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Biomedical subjects

J F Smits

Publications and source records attributed to J F Smits.

141 records · Page 8Linked to original sources
PubMed1980

Is the antihypertensive effect of propranolol caused by an action within the central nervous system?

Propranolol in doses from 0.01 to 5 mg/kg x day was infused intracerebroventricularly (i.c.v.) in conscious unrestrained spontaneously hypertensive rats during 5 days by using Alzet osmotic minipumps. When given by this route, brain concentrations achieve values that are approximately 100-fold higher than those after s.c. infusion of equal doses, whereas plasma-levels are comparable. In this study we compared the dose needed to lower blood pressure upon i.c.v. infusion with the dose of 5 mg/kg x day dl-propranolol, which we reported earlier to induce a long lasting bradycardia and antihypertensive effect when infused s.c. Vehicle, 0.01 and 0.1 mg/kg x day of dl-propranolol, did not have any effect on mean arterial pressure or heart rate. Infusion (i.c.v.) of 1 mg/kg x day lowered heart rate during the first 4 days of the infusion. On the fifth day, this effect had disappeared. Also, during the first 2 days of the infusion a reduction of mean arterial pressure was observed, but thereafter pressure was at control levels. Infusion of 5 mg/kg x day of dl-propranolol reduced heart rate significantly from the first day of infusion throughout the whole infusion-period. On the other hand, mean arterial pressure was lowered with a delay of 1 day. It remained significantly below control values throughout the rest of the experimental period. d-Propranolol in a dose of 5 mg/kg x day i.c.v. did not have any effects. Since upon i.c.v. infusion the dose needed for a blood pressure lowering effect is the same as that needed for a s.c. infusion, in spite of 100-fold higher brain-levels, it is concluded that the antihypertensive effect of propranolol in spontaneously hypertensive rats is not caused by an action of the drug in the central nervous system.

Animals↗
PubMed1979

The role of the baroreceptor reflex in the cardiovascular effects of propranolol in the conscious spontaneously hypertensive rat.

1. The role of baroreceptors in the cardiovascular mechanism of action of DL-propranolol has been studied by comparing the acute effects of subcutaneous injection of 1 and 5 mg/kg (3.3 x 10(-6) and 16.5 x 10(-6) mol/kg) of this drug in conscious baroreceptor-denervated spontaneously hypertensive (SH) rats with those in sham-operated control SH rats. 2. At 5 mg/kg (16.5 x 10(-6) mol/kg) propranolol caused a small, but significant, increase in blood pressure in sham-operated SH rats, whereas both after 1 and 5 mg/kg (3.3 x 10(-6) and 16.5 x 10(-6) mol/kg) immediate hypotension was observed in baroreceptor-denervated animals. 3. Heart rate dropped rapidly after injection of 1 or 5 mg/kg (3.3 x 10(-6) and 16.5 x 10(-6) mol/kg) propranolol both in the baroreceptor-denervated and sham-operated SH rats. Bradycardia was significantly larger in the baroreceptor-denervated animals after an injection of 5 mg/kg (16.5 x 10(-6) mol/kg). 4. It is concluded that the lack of an early hypotensive effect of propranolol in intact animals is caused by an increased baroreceptor reflex activity as a consequence of the fall in cardiac output.

Animals↗
PubMed1979

Steady-state disposition of propranolol and its total metabolites in the spontaneously hypertensive rat: chronic subcutaneous vs. intracerebroventricular infusion with osmotic minipumps.

The steady-state disposition of propranolol and its total metabolites was measured after 6 day continuous subcutaneous (1 mg/kg/day) or intracerebroventricular (i.c.v., 0.01 and 1 mg/kg/day) infusion of dl-[3H]propranolol with osmotic minipumps in spontaneously hypertensive rats. After 2 days daily excretion of total radioactivity was 70% or more of the total dose infused each day. Steady-state plasma concentrations (day 3 and 6) of propranolol and its total metabolites did not differ significantly during subcutaneous or i.c.v. infusion of 1 mg/kg/day. During i.c.v. infusion with 0.01 mg/kg/day these concentrations were only 0.01 to 0.02 times as high. Propranolol and its total metabolite concentrations did not differ significantly in peripheral tissues during subcutaneous or i.c.v. infusion of 1 mg/kg/day, whereas brain propranolol concentrations were 40- to 600-fold higher during i.c.v. infusion. During i.c.v. infusion with 0.001 mg/kg/day, peripheral propranolol and total metabolite concentrations were only 0.003 to 0.02 times those following 1 mg/kg/day. Brain propranolol concentrations after 0.01 mg/kg/day i.c.v. were in the same range as those following 1 mg/kg/day subcutaneously. The data suggest that the osmotic minipump is a useful tool for creating and maintaining a steady-state for propranolol in spontaneously hypertensive rats. Moreover, by i.c.v. placement of the pump outlet the brain can be selectively perfused with this agent for a prolonged period of time.

Animals↗
PubMedDate not supplied

Fatty acid-binding proteinuria diagnoses myocardial infarction in the rat.

Cytoplasmic heart-type fatty acid-binding protein (H-FABPc) is a low molecular weight protein with abundant presence in the myocardium. Upon ischemia it is released from the heart and can subsequently be detected in plasma and urine. In this study, the value of measurement of H-FABPc excreted into urine for the diagnosis of myocardial infarction (MI) is investigated in the rat. To this end, firstly the kinetic behaviour of H-FABPc in plasma was examined and its release into urine quantified. After injection of purified H-FABPc in normal animals, a net recovery in urine of 14-29% was found. The kinetic behaviour of H-FABPc in plasma was characterized by a total clearance of 0.33 ml/min and a half-life value of total elimination of about 270 min. Knowing these plasma characteristics of H-FABPc, a comparison was made between the cumulative amounts of H-FABPc released in the 24-hour urine of MI rats and of sham-operated animals. In MI rats, with a mean morphometric MI size of 43%, the mean total amount of H-FABPc excreted into urine was 79 micrograms, while in sham-operated rats this was 23 micrograms. This difference between both groups is significant (p < 0.001). It is concluded that urinary H-FABPc can be used as a noninvasive marker for MI in the rat.

Animals↗
PubMedDate not supplied

Acute hemodynamic effects of coronary artery ligation in conscious rats.

Because of the growing interest in the use of coronary artery ligation (CAL) in rats as a model for studies on heart failure, we have investigated the acute hemodynamic changes following CAL in conscious rats. Animals were equipped for measurement of cardiac output (CO), arterial pressure (MAP), and central venous pressure (CVP). These parameters were measured before CAL, immediately after, and 24 h after. Furthermore, peak CO, obtained by rapid infusion of 12 ml Ringer's solution (in 1 min) was measured 2 days before and 1 day after CAL. CAL resulted in immediate reduction of CO, because of reduced stroke volume (SV). CO as well as SV were inversely correlated with infarct size as determined 24 h after CAL. Heart rate (HR) and MAP did not change. Twenty-four hours later, CO was still reduced. MAP was now reduced, possibly as a result from resetting of nervous reflex mechanisms. Before CAL, peak CO and SV were similar in CAL and sham animals. At 24 h after CAL, these parameters were greatly reduced in CAL rats. Peak values were strongly correlated to infarct size. Results indicate that CAL in rats leads to hemodynamic changes similar to the ones observed following myocardial infarction in man. Cardiac function is related to infarct size and is altered both at rest and during maximal stimulation.

Animals↗
PubMedDate not supplied

Antihypertensive effect of propranolol in conscious spontaneously hypertensive rats: central hemodynamics, plasma volume, and renal function during beta-blockade with propranolol.

In order to obtain a better insight into the hemodynamic changes during beta-blockade, we measured central hemodynamics, plasma volume, and renal function during both acute and long-term beta-blockade in conscious spontaneously hypertensive rats (SHR). Acutely, both 1 and 5 mg/kg propranolol immediately decreased heart rate (HR) and cardiac output (CO). However, total peripheral resistance (TPR) rose sharply, thus preventing mean arterial pressure (MAP) from falling during the first hours after injection. After 4 h TPR had returned to control values and, because CO was still reduced, MAP was lowered. This decrease of MAP persisted for more than 20 h. During 5-day infusion of propranolol (5 mg/kg/day) CO fell on the 1st day and remained lowered during the 5-day period. MAP was lowered from the second day onward. Despite the reduced CO and MAP, plasma volume (PV) did not increase during the 5-day infusion. Acute injection of 5 mg/kg/day did, however, result in a decreased PV at 1 h postinjection. In this time span central venous pressure remained unchanged. Quantitation of water and sodium excretion revealed an immediate diuresis and natriuresis after acute administration of propranolol. This occurred despite a reduced glomerular filtration rate and effective renal plasma flow, as quantitated by indicator clearance methods. We conclude that propranolol reduced tubular sodium reabsorption, possibly through blockade of tubular beta-receptors. This effect may be essential for the long-term antihypertensive efficacy of beta-blockers because it prevents sodium and water retention in a state of reduced MAP and CO.

Animals↗
PubMedDate not supplied

Effects of chemical sympathectomy on angiotensin II-induced neointimal growth in the balloon-injured rat carotid artery.

To investigate the role of the sympathetic nervous system in angiotensin II (AngII)-stimulated medial and neointimal smooth muscle cell (SMC) replication, we sympathectomized rats with 6-hydroxydopamine (6-OHDA) in which the left carotid artery was injured by a balloon catheter. Balloon injury is associated with a loss of specific [3H]-prazosin binding. AngII (250 ng/kg/min), infused 2 weeks after balloon injury of the rat left carotid artery, increased systolic blood pressure by approximately 70 mm Hg. There was no effect of 6-OHDA on this pressor response. AngII increased the cumulative 5-bromo-2'-deoxyuridine (BrdU) labeling fraction (LF) in the uninjured right carotid media and the injured left carotid neointima as compared to controls (5.7+/-1.6% vs. 0.4+/-0.1%, p<0.05; 10.6+/-0.9% vs. 5.0+/-0.8%, p<0.05, respectively). 6-OHDA decreased the AngII-induced increase in LF in the media of the uninjured right carotid artery (AngII/6-OHDA 0.9+/-0.2% vs. AngII 5.7+/-1.6%, p < 0.05). 6-OHDA did not decrease the AngII-induced increase in LF in both the injured left carotid media and neointima at 4 weeks after balloon injury. The effects of chemical sympathectomy were comparable with those obtained 12 weeks after balloon injury. Thus, the data show that the sympathetic nervous system mediates the AngII-induced increase in SMC DNA synthesis, but only in the uninjured carotid media. This indicates a differential regulation of AngII-induced SMC replication in injured and uninjured vessels.

Angiotensin II↗
PubMedDate not supplied

Increased responsiveness of the vascular bed to angiotensin I, angiotensin II and phenylephrine in acute and chronic ischemic hindlimbs in rats.

Ischemia activates several compensatory mechanisms to restore blood supply. To investigate possible changes in the reactivity of blood vessels after acute and chronic ischemia of skeletal muscle, the response (resistance changes) of the vascular bed to angiotensin II (AII) and phenylephrine (PE) in a hindlimb perfusion model were studied in control, acutely ischemic (45 min) and chronically ischemic (4 weeks) spontaneously hypertensive rats. Furthermore, the effects of angiotensin I (AI) were studied to investigate the involvement of local angiotensin-I-converting enzyme (ACE) in adaptive responses. Ischemia was induced by partial occlusion of the left common iliac artery. Both in acute and chronic ischemia, the reactivity (maximal resistance change) of the vascular bed in the ischemic hindlimb to AI, AII and PE was increased only in severe ischemia (residual flow < 40%), whereas the sensitivity (ED50) was not influenced. The increase in reactivity was comparable for AI and AII, implying that local ACE seems not to be involved. These results suggest that severe ischemia of skeletal muscle results in nonselective hyperreactivity of the vascular bed, which may be due to alterations of receptor-linked mechanisms or ultrastructural changes of blood vessels.

Acute Disease↗
PubMedDate not supplied

Angiotensin II induces media hypertrophy and hyperreactivity in mesenteric but not epigastric small arteries of the rat.

We examined effects of a 2-week infusion of angiotensin II (AII, 250 ng x kg[-1] x min[-1]) on properties of mesenteric resistance arteries (MrA) and superior epigastric arteries (SEA) of male Wistar rats. Histochemistry and pharmacological tools showed that MrA are densely innervated, whereas SEA are only sparsely innervated. AII infusion resulted in a significant elevation in mean arterial pressure and in plasma AII and noradrenaline levels. Organ chamber studies and morphometry were used to determine arterial contractile reactivity and structure. After AII infusion, in MrA (i) maximal contractile responses to 125 mM K+, noradrenaline, serotonin and adrenergic nerve stimulation were significantly increased, without modification of the sensitivity to these stimuli and (ii) a significant increase in media cross-sectional area and media thickness was observed without alterations in lumen diameter. The observed increase in vascular reactivity could fully be attributed to the observed increase in wall mass since no alterations in maximal active wall stress were noted. In SEA, no significant changes in responsiveness to vasoconstrictor stimuli or in wall structure were observed. These findings suggest that perivascular nerves are involved in the hypertrophy and subsequent hyperreactivity of small arteries in rats exposed for 2 weeks to a low dose of AII.

Angiotensin II↗
PubMedDate not supplied

Hemodynamic characterization of hypertension induced by chronic intrarenal or intravenous infusion of norepinephrine in conscious rats.

The present study was designed to determine the hemodynamic changes underlying the hypertension induced by chronic intrarenal infusion of norepinephrine (NE) in conscious rats. NE was infused for a 5-day period intrarenally with osmotic minipumps via a chronic catheter in the right suprarenal artery at rates of 4 and 36 micrograms . kg-1 . hr-1 or intravenously at a rate of 36 micrograms . kg-1 . hr-1. Control rats received a 1 microliter . hr-1 intrarenal infusion of pyrogen-free 0.9% NaCl. In separate experiments, short-term effects were measured continuously during a 22- to 24-hour intrarenal infusion of 4 and 36 micrograms NE . kg-1 . hr-1 or intravenous infusion of 36 micrograms NE . kg-1 . hr-1. Intrarenal infusion of NE produced a more pronounced long-term hypertensive effect than infusion of the same dose intravenously. This hypertension was characterized by a rapid and sustained increase in total peripheral resistance index (TPRI). Despite of the initial renal vasoconstriction, specifically produced during the first 24 hours of intrarenal NE application, cardiac index (CI) in parallel to stroke volume index (SVI) decreased significantly during intrarenal as well as during intravenous NE infusion. Furthermore, no signs of sodium retention were observed. Both rates of intrarenal NE infusion have been shown previously to produce a significant long-term increase in plasma potassium concentration, and the present study indicates that this is presumably the result of decreased urinary potassium output. It is concluded that chronic hypertension produced by intrarenal or intravenous infusion is not volume-dependent. The relatively greater increase in TPRI during intrarenal NE infusion is attributed to vascular wall receptor sensitization by increased plasma potassium levels resulting from effects of intrarenally present NE on tubular cation exchange mechanisms.

Animals↗
PubMedDate not supplied

Stereospecificity of beta-adrenoceptor blockade and renal vasodilatation by tertatolol.

To investigate the stereospecificity of beta-adrenoceptor blockade and renal vasodilatation by tertatolol, the regional hemodynamic effects of the 2 stereo-isomers of tertatolol (d-tertatolol and l-tertatolol) were compared in conscious spontaneously hypertensive rats. Furthermore, the effects of a combination of d-tertatolol and dl-propranolol were studied. l-Tertatolol and the combination of beta-blockers lowered heart rate and caused an early increase and a late decrease of blood pressure. l-Tertatolol, but not the combination of dl-propranolol and d-tertatolol, decreased renal resistance at 3-4 hr after injection. Injections of d-tertatolol alone did not cause any effect. Since effects of l-tertatolol are fully comparable to effects previously observed with dl-tertatolol, and d-tertatolol was devoid of any effects, both alone and in combination with dl-propranolol, we conclude that both beta-adrenoceptor blockade and renal vasodilatation are stereospecific for the l-isomer of tertatolol.

Adrenergic beta-Antagonists↗