Calcium channel blockade with verapamil. Effects on blood pressure, renal, and myocardial adrenergic, cholinergic, and calcium channel receptors in inbred Dahl hypertension-sensitive (S/JR) and hypertension-resistant (R/JR) rats.

Verapamil HCl was chronically administered to inbred Dahl S/JR and R/JR rats maintained on a diet containing 8.0% NaCl (w/w) and the effects on blood pressure (BP) and heart rate (HR) were investigated. Treatment over a 4-week period via implanted miniosmotic pumps attenuated but did not prevent the development of salt-induced hypertension (HT) in the S/JR rat. Elevated HR, possibly reflexive in origin, was observed in S/JR rats that received verapamil but not in similarly treated R/JR rats. Although verapamil retarded the development of HT in S/JR rats, BP rose to moderately hypertensive levels, and the ventricle/body weight ratio was elevated by the termination of the study. The effect of verapamil on the density and affinity of alpha 1-, alpha 2-, and beta-adrenergic, muscarinic cholinergic, and calcium channel receptors in renal and ventricular membranes was also assessed. The density of renal and ventricular alpha 1- and beta-adrenoceptors was not affected by chronic drug treatment. The density of renal alpha 2- and beta-adrenoceptors was greater in the S/JR strain than in the R/JR strain, regardless of the treatment. The density of muscarinic cholinergic and calcium channel receptors in the ventricle was not affected by the treatment. The results of this study suggest that the long-term antihypertensive effects of verapamil in the S/JR rat do not involve an alteration in the binding characteristics of adrenergic, cholinergic, or calcium channel receptor sites in ventricular and renal membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Ontogeny of blood pressure in the inbred Dahl hypertension-sensitive and -resistant rat.

The inbred S/JR rat is characterized by a genetic predisposition to NaCl-induced hypertension. Although mature S/JR but not R/JR rats develop hypertension when fed a high NaCl-containing diet, this effect has not been examined during early neonatal development. S/JR and R/JR dams were maintained on 0.15% (w/w) or 8% (w/w) NaCl diets throughout gestation and lactation. Measurements of mean abdominal aortic blood pressure (MAP) were obtained in anesthetized offspring at 5, 15, and 25 days of age. This was greater in neonatal S/JR rats than R/JR rats at 5, 15, and 25 days of age. A hypertensinogenic effect of 8% NaCl was seen in R/JR at 5 and 15 days. The results indicate that the ontogeny of MAP can be influenced by pre- and postnatal dietary NaCl. More importantly, elevated MAP in the S/JR strain is a distinguishing characteristic evident throughout the neonatal period of development.

Salt intake and renal hemodynamics in immature and mature Dahl salt-sensitive (DS/JR) and salt-resistant (DR/JR) rats.

To determine if abnormalities in the maturation of renal function in Dahl salt-sensitive rats are associated with the development of hypertension, studies were performed in anesthetized 3 week old salt-sensitive (DS/JR) and salt-resistant (DR/JR) rats whose mothers were maintained on 0.15% (low-salt) during gestation and either 0.15% or 2.0% (high-salt) NaC1 diets after parturition. Mature DS/JR and DR/JR rats were maintained on either 0.15% or 2.0% NaC1 diets after weaning and studied at 8 to 9 weeks of age. High-salt diet raised blood pressure (BP) and reduced glomerular filtration rate (GFR) and renal blood flow (RBF) in mature DS/JR rats, but had no effect on BP, GFR and RBF in mature DR/JR rats. In immature DS/JR and DR/JR animals, high-salt intake resulted in poor growth with reductions in GFR and RBF in the DS/JR group. The response to acute volume expansion, (5% body weight physiologic saline infusion) differed among the groups. Mature rats all vasodilated while immature high-salt DS/JR did not, and immature low-salt DS/JR vasoconstricted. These studies demonstrated that both mature and immature DS/JR rats evidence abnormal responses to acute and chronic salt loading. Early exposure to high-salt intake affects the maturation of renal function in the DS/JR group. An enhanced vascular sensitivity to sodium is present at critical periods of postnatal development in DS/JR rats.

Atrial antinatriuretic factor in the developing Dahl hypertensive rat.

In order to determine the developmental pattern of atrial concentrations of atrial natriuretic factor (ANF) in the Dahl hypertension-prone rat, atrial ANF concentrations were measured in inbred hypertension-prone (S/JR) and hypertension-resistant (R/JR) Dahl rats at 5, 15, 25, and 51 days of age. In both strains, atrial ANF concentrations peaked at 15 days of age. Atrial ANF concentrations did not differ between the two strains from 5 to 25 days of age. However, by 51 days of age, atrial ANF concentrations in the S/JR rat were significantly greater than those of the R/JR rat. Combining these data with developmental patterns of plasma renin activity in S/JR rats suggests the possibility that the S/JR rat may become intravascularly volume-expanded between 25 and 51 days of age. This volume expansion may contribute to the etiology of hypertension in this model of essential hypertension.

Long-term deficits in passive avoidance responding following experimental febrile convulsions during infancy.

Human infantile febrile convulsions are occasionally associated with later deficits in cognitive and motor performance. In the present report, experimental febrile convulsions during various stages of infancy in the rat were investigated. Infant rats that were subjected to a single hyperthermia-induced convulsion at 10, 15, or 20, but not 5, days of age required more trials than controls to acquire a step-down passive avoidance response when tested as adults (50-60 days of age). Although rats that were subjected to a series of convulsions during infancy also evinced deficits in passive avoidance responding at adulthood, the magnitude of the effect was not appreciably greater than that following a single convulsion. The present results indicate that a single experimental febrile convulsion during infancy can have long-term effects on subsequent behavior.

Genetic predisposition to hypertension, elevated blood pressure and pain sensitivity: a functional analysis.

Pain sensitivity was examined in Dahl hypertension-sensitive (DS) and Dahl hypertension-resistant (DR) rats. The results indicated that hypertensive DS rats had a reduced sensitivity to painful stimulation compared to normotensive DS rats or compared to DR rats. Furthermore, the lower pain sensitivity of even normotensive DS vis-a-vis normotensive DR rats was not due to genetic factors but due to slight variations in blood pressure between lines. These results provide additional experimental support for the contention that elevations in blood pressure result in decreased pain sensitivity.

The effect of kainic acid on cholinergic enzymes and receptors in the amygdala complex of the rat.

Kainic acid (KA) was injected into the amygdala (AM) complex of the rat and its effect on the cholinergic enzymes, choline acetyltransferase (CAT) and acetylcholinesterase (AChE), and the binding of the muscarinic ligand, [3H]quinuclidinyl-benzilate (QNB) and the nicotinic ligand [125I]alpha-bungarotoxin (aBuTX) was investigated. Ka produced a loss of approximately 35% of the CAT activity in the AM. However, no effect on AChE activity was observed. A 30--50% decrease in the number of muscarinic and nicotinic receptor sites was also found. CAT, AChE and QNB binding in the AM contralateral to the injection did not change. However, the binding of aBuTX was found to decrease by approximately 40%. The present results suggest that the loss of CAT activity in the AM after treatment with KA is due to the destruction of cholinergic neurons within the AM. The lack of effect on AChE suggests that the major cholinergic input to the AM is not affected by KA. In addition, the loss of nicotinic receptors in the contralateral AM may reflect anterograde degeneration of terminals that have nicotinic sites located on them, or may be secondary to the elicitation of intense seizure activity evoked by the KA.

Alpha 1- and alpha 2-adrenoceptor binding in the Dahl rat model of hypertension.

Dahl sensitive rats on a high salt diet (DSH group) developed significant elevations in blood pressure (BP). Sensitive rats maintained on a low salt diet (DSL group) and Dahl resistant rats on a high or low salt diet (DRH and DRL groups, respectively) remained normotensive. The DSH and DRH groups displayed a lower density of alpha 2-adrenoceptors (as measured with [3H]-clonidine) in the cerebral cortex than normotensive DSL and DRL groups. In contrast, the density of alpha 2-adrenoceptors in the medulla was significantly lower in the DSH group than the DSL group, but significantly higher in the DRH group compared to the DRL group. The density of alpha 1-adrenoceptors (as measured with [3H]-WB4101) in the hypothalamus was lower in the DSH group than the DSL group but greater in the DRH group than the DRL group. The results suggest that the sensitive and resistant lines can be distinguished by the density of alpha 1- adrenoceptors in the hypothalamus and medulla, respectively. The interactive effects of dietary NaCl and susceptibility to hypertension on adrenoceptors lend further support to the hypothesis that the genetic predisposition to hypertension is associated with a disruption in central adrenergic activity.

Fear-potentiated startle response in mice: genetic analysis of the C57BL/6J and DBA/2J intercross.

The role of genetic factors in the fear-potentiated startle (FPS) response was examined in the inbred C57BL/6J (B6) and DBA/2J (D2) mouse strains. Mice in the D2 strain displayed a significant potentiation in the acoustic startle response (ASR) when presented with a visual condition stimulus (CS) previously paired with an aversive unconditioned stimulus (US). The maximal FPS response was observed following 20 conditioning trials but a near maximal response was noted following as few as five trials. Forty conditioning trials produced a significant reduction in the FPS response that may be related to overtraining. The FPS response in the B6 strain was significantly lower than the D2 strain, regardless of the number of conditioning trials. The contrasting FPS responses were not related to differences in auditory sensitivity known to exist between these strains. Analysis of a full Mendelian cross formed from the B6 and D2 strains found that the FPS response was a highly heritable trait, best described by a simple additive model of inheritance and with a broad-sense heritability of 0.46. The distribution of the FPS response in F2 hybrids formed from the intercross of the D2 and B6 strains was continuous which suggests a multigenic substrate. The light + noise and noise-alone trial types were highly correlated, but no association was detected between the baseline ASR amplitude and the FPS response. Mice from the phenotypic extremes of the F2 distribution displayed FPS responses that were more extreme than either of the progenitor strains. However, both baseline startle amplitude and the salience of auditory stimuli did not differ in these groups. The results of this study confirm an early report by Falls et al. (1997), and provide additional quantitative genetics information necessary for the eventual mapping of the chromosomal regions or genes associated with the FPS response in mice.

Frontal lobe and kindling in the rat.

To test the hypothesis that the cortex participates in amygdaloid kindling in rats, bilateral aspiration lesions were made in various cortical areas in rats prior to kindling. Lesions in orbital cortex (on the dorsal lip of the rhinal sulcus) or prefrontal cortex (area 10) significantly retarded the rate of amygdaloid kindling; lesions in motor cortex, anterior cingulate cortex, or visual cortex were without effect. Detailed analysis indicated that the orbital lesioned and frontal-lesioned rats kindled relatively normally up to the second-last stage of amygdaloid kindling, in which stage they perseverated significantly longer than the controls and the other lesioned rats. These results suggest that areas of the frontal lobe participate in the elaboration and generalization of amygdaloid seizures in rats. Although retarded in rate, kindling nonetheless occurred in the lesioned rats, indicating that these cortical areas are not essential for the development of amygdaloid seizures.

Ontogeny of plasma renin activity in the Dahl rat model of essential hypertension.

Plasma renin activity (PRA) is characteristically lower in the Dahl salt-sensitive (S) rat than in the salt-resistant (R) rat. To establish whether PRA differs between these strains at birth or subsequently becomes suppressed in the Dahl S rat, the ontogeny of PRA was studied in inbred Dahl hypertension-prone (S/JR) and hypertension-resistant (R/JR) rats from 5 to 51 days of age. Pregnant dams and postweaning pups were maintained on diets containing either 0.15% or 0.69% sodium chloride (w:w). Although PRA clearly distinguished the two strains in young adulthood, it was not lower in the S/JR pups at 5 and 15 days of age. However, PRA was greater in rat pups suckling dams consuming the low salt diet. These results suggest that suppressed PRA in S/JR rats is an acquired trait, perhaps occurring secondary to other physiological abnormalities and that maternal diet influences PRA in the suckling Dahl rat.

The effect of atropine or atropine methylnitrate on salt-induced hypertension in the inbred S/JR and R/JR Dahl rat.

The cholinergic antagonists atropine (ATR) and atropine methylnitrate (ATRMN) were chronically administered to inbred Dahl hypertension-sensitive (S/JR) and -resistant (R/JR) rats maintained on an 8.0% NaCl-containing diet. The effects on blood pressure (BP), heart rate (HR), and mortality were then examined during and after a four week period of treatment. Administration of ATR (7.2 mg/day) or ATRMN (2.4 mg/day) attenuated the development of salt-induced hypertension (HT) in the S/JR strain but had relatively little effect on BP in the R/JR strain. HR during the treatment period was significantly greater in S/JR and R/JR rats that received ATR or ATRMN than vehicle-treated controls. Each drug also reduced HT-related mortality in S/JR rats. In general, the effects of ATR on BP and mortality were greater than those of ATRMN. However, the results suggest that the central and peripheral cholinergic systems participate in the development of salt-induced HT in the S/JR rat.

Changes in the convulsive threshold in the developing rat following chronic administration of pentylenetetrazol.

The acute and chronic effects of pentylentetrazol (PTZ) on convulsive behavior in the developing rat pup were investigated. Acute treatment at 10 or 15 days of age with 50 or 80 mg/kg evoked clonic or tonic-clonic convulsions from all rats. However, daily administration of equivalent dose levels from 5 to 16 days of age was associated with a marked reduction in the incidence of these convulsions. Alternate day treatment from 5 to 16 days of age with 80 mg/kg or an ascending series of dose levels (10 mg/kg/day increments) was not accompanied by a reduction in convulsive behavior. The present results indicate that treatment of infant rats with PTZ is followed by a 24-48 h increase in convulsive threshold. This phenomenon may be associated with a developmental process since daily treatment past 15 days of age was characterized by a gradual reappearance of convulsive behavior.

Potentiation of hyperthermia-induced convulsions in the developing rat by previous treatment with pentylenetetrazol.

Infant rats were subjected to pentylenetetrazol-induced convulsions on alternate days from 5 to 13 days of age. At 17 days of age, their susceptibility to the convulsant effects of hyperthermia was examined. It was found that previous pentylenetetrazol-induced convulsions caused a significant facilitation in the development of hyperthermia-induced convulsions. The development of hyperthermia-induced convulsions was also facilitated in rat pups of a similar age after acute pretreatment with a subconvulsive dose of pentylenetetrazol. The results of this study indicate that cross sensitization between convulsant agents is possible in the developing rat. In addition, although the nervous system of the immature rat is not fully developed, the central substrates of this process evince adultlike characteristics.

Experimental febrile convulsions: long-term effects of hyperthermia-induced convulsions in the developing rat.

The susceptibility of infant rats to experimental febrile convulsions was investigated. Rats were subjected to a single hyperthermia convulsion at 5, 10, 15, or 20 days of age or the a series of convulsions from 5 to 20 days of age. Susceptibility to the experimental febrile convulsion decreased with age in all rats except those subjected to multiple convulsions. In this group, susceptibility tended to increase. This results is discussed in terms of its similarity to the kindling phenomenon and to the incidence of recurrent febrile convulsions in the human infant. Sex differences in susceptibility to the convulsion were examined, but none were found. Mature rats that had been subjected to experimental febrile convulsions as infants were found to be significantly more susceptible to a convulsive dose of pentylenetetrazol than controls. The results of this study indicate that even a single experimental febrile convulsion during infancy can exert a long-lasting, if not permanent, enhancement in seizure susceptibility. The similarities between the present findings and human infantile febrile convulsions are discussed.

Pre- and neonatal exposure of the Dahl rat to NaCl: development and regional distribution of myocardial alpha 1-adrenergic and cholinergic receptor sites.

The prenatal and/or postweaning effects of a hypertensinogenic high NaCl-containing diet (8.0% NaCl, w/w) on (1) the regional distribution of alpha 1-adrenoceptors and muscarinic cholinergic receptor sites in the heart and (2) the predisposition/resistance to hypertension (HT) were assessed in the inbred Dahl HT-sensitive (S/JR) and HT-resistant (R/JR) rat. The density of alpha 1-adrenoceptors was reduced in the left ventricle but not consistently affected in the ventricular septum, right ventricle, or atria of S/JR offspring with NaCl-induced HT. Both normotensive and hypertensive S/JR rats also displayed a significantly greater density of cholinergic receptor sites in the atria but few consistent alterations in other regions of the heart, compared to R/JR rats. Maternal diet had no effect on the predisposition/resistance to salt-induced HT and little effect on the regional development of alpha 1-adrenoceptors and cholinergic receptor sites. The results of this study suggest that the reduced density of ventricular alpha 1-adrenoceptors in the S/JR strain is a consequence of HT while the elevated density of cholinergic receptors in the atria may be related to the genetic predisposition/resistance to HT.

Differential ontogeny of alpha 1-adrenergic and cholinergic receptor sites in the atria and ventricles of the inbred Dahl hypertension-sensitive (S/JR) and -resistant (R/JR) rat.

The ontogeny of atrial and ventricular alpha 1-adrenergic and muscarinic cholinergic receptor sites was investigated in inbred Dahl hypertension-sensitive (S/JR) and -resistant (R/JR) rats between 5 and 150 days of age. The density of sites in both cardiac regions was generally greater in the neonate than mature rat. A marked proliferation of sites was observed in neonatal and young adult rats that occurred in the following order: ventricular cholinoceptors----ventricular adrenoceptors----atrial cholinoceptors----atrial adrenoceptors. The density of ventricular adrenoceptors was greater in the S/JR rat than the R/JR rat at 5 days of age. At 150 days of age, the density of sites was less in the S/JR rat than the age-matched R/JR rat or the normotensive 50-day-old S/JR rat. The development of atrial adrenoceptors was similar between the strains, regardless of the blood pressure. The density of ventricular cholinergic receptors was greater in the S/JR strain at 5 and 15 days of age. However, the density of atrial cholinergic sites was consistently greater in the S/JR strain throughout development. The results of this study suggest that: (1) significant prenatal receptor development occurs in the heart; (2) receptor development may precede the functional maturation of postganglionic autonomic efferents; and (3) distinguishing differences in the regional density of alpha 1-adrenergic and muscarinic cholinergic binding sites are present between S/JR and R/JR rats at much earlier points in development than previously shown.