Effects of reinforcement rate and delay on the acquisition of lever pressing by rats.

The acquisition of lever pressing by naive rats, in the absence of shaping, was studied as a function of different rates and unsignaled delays of reinforcement. Groups of 3 rats were each exposed to tandem schedules that differed in either the first or the second component. First-component schedules were either continuous reinforcement or random-interval 15, 30, 60 or 120 s; second-component schedules were fixed-time 0, 1, 3, 6, 12, or 24 s. Rate of responding was low under continuous immediate reinforcement and higher under random-interval 15 s. Random interval 30-s and 60-s schedules produced lower rates that were similar to each other. Random-interval 120 s controlled the lowest rate in the immediate-reinforcement condition. Adding a constant 12-s delay to each of the first-component schedule parameters controlled lower response rates that did not vary systematically with reinforcement rate. The continuous and random-interval 60-s schedules of immediate reinforcement controlled higher global and first-component response rates than did the same schedules combined with longer delays, and first-component rates showed some graded effects of delay duration. In addition, the same schedules controlled higher second-component response rates in combination with a 1-s delay than in combination with longer delays. These results were related to those from previous studies on acquisition with delayed reinforcement as well as to those from similar reinforcement procedures used during steady-state responding.

Effect of IgG-coated erythrocytes and lipopolysaccharide (LPS) tolerance on the depression of vascular reactivity caused by LPS.

Previous studies have shown that the injection of IgG-coated erythrocytes (EIgG) increased the mortality rate caused by bacterial lipopolysaccharide (LPS) and that animals made tolerant to LPS show a decrease in the mortality rate caused by LPS. The present study determined the effect of the injection of EIgG and of LPS tolerance on the depression of vascular reactivity caused by LPS in vivo or in vitro. For in vivo studies, LPS was injected intravenously into rats 2 h after the injection of E or EIgG. Aortae were removed 90 min after the injection of LPS, and cumulative concentration-response curves to phenylephrine were performed in helically cut aortic strips. LPS (.1 mg/kg) caused a 21% decrease in the maximum tension developed in response to phenylephrine in aortae from animals given erythrocytes. In contrast, animals given EIgG showed a 63% decrease in maximum tension following the injection of this dose of LPS. For in vitro studies, the depression of vascular reactivity caused by incubation with LPS of aortae from rats injected with EIgG was determined. As with the in vivo studies, there was a greater depression of vascular reactivity caused by incubation with LPS of aortae taken from animals injected with EIgG. Similar studies were carried out with rats made tolerant to LPS. Tolerance was induced by giving a regimen of five daily injections of LPS. Following the injection of LPS (1 mg/kg), the maximum tension of aortae from sham tolerant animals was depressed 63%, while aortae from LPS tolerant animals were depressed only 16%.(ABSTRACT TRUNCATED AT 250 WORDS)

Varying the temporal placement of a drinking opportunity in a fixed-interval schedule.

Three rats, lever pressing for food delivered on a fixed-interval 128-s schedule, were presented with a 16-s opportunity to drink from a retractable water source. The temporal placement of the water probe within the reinforcement cycle was varied sequentially, in steps of 16 s. Although the lever-pressing pattern was modulated by the intercalated water probe, water consumption during the probe itself was a decreasing function of time from the following reinforcer. These results were interpreted as evidence against the notion that schedule-induced drinking is a "ubiquitous" phenomenon and are congruent with results from other "intruded stimulus" experiments.

Vascular contractile potency of endothelin-1 is increased in the presence of monocytes or macrophages.

Accumulation of inflammatory cells and altered responsiveness to vasoactive mediators are commonly observed events in atherosclerotic vessels. We studied the effect of monocytic cells on endothelin-1 (ET-1)-induced contraction of strips of guinea pig carotid artery. The vascular contractile potency of ET-1 was increased markedly in the presence of human peripheral blood monocytes, guinea pig alveolar macrophages (M phi), and the human monocytic cell line, THP-1. Specific binding of 125I-labeled ET-1 to these cells was detected, and Scatchard analysis indicated a dissociation constant value of approximately 1 nM. In contrast, the human monocytic cell line, U-937, failed to bind 125I-ET-1 and did not alter ET-1 potency, suggesting that the ability of monocytic cells to increase ET-1 potency requires expression of ET receptors. Selective inhibition of ET-1 binding to vascular smooth muscle with BQ-123, an ETA receptor antagonist that does not inhibit ET-1 binding to monocytes, resulted in complete inhibition of vascular contraction. These data indicate that ET-1-induced vasoconstriction may be increased by monocytic cells via stimulation of monocyte endothelin receptors.

The activity of rats in a swimming situation as a function of water temperature.

Previous research has shown that time before drowning in rats decreases gradually as stress is increased by varying water temperature in the swimming situation. In the present research, the activity of swimming rats appeared to be a U function of varying water temperature, lending support to the notion that activity is a behavioral measure that estimates the rats chances of survival in the water. This conclusion was further supported by the covariation of activity with a different behavioral measure of survival. In addition, activity during sessions decreased gradually, suggesting that a lowered activity is an adaptive response in the rat. Activity, thus, appears to be negatively correlated to the rat's survival chances under colder (14-23 degrees) and warmer (23-47 degrees) temperatures; i.e., in a more stressful situation, including extreme fear. It may be, therefore, that a decrease in activity obtained in present laboratory models (i.e., immobility) is more relevant to the extinction of fear than despair, as reported by other researchers.

Vascular responsiveness in rats resistant to aldosterone-salt hypertension.

Wistar-Furth rats have been shown to be resistant to mineralocorticoid-salt hypertension, but the mechanism for this resistance is unknown. In the current experiments, adult male Wistar and Wistar-Furth rats were given a subcutaneous aldosterone infusion (0.15 microgram/hr) for 4 weeks, and changes in blood pressure and vascular reactivity were studied. Rats received a 1% NaCl, 0.2% KCl solution to drink. After 4 weeks of aldosterone infusion, systolic blood pressure measured using a tail-cuff technique had increased by 60 mm Hg in Wistar rats but was unchanged in Wistar-Furth rats. Hypokalemia occurred in both strains in response to the aldosterone infusion. Isolated, helically cut strips of common carotid artery and aorta were prepared for isometric force recording. Cumulative concentration-response curves to norepinephrine, serotonin, KCl, calcium, nitroprusside, and acetylcholine were performed in carotid artery strips, and concentration-response curves to ouabain were performed in aortic strips. Increased vascular contractile sensitivity to KCl, ouabain, norepinephrine, and serotonin was observed in vessels from Wistar rats treated with aldosterone and salt. The same treatment in Wistar-Furth rats produced only increased vascular sensitivity to ouabain and serotonin, and these changes were of smaller magnitude than those seen in Wistar rats. Aldosterone-salt treatment produced decreased vascular sensitivity to acetylcholine and nitroprusside in both Wistar and Wistar-Furth rats. These results support the hypothesis that resistance of Wistar-Furth rats to aldosterone-salt hypertension is due to resistance to the effects of aldosterone-salt treatment that normally result in increased vasoconstrictor sensitivity.

Dimaprit--induced neurotoxicity.

The neurotoxicity of the histamine H2 agonist dimaprit was characterized. Dimaprit (100 micrograms administered into the lateral cerebral ventricle) induced a large area of brain necrosis 1-3 days later which was uniformly lethal. Lower doses caused dose - related effects on survival, gross brain pathology and body weight. Experiments with other H2 agonists and H2 antagonists, together with studies by others demonstrating a similar toxicity of the congener homodimaprit suggest that the neurotoxicity of dimaprit is independent of brain H2 receptors. Although dimaprit is a useful tool for the characterization of H2 receptor responses, the present results show that this agent must be used with caution, if at all, in classifying brain H2-receptor mediated events.

Acetylated endothelin-1 is a constrictor in guinea pig lung vasculature but not in isolated vascular strips.

We examined the relative importance of the two amino groups of endothelin-1 in mediating pulmonary vasoconstrictor activity. Complete acetylation of prefolded endothelin-1 (fAcET-1[AcK9]) yielded a product with vasoconstrictor properties (EC50 = 0.52 +/- 0.04 nM) in isolated Ringer-perfused guinea pig lungs similar to native endothelin-1 (EC50 = 0.31 +/- 0.05 nM). However, fAcET-1[AcK9] exhibited a marked reduction in potency when assessed by contraction of isolated guinea pig pulmonary artery strips or by contraction of carotid artery or aortic strip preparations. fAcET-1[AcK9] at concentrations up to 100 nM failed to induce appreciable contraction of any vascular strip preparation. In contrast, endothelin-1 had an EC50 of 1.46 +/- 0.32 to 1.88 +/- 0.19 nM in various vessel preparations. The differences in response to fAcET-1[AcK9] in the intact lung vs. strip preparation suggest different receptor populations in the two preparations. The importance of specific amino groups for contractile activity in the vascular strip preparation was explored by acetylation of individual sites (amino terminus or lysine sidechain) or both sites during peptide synthesis to produce AcET-1, ET-1[AcK9], and AcET-1[AcK9], respectively. The order of potency was endothelin-1 much greater than ET-1[AcK9] greater than AcET-1 greater than AcET-1[AcK9]. These results suggest that chemical modifications (e.g., biotinylation) should be made preferentially at the lysine-9 sidechain in order to retain maximal biological activity in vascular strip preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostanoids contribute to endothelium-dependent coronary vasodilation in guinea pigs.

This study characterizes the contribution of prostanoids to endothelium-dependent responses in two vascular regions of the guinea pig. We compared the mechanisms of relaxation responses to acetylcholine and adenosine triphosphate (ATP) in the coronary vasculature and in the abdominal aorta of the guinea pig. Endothelium-dependent responses were examined in an isolated, potassium-arrested guinea pig heart utilizing a modified Langendorff preparation. Coronary vessels were constricted with prostaglandin F2 alpha and dilated with acetylcholine (10(-9)-10(-6) mol) or ATP (10(-10)-10(-7) mol) before and after exposure to indomethacin (14 microM, n = 6) or ibuprofen (150 microM, n = 5). Helically cut strips of abdominal aorta (n = 6) were suspended in isolated tissue baths for measurement of isometric force. Relaxation to acetylcholine (5.5 x 10(-7) M) and ATP (10(-5) M) was quantified in strips contracted with norepinephrine before and after exposure to indomethacin (14 microM). In addition, the endothelium was damaged by exposing vessels to free radicals generated by electrolysis of the buffer (4 Hz, 9 V, 1 ms, 5 min). Following electrolysis of the buffer, relaxation responses to acetylcholine and ATP were significantly attenuated in both preparations. In the perfused heart, endothelium-dependent dilatation to acetylcholine, but not ATP were significantly inhibited in the presence of indomethacin or ibuprofen. In contrast, acetylcholine- and ATP-induced relaxation responses in the aorta were not altered by indomethacin. We conclude that prostaglandins contribute to acetylcholine-induced dilatation in the coronary bed but not in the abdominal aorta of the guinea pig. Furthermore, in the coronary bed, different endothelial factors mediate relaxation to acetylcholine and ATP.

Increased vascular reactivity to Bay K 8644 in genetic hypertension.

These experiments compared potential-operated calcium channel function in smooth muscle from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Carotid artery strips from adult male SHRSP and WKY rats were suspended in tissue baths for isometric force recording. Contractile force was expressed as percent of response to 100 mmol/l KCl. Vascular strips from SHRSP were more sensitive to KCl (ED50 = 25 mmol/l) compared to strips from WKY rats (ED50 = 37 mmol/l). The calcium channel agonist Bay K 8644 (2.8 x 10(-10) to 2.8 x 10(-7) mol/l) produced tonic contractions in carotid artery strips from SHRSP (34% of the contractile response to 100 mmol/l KCl) but not in those from WKY rats. Incubation of vascular strips in 1.8 or 6 x 10(-10) mmols/l norepinephrine did not alter the maximal contractile response to Bay K 8644 in either strain of rats. In 12 mmol/l KCl, the maximal contractile response to Bay K 8644 was increased in both SHRSP (71%) and WKY rats (25%). In 18 mmol/l KCl, maximal contractile responses to Bay K 8644 in the two strains were similar (SHRSP = 73%, WKY = 76%). Removal of the endothelium did not significantly affect contractile responses to Bay K 8644 in either strain of rats. There were no differences in contractile responses to the calcium ionophore A23187 or in nifedipine-induced relaxation of potassium-activated vessels between carotid arteries from SHRSP and WKY rats. In summary, these results suggest that a difference in voltage-operated calcium channel function may underlie the increased sensitivity of SHRSP vascular smooth muscle to depolarizing stimuli.

Effect of felodipine on blood pressure and vascular reactivity in stroke-prone spontaneously hypertensive rats.

Isolated tail arteries from stroke-prone spontaneously hypertensive rats (SHRSP), but not from normotensive Wistar-Kyoto rats (WKY), exhibit oscillatory contractions in response to norepinephrine. Previous studies indicate that the mechanism for these oscillations involves altered membrane calcium and/or potassium handling, and that this vascular change is a genetic defect associated with hypertension in SHRSP. The purpose of this experiment was to determine whether treatment of SHRSP with the calcium entry blocker felodipine would alter oscillatory activity. Adult SHRSP and WKY rats were treated orally with felodipine for 8 weeks. Felodipine treatment produced a significant decrease in blood pressure in SHRSP (control SHRSP: 240 +/- 7 mmHg, n = 6; felodipine-treated SHRSP: 164 +/- 8 mmHg, n = 5, P less than 0.05; tail-cuff method). Helically-cut tail artery strips from all rats were mounted in tissue baths for isometric force recording and exposed to norepinephrine (6 x 10(-9) to 6 x 10(-6) mol/l) for 20 min at each concentration. Oscillatory activity was defined as the sum of the magnitudes of all phasic contractions occurring during the final 10 min of norepinephrine incubation. Oscillatory activity was markedly reduced in tail arteries from felodipine-treated SHRSP when compared with control SHRSP. Felodipine also inhibited oscillatory activity when added directly to the tissue bath. It seems, therefore, that felodipine may lower blood pressure in SHRSP, at least in part, by correcting the genetic defect responsible for oscillatory activity.

Adrenal-dependent change in vascular reactivity in stroke-prone spontaneously hypertensive rats.

Tail arteries from stroke-prone spontaneously hypertensive rats (SHRSP) exhibit oscillatory contractions in response to norepinephrine. This type of oscillatory behavior does not occur in tail arteries from normotensive Wistar-Kyoto rats (WKY). We have shown that the traits of norepinephrine-induced oscillatory activity and high blood pressure are genetically associated in SHRSP, suggesting that oscillatory activity is a primary vascular abnormality that contributes to hypertension in this strain. In the present experiments, two approaches were used to test the hypothesis that adrenal mineralocorticoids modulate expression of this genetically determined vascular abnormality in SHRSP. First, the effect of adrenalectomy on blood pressure and oscillatory activity was determined in SHRSP that underwent bilateral adrenalectomy 3 weeks before experimentation. Second, the effect of deoxycorticosterone acetate (DOCA)-salt treatment on blood pressure and oscillatory activity was determined in 1) rats with no genetic background for oscillatory activity (WKY) and 2) progeny of SHRSP x WKY (F1 rats). Helically cut tail artery strips from all rats were mounted in isolated tissue baths for isometric force recording. Vessels were exposed to norepinephrine (6 x 10(-10) to 6 x 10(-6) M) for 20 minutes at each concentration. Oscillatory activity was defined as the sum of the phasic contractile amplitudes for all oscillations occurring during the final 10 minutes of norepinephrine incubation. Adrenalectomy markedly decreased blood pressure and oscillatory activity in SHRSP.(ABSTRACT TRUNCATED AT 250 WORDS)

Area postrema ablation and vascular reactivity in deoxycorticosterone-salt-treated rats.

In rats, central administration of the neurotoxin 6-hydroxydopamine prevents hypertension and certain functional vascular changes after deoxycorticosterone (DOC)-salt treatment. In this study, the effect of electrolytic ablation of the area postrema on blood pressure and vascular reactivity in DOC-salt-treated rats was examined. Four treatment groups of rats were studied (n = 5 in each): area postrema lesion, DOC-salt (DOC pivalate, 5 mg/wk s.c. for 5 weeks); sham lesion, DOC-salt; area postrema lesion, control; and sham lesion, control. Helically cut strips of carotid artery, aorta, and mesenteric artery were prepared for isometric force recording. Area postrema lesion attenuated hypertension in DOC-salt rats (mean arterial pressure, 107 vs 123 mm Hg in area postrema lesion and sham lesion rats, respectively; chronic aortic catheter). Vascular strips from sham lesion-control rats. These changes in vascular reactivity also were observed in area postrema lesion-DOC-salt rats. DOC treatment in rats on a normal sodium intake did not result in hypertension or increased vascular reactivity. In summary, integrity of the area postrema is necessary for hypertension but not for changes in vascular reactivity, in DOC-salt rats. It appears that 1) changes in vascular reactivity may be necessary, but they are not sufficient to produce DOC-salt hypertension, and 2) if these vascular changes are secondary to a central nervous system effect, they are mediated by a pathway distinct from the area postrema.

Area postrema is critical for angiotensin-induced hypertension in rats.

The effect of surgical ablation of the area postrema on acute (5-10 minutes) and chronic (5-10 days) increases in mean arterial pressure produced by intravenous infusion of angiotensin II in conscious, instrumented rats was studied. In agreement with previous studies, pressor responses of area postrema-ablated rats (n = 11) to acute angiotensin II infusion were identical to those of control sham-lesioned rats (n = 13). In these same rats, however, a 5-day infusion of angiotensin II produced a sustained hypertension in the sham-lesioned group whereas mean arterial pressure was increased only transiently (1-3 days) in the area postrema-ablated rats. No differences before infusion of arterial pressure, heart rate, water intake, urinary sodium excretion, and urinary potassium excretion were observed between sham-lesioned and area postrema-ablated rats; only arterial pressure was changed significantly during angiotensin II infusion in either group. Twenty-four hours after terminating angiotensin II infusion, mean arterial pressure was within the normotensive range in both sham-lesioned and area postrema-ablated rats. In a separate group of sham-lesioned (n = 13) and area postrema-ablated (n = 12) rats, angiotensin II was infused intravenously for a 10-day period; mean arterial pressure was increased significantly over the entire 10-day infusion in sham-lesioned rats, but for only 1 day in area postrema-ablated rats. An intact area postrema appears necessary for the development of chronic, but not acute, hypertension during intravenous infusion of angiotensin II in the rat.

Effect of inhibition of central angiotensin pressor mechanisms on blood pressure in spontaneously hypertensive rats.

The present experiments were designed to elucidate the role of central angiotensin II (AII) mechanisms in maintenance of established hypertension in adult spontaneously hypertensive rats (SHR) by determining the blood pressure response to chronic intraventricular (i.v.t.) infusion of the converting enzyme inhibitor teprotide or the AII receptor antagonist 1sar,8Thr-AII (sarthran). Male SHR (240-300 g) were given chronic indwelling arterial and venous catheters and bilateral lateral cerebral ventricular cannulae. The acute pressor responses to successive intravenous infusions of AII (sarthran experiments) or angiotensin I (AI; teprotide experiments) and to an intraventricular bolus injection of AII or AI were determined in the conscious rats. A 5-day intraventricular infusion of sarthran (1 or 6 micrograms/h) or teprotide (10 micrograms/h) in isotonic saline was maintained by subcutaneously implanted osmotic minipumps, and pressor responses were retested on the 5th day of intraventricular infusion. Five-day intraventricular sarthran infusion at 1 and 6 micrograms/h reduced the pressor response to intraventricular AII by 48 and 74%, respectively, while intraventricular teprotide (10 micrograms/h) inhibited the pressor response to intraventricular AI by 25%. None of the intraventricular infusions significantly decreased pressor responsiveness to intravenous AII or AI. In separate groups of SHR, tail-cuff blood pressure was monitored before, during, and after a 1-week intraventricular teprotide infusion (10 micrograms/h) or successive intraventricular infusions of sarthran at 1 microgram/h for 2 weeks followed by 6 micrograms/h for 1 week. Neither chronic intraventricular sarthran or teprotide caused a significant lowering of blood pressure in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium influx and vascular reactivity in systemic hypertension.

Numerous studies have focused on functional vascular changes that characterize the hypertensive state. Recent evidence that suggests that increased vascular reactivity in hypertension is due to changes in the delivery of activator Ca++ through channels in the cell membrane will be reviewed. The primary evidence supporting this hypothesis comes from studies that characterize the effects of Ca++-free solution and calcium channel blockers on contractile properties of isolated vascular smooth muscle. In the present study, experiments were performed to investigate the role of Ca++ influx in vascular contractions produced by interventions that cause membrane depolarization. Isometric tension development in helical strips of carotid arteries from stroke-prone spontaneously hypertensive rats in response to elevated K+ and tetraethylammonium chloride was greater than that in carotid arteries from Wistar-Kyoto normotensive rats. The rate of tension development to K+-free solution in carotid arteries from stroke-prone spontaneously hypertensive rats was faster than in Wistar-Kyoto normotensive rat arteries. Contractile responses to all 3 depolarizing interventions were reduced in arterial strips incubated in Ca++-free solution containing the chelator ethylene glycol bis-(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid and in arterial strips treated with the Ca++ channel blocker verapamil. These results are consistent with the hypothesis that constrictor stimuli that produce membrane depolarization cause an opening of Ca++ channels in the plasma membrane that are sensitive to the organic channel blockers. Further, a change in Ca++ permeability or membrane depolarizing mechanisms contributes to increased contractile responsiveness in carotid arteries of stroke-prone spontaneously hypertensive rats.

Effect of antihypertensive therapy on a vascular change in genetically hypertensive rats.

Isolated tail arteries from stroke-prone spontaneously hypertensive rats (SHRSP), but not normotensive Wistar-Kyoto (WKY) rats, exhibit oscillatory contractions in response to norepinephrine. To establish whether this vascular abnormality is secondary to elevated arterial pressure, SHRSP and WKY were treated with hydralazine and hydrochlorothiazide from weaning to 4 months of age. Hydralazine and hydrochlorothiazide treatment significantly attenuated hypertension development in SHRSP (systolic blood pressure: control SHRSP = 219 +/- 9 mmHg; treated SHRSP = 143 +/- 5 mmHg at 15 weeks of age). Helically-cut tail artery strips from all rats were mounted in tissue baths for isometric force recording and exposed to norepinephrine (6 x 10(-10)-6 x 10(-6) M) for 20 min at each concentration. Oscillatory activity was defined as the sum of the magnitudes of all phasic contractions occurring during the final 10 min of NE incubation. There was no significant difference in the magnitude of oscillatory activity between hydralazine/hydrochlorothiazide-treated SHRSP and control SHRSP. From these results we conclude that norepinephrine-induced oscillatory activity in SHRSP is a primary vascular abnormality that is not secondary to high blood pressure.

Genetic basis for altered vascular responses to ouabain and potassium-free solution in hypertension.

Many properties intrinsic to vascular smooth muscle are altered in hypertension. It is unknown whether these abnormalities are primary traits that may contribute to the etiology of hypertension or whether these vascular differences between the hypertensive and normotensive strains are inherited independently of genetic factors that predispose to hypertension. To determine if genetic factors responsible for the predisposition for hypertension may be the same as or linked to genetic factors determining a specific vascular response, adult stroke-prone spontaneously hypertensive rats (SHRSP), normotensive Wistar-Kyoto (WKY) rats, and progeny of genetic crosses of SHRSP and WKY rats (F1, F2, F1 X WKY, F1 X SHRSP) were studied. Rats were killed and helical aortic strips were mounted in a tissue bath for isometric force recording. Contractile responses to 10(-3) M ouabain (expressed as a percent of force generated to a maximal depolarizing stimulus) were greater in aortas from SHRSP (90 +/- 9%) compared with aortas from WKY rats (38 +/- 5%, P less than 0.05). The half time for contraction in K+-free solution was more rapid in aortas from SHRSP (21 +/- 4 min) when compared with aortas from WKY rats (48 +/- 4 min, P less than 0.05). A significant positive correlation between blood pressure (tail-cuff method) and the contractile response to 10(-3) M ouabain was observed in the segregating F2 progeny. In contrast, no correlation between blood pressure and the half time for contraction in K+-free solution was observed in the segregating F2 progeny.(ABSTRACT TRUNCATED AT 250 WORDS)