesenteric and hindquarter resistance were calculated. After i.v. administration, hydralazine and CGP 18137A were equally potent with regard to their blood pressure-lowering effect in a dose range of 0.1 to 1 mg/kg. Hydralazine was more effective than CGP 18137A in lowering renal and hindquarter resistance. Neither of the two drugs, however, caused preferential dilation in any of the three beds studied. CGP 22979A in doses of 1 to 30 mg/kg caused a much smaller acute blood pressure-lowering response. However, already at low doses (1-10 mg/kg) it caused a significant reduction of renal resistance, without affecting either hindquarter or mesenteric resistance. At the highest dose (30 mg/kg), selectivity was no longer retained, which is probably due to excessive leakage of the active vasodilator into the peripheral circulation. These findings suggest that CGP 22979A is a renal-selective prodrug for CGP 18137A and thereby is capable of preferentially dilating the renal vasculature in conscious unrestrained spontaneously hypertensive rats.

Animals↗
PubMed1985

Effects of the renal vasodilator prodrug CGP 22 979A and its parent compound CGP 18 137A on renal and central hemodynamics in conscious spontaneously hypertensive rats.

In a previous study we reported that the renal prodrug CGP 22 979A (N-acetyl-L-glutamic acid-N-[N2-(5-n-butyl-2-pyridyl)-hydrazide) causes selective renal vasodilation in conscious spontaneously hypertensive rats (SHR) in doses up to 10 mg/kg. The hydralazine-like parent compound CGP 18 137A (2-hydrazino-5-n-butyl-pyridine) causes general vasodilatation. In the present study we report on renal hemodynamics, excretion of water and sodium and central hemodynamic effects of CGP 18 137A and CGP 22 979A in conscious, unrestrained SHR. CGP 18 137A (1 mg/kg) reduced effective renal plasma flow [measured as plasma clearance of [125I]p-aminohippuric acid] and glomerular filtration rate (measured as plasma-clearance of 51Cr-EDTA), in the first hour after injection. CGP 22 979A (3-30 mg/kg) dose-dependently increased effective renal plasma flow, but not glomerular filtration rate thus reducing filtration fraction. In spite of the lack of increase of glomerular filtration rate, CGP 22 979A increased excretion of sodium and water in a separate group of SHR. CGP 18 137A reduced renal excretory function slightly. In another group of conscious SHR we studied the effects of CGP 18 137A and CGP 22 979A on central hemodynamics. These animals had an electromagnetic flow-probe on the ascending aorta, to measure cardiac output (CO). Mean arterial pressure was measured from a chronic catheter in the abdominal aorta. Total peripheral resistance (TPR) and stroke volume were calculated. CGP 18 137A (0.3-1 mg/kg) reduced mean arterial pressure and TPR whereas CO increased immediately after injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Haemodynamic effects of bromocriptine in the conscious spontaneously hypertensive rat.

The systemic haemodynamic effects of 0.3 mg kg-1 bromocriptine s.c. in conscious, chronically instrumented spontaneously hypertensive rats (SHR) has been investigated. Bromocriptine caused a gradual, long-lasting significant fall in mean arterial pressure with a maximum of 26 +/- 3 mmHg (-17%). The fall was related to a significant decrease in stroke volume index (-9 +/- 2 microliters 100 g-1; -10%) and cardiac index (-3.9 +/- 0.8 ml min-1 100 g-1; -12%). No significant changes in heart rate or total peripheral resistance index were observed. These data do not support previous suggestions that the antihypertensive effect of bromocriptine is caused by inhibition of the release of vasopressor substances. It is suggested that bromocriptine causes a reduction of venous return of the blood to the heart, possibly related to intrarenal effects.

Animals↗
PubMed1984

Activation of afferent renal nerves by intrarenal bradykinin in conscious rats.

Bradykinin was infused intravenously and into the right renal artery of conscious rats that were chronically instrumented with catheters and miniaturized pulsed-Doppler flow probes. The effects on regional hemodynamics were compared with those in animals in which the infused kidney was denervated as well as in animals anesthetized with pentobarbital sodium. In intact rats bradykinin (1 microgram/min) caused an immediate increase in mean arterial blood pressure (MAP, 27 +/- 4 mmHg), heart rate (HR, 67 +/- 11 beats/min), mesenteric resistance (MR, 32 +/- 10%), and both right (RRR, 42 +/- 14%) and left renal resistance (LRR 21 +/- 8%). These effects were significantly different from those during intravenous infusion of the same dose of bradykinin (MAP, 6 +/- 3 mmHg; HR, 31 +/- 7 beats/min; MR, -21 +/- 5%; RRR, 8 +/- 4%; LRR, 6 +/- 3%). Pentobarbital greatly attenuated the responses to intrarenal bradykinin. In conscious animals denervation of the infused kidney completely abolished the cardiovascular effects of intrarenal bradykinin. In a separate group of animals, chlorisondamine (7.5 mg/kg iv) completely blocked the increases in MAP and HR during intrarenal bradykinin (1 microgram/min). It is concluded that selective renal administration of bradykinin alters afferent renal nerve activity and that this results in hemodynamic changes consistent with efferent sympathetic activation.

Afferent Pathways↗
PubMed1984

Evaluation of renal function during intrarenal norepinephrine infusion in conscious rats.

Previous studies have shown that intrarenal infusion of norepinephrine (NE) causes acute renal failure in anesthetized dogs and rats. We hypothesized that anesthesia prevents the kidney of escaping from the ischemic insult. In this paper, we report measurements of renal function parameters during acute as well as during chronic intrarenal NE infusion in conscious freely moving rats. Intrarenal NE application in doses of 4 and 36 micrograms/kg X h was performed via the suprarenal artery by means of subcutaneously implanted minipumps. During acute intrarenal NE infusion over a 2-hour period in anesthetized as well as conscious rats, renal blood flow (RBF) was determined by means of the pulsed Doppler flowmeter technique. During long-term NE administration for 5 days, glomerular filtration rate (GFR) was determined as clearance of 51Cr-EDTA and effective renal plasma flow (ERPF) as clearance of 125I-hippuric acid. Clearance measurements were performed on control day, and on the 1st and 4th day of intrarenal NE infusion; furthermore, on the 1st and 4th day after stopping the intrarenal NE infusion. Acute intrarenal administration of doses of NE higher than 12 micrograms/kg X h, in anesthetized rats immediately reduced RBF to zero levels. However, in conscious rats, neither acute nor chronic intrarenal NE application induced severe long-lasting reductions in GFR or RBF respectively ERPF at any dose of NE applied. Therefore, we conclude that no acute renal failure is induced during intrarenal NE infusion in conscious rats; this is probably due to protective neurogenic mechanisms which are relatively inactivated during pentobarbital anesthesia.

Acute Kidney Injury↗
PubMed1984

Calcium antagonists: systemic and regional haemodynamic effects in conscious spontaneously hypertensive rats (SHR).

The systemic and regional (renal, mesenteric and hindquarter) haemodynamic effects of the calcium antagonists verapamil, nifedipine and PY 108-068 [diethyl 4-(2, 1, 3-benzoxadiazol-4-yl)-1, 4-dihydro-2, 6-dimethylpyridine-3, 5-dicarboxylate] were studied in conscious, chronically instrumented spontaneously hypertensive rats (SHR). All three calcium antagonists caused a dose-dependent fall in mean arterial pressure (MAP) and total peripheral resistance. In intact animals the fall in resistance was related primarily to a vasodilatation in the hindquarter (mainly muscular) vascular bed. During the early fall in blood pressure a reflex rise in cardiac output and heart rate was observed following nifedipine and PY 108-068, but not after verapamil. Following sinoaortic baroreflex denervation the dose-response curve for the calcium antagonist-induced fall in blood pressure and total peripheral resistance was shifted to the left. Moreover, the calcium antagonists then caused a comparable degree of vasodilation in all three vascular beds studied. It is concluded that calcium antagonists preferentially dilate the muscular bed in intact animals; however, sinoaortic baroreflex denervation unmasks an unselective pattern of vasodilatation.

Animals↗
PubMed1983

Hemodynamic effects of the arteriolar vasodilators hydralazine, dihydralazine and endralazine in the conscious spontaneously hypertensive rat.

The hemodynamic effects of the vasodilators hydralazine, dihydralazine and endralazine were studied in conscious, unrestrained spontaneously hypertensive rats (SHR) equipped for chronic hemodynamic measurements. The arteriolar vasodilators hydralazine (0.3 mg/kg i.a.) and dihydralazine (0.3 mg/kg i.a.) caused a rapid fall in blood pressure and peripheral resistance, lasting up to 24 h in the case of dihydralazine. Immediately after injection, the cardiac output and heart rate were increased significantly. These effects only lasted for 1-2 h. The hemodynamic pattern of the new vasodilator endralazine (0.1-1 mg/kg i.a.) was very similar, with a duration of action similar to that of dihydralazine. The role of baroreceptor reflexes in the early hemodynamic effects of vasodilators was studied by comparing the effects of 0.3 mg/kg hydralazine in baroreflex-denervated and non-denervated SHR. The decrease in blood pressure and peripheral resistance was significantly larger in the denervated SHR, whereas increases in cardiac output and heart rate were almost completely absent in these animals. These data suggest that baroreceptor reflexes oppose the early fall in blood pressure and peripheral resistance induced by vasodilators. However, the activity of the baroreflex seems of very short duration, suggesting a rapid adaptation to the prevailing blood pressure. Moreover, the data show that endralazine is an effective arteriolar vasodilator in conscious SHR.

Animals↗
PubMed1983

Blood pressure response to chronic low-dose intrarenal noradrenaline infusion in conscious rats.

Sodium chloride solution (0.9%) or noradrenaline in doses of 4, 12 and 36 micrograms h-1 kg-1 was infused for five consecutive days, either intrarenally (by a new technique) or intravenously into rats with one kidney removed. Intrarenal infusion of noradrenaline caused hypertension at doses which did not do so when infused intravenously. Intrarenal compared with intravenous infusion of noradrenaline caused higher plasma noradrenaline concentrations and a shift of the plasma noradrenaline concentration-blood pressure effect curve towards lower plasma noradrenaline levels. These results suggest that hypertension after chronic intrarenal noradrenaline infusion is produced by relatively higher levels of circulating noradrenaline and by triggering of an additional intrarenal pressor mechanism.

Animals↗
PubMed1983

Chronic local infusion into the renal artery of unrestrained rats.

A method is described for providing chronic access to the right renal artery of unrestrained rats. It consists of insertion of a very thin (OD 0.2 mm) catheter into the right suprarenal artery of Wistar rats. The suprarenal artery originates from the right renal artery. After the cannula has been guided subcutaneously to the neck, it is connected to an Alzet osmotic minipump. The method has a success ratio of over 90% for periods up to 14 days. In the present study, we investigated the effects of catheter implantation on renal hemodynamics in uninephrectomized rats that were infused with saline for 2, 6, or 14 days. Values were compared with those obtained in control rats. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were estimated from plasma clearances of 51Crethylenediaminetetraacetic acid and 125I-p-aminohippuric acid, respectively. Mean arterial pressure was between 107 +/- 2 and 116 +/- 2 mmHg in all animals. Neither GFR nor ERPF was influenced by catheter implantation. It is concluded that the method does not interfere with renal function.

Animals↗
PubMed1983

Hemodynamic actions of diuretic agents.

The blood pressure lowering effect of diuretics in hypertensive disease is well documented. The hemodynamic actions underlying this antihypertensive effect differ in the early phase from the effects observed during long-term treatment. This article first describes new experiments on the hemodynamic effects of three diuretics, viz. hydrochlorothiazide, chlorthalidon and furosemide in conscious, chronically instrumented spontaneously hypertensive rats. This animal model was chosen in view of its good applicability for the study of the hemodynamics of antihypertensive drug action. Results show a marked early fall in stroke volume and cardiac index with all three diuretics. Mean arterial blood pressure was decreased only after a delay of several hours, because of an early large increase in total peripheral resistance. This article furthermore discusses possible mechanisms involved in the long-term return of peripheral resistance close to or below pre-treatment values. On the basis of data in the literature it is concluded that adaptation of baroreceptor reflexes, auto-regulatory responses of the peripheral vascular resistance and enhanced production of endogeneous vasodilator substances play an increasingly important role during the long-term hemodynamic actions of diuretic agents.

Animals↗
PubMed1982

Baroreflex sensitivity during the development of spontaneous hypertension in rats.

1. Baroreflex sensitivity was studied in relation to the development of spontaneous hypertension in rats (SH rats), with normotensive Wistar-Kyoto (WKY) rats as controls. Conscious, freely moving animals were studied at different times, ranging from 4 to 20 weeks after birth. 2. The youngest SH rats (4-6 weeks; n = 10) already had significantly (P less than 0.01) higher mean arterial blood pressure (112 +/- 2 mmHg) than WKY rats of corresponding age (95 +/- 4 mmHg; n = 10). Baroreflex sensitivity did not differ at this age (0.37 +/- 0.04 vs 0.38 +/- 0.05 ms/mmHg). 3. Mean arterial pressure increased rapidly in SH rats during further development, reaching a value of 166 +/- 3 mmHg in 12-20 week old animals (n = 25). In equally old WKY rats blood pressure was significantly (P less than 0.001) lower (110 +/- 6 mmHg, n = 25). Baroreflex sensitivity did not change during development of SH rats (0.40 +/- 0.03 ms/mmHg in 12-20 weeks old SH rats), whereas it increased two- to three-fold in WKY rats (0.93 +/- 0.08 ms/mmHg, P less than 0.001). 4. It is concluded that an increase in baroreflex sensitivity is part of the development of a normotensive cardiovascular system, whereas in SH rats responsiveness of the baroreceptor reflex remains depressed during the development and stabilization of hypertension.

Animals↗
PubMed1982

The mechanisms of antihypertensive action of beta-adrenergic receptor blocking drugs.

Beta-adrenergic receptor blockers lower blood pressure in hypertensive patients and spontaneously hypertensive rats (SHR). The fall in blood pressure is associated with a complex chain of hemodynamic events. The transient effects differ from long-term changes. After reviewing the dynamics of beta-blocker induced hemodynamic changes, we propose a scheme to explain both short-term and long-term effects. In this scheme it is suggested that the primary effects are (1) a fall in cardiac output through blockade of cardiac beta-adrenergic receptors and (2) a promotion of renal tubular sodium and water loss by blockade of renal tubular beta-adrenergic receptors. The initial reactions of the cardiovascular control system to these effects as well as the final adaptations are discussed. It is suggested that for future developments in the field of beta-adrenergic control of blood pressure further analysis of the renal tubular sympathetic control of sodium and water excretion is necessary.

Adrenergic beta-Antagonists↗