Regulation Of Systemic Blood Pressure Research Articles

β-Endorphin in the median preoptic nucleus modulates the pressor response induced by subcutaneous hypertonic sodium chloride

Considerable evidence has been gathered involving the endogenous opioid system in blood pressure regulation. In the present study, we investigated the effect of administering β-Endorphin into the median preoptic nucleus (MnPO) on blood pressure (BP) and heart rate (HR) and whether this administration was capable of modulating the pressor response observed after an acute increase in plasma osmolality. In urethane-anaesthetized Wistar rats, different doses of β-Endorphin (1, 10, 25 ng) were microinjected into the MnPO to elucidate a putative role for β-Endorphin in BP and HR regulation. Additionally, we evaluated the modulatory effect of the β-Endorphin injection (25 ng) into the MnPO on the pressor response to subcutaneous sodium chloride solution administration (2 M NaCl, 0.1 ml/10 gbw). The MnPO-β-Endorphin microinjection resulted in a dose-dependent hypotensive and bradycardic effect and pre-treatment with the opioid antagonist, naloxone (100 ng), injected in the same nucleus, significantly antagonized the cardiovascular response to β-Endorphin administration in the MnPO. On the other hand, a microinjection of β-Endorphin (25 ng) into the median preoptic nucleus abolished the pressor response to a subcutaneous injection of hypertonic saline. It is concluded from these results that β-Endorphin-MnPO administration produces a decrease in BP and HR in normotensive animals and also inhibits the pressor response evoked by an acute increase in plasma osmolality.

The emerging role of ACE2 in physiology and disease

The renin–angiotensin–aldosterone system (RAAS) is a key regulator of systemic blood pressure and renal function and a key player in renal and cardiovascular disease. However, its (patho)physiological roles and its architecture are more complex than initially anticipated. Novel RAAS components that may add to our understanding have been discovered in recent years. In particular, the human homologue of ACE (ACE2) has added a higher level of complexity to the RAAS. In a short period of time, ACE2 has been cloned, purified, knocked‐out, knocked‐in; inhibitors have been developed; its 3D structure determined; and new functions have been identified. ACE2 is now implicated in cardiovascular and renal (patho)physiology, diabetes, pregnancy, lung disease and, remarkably, ACE2 serves as a receptor for SARS and NL63 coronaviruses. This review covers available information on the genetic, structural and functional properties of ACE2. Its role in a variety of (patho)physiological conditions and therapeutic options of modulation are discussed. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Pathophysiology of Hypertension During Preeclampsia: Role of Inflammatory Cytokines

Preeclampsia is defined as new onset hypertension with proteinuria during pregnancy. The initiating event in preeclampsia is postulated to be reduced uteroplacental perfusion which leads to widespread dysfunction of the maternal vascular endothelium. Inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF alpha) are thought to be important links between placental ischemia and cardiovascular and renal dysfunction. Supporting a potential role of cytokines in preeclampsia are findings that plasma levels of TNF and IL-6 are elevated in women with preeclampsia. Important blood pressure regulatory systems such as the renin-angiotensin system, sympathetic nervous system, and endothelial factors interact with pro-inflammatory cytokines such as IL-6 and TNF. Pro-inflammatory cytokines also affect vascular function and endothelium-derived factors involved in blood pressure regulation. Thus, endothelial dysfunction associated with preeclampsia may be mediated by cytokines. Recent studies have indicated that chronic reductions in placental perfusion in pregnant animals are associated with enhanced production of inflammatory cytokines, such as TNF alpha and IL-6. In addition, chronic infusion of either TNF alpha or IL-6 into normal pregnant rats results in significant increases in arterial pressure and a decrease in renal hemodynamics. TNF alpha activates the endothelin system in placenta, renal and vascular tissues whereas IL-6 stimulates the renin-angiotensin system. Collectively, these findings suggest that inflammatory cytokines play a role in causing hypertension in response to chronic reductions in uterine perfusion during pregnancy by activating multiple neurohumoral and endothelial factors. Keywords: endothelin (ET-1), IL-6, tumor necrosis factor (TNF) alpha, rennin-angiotensin system (RAS), angiotensin II

Chronic 5‐HT: An unexpected depressor in mineralocorticoid hypertension

Serotonin (5-HT) is a vasoactive autocoid, but its role in systemic blood pressure regulation is unclear. The role of 5-HT in hypertension is not understood though arteries from different models of hypertension are hypercontractile to 5-HT. We hypothesized that chronic 5-HT infusion would lead to increased blood pressure and arterial 5-HT content in normotensive rats; these responses would be enhanced in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. 5-HT (25 ug/kg/min) or vehicle was administered via osmotic pump for 1 week to normotensive and established hypertensive rats. Within 24 hours post-pump implantation, radiotelemeter measurement of mean arterial pressure in the normotensive 5-HT infused group fell 23 mmHg (table). This hypotensive response was enhanced in the DOCA 5-HT infused group in which mean arterial pressure fell 63 mmHg. These findings are the first to demonstrate the long-term effects of 5-HT on blood pressure, and indicate the net effect of chronic increases in circulating 5-HT is decreased blood pressure. This is counterintuitive given arterial hyperresponsiveness to 5-HT in vivo and in vitro, suggesting the effects of 5-HT in the cardiovascular system are considerably more complex than currently appreciated. Mean Arterial Pressure (mmHg)

Regulator of G-Protein Signaling-2 as a Candidate Gene

The “mosaic theory” of hypertension has been the prevailing dogma since its enunciation more than a half century ago. However, the ongoing search has been to determine which of the myriad of alterations in blood pressure regulatory systems occurs earliest in the process and are critical in the maintenance of the hypertensive state. Much of that focus has been directed to the determinants of increased peripheral resistance—perhaps the hallmark of the hypertensive state. The mechanisms underlying this abnormality reflect a combination of both structural and functional factors. From a functional perspective, peripheral resistance reflects a net balance between vasoconstrictor and vasodilator mechanisms. Defects in vasodilator mechanisms and enhancement of vasoconstrictor mechanisms have been described in human hypertension as well as in animal models. Central among these mechanisms have been alterations in G-protein-coupled receptor (GPCR) signaling pathways. Alterations in GPCR-signaling pathways in the hypertensive state are probably best explained by alterations downstream from the receptor. For those GPCRs linked to Gs and adenylyl cyclase activation, the impairment in GPCR/ G-protein “coupling” reflects both decreased G-protein function as well as the impact of increased expression/activity of the G-protein receptor kinases that interdict GPCR/G-protein signaling.1 For those mechanisms linked to vasoconstrictor process (via either Gi or Gq) the alterations also appear to be generalized across a range of receptors, consistent with a “downstream” effect.2 For …

Angiotensin-II Type 1 Receptor–Mediated Hypertension in D 4 Dopamine Receptor–Deficient Mice

Dopamine receptors are important in systemic blood pressure regulation. D4 receptors are expressed in the kidney and brain, but their role in cardiovascular regulation is unknown. In pentobarbital-anesthetized mice, systolic and diastolic blood pressures were elevated in sixth-generation D4 receptor-deficient (D4(-/-)) mice and in tenth-generation D4(-/-) mice compared with D4 wild-type (D4(+/+)) littermates. The conscious blood pressures measured via a chronic arterial (femoral) catheter or telemetry (carotid) were also higher in D4(-/-) mice than in D4 littermates. Basal renal and plasma renin concentrations were similar in the 2 mouse strains. The protein expression of angiotensin II type 1 receptor was increased in homogenates of kidney (330+/-53%, n=5) and brain (272+/-69%, n=5) of D4(-/-) mice relative to D4(+/+) mice (kidney: 100+/-12%, n=5; brain: 100+/-32%, n=5). The expression of the receptor in renal membrane was also increased in D4(-/-) mice (289+/-28%, n=8) relative to D4(+/+) mice (100+/-14%, n=10). In contrast, the expression in the heart was similar in the 2 strains. Bolus intravenous injection of angiotensin II type 1 receptor antagonist losartan initially decreased mean arterial pressures to a similar degree in D4(-/-) and D4(+/+) littermates. However, the hypotensive effect of losartan dissipated after 10 minutes in D4(+/+) mice, whereas the effect persisted for >45 minutes in D4(-/-) mice. We conclude that the absence of the D(4) receptor increases blood pressure, possibly via increased angiotensin II type 1 receptor expression.

The assessment of baroreflex sensitivity in patients with chronic kidney disease: implications for vasomotor instability

Autonomic dysfunction is well recognized in chronic kidney disease. The baroreflex arc is an important component of the autonomic nervous system and influences vasodilatation and heart rate in response to information derived from baroreceptors located in the aorta and common carotid arteries. Appropriate regulation of systemic blood pressure is therefore dependent upon the integrity and normal function of the baroreflex arc. Vasomotor instability during haemodialysis has traditionally been identified as a pathophysiological state largely due to the failure of compensatory mechanisms during ultrafiltration. This review article discusses autonomic dysfunction as a key factor contributing to the systemic haemodynamic instability that may occur during dialysis. Relationships have begun to be established between markers of reduced baroreflex sensitivity and abnormal cardiovascular structure, such as left ventricular dysfunction, left ventricular hypertrophy and arterial stiffness. Pathological relationships between cardiovascular structure and function remain important in the understanding of both haemodynamic instability and cardiovascular mortality in chronic kidney disease patients. Understanding the associations between conventional markers of haemodynamic instability and autonomic function will allow early identification of patients likely to benefit from individualizing dialysis therapy.

Lessons from soluble guanylate cyclase alpha1 knockouts

SGC is a heme containing heterodimer having two known active isoforms, α1β1 and α2β1. Particularly the former is suspected to be important in smooth muscle relaxation while the latter would be involved in neurologic systems. Since no isoform specific inhibitors exist, we generated knockout mice for the α1 isoform in order to investigate its function in the systems involving the NO/sGC pathway. The deletion of exon 6 resulted in mice expressing a non-frameshifted inactive protein. Hence the mice could be considered as cyclase death knockins, avoiding phenotypes due to enzyme function independent structural functions of the protein. We observed that these knockout mice retained full viability and fertility. The male mice developed hypertension around 12 to 14 weeks of age while the female mice did not. Ovariectomy did not influence the blood pressure in a different way than in wild type littermate controls. Both in the male and female knockout mice the NOS-inhibitor L-NAME raised the blood pressure to a similar extent as in wild type mice. NO-donors lowered blood pressure in male but not female mice. These observations show that the importance of the NO/sGC system in blood pressure regulation is gender-specific and that in female mice other mechanisms, probably EDHF, play the major role. It furthermore demonstrates that NO has sGCα1β1 independent activities in blood pressure regulation, either acting through the sGCα2β1 isoform or through sGC independent mechanisms such as direct influence on K+ channels. Phenotyping in a NOS-1 dependent system showed that α1β1 is also involved in NOS-1 derived NO signalling. In parallel experiments in supposedly NOS dependent shock models that could be inhibited by methylene blue we observed that the shock was retained even in the absence of NO, and based upon ion channel inhibition, probably is due to (an) EDHF.

ROLE OF THE CENTRAL NUCLEUS OF THE AMYGDALA IN THE CONTROL OF BLOOD PRESSURE: DESCENDING PATHWAYS TO MEDULLARY CARDIOVASCULAR NUCLEI

1. One of the key areas that links psychologically induced stress with the blood pressure-regulatory system is the central nucleus of the amygdala (CeA). This is an integratory forebrain nucleus that receives input from higher centres in the forebrain and has extensive connections with the hypothalamus and the medulla oblongata, areas involved in the regulation of the cardiovascular reflexes. 2. Based on studies using electrical or chemical stimulation or electrolytic lesions of the CeA, it has become clear that the CeA plays an important role in the regulation of blood pressure in response to stressful or fearful stimuli. 3. Two important medullary areas known to receive projections from the CeA are the nucleus tractus solitarius (NTS) and the rostral ventrolateral medulla (RVLM). The NTS is the site of the first synapse for afferent fibres originating from baroreceptors, chemoreceptors and the heart, whereas the RVLM contains neurons that maintain resting blood pressure and sympathetic nerve activity via projections to sympathetic preganglionic neurons in the intermediolateral cell column of the thoracolumbar spinal cord. 4. Electron microscopic studies using combined anterograde tracing and pre- and post-embedding immunogold labelling have shown that the pathways originating from the CeA to the NTS are inhibitory and may use GABA as a neurotransmitter. The results of these studies suggest that blood pressure changes produced by activation of the CeA may be mediated by attenuation of baroreceptor reflexes through a GABAergic mechanism at the level of the NTS. 5. Neuronal tract tracing combined with neurofunctional studies using the Fos protein as a marker of activated neurons indicate that the CeA projects directly to baroreceptive neurons in the NTS and RVLM that are activated by changes in blood pressure. 6. In conclusion, studies that have examined the efferent pathways of the CeA suggest that CeA neurons with projections to medullary baroreceptive neurons may play a vital role in the reflex changes in sympathetic nerve activity that are involved in blood pressure regulation in response to stress or anxiety.

Angiotensin II AT 2 receptor localization in cardiovascular tissues by its antibody developed in AT 2 gene-deleted mice

In contrast to well-established physiological roles of the angiotensin II type 1 receptor (AT 1), the significance of the type 2 receptor (AT 2) remains largely unclear. AT 2-knockout (AT 2KO) mice have a phenotype associated with mild hypertension. This implies that AT 2 has a role for the regulation of blood pressure. To gain insight into the mechanism by which AT 2 regulates systemic blood pressure, we have investigated the expression of the AT 2 receptor protein in adult rat cardiovascular tissues, using a newly developed polyclonal anti-AT 2 antiserum that was successfully obtained in the AT 2KO mice by immunizing with a peptide fragment of the receptor protein. In blood vessels, a stronger immunoreactivity was observed in endothelial cells than in the muscular media of resistant arteries. In the thoracic aorta, AT 2 was observed only in muscular media. Abundant AT 2 immunoreactivity was detected in perivascular nerve fibers. In the heart, positive immunostaining for AT 2 was restricted to the coronary blood vessels. These data suggest that AT 2 expressed in the vascular endothelial cells and muscular media in resistant arteries may play a pivotal role in systemic blood pressure regulation. AT 2 was observed for the first time in the perivascular nerve fibers and may also play a role in neuronal blood pressure regulation.

Etomidate alters calcium mobilization induced by angiotensin II in rat aortic smooth muscle cells.

Etomidate is widely used for induction of anesthesia in the hemodynamically compromised patient, because of its moderate direct effect on arterial vasomotoricity and cardiac function, but its effect on blood pressure regulatory systems is not known. We studied the effect of etomidate (10(-8) to 10(-4) mol.L) on Ca++ mobilization elicited by angiotensin II (Ang II) in cultured aortic smooth muscle cells (VSMC) from 6-week-old Wistar Kyoto rats. Intracellular Ca++ (Cai++) variation was assessed in Fura 2-loaded VSMC, using fluorescent imaging microscopy. Ang II (10(-6) mol.L(-1))-induced transient Cai++ mobilization from internal stores was assessed in the absence of external Ca++. Ca++ influx was assessed upon reintroduction of external Ca++ (10(-3) mol.L(-1)). Etomidate moderately decreased both the amplitude (etomidate 10(-4) mol.L(-1): 68% of control value, P < 0.001) and the slope of Cai++ increase (56% of control, P < 0.001) from internal stores induced by Ang II. PD2 values (PD2 = -log(EC50)) for amplitude and slope were 6.4 +/- 0.7 and 6.0 +/- 0.3, respectively. Ang II-elicited Ca++ influx was also significantly decreased (45% of control, P < 0.001; PD2 = 5.5 +/- 0.3). Etomidate alters the Ca++ mobilization elicited by Ang II in rat aortic VSMC, suggesting that the vascular response to Ang II may be altered during etomidate anesthesia. However, this effect was observed at high concentration of etomidate, and may be limited when low doses of etomidate are used.

Excessive zinc intake elevates systemic blood pressure levels in normotensive rats ??? potential role of superoxide-induced oxidative stress

The present study was designed to examine whether or not excessive Zn intake affects systemic blood pressure (BP) levels in a normotensive state. Systolic BP (SBP) and mean arterial pressure (MAP) before and after administration of the nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME) or the exogenous superoxide scavenger, tempol and the activity of the endogenous superoxide scavenger, Cu/Zn-superoxide dismutase (SOD) and levels of endothelial type (e)NOS mRNA and protein in the thoracic aorta were analyzed in male Sprague-Dawley rats fed a standard diet containing 0.005% Zn or a high Zn diet containing 0.5% Zn for 8 weeks. SBP and MAP levels observed at the end of dietary conditioning were significantly elevated in rats fed a high Zn diet relative to rats fed a standard diet. Administration of L-NAME caused an increase in MAP levels in rats fed a standard and a high Zn diet, demonstrating the involvement of the vasodilator, nitric oxide (NO) in the regulation of systemic BP in the two groups of rats. However, the expression of eNOS mRNA and protein in the thoracic aorta was not significantly different between rats fed a standard and a high Zn diet. On the other hand, administration of tempol led to a decrease in MAP levels in rats fed a standard and a high Zn diet, indicating the participation of the oxygen free radical, superoxide in the modification of systemic BP in the two groups of rats. As reported recently, the mechanism involved is due likely to a decrease in the action of the vasodilator, NO through the formation of peroxynitrite based on the non-enzymatic reaction of superoxide and NO. In addition, tempol treatment dramatically restored MAP levels in rats fed a high Zn diet to levels comparable with those observed in rats fed a standard diet, indicating that an elevation in systemic BP levels seen in rats fed a high Zn versus a standard diet is presumably brought by a reduction in the action of the vasodilator, NO resulting from an increase in the action of superoxide. The activity of Cu/Zn-SOD in the thoracic aorta was significantly reduced in rats fed a high Zn diet relative to rats fed a standard diet, appearing to at least in part, play a role in an increase in the action of superoxide in the vessel wall of rats fed a high Zn diet. Excessive Zn intake may be a factor to elevate systemic BP levels in a normotensive state presumably through the oxidative stress caused by superoxide.

Increased blood pressure in transgenic mice expressing both human renin and angiotensinogen in the renal proximal tubule.

The purpose of this study was to evaluate the physiological significance of a tissue renin-angiotensin system in the proximal tubule of the kidney. To accomplish this, we produced mice that express human renin (hREN) under the control of the kidney androgen-regulated promoter (KAP), which is androgen responsive. One of the lines expressed the hREN transgene primarily in the kidney. Renal expression of the transgene was undetectable in females but could be induced by testosterone treatment. Because the renin-angiotensin system is species specific, we bred KAP2-hREN mice with the mice expressing human angiotensinogen under the same promoter (KAP-hAGT) to produce offspring that expressed both transgenes. We measured mean arterial blood pressure (MAP) in the carotid artery of double-transgenic and control mice using radiotelemetry. Double-transgenic female mice had a normal baseline MAP (116 +/- 4 mmHg, n = 8), which increased by 15 mmHg after 2 wk of testosterone treatment, and returned to baseline after elimination of the testosterone pellet. The change in arterial pressure paralleled the change in plasma testosterone. There was no MAP change in testosterone-treated control littermates. We conclude that dual production of renin and angiotensinogen in the renal proximal tubule can result in a systemic increase in arterial pressure. These data support a role for a tissue-specific renin-angiotensin system in the renal proximal tubule that contributes to the regulation of systemic blood pressure.

プラゾシンの降圧効果に及ぼすメトプロロールの影響 - 血圧調節機構を考慮したPK-PD解析 -

プラゾシンの降圧効果に及ぼすメトプロロールの影響 - 血圧調節機構を考慮したPK-PD解析 -

Contribution of sympathetic nervous system activity during administration of carvedilol in rats with dilated cardiomyopathy.

We investigated the contribution of the sympathetic nervous system (SNS) in maintaining blood pressure during administration of carvedilol in rats with dilated cardiomyopathy, and examined whether SNS hyperactivity induced by high-dose carvedilol is related to severity of heart failure. The hypotensive effect of carvedilol in rats with heart failure (Group F) was not significantly different to that in rats without (Group N). However, enhancement of the plasma norepinephrine concentration during carvedilol administration in Group F was higher than in Group N. The constitutive plasma NE concentration in Group F (562 +/- 146 pg/ml) was significantly higher than in Group N (203 +/- 55 pg/ml) and there was a significant positive correlation between the heart weight to body weight ratio and the plasma norepinephrine concentration. Values for the maximal effect of the norepinephrine hypertensive effect during norepinephrine intravenous infusion (Emax) decreased, and plasma norepinephrine concentrations at half-maximal effect of the norepinephrine hypertensive effect (EC50) increased in Group F compared with Group N (20.8 +/- 6.1 and 28.6 +/- 2.2 mmHg, and 4.5 +/- 1.9 and 1.5 +/- 0.2 ng/ml, respectively). These results suggested that the number of receptors (Emax) and sensitivity (EC50) to the norepinephrine hypertensive effect decreased in Group F. Changes in these parameters in Group F corresponded with the results of a beta-adrenergic receptor binding assay using I-125 iodocyanopindolol (Bmax = 32 +/- 4 in Group F and 53 +/- 2 fmol/mg protein in Group N). These results showed that the SNS (presynaptic) activity increased and the SNS receptor sensitivity in the blood pressure regulation system decreased in heart failure. Therefore, high-dose carvedilol treatment should be used with caution to avoid worsening heart failure.

Augmentation of the push-pull effect by terminal aortic occlusion during head-down tilt.

Tolerance to positive vertical acceleration (Gz) gravitational stress is reduced when positive Gz stress is preceded by exposure to hypogravity, which is called the "push-pull effect." The purpose of this study was to test the hypothesis that baroreceptor reflexes contribute to the push-pull effect by augmenting the magnitude of simulated hypogravity and thereby augmenting the stimulus to the baroreceptors. We used eye-level blood pressure as a measure of the effectiveness of the blood pressure regulatory systems. The approach was to augment the magnitude of the carotid hypertension (and the hindbody hypotension) when hypogravity was simulated by head-down tilt by mechanically occluding the terminal aorta and the inferior vena cava. Sixteen anesthetized Sprague-Dawley rats were instrumented with a carotid artery catheter and a pneumatic vascular occluder cuff surrounding the terminal aorta and inferior vena cava. Animals were restrained and subjected to a control gravitational (G) profile that consisted of rotation from 0 Gz to 90 degrees head-up tilt (+1 Gz) for 10 s and a push-pull G profile consisting of rotation from 0 Gz to 90 degrees head-down tilt (-1 Gz) for 2 s immediately preceding 10 s of +1 Gz stress. An augmented push-pull G profile consisted of terminal aortic vascular occlusion during 2 s of head-down tilt followed by 10 s of +1 Gz stress. After the onset of head-up tilt, the magnitude of the fall in eye-level blood pressure from baseline was -20 +/- 1.3, -23 +/- 0.7, and -28 +/- 1.6 mmHg for the control, push-pull, and augmented push-pull conditions, respectively, with all three pairwise comparisons achieving statistically significant differences (P < 0.01). Thus augmentation of negative Gz stress with vascular occlusion increased the magnitude of the push-pull effect in anesthetized rats subjected to tilting.

Resolving the composite trait of hypertension into its pharmacogenetic determinants by acute pharmacological modulation of blood pressure regulatory systems.

Acute pharmacogenetic analysis was carried out in an intercross F2 population derived from Prague hypertensive-hypertriglyceridemic and Lewis rats. Quantitative trait loci (QTL) mapping was performed for baseline blood pressure (BP) and for BP after blockade of the renin-angiotensin system by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide system by N(G)-nitro- L-arginine methyl ester. Two significant loci for baseline BP were found on chromosome (Chr) 3 (logarithm of likelihood, LOD, 3.8) and Chr 5 (LOD 3.6), and one suggestive locus on Chr 1 (LOD 2.7). The QTL on Chr 3 persisted after treatment with the three agents while the QTL on Chr 5 and Chr 1 disappeared after pentolinium administration. This suggests independence of the locus on Chr 3 from each acute BP regulatory system examined, whereas the loci on Chr 5 and Chr 1 appeared to be controlled mainly by the SNS. Although not apparent at baseline, a significant locus appeared on Chr 8 (LOD 7.0) after blockade of the SNS, and NO system blockade led to the appearance of a new QTL on Chr 1 (LOD 3.6), indicating the contribution of the inhibited systems to these loci. Pharmacogenetic dissection of the BP trait is a powerful tool to unravel the underlying physiological mechanisms of QTL affecting baseline BP and to identify specific QTL for the response to drugs. This pharmocogenetic approach enabled us to determine the main causative acute BP regulatory systems and should lead to better selection of suitable antihypertensive drugs for individual patients.

The alpha(1D)-adrenergic receptor directly regulates arterial blood pressure via vasoconstriction.

To investigate the physiological role of the alpha(1D)-adrenergic receptor (alpha(1D)-AR) subtype, we created mice lacking the alpha(1D)-AR (alpha(1D)(-/-)) by gene targeting and characterized their cardiovascular function. In alpha(1D)-/- mice, the RT-PCR did not detect any transcript of the alpha(1D)-AR in any tissue examined, and there was no apparent upregulation of other alpha(1)-AR subtypes. Radioligand binding studies showed that alpha(1)-AR binding capacity in the aorta was lost, while that in the heart was unaltered in alpha(1D)-/- mice. Non-anesthetized alpha(1D)-/- mice maintained significantly lower basal systolic and mean arterial blood pressure conditions, relative to wild-type mice, and they showed no significant change in heart rate or in cardiac function, as assessed by echocardiogram. Besides hypotension, the pressor responses to phenylephrine and norepinephrine were decreased by 30-40% in alpha(1D)-/- mice. Furthermore, the contractile response of the aorta and the pressor response of isolated perfused mesenteric arterial beds to alpha(1)-AR stimulation were markedly reduced in alpha(1D)-/- mice. We conclude that the alpha(1D)-AR participates directly in sympathetic regulation of systemic blood pressure by vasoconstriction.

Zn DEFICIENCY AGGRAVATES HYPERTENSION IN SPONTANEOUSLY HYPERTENSIVE RATS: POSSIBLE ROLE OF Cu/Zn-SUPEROXIDE DISMUTASE

Using spontaneously hypertensive rats (SHR) fed a standard or a Zn-deficient diet for 4 weeks, we examined whether Zn deficiency affects systemic blood pressure (BP) levels in a genetically hypertensive state through a fall in the activity of Cu/Zn-superoxide dismutase (SOD). SHR fed a Zn-deficient diet had a progressive increase in systolic BP during the dietary conditioning. Consequently, SHR fed a Zn-deficient diet exhibited significantly increased levels of systolic BP by 2 weeks after the start of dietary treatment when compared with SHR fed a standard diet. Similarly, levels of basal mean arterial pressure (MAP) observed at the end of dietary treatment were SHR fed a Zn-deficient diet>SHR fed a standard diet. Administration of the nitric oxide synthase (NOS) inhibitor, L-NAME, caused an increase in MAP levels in the two groups of rats, demonstrating the involvement of the vasodilator, nitric oxide (NO), in the regulation of systemic BP in a genetically hypertensive state. The expression of endothelial (e) NOS mRNA and protein in the thoracic aorta paralleled basal MAP levels in the two groups of rats, suggesting the counter-regulation of eNOS against the developed hypertensive state in SHR fed a Zn-deficient diet. On the other hand, administration of the superoxide scavenger, tempol (a SOD mimetic compound), led to a decrease in MAP levels in the two groups of rats, indicating the participation of the oxygen free radical, superoxide, in an increase in systemic BP in a genetically hypertensive state. As reported recently, the mechanism involved is due likely to a decrease in the action of the vasodilator, NO, based on the formation of peroxynitrite coming from the non-enzymatic reaction of superoxide and NO. In addition, tempol treatment completely restored MAP levels in SHR fed a Zn-deficient diet to levels comparable to those observed in SHR fed a standard diet, indicating that a further increase in systemic BP levels seen in SHR fed a Zn-deficient vs. a standard diet is presumably brought by a reduction in the action of the vasodilator, NO, resulting from an increase in the action of superoxide. The activity of the superoxide scavenger, Cu/Zn-SOD, in the thoracic aorta was significantly decreased in SHR fed a Zn-deficient diet relative to SHR fed a standard diet. It appears that a decrease in the activity of Cu/Zn-SOD observed in the thoracic aorta of SHR fed a Zn-deficient diet at least in part plays a role in an increase in the action of superoxide in this model. Thus, Zn deficiency may be a factor to develop genetic hypertension presumably through the oxidative stress caused by superoxide.

Role of dopamine receptors in the kidney in the regulation of blood pressure.

Regulation by dopamine of cardiovascular function, renal function and systemic blood pressure regulation is multifaceted. Each of the five dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors regulate blood pressure by influencing the central or peripheral nervous system; others influence epithelial transport and regulate the secretion and receptors of several humoral agents. The D1, D3, and D4 receptors interact with the renin-angiotensin system, while the D2 and D5 receptors interact with the sympathetic nervous system to regulate blood pressure.