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Biomedical subjects

J F Smits

Publications and source records attributed to J F Smits.

At least 91 records · Page 5Linked to original sources
PubMed1991

Angiotensin I converting enzyme inhibitors and cardiac remodeling.

Angiotensin I converting enzyme (ACE) inhibitors are widely used in the treatment of heart failure. It is not known whether the beneficial effects of ACE inhibition are only due to a reduction in pre- and afterload or whether ACE inhibition also has direct effects on cardiac remodeling processes after myocardial infarction. In addition, the effects of differential timing of the treatment are not known. The left coronary artery was ligated in rats to induce a myocardial infarction. Control rats received no treatment. Captopril was given via s.c. placed minipumps (500 micrograms/kg.h) in the first 3 weeks or in the third and fourth week after induction of the myocardial infarction. The structural changes of the heart were investigated. Early after ligation the left ventricle was dilated in association with a marked, but transient DNA synthesis in the remaining left ventricle; the amount of collagen also increased. Early captopril treatment blocked this response, while late treatment had no effects. We suggest that the negative effects of early captopril treatment are due to an interference with the normal adaptive responses of the heart to the loss of muscle, probably through interactions at the cellular level.

Adaptation, Physiological↗
PubMed1990

Beneficial hemodynamic effects of two weeks' milrinone treatment in conscious rats with heart failure.

Milrinone is a phosphodiesterase inhibitor which combines vasodilating effects with inotropic effects. Hemodynamic improvement after acute administration and increased survival with chronic milrinone therapy in rats with heart failure have been reported before, and suggest long-term hemodynamic improvement. However, no detailed hemodynamic studies are available on prolonged milrinone therapy in rats with heart failure. Therefore, the hemodynamic effects of 2 weeks' milrinone therapy were now investigated in conscious rats with heart failure due to myocardial infarction. The effects were compared to hemodynamic changes after acute administration. Acute milrinone increased the baseline cardiac output in infarcted rats by increasing heart rate rather than stroke volume. However, the maximal cardiac output achieved when the heart was stimulated through a volume load was improved due to increased stroke volume as well as increased heart rate. The increase in maximally stimulated cardiac output after acute milrinone was found to be related to infarct size. Two weeks' milrinone therapy in chronically infarcted rats dose dependently restored the hemodynamic changes which were caused by infarction. In contrast to acute administration, two weeks' milrinone restored cardiac function without an increase in heart rate. The effects were achieved at a rate of administration which presumably has no acute inotropic effects. The data indicate that acute milrinone in infarcted rats has vasodilating effects. Positive inotropic effects, possibly masked by concomitant venodilatation at baseline conditions, became overt after stimulation by volume loading. Long-term milrinone dose dependently restored cardiac function in infarcted rats without effects on heart rate or mean arterial pressure, suggesting that different mechanisms may be involved.

Animals↗
PubMed1990

Atrial natriuretic factor increases albumin extravasation in conscious rats.

Atrial natriuretic factor (ANF) lowers blood volume in intact and anephric experimental animals. The latter observation suggests extravasation of plasma at the level of the microcirculation. In view of the differential regional hemodynamic responses to ANF, the present study investigates possible regional differences in plasma extravasation measured as regional albumin clearances in skeletal muscle, lung, brain, ileum, and skin. In control animals, there were pronounced regional differences in clearances with highest values in ileum (0.248 +/- 0.015 microliter/min.g tissue) and lowest in brain (0.010 +/- 0.002 microliter/min.g tissue). Plasma-volume was 3.58 +/- 0.07 ml/100 g b.w. ANF (1 microgram/kg.min) significantly reduced plasma-volume (3.20 +/- 0.06 ml/100 g b.w.). This was associated with significantly increased albumin clearances in skeletal muscle and ileum, but not in other tissues examined. The data indicate that ANF increases albumin extravasation. This suggests that, besides effects on renal function and vascular tone, ANF also affects blood volume through influencing the relationship between intra- and extravascular volume.

Animals↗
PubMed1990

Physiological role of ANP under resting and volume expanded conditions in normotensive rats.

To study the physiological role of the atrial natriuretic peptide in the control of hemodynamics and renal function, circulating ANP was reduced by surgical bilateral atrial appendectomy (circulating ANP levels: 153 +/- 15 pg/ml for sham animals, and 95 +/- 11 pg/ml for appendectomized rats) and the relationships between central venous pressure (CVP), plasma ANP and renal function were studied. Mean arterial pressure (MAP), heart rate (HR), CVP, plasma ANP, urine volume (UV) and sodium (UVNa) excretion were measured under basal conditions, during and after a volume load of 6 ml iso-oncotic Ringer's solution. Basal hemodynamic variables were not different between sham and appendectomized rats. CVP was significantly higher during the volume load in appendectomized rats whereas other hemodynamics were not different during and after the volume load. Plasma ANP was significantly reduced in appendectomized rats before, during and after the volume load. Basal urine and sodium excretion were not different whereas stimulated urine and sodium excretion were significantly reduced in appendectomized rats. ANP levels were not totally dependent on CVP during volume load and urine and sodium excretion were of late onset, compared to the onset of increased circulating ANP. This study indicates that circulating ANP plays an important role in volume expanded conditions but there is a dissociation between circulating ANP and renal excretion. Our data suggest involvement of a volume shift from intra-to extravascular space.

Analysis of Variance↗
PubMed1990

The pharmacology of calcium antagonists: a review.

Calcium antagonists are a group of drugs with widely varying pharmacological properties and a broad range of therapeutic applications. At least four major types of calcium antagonists can be distinguished on the basis of chemical structures and profile of activity: phenylalkylamines, dihydropyridines, benzothiazepines, and piperazines. Each of these subgroups interferes with calcium transport over excitable membranes. Different types of calcium channels have been identified. The molecular properties as well as the differential binding characteristics of the subgroups of calcium antagonists have been defined. Although all calcium antagonists share an ability to dilate blood vessels, there is a marked difference in potency and selectivity, even within the individual subgroups. The dihydropyridines are relatively selective antagonists of vascular smooth muscle cell calcium uptake. They have a marked sensitivity to inhibit myogenic vascular tone. This may contribute to their predominant in vivo effect on vascular beds characterized by a relatively high myogenic tone, such as the coronary and skeletal muscle beds. Additional mechanisms contributing to the antihypertensive mode of action of dihydropyridines may include an interference with neural control of the circulation as well as intrarenal actions to promote electrolyte and water excretion. A relatively unexplored area of potential importance in the long-term mode of antihypertensive action of calcium antagonists is their effect on the structural design of blood vessels.

Animals↗
PubMed1990

Renal selective N-acetyl-gamma-glutamyl prodrugs: a study on the mechanism of activation of the renal vasodilator prodrug CGP 22979.

1. In this study the processes underlying the renal selectivity of the vasodilator prodrug CGP 22979 (N-acetyl-L-glutamic acid-N-[N2-(5-n-butyl-2-pyridyl) hydrazide]) were studied in rats. 2. The active drug CGP 18137 (2-hydrazino-5-n-butyl pyridine) selectively accumulated in the renal tissue following administration of the prodrug. 3. The kidney concentrations of active drug following prodrug administration were significantly lower than control values when either buthionine sulphoximine, glutathione or probenecid was coadministered (29 +/- 11; 33 +/- 14 and 61 +/- 20% of control values, respectively). Inhibition of gamma-glutamyl transpeptidase by AT-125 did not cause a significant decrease of renal CGP 18137 levels. 4. In order to correlate tissue drug concentrations with pharmacological effect, the renal haemodynamic responses to CGP 22979 were measured and the effect of buthionine sulphoximine, glutathione and AT-125 on these responses evaluated. All three of the compounds attenuated the renal response to the prodrug: an approximately 50% lesser decrease in renal resistance was found. The compounds had no effect on the haemodynamic actions of CGP 18137 itself. 5. In vitro, it was found that kidney cytosol was able to convert the prodrug, whereas microsomes were not, unless acylase was added. 6. The results indicate that, upon prodrug administration, gamma-glutamyl transpeptidase is not involved in the renal accumulation of CGP 18137 but is partly responsible for the renal haemodynamic responses to CGP 22979. Active transport of the prodrug into the tubular cells appears to be the major reason for the renal selectivity. A model is proposed for the renal action of CGP 22979, in which the important parts are the uptake of the prodrug via a transport system followed by an intracellular conversion to the active drug.

Animals↗
PubMed1989

Acute arteriolar vasoconstriction following furosemide in conscious spontaneously hypertensive rats.

In a previous study in conscious spontaneously hypertensive rats (SHR), we observed an immediate decrease in the cardiac index (CI) and an increase in the total peripheral resistance index (TPRI) following the administration of furosemide. The present study was designed to evaluate the regional hemodynamic effects and the involvement of sinoaortic baroreceptors in the increase in TPRI. In SHR instrumented for the measurement of central hemodynamics, 8 mg.kg-1 furosemide decreased CI from 31.0 +/- 2.5 ml.min-1.100 g bw-1 by 9.5 +/- 1.3 ml.min-1.100 g bw-1 (n = 7). TPRI increased maximally from 5.7 +/- 0.8 by 2.7 +/- 0.5 mm Hg.min.100 g bw.ml-1. The effect on TPRI was not affected by sinoaortic denervation (SAD) to abolish arterial baroreflexes. However, furosemide induced a significantly greater decrease in CI (-12.6 +/- 1.2 ml.min-1.100 g bw-1; n = 7) after SAD. Furosemide effectively reduced the mean arterial pressure in SAD SHR (-21 +/- 9 mm Hg) but not in sham-denervated SHR. Furosemide (8 mg.kg-1) reduced renal, mesenteric and hindquarter blood flow to a comparable extent (approximately 20%) in intact SHR. The reduction in renal flow at 3.5 min after injection (-17.9 +/- 4.1%; n = 8) was significantly greater than the reduction in mesenteric (-7.1 +/- 4.7%) and hindquarter blood flow (-4.2 +/- 3.7%), suggesting that the renal bed responds faster. Thereafter, the flow reductions in the three beds were not different. The results show that furosemide causes a general vasoconstriction in conscious SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Liver blood flow measurement in the rat. The electromagnetic versus the microsphere and the clearance methods.

This study describes the simultaneous measurement of hepatic arterial and portal venous blood flow in the pentobarbital anesthetized rat by means of electromagnetic flowmeters. Hepatic arterial flow was 0.21 +/- 0.02 mL/min/g liver, and portal venous flow was 1.53 +/- 0.19 mL/min/g liver (n = 20). Flows remained stable for more than 3 hr. A clear advantage of the electromagnetic technique is that it allows the continuous simultaneous separate measurement of hepatic arterial and portal venous blood flow. Simultaneous measurement of hepatic blood flow by the electromagnetic method and the microsphere method yielded almost identical results. Adenosine infusion (100 micrograms/min) did not affect hepatic blood flow measured electromagnetically nor via the microsphere technique. The suitability of indocyanine green (ICG) as an indicator of hepatic blood flow was evaluated by comparing the ICG clearance at steady-state conditions to the values of liver flow obtained by direct electromagnetic measurement. ICG clearance was only 30% of the electromagnetically measured blood flow. These data strongly suggest that ICG clearance does not reflect liver flow in the rat. Intravenous infusion of the vasoactive agents phenylephrine (2, 4, 10 micrograms/min during 5 min) and adenosine (20, 40, 200 micrograms/min) did not affect portal venous nor hepatic arterial flow, measured by the electromagnetic method, although brisk effects on mean arterial blood pressure were observed. This suggests autoregulatory responses of the hepatic vascular bed. The data suggest that electromagnetic flowmeters may be used to measure portal venous and hepatic arterial flow simultaneously in anesthetized rats. The continuous measurement of both flows simultaneously offers a clear advantage over other methods of hepatic flow measurement.

Adenosine↗
PubMed1989

Antihypertensive action of beta-adrenoceptor blocking drugs. The role of intrarenal mechanisms.

The different modes of antihypertensive action of beta-adrenoceptor blocking drugs are reviewed with a special emphasis on renal mechanisms of action. Beta-adrenoceptors occur in the kidney at the level of the juxtaglomerular and tubular cells. Direct intrarenal effects of beta-blockers include the decrease in renin release and the enhanced tubular excretion of fluid and electrolytes. Beta-blockers also influence renal function in a more indirect way by altering the activity of different extrarenally formed hormones with an effect on fluid and electrolyte excretion, such as angiotensin II, atrial natriuretic factors and prostaglandins. Several beta-blockers have an additional effect on the renal vasculature. One of these, tertatolol, is a renal vasodilator beta-blocker in different species. The possible mechanisms of renal vasodilatation of tertatolol are reviewed. It is concluded that the shift of the renal pressure-diuresis curve is an essential feature in the mode of long-term antihypertensive action of beta-blockers.

Adrenergic beta-Antagonists↗
PubMed1989

Effects of complete renal denervation and selective afferent renal denervation on the hypertension induced by intrarenal norepinephrine infusion in conscious rats.

To test the hypothesis that continuous intrarenal norepinephrine (NE) infusions produce hypertension via activation of afferent renal nerves (ARN), rats were subjected to complete renal denervation (RN-x), selective renal deafferentation (ARN-x) or sham surgery, prior to infusion of NE. In the pre-infusion period, mean arterial pressure (MAP) was significantly lower in RN-x than in ARN-x or sham-operated rats. Plasma renin concentration (PRC) was significantly reduced following ARN-x, but not RN-x. During 5-day intrarenal infusions of 4, 12 or 36 micrograms NE/kg per h, MAP rose to similar levels in RN-x and sham-RN-x rats. However, RN-x rats exhibited significantly elevated PRC levels, suggesting that denervation supersensitivity masked the possible effects of RN-x. In sham-RN-x rats, MAP increased significantly more during intrarenal infusion of 12 micrograms NE/kg per h than during intravenous infusion of the same amount. In ARN-x rats, MAP rose to a similar degree during intravenous and intrarenal infusions. The pressor responses in the ARN-x rats, however, were not significantly smaller at any point than those in intact rats. PRC rose to comparable levels in ARN-x and intact rats. Thus, in normotensive rats, efferent renal nerves (ERN) but not ARN are of functional significance in maintaining basal blood pressure. ARN may be involved in the control of renin release. Since neither RN-x nor ARN-x attenuated the development of hypertension, renal nerves are not necessary for the full expression of hypertension in this model.

Afferent Pathways↗
PubMed1989

Hemodynamic effects of activation of renal and mesenteric sensory nerves in rats.

Afferent nerves from the kidney and mesentery reflexly influence the cardiovascular system when activated. To examine the specificity of these reflexes, comparisons were made of the regional hemodynamic responses elicited by intra-arterial infusion of various agents into the renal (ir) and mesenteric (im) circulation. Experiments were performed in conscious rats, chronically instrumented with Doppler flow probes. Local ir as well as im infusions of bradykinin caused a hemodynamic reflex pattern characterized by a dose-dependent increase in arterial pressure, heart rate, and resistance in the renal and mesenteric vascular beds, whereas hindquarter resistance did not change. Similar hemodynamic reflex patterns were evoked by ir and im infusions of adenosine and 5-hydroxytryptamine. Thus neither application of different chemicals nor their route of infusion resulted in qualitatively different hemodynamic reflex patterns. This suggests that afferent nerve fibers from the kidney and mesentery share a common physiological function.

Adenosine↗
PubMed1989

Role of afferent renal nerves in spontaneous hypertension in rats.

In the present study we examined sympathetic function and baroreceptor reflex sensitivity in adult spontaneously hypertensive rats (SHR) after a selective transection of afferent renal nerves in the prehypertensive and established phases of hypertension. Renal deafferentation performed between 3 and 4 weeks after birth did not influence the course of the development of high blood pressure when compared with sham-operated rats. Mean arterial pressure, heart rate, and plasma norepinephrine concentrations were similar in both groups when measured at 13 weeks after renal deafferentation. However, blood pressure responses to ganglionic blockade with hexamethonium were significantly reduced in the renal deafferented SHR. Baroreceptor reflex sensitivity, assessed by heart rate responses to blood pressure changes induced by phenylephrine and nitroprusside, was significantly enhanced in these rats. When renal deafferentation was performed in adult SHR with established hypertension, mean arterial pressure decreased slightly but significantly by 5%. Heart rate, plasma norepinephrine concentrations, and responses to hexamethonium were not affected by this procedure. However, in the renal deafferented adult SHR, heart rate responses to phenylephrine but not to nitroprusside were significantly increased. Thus, in contrast to efferent renal nerves, afferent renal nerves do not play an important role in the development and maintenance of high blood pressure in SHR, but may contribute to the mechanisms that alter sympathetic function and baroreceptor reflex sensitivity in SHR during the development of hypertension.

Afferent Pathways↗
PubMed1989

Renal nerves in hypertension.

In experimental hypertension, renal denervation prevents or delays the onset of the disease. Classically, renal denervation implies surgical interruption of the renal nerve bundles. This results in destruction of efferent as well as afferent renal nerves. Efferent renal nerves may directly alter renal function and/or humoral mechanisms like the renin-angiotensin-aldosterone system, thereby affecting blood pressure. Afferent renal nerves, on the other hand, may modulate sympathetic nervous and neurohumoral mechanisms that are involved in blood pressure control. Thus, each nerve population may contribute to the disease. Evidence for such involvements of both sections of the renal nervous system is discussed.

Afferent Pathways↗
PubMed1988

Microcirculatory changes in cremaster muscle during early spontaneous hypertension in the rat.

The microcirculatory control of flow was studied in the cremaster muscle of 5- to 6-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) using intravital microscopic techniques. Arterioles were classified according to a functional branching order from A1-A4 vessels. Capillary architecture was measured in a separate series of experiments. No significant differences were found in the WKY or SHR vessel diameters, with the exception of third-order arterioles, which were slightly, but significantly, larger in SHR. However, the number of A3 and A4 vessels as well as the capillary density was significantly lower in SHR than in WKY. The differences were even more pronounced during maximal vasodilation induced by local application of 10(-3) mol/l adenosine. The data show that rarefaction of small blood vessels rather than decreased arteriolar diameter is an early characteristic of spontaneous hypertension in the rat.

Age Factors↗
PubMed1988

Long-term renal vasodilator effect of the beta-adrenoceptor blocker tertatolol in conscious spontaneously hypertensive rats.

In conscious spontaneously hypertensive rats (SHR), 5-day intravenous infusions with the beta-adrenoceptor blockers propranolol (5 mg/kg/day) or tertatolol (0.5 mg/kg/day) caused a chronic reduction of blood pressure (-12% +/- 1% and -28% +/- 1%, respectively, on day 5) and heart rate (-13% +/- 3% and -8% +/- 2%, respectively, on day 5). Propranolol infusion led to a 23%-31% reduction of blood flow through the renal, mesenteric, and hindquarter vascular bed. Tertatolol caused similar flow reductions, with the exception of the renal vascular bed, which was dilated. Tertatolol induced reduction of renal vascular resistance of 29% +/- 2% on day 5. These studies show a long-term renal vasodilatory activity of tertatolol during chronic administration to SHR.

Adrenergic beta-Antagonists↗