Hypotensive properties of antibodies directed against an endogenous pressor peptide isolated from rat blood

Hypertensive factor (HF), a compound isolated from the erythrocytes of rats and tentatively identified as a peptide, has been shown to influence tissue calcium metabolism and induce prolonged blood pressure elevation. In the present study, we investigated the biological properties of antibodies directed against this peptide. Partially purified antibody preparations significantly decreased HF stimulation of lanthanum-resistant calcium uptake in rat aortic tissue in vitro. Infusion of the antibody preparation into spontaneously hypertensive (SH) or normotensive Sprague-Dawley rats resulted in a rapid decline in mean blood pressure of 54 and 34 Torr (1 Torr = 133.332 Pa), respectively. In contrast, infusion of the serum immunoglobulin preparations from controls (unimmunized and ovalbumin-immunized rabbits) had no significant effect on the blood pressure of SH or normotensive rats. The systolic blood pressure of SH rats was reduced for at least 72 h following a single injection of the antibody preparations, whereas the blood pressure of normotensive rats had returned to normal levels within 24 h following antibody injection. The results indicate that the anti-HF antibody preparation antagonizes the stimulation of calcium uptake by the peptide and acutely lowers blood pressure in SH and normotensive rats.     

Involvement of atrial natriuretic peptide in blood pressure reduction induced by estradiol in spontaneously hypertensive rats

The aim of the present study was to determine the involvement of atrial natriuretic peptide (ANP) in blood pressure (BP) alterations induced by estradiol treatment. Spontaneously hypertensive rats (SHR) and Wistar rats (WR) were ovariectomized and, after 3 weeks, were injected daily for 4 days with estradiol benzoate (E2; 5 microg/100 g/day) or a vehicle. One day after the last injection, the animals were decapitated, blood was collected, and both right and left atrial appendages were quickly removed for determination of ANP by radioimmunoassay (RIA), or used for ANP mRNA determination. Estradiol treatment induced a significant reduction of blood pressure in SHR, but not in WR. This reduction was correlated with the increase of plasma ANP levels that were significantly increased in E2-treated, compared with vehicle-treated, SHR. E2-treated SHR showed significant increases in ANP concentration in the right and left atria compared to the vehicle-treated animals. These observations were confirmed by ANP mRNA. In summary, the present study shows that short-term estradiol treatment reduces the blood pressure of ovariectomized SHR, but not of WR. This reduction was highly correlated with increased plasma estradiol and ANP levels. These results suggest that ANP is involved in mediating the effect of estradiol on blood pressure reduction.     

Hypoxic pressor response, cardiac size, and natriuretic peptides are modified by long-term intermittent hypoxia.

We investigated whether the effect of long-term intermittent hypoxia (LTIH) on cardiovascular function may be modified by preexisting genetic traits. To induce LTIH experimentally, cycles of 90-s hypoxia (nadir 6%) followed by 90-s normoxia were applied to six Wistar-Kyoto and six spontaneously hypertensive rats during 8 h daily. Comparison with the same number of control animals after 70 days revealed no alteration of intra-arterial blood pressure or heart rate. Blood pressure responsiveness to a brief hypoxic stimulus was enhanced in the LTIH animals, regardless of strain, whereas the hypoxia-induced increase in heart rate was abolished. In the spontaneously hypertensive but not the Wistar-Kyoto rats, LTIH increased left ventricular weight-to-body weight ratio and content of atrial natriuretic peptide mRNA. Expression of B-type natriuretic peptide was unchanged (Northern blot). Slightly increased right ventricular weight-to-body weight ratios in the LTIH animals were associated with higher right ventricular atrial natriuretic peptide and B-type natriuretic peptide mRNA amounts. Consequently, the effects of LTIH on different components of cardiovascular function appear incompletely related to each other and differentially influenced by constitutional traits.     

Natriuretic and hypotensive effects of brain natriuretic peptide (BNP) in spontaneously hypertensive rats

Effects of four doses (0.1, 0.2, 1.0 and 2.0 nmol/kg) of brain natriuretic peptide (BNP) on natriuresis and blood pressure were investigated in anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). An intravenous injection of 1.0 and 2.0 nmol/kg of BNP caused a significant increase of natriuresis and reduction of blood pressure in SHR and WKY. These effects were essentially identical to the effects of atrial natriuretic peptide (ANP). Remarkable bioactivity elicited by BNP rasises the possibility that BNP has a role in the regulation of blood pressure and water-electrolyte balance. On the other hand, when the effects of BNP on both strains of rats were compared with those of alpha-human ANP reported previously, the hypotensive effect of BNP was less than those of alpha-human ANP only in SHR. It is suggested that BNP might have different bioactivity than that of ANP in SHR.     

Increased reactive oxygen species contributes to kidney injury in mineralocorticoid hypertensive rats.

Hypertension is associated with increased reactive oxygen species (ROS). Renal ROS production and their effects on renal function have never been investigated in mineralocorticoid hypertensive rats. In this study we hypothesized that increased ROS production in kidneys from deoxycorticosterone (DOCA)-salt rats contributes to adverse renal morphological changes and impaired renal function in DOCA-salt hypertensive rats. We also determined whether ROS-induced renal injury was dependent on blood pressure. DOCA-salt hypertensive rats exhibited a marked increase in blood pressure, renal ROS production, glomerular and tubular lesions, and microalbuminuria compared to sham rats. Treatment of DOCA-salt hypertensive rats with apocynin for 28 days resulted in attenuation of systolic blood pressure and improvement of renal morphology. Renal superoxide level in DOCA-salt rats was 215% of sham-operated rats and it was significantly decreased to 140% with apocynin treatment. Urinary protein level was decreased from 27 +/- 3 mg/day in DOCA-salt hypertensive rats to 9 +/- 2 mg/day. 28 days of Vitamin E treatment also reduced renal injury in regard to urinary protein level and renal morphology but had no effect on blood pressure in DOCA-salt rats. Increased urinary 8-isoprostane, a marker for oxidative stress, in DOCA-salt hypertensive rats (55 +/- 8 ng/day) was diminished by vitamin E treatment (24 +/- 6 ng/day). These data suggest that renal injury characteristic of mineralocorticoid hypertension is associated with oxidative stress and is partly independent of blood pressure.     

Discontinuation syndrome after continuous infusion of clonidine in the spontaneously hypertensive rat

In conscious spontaneously hypertensive rats prepared with permanent indwelling aortic catheters the continuous infusion of clonidine (500 μg/kg/day) via an ALZET miniosmopump induced significant reductions in blood pressure and heart rate. These effects were well sustained during 12 days of treatment. A marked overshoot in heart rate was observed following withdrawal of clonidine administration. The tachycardia persisted for more than 36 hours. Mean arterial pressure exceeded control level slightly in the immediate withdrawal period only, whereas significant blood pressure lability was observed for more than 36 hours. These withdrawal symptoms were accompanied by an elevation of plasma noradrenaline concentration. The present study shows the consistent antihypertensive and bradycardic activities of clonidine during 12 days of infusion in spontaneously hypertensive rats. Furthermore, this model may provide a useful tool in the study of withdrawal phenomena of antihypertensive drugs.     

Role of calcitonin gene-related peptide in the phenol-induced neurogenic hypertension in rats

Previous investigations have demonstrated that capsaicin-sensitive sensory nerves are involved in the development of hypertension in some rat models of hypertension. To determine the role played by calcitonin gene-related peptide (CGRP; the predominant neurotransmitter in capsaicin-sensitive sensory nerves) in a rat model of neurogenic hypertension, in which hypertension was induced by injecting 50 microl of 10% phenol in the lower pole of the left kidney, systolic blood pressure (SBP) was monitored by the tail-cuff method throughout the experiment. Fifteen days after injection of phenol, mean arterial pressure (MAP), concentrations of CGRP in the plasma, the expression of CGRP mRNA in dorsal root ganglia (DRG) and CGRP content in laminae I and II of the spinal cord were measured. SBP was significantly increased 5 days after the intrarenal injection of phenol (164+/-7 mm Hg, p<0.01). At the end of experiment, blood pressure (BP) was significantly elevated in the phenol-injected rats compared with the controls (SBP: 187+/-6 vs. 122+/-4 mm Hg, p<0.01; MAP: 157.56+/-3.02 vs. 103.80+/-2.04 mm Hg, p<0.01). Treatment with capsaicin, which selectively depletes neurotransmitters from the capsaicin-sensitive nerves, failed to enhance the development of hypertensive responses to the intrarenal injection of phenol. Intravenous administration of CGRP(8-37), the specific CGRP receptor antagonist, also failed to increase the already elevated MAP. The expression of CGRP mRNA (both alpha- and beta-CGRP isoforms), the content of CGRP in laminae I and II of the dorsal horn of the spinal cord and the concentration of CGRP in the plasma was decreased in the rats treated with phenol. These results suggest that CGRP does not play a counterregulatory role in the phenol-induced hypertensive rats, and support the hypothesis that reduction of CGRP (alpha and beta isoforms) could contribute to a blood pressure elevation in this setting.     

Stress-induced hypertension: effects of adrenalectomy and corticosterone replacement

The effect of adrenalectomy on the hypotensive response induced by social deprivation was studied in a line of Wistar-derived rats. Prior removal of the adrenal gland by surgery was found to prevent the elevation in systolic or diastolic blood pressure observed in sham-operated isolated rats. The social deprivation-induced hypertensive response ran parallel with an increase in the levels of plasma corticosterone. Supplementation therapy with this glucocorticoid in previously adrenalectomized animals restored the levels of plasma corticosterone to normal and made the rats able to respond to social deprivation with an elevation in arterial pressure. Thus, corticosterone plays a "permissive" role in the elevation of blood pressure due to isolation. Apparently, this effect is dependent upon genetic, maturational and environmental factors since it is only evident in some lines of Wistar rats.     

Pressor responsiveness to vasopressin in spontaneously hypertensive rats

The present study was designed to find out whether pressor responsiveness to vasopressin (AVP) is altered in spontaneously hypertensive rats (SHR) in comparison with their normotensive controls (WKY). Blood pressure and heart rate changes after injection of graded doses of 2.5, 5.0 and 10.0 ng of AVP (Calbiochem) i.v. were compared in 9 conscious, unrestrained spontaneously hypertensive (SHR) and 11 normotensive Wistar Kyoto (WKY) rats, chronically instrumented with venous and arterial catheters. The threshold dose necessary to elicit a significant increase in blood pressure and reduction of heart rate was lower in WKY than in SHR. At each dose level the blood pressure elevation persisted for a longer period in WKY than in SHR. Bradycardia was greater in WKY than in SHR both in absolute terms and in relation to the blood pressure increase. Thus, the results reveal diminished pressor responsiveness to moderate doses of AVP in SHR in spite of suppressed reflex bradycardia. It is suggested that the peripheral action of AVP on the vascular system is attenuated in SHR.     

Hypertensive factor: calcium stimulatory activity obtained from different tissues and animal species

It was recently shown that a peptide (hypertensive factor, HF) isolated from erythrocyte hemolysates from spontaneously hypertensive rats induced a prolonged elevation of blood pressure in normotensive rats. In addition, the peptide produced a marked stimulation of the in vitro uptake of lanthanum-resistant calcium by the aortae and enhanced the contractile response of aortic rings to constrictor agents. The present report describes findings of calcium stimulatory activity, enhancement of contractile function, or pressor activity in extracts of homogenates from several tissues of the rat and from erythrocyte hemolysates of several mammalian species. Significant stimulation of calcium uptake in aortic rings was obtained with preparations from rat brain, liver, and kidney. The activity per weight of tissue was similar for brain and kidney (approximately 2 units/g), while liver exhibited somewhat higher concentrations (4 units/g). The diffusate of cardiac tissue did not significantly alter in vitro calcium uptake by aortae. The injection of the cardiac and liver diffusates into normotensive Wistar-Kyoto rats produced slight (10 Torr) (1 Torr = 133.3Pa) and moderate (25 Torr) elevations of blood pressure, respectively. Finally, a peptide purified from homogenates of rat brain by the protocol developed for the purification of HF from erythrocytes was shown to significantly enhance the contractile response of aortic rings to K+ and norepinephrine. Diffusates of erythrocytes from the rat, rabbit, dog, and guinea pig each caused a significant stimulation of calcium uptake and contained approximately the same level of activity (500 units/L of whole blood). Diffusates prepared from outdated human erythrocytes had no significant effect on calcium uptake, whereas those of freshly drawn samples exhibited high levels of activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced ganglionic responses to substance P in spontaneously hypertensive rats

Intravenous injection of substance P (SP) increases blood pressure in normotensive rats by stimulating sympathetic ganglia. This study compared the effects of SP to increase renal nerve firing and blood pressure in normotensive and hypertensive rats treated with chlorisondamine. The increase in renal nerve firing was greatest in spontaneously hypertensive rats (SHR), intermediate in Wistar rats, and least in Wistar-Kyoto (WKY) rats. Blood pressure was increased more in SHR than in Wistar rats. Blood pressure was not increased in WKY rats. Responses to the ganglionic stimulant 1,1-dimethyl-4-phenylpiperazinium were the same in the three strains. These results suggest that there is a selective increase in the action of SP on sympathetic ganglia of SHR and that ganglion responsiveness to SP is correlated with its effect on blood pressure.     

Comparison of the effect of hypoxia on the secretion of the atrial natriuretic factor in spontaneously hypertensive and normotensive rats.

The effect of short lasting hypoxia on blood pressure, plasma atrial natriuretic peptide level and number of specific atrial granules were studied in 26 male spontaneously hypertensive and 24 normotensive Wistar rats. A great difference occurred in ANP secretion between hypertensive and normotensive rats. In the hypertensive animals elevated plasma ANP concentration (130 +/- 27 pg/ml) and decreased granularity in the right atria (73 +/- 2) were found on the first day of hypoxia with a slight elevation in urinary sodium content versus normotensive controls. The blood pressure also decreased although not significantly (190 +/- 14 mm Hg). In Wistar rats increased plasma ANP (130 +/- 34 pg/ml) and decreased atrial granularity versus normotensive controls (72 +/- 10 in the left and 113 +/- 16 in the right atrium) were observed only on the third day of hypoxia without changes in blood pressure and natriuresis. In SHR the rapid but short timed ANP release might be of right atrial origin and probably the consequence of a continuous and perhaps increased secretion of the peptide in normoxic conditions too. In Wistar rats the plasma ANP elevation could be secondary due to the increased plasma level of different vasoactive hormones to hypoxia. In the altered effect of ANP in hypertensive and normotensive hypoxic animals, structural and functional changes in the vascular bed may play a role.     

Relationships between physical training and DOCA hypertension in rats.

Swimming, if undertaken for 1 hr/day, 3 days/week for 6 weeks prior to treatment with DOCA, unilateral nephrectomy, and salt-loading, delayed the development of hypertension in rats. If the swimming were undertaken concurrently with or after initiation of treatment with the above hypertensive regime, then it was without effect on the level of blood pressure attained or the length of time required to attain a given blood pressure. Swimming in itself resulted in a significant increase in arterial blood pressure. Previous training, such as swimming, may delay the development of hypertension through an alteration in vascular structure or smooth muscle sensitivity. The increase in blood pressure noted in physically trained rats may be a consequence of the training regime itself acting as a stressor.     

Heart rate reflex responses during gestation in normotensive and spontaneously hypertensive rats following angiotensin II and vasopressin

Gestation in the human and in rats is accompanied by a decrease in blood pressure and a reduction of the pressor response to vasoconstrictor agents. In humans, the decreased vascular reactivity to angiotensin II (AII) may occur simultaneously with a state of increased baroreceptor sensitivity. We have consequently evaluated the heart rate response to elevation of blood pressure following administration of either AII or arginine8-vasopressin (AVP) in conscious unrestrained, nonpregnant, or term-pregnant normotensive rats (Sprague-Dawley, SDR; Wistar-Kyoto, WKR) and in spontaneously hypertensive rats (SHR). The decrease in heart rate in response to increase in blood pressure by AII in nonpregnant animals was similar in SDR and SHR, but much greater in WKR. The heart rate response to increase in blood pressure by AVP was similar in all three strains of cycling rats. Gestation (20th day) did not change the heart rate response to increase in blood pressure by AII in normotensive animals, but increased slightly the reflex responses in SHR, as shown by a significant increase of the slope of the relationship of the decrement in heart rate versus the increment of blood pressure. The heart rate response to increase in blood pressure by AVP was greater during gestation in normotensive SDR and WKR, but not in SHR. These results show that the heart rate responses to an increase in blood pressure by vasoconstrictor peptides is dependent on the strain of animals used and suggest that the baroreceptor reflexes play a minor role in the blunted effect of vasconstrictor agens at the end of gestation in normotensive and spontaneously hypertensive rats.     

The antihypertensive activity of angiotensin-converting enzyme inhibitory peptide containing in bovine lactoferrin

Angiotensin I-converting enzyme (ACE) inhibitory peptide was isolated from the bovine lactoferrin hydrolysate using peptic hydrolysis by 2-step of reverse-phase high-performance liquid chromatography. This peptide was identified as Leu-Arg-Pro-Val-Ala-Ala and it produced a concentration-dependent inhibition of ACE activity in vitro with an IC50 value of about 4.14 microM. Also, this inhibition was identified as noncompetitive from the Lineweaver-Burk plot. Moreover, the antihypertensive activity of Leu-Arg-Pro-Val-Ala-Ala was investigated by the intravenous injection into spontaneously hypertensive rats (SHRs). A dose-dependent reduction of systolic blood pressure by this peptide was observed at 60 min after injection and it maximally decreased the blood pressure at a rate of 1 nmol/ml/kg. The blood pressure lowering activity of this peptide was calculated as 210% of captopril (10 pmol/ml/kg) that was used as positive control. Otherwise, identification of this peptide in the blood of SHRs was carried out chromatographically. Reduction of blood pressure coincides with the peak peptide concentration in the serum. Thus, we conclude that this peptide inhibits ACE activity in vitro and lowers systolic blood pressure in spontaneously hypertensive rat.     

Prolactin and LH release in response to vasoactive intestinal peptide (VIP) administration in spontaneously hypertensive and normotensive rats.

Vasoactive intestinal peptide (VIP) was injected intravenously at a dose of 10 micrograms in spontaneously hypertensive and normotensive Wistar-Kyoto rats. In order to evaluate the hemodynamic and hormonal effects of this peptide, the mean arterial pressure, heart rate as well as a serum rLH and rPRL levels, the contents of LH-RH in hypothalamus and the content of LH in pituitary tissue were determined. The same procedure was applied in rats receiving placebo. Serum rPRL concentration was measured additionally after combined administration of VIP+dopamine. VIP injection produced a decrease in mean arterial pressure and an increase in heart rate in both spontaneously hypertensive and normotensive rats. Serum rPRL concentration was significantly increased at 10 minutes after injection. The combined therapy (VIP+dopamine) partially inhibited this response. Serum rLH concentration, the content of LH-RH in hypothalamic tissue as well as the content of pituitary LH after VIP injection in spontaneously hypertensive and normotensive rats did not differ from the values obtained for the control group. Conclusions: 1. VIP injection produced the dramatic hypotensive effects in hypertensive rats; 2. A marked increase in PRL concentration in response to VIP was partially inhibited by dopamine in hypertensive and normotensive rats; 3. VIP injection did not change LH-RH and LH release in both hypertensive and normotensive rats.     

Effect of celecoxib on the antihypertensive effect of losartan in a rat model of renovascular hypertension

Certain nonsteroidal anti-inflammatory drugs have been reported to elevate blood pressure in some hypertensive patients, who are either untreated or treated with antihypertensive agents. This study was undertaken to determine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the antihypertensive effects of the angiotensin II type 1 receptor (AT1) antagonist, losartan potassium. We studied the effect of oral treatment with losartan (30?mg/kg), celecoxib (3?mg/kg), and their combination on the mean arterial blood pressure (MAP), plasma renin activity (PRA), and plasma prostaglandin E2 (PGE2) in male Sprague-Dawley rats with renovascular hypertension (RVH) induced by partial subdiaphragmatic aortic constriction. Treatment was continued for 7 days after aortic coarctation. Aortic coarctation led to significant increases in the MAP, PRA, and plasma PGE2. In RVH rats, losartan treatment caused a significant decrease of MAP with a significant increase in both plasma PGE2 and PRA. Celecoxib caused a nonsignificant change in MAP with a significant decrease in the raised levels of plasma PGE2 and PRA. Concomitant administration of celecoxib and losartan did not significantly affect the lowering effect of losartan on MAP with a subsequent significant decrease in the plasma PGE2 and PRA in RVH rats. Therefore, celecoxib could be used in renin-dependent hypertensive patients who receive losartan, without fear of a rise in their blood pressure.     

Effect of losartan on the blood-brain barrier permeability in diabetic hypertensive rats

Our previous publication has stressed the benefits of losartan, an angiotensin II receptor blocker, on the permeability of blood-brain barrier (BBB) and blood pressure during L-NAME-induced hypertension. This study reports the impacts of anti-hypertensive treatment by losartan on the brain endothelial barrier function and the arterial blood pressure, during acute hypertension episode, in experimentally diabetic hypertensive rats. Systolic blood pressure measurements were taken with tail cuff method before and during administration of L-NAME (0.5 mg/ml). We induced diabetes by using alloxan (50 mg/kg, i.p). Losartan (3 mg/kg, i.v) was given to rats following the L-NAME treatment. Acute hypertensive vascular injury was induced by epinephrine (40 microg/kg). The BBB disruption was quantified according to the extravasation of the Evans blue (EB) dye. L-NAME induced a significant increase in arterial blood pressure on day 14 in normoglycemic and hyperglycemic rats (p < 0.05). Losartan significantly reduced the increased blood pressure in hypertensive and diabetic hypertensive rats (p < 0.01). Epinephrine-induced acute hypertension in diabetic hypertensive rats increased the content of EB dye dramatically in cerebellum and diencephalon (p < 0.01) and slightly in both cerebral cortex (p < 0.05). Losartan treatment reduced the increased BBB permeability to EB dye in the brain regions of diabetic hypertensive rats treated with epinephrine (p < 0.05). This study indicates that, in diabetic hypertensive rats, epinephrine administration leads to an increase in microvascular-EB-albumin efflux to brain, however losartan treatment significantly attenuates this protein's transport to brain tissue.     

Effect of Clostridium perfringens Beta Toxin on Blood Pressure of Rats

Guanethidine treatment or adrenal medullectomy significantly inhibited the elevation in blood pressure induced by Clostridium perfringens beta toxin, and the combination of the two drastically reduced the pressure rise, to less than 19% of that in control rats. When rats were pretreated with tetrodotoxin or hexamethonium, the toxin-evoked rise was significantly inhibited. Elevation in blood pressure induced by the toxin in spinal rats tended to be less than that in control rats. When investigated by a microscopical technique, arteriolar constriction in the mesenteric vasculature was observed after the blood pressure elevation induced by the toxin reached a maximum. Blood flow in the skin decreased with an increase in blood pressure following intravenous injection of the toxin. It is concluded that beta toxin acts on the autonomic nervous system and produces arterial constriction.     

Changes in systolic arterial blood pressure in normal and spontaneously hypertensive rats produced by acute administration of inhibitors of prostaglandin biosynthesis

Six non-steroidal agents having the property of being able to inhibit prostaglandin (PG) biosynthesis or action were tested for their ability to affect systolic blood pressure in unanesthetized normotensive (WKY) and Spontaneously Hypertensive Rats (SHR). In WKY and pre-hypertensive young SHR, s.c. injection of indomethacin (1.0 mg/kg) had no significant effect on blood pressure measured 30 minutes after injection. In older SHR, indomethacin (15 mg/kg) caused a significant pressor response, while in age - matched WKY, this dose had no significant effect. Indomethacin also showed a prohypertensive action in 10–14, 23–38 and 23–27 week old SHR with doses of 1.0 and 3.0 mg/kg, respectively. Tiaramide (5 mg/kg), ETYA (5 mg/kg), tolmetin (25 mg/kg), and meclofanamate (15 mg/kg) caused a significant elevation of blood pressure in mature (7–8 month old) SHR. Age matched WKY showed no significant response to the same doses of these four agents. Fenoprofen (75 mg/kg) caused a significant elevation in pressure in 12–13 week old SHR which persisted for at least 2 hours. Tiaramide had no significant effect on pre-hypertensive SHR. The results are consistent with the concept that inhibition of prostaglandin synthesis may result in a diminished turnover of antihypertensive prostaglandins in SHR which are being elaborated in response to the hypertensive state. In normal rats and pre-hypertensive SHR, inhibition of prostaglandin synthesis or function may not result in a hypertensive response since pro-hypertensive factors either are absent, or other antihypertensive substances may still predominate to help maintain normal blood pressure.