Rabbits were treated with guanabenz, clonidine and rilmenidine for 6 days via osmotic minipumps. Blood pressure, heart rate and responses to intracisternal clonidine were measured after 1 and 6 days treatment. Radioligand binding to forebrain and hindbrain membranes after 6 days treatment was examined using [3H]yohimbine to measure the number of adrenergic binding sites and [3H]clonidine and [3H]idazoxan to assess nonadrenergic imidazoline sites. No change in nonadrenergic imidazoline binding was observed but adrenergic binding was decreased in forebrain and hindbrain by guanabenz and in hindbrain by clonidine treatment. Resting heart rate was decreased after 1 day's treatment with partial recovery by day 6. At this time heart rate significantly reduced in the clonidine and rilmenidine treated groups but not the guanabenz group. No significant change in baseline blood pressure was observed in normotensive rabbits. Both depressor and bradycardia responses to intracisternal clonidine were attenuated after 1 day's dosing but only depressor responses were influenced after 6 days. Blood pressure and heart rate thus appeared to be regulated independently. It is possible that imidazoline receptors predominate in the central control of blood pressure while central alpha-2 adrenoceptors play a greater part in heart rate regulation.
The relationship between regular alcohol consumption and blood pressure elevation is now firmly established. Outstanding issues which will be discussed relate to the nature of the dose response curve, interactions between alcohol and other dietary and behavioural factors, mechanisms involved and the question of any protective influence of alcohol on atherosclerotic and ischaemic cardiovascular disease associated with hypertension. Alcohol is an important contributory to the prevalence of hypertension, and resistance to drug therapy in drinking communities. Heavy drinking and binge drinking increases the risk of stroke.
The question whether some classes of antihypertensive drugs have an antiatherogenic action independent of the antihypertensive one has been investigated through a large series of experimental studies; on the other hand, clinical evidence is still rather scanty. Most experimental investigations have shown a significant antiatherogenic action of the antihypertensive compounds, but only when the drug is administered simultaneously with the atherogenic stimulus (mostly cholesterol feeding). When the drug is administered weeks or months after the beginning of atherosclerosis (as in the Watanabe heritable hyperlipemic rabbit), no antiatherogenic effect has been shown, with a single exception. Although the most numerous data available are on calcium antagonists, almost all antihypertensive classes tested have shown some favorable effect on some experimental model. The few clinical studies completed so far are on coronary patients; they have provided arteriographic evidence that various calcium-antagonists have little effect on well-developed lesions and display a beneficial action on new or early lesions only. Ultrasound studies are now underway to compare the effects of calcium-antagonists and diuretics on asymptomatic carotid atherosclerotic lesions in hypertensive patients.
We performed renal function studies in dogs with chronic renovascular hypertension produced by complete occlusion of a renal artery. In addition, we evaluated in anesthetized dogs the acute effects of a novel angiotensin converting enzyme inhibitor, CGS 16,617, on renal function and plasma neurohormones (epinephrine, norepinephrine and vasopressin) 4 weeks after initiation of 2 kidney, 1 clip hypertension. CGS 16,617 effectively decreased blood pressure in renal hypertensive animals. This response was associated with suppression of angiotensin II indicating effective converting enzyme inhibition. In the non-clipped kidney, acute administration of CGS 16,617 increased effective renal plasma flow but not glomerular filtration rate and urinary sodium excretion. In the clipped kidney, CGS 16,617 caused no change in any parameter of renal function. Plasma norepinephrine, epinephrine and vasopressin were unaffected by administration of CGS 16,617. These studies showed that chronic occlusion of a renal artery does not result in renal infarction because of a compensatory increase in the amount of blood provided through capsular collateral vessels. The collateral circulation which has developed in the clipped kidney explains the lack of a converting enzyme inhibitor effect.
The acute sensitivity to sodium loading has been investigated in 26 borderline hypertensive patients (BHT) undergoing acute i.v. NaCl infusion. Measurements included blood pressure (BP), forearm vascular reistance (FVR) and venous distensibility (VV30), plasma renin activity (PRA), plasma aldosterone, plasma atrial natriuretic factor (ANF), and plasma levels of endogeneous Na+/K+ ATPase inhibitor. Sodium loading was associated with a greater than 8% increase in mean BP in 12 patients defined as salt-sensitive (NaCl-SENS) in comparison to salt-insensitive (NaCl-INSENS) subset. NaCl-SENS patients in comparison to NaCl-INSENS exhibited 1) a greater baseline VV30 (2.1 vs 1.4 ml/100 ml;p<.005), and a response to saline characterized by 2) increased FVR (21.4 vs -6.5 %;p<.005), 3) blunted PRA suppression (-42 vs -67 %;p<.05), 4) delayed ANF response and 5) release of a Na+/K+ ATPase inhibitor. Post-loading cumulative urinary sodium excretion was reduced in NaCl-SENS borderline hypertensives compared to NaCl-INSENS (2.6 vs 3.8 umol/min/Kg;p<.05). We conclude that acute salt-sensitivity in BHT is characterized by a blunted hormonal response to sodium loading which could be responsible of the activation of hemodynamic as well as humoral mechanisms leading to progressive blood pressure increase.
Using two oligonucleotide probes which were synthesized based on the amino acid sequences of tryptic fragments obtained from purified bovine lung endothelin(ET) receptor, we isolated a cDNA encoding non-isopeptide-selective type of ET receptor (ETB) from a human liver cDNA library. The cDNA encoded a protein of 426 amino acid residues with putative seven transmembrane segments, exhibiting a significant similarity with the G-protein-coupled receptor superfamily. The deduced amino acid sequence of human ETB receptor was 88% and 64% identical to those of rat lung ETB receptor and human ET-1-specific(ETA) receptor, respectivaly. COS cells transfected with the cloned cDNA expressed the binding sites with high affinity for every ET or sarafotoxin(SRT) isopeptide. Modification of disulfide bridges, a N-terminal amino acid or C-terminal hydrophobic residues of the isopeptides markedly reduced their binding affinity for the expressed ETB receptor (Fig.), suggesting that ETB receptor recognizes the common structures for ET/SRT. The ETB mRNAs were significantly expressed in porcine aortic intima but not in the media, which supports the previous observation by us [FEBS Lett. (1991) 282 103–106].
The vasoconstrictor effects of endothelin-1 were studied in perfused mesenteric vascular beds (MVB) and aortic rings of 4-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar Kyoto rats (WKY). Mean blood pressure (124 +/- 4 vs. 97 +/- 3 mmHg) and initial perfusion pressure in the MVBs (25 +/- 2 vs. 19.7 +/- 1.2) were significantly higher in SHR. Reactivity to endothelin-1 was increased in MVBs of SHR, as indicated by the maximum perfusion pressure obtained (223 +/- 8 vs 155 +/- 7 mmHg, p less than 0.001), whereas there was no significant difference in sensitivity between the two strains (EC50 values: 50 +/- 12 and 80 +/- 15 pmol, respectively). By contrast, in aortic rings reactivity and sensitivity to endothelin-1 were similar in both strains, (EC50s: 1.8 +/- 0.12 and 1.4 +/- 0.1 nM). Reactivity to norepinephrine was increased in MVBs, but reduced in aortic rings of SHR. The unchanged sensitivity to endothelin-1 and the unspecifically increased reactivity in the MVBs of SHR to endothelin-1 and norepinephrine indicate rather a change in vascular structure and not a functional abnormality. These results suggest that hyperreactivity to endothelin-1 may not be a primary hypertensive mechanism in genetic hypertension.
The mechanisms of anti-hypertensive effect of diuretics remain unknown. The purpose of this study was to test the hypothesis that long-term treatment with chlorthalidone decreases the responsiveness of resistance vessels to neurohormones. The study was performed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats with and without treatment with chlorthalidone (Chlor. 8 mg/day, for 20 days). Resting mean arterial pressure in freely moving state was significantly reduced in DOCA-salt-Chlor rats when compared to DOCA-salt rats (116 +/- 3 vs 147 +/- 7 mmHg, respectively). Chlorthalidone treatment reduced the high plasma sodium content observed in DOCA-salt rats to the same levels observed in normotensive control groups. Results obtained in isolated perfused mesenteric arteries showed: a) the increase in perfusion pressure elicited by norepinephrine (NE), serotonin (SE) and vasopressin (VP) was significantly greater in DOCA-salt than in DOCA-salt + Chlor rats or control normotensive rats; b) the endothelium removal increased the pressor responses to NE, SE and VP in a similar way in all groups. These data provide evidence that long-term chlorthalidone treatment reduces vascular hyperresponsiveness to these neurohormones. In addition, these results indicate that this reduction in vascular hyperresponsiveness, associated with a decrease in extracellular sodium level, could be a possible mechanism by which the diuretics reduce the high blood pressure.
Rates of sodium (Na+)-stimulated lithium (Li+) efflux (Na(+)-Li+ countertransport) and ouabain-sensitive Na+ efflux (Na+ pump) were determined in erythrocytes of Chinese normotensive and hypertensive subjects. Near-maximal rate of Na(+)-Li+ countertransport was found to be significantly higher in hypertensive than normotensive subjects. No significant difference was observed for the rate of Na+ pump between them. A second series of study involved normotensive subjects without and with hypertensive parent(s) (group A and B, respectively) and hypertensive subjects (group C). We found that the rate of Na(+)-Li+ countertransport in group A was significantly lower than that of group B and C, while no difference existed between group B and C. No significant difference was observed for the rate of Na+ pump among the three groups. Our results suggested that Na(+)-Li+ countertransport activity could be a genetic marker for essential hypertension in Chinese, similar to that as proposed in Caucasians.
Recent data suggest that echocardiographic left ventricular (LV) hypertrophy is associated with increased cardiovascular morbidity and mortality. Based upon application of sex-specific echocardiographic criteria for LV hypertrophy, the clinical characteristics of 863 subjects with and 4097 subjects without LV hypertrophy are examined. Subjects with LV hypertrophy are older, more obese, have higher blood pressure, and are more likely to have pre-existing coronary artery disease. In addition subjects with LV hypertrophy have a higher prevalence of reduced echocardiographic fractional shortening. We conclude that subjects with echocardiographic LV hypertrophy are at high risk for cardiovascular disease complications by virtue of their clinical profile. Additional investigation of the benefits of therapeutic interventions directed toward the prevention or regression of LV hypertrophy is warranted.
The association of liver cirrhosis with arterial essential hypertension has been previously described. The present study extends the previous reports by investigating the hormonal relationships that may occur in patients with established essential hypertension associated to liver cirrhosis. We studied the renin-angiotensin, the adrenergic systems and other vasoactive hormones such as arginine-vasopressin, atrial natriuretic peptide, endothelin and parathyroid hormone in cirrhotic patients with and without essential hypertension. The data suggested that the coincidence of arterial hypertension in cirrhotic patients was characterized by the following findings: a decreased renin-angiotensin activity; a reduced systemic vasodilatation; an increased peripheral pressor effect of vasoactive hormones and an increased effective blood volume.
A practical new method for measuring serum guanosine-5'-monophosphate (GMP) was developed and three experiments were performed using this method.In the first, we observed the reduction of blood pressure (BP) and the elevation of serum GMP level persisting for 3 hours in male Japanese White Rabbits administered GMP, 50 mg/kg given as a single oral dose. In the second, 6-week-old male spontaneously hypertensive rats (SHR) received GMP, 200 mg/kg/day, orally for 8 weeks. The systolic BP in the GMP-treated rats, which averaged 170.2 mmHg, was lower than that of the control group, which averaged 188.0 mmHg. Arteriosclerotic findings were milder in the GMP-treated SHR as compared to the control. In the third experiment, the serum GMP level was measured in humans. We observed a significant negative correlation between the serum GMP concentration and systolic or diastolic BP. In conclusion, GMP reduced the BP in experimental animals, suggesting that it may be useful as an antihypertensive agent.
To elucidate the importance of diastolic blood pressure in the definition of salt-sensitive hypertension, we studied 54 male subjects, 36 of whom had untreated, mild essential hypertension. The subjects received a 120 mmol/d Na (as the chloride salt) diet for six days. Thereafter they received a 10 mmol/d Na diet for eight days followed by a 400 mmol/d Na diet for another 8 days. Blood pressure was measured hourly "around the clock" on the last day of each diet; the averaged systolic, diastolic and mean blood pressure values were compared. In 22 subjects diastolic blood pressure increased, when salt intake was increased from 10 to 400 mmol/d. In 18 of these 22 subjects systolic blood pressure increased as well. In 20 subjects, systolic blood pressure increased with salt loading while diastolic blood pressure decreased. In 13 subjects both systolic and diastolic blood pressure decreased with increased salt intake. We defined those subjects showing an increase in diastolic blood pressure as salt-sensitive. If mean blood pressure were used to define salt-sensitivity, 8 of our subjects would have been labeled as salt-sensitive who actually decreased their diastolic blood pressure with salt loading. We suggest that consideration of systolic and diastolic blood pressure responses gives better insight into identifying volume and resistance-related phenomena in salt-sensitive hypertension, than does the consideration of mean blood pressure alone. The definition of salt-sensitivity may require reassessment.
The concept of community intervention in the field of cardiovascular disease prevention was introduced in the late sixties and early seventies. The WHO European Collaborative Trial in the multifactorial prevention of coronary heart disease used communities (factories) in a traditional controlled trial. The intervention used in this trial was an extension of a medical care model with preventive elements. The first two major community intervention projects in CVD prevention - the North Karelia project and the Stanford Heart Disease Prevention Programme - were the basis of further WHO and NHLBI coordinated projects. They have used community-based population-wide strategies including existing community leadership, social networks, mass campaigns and extensive direct education for the general population. In the evaluation of those projects quasi-experimental models are used because "perfect experiments" are not possibLe. Some projects have proven the feasibility of community intervention and its positive impact on lifestyles and cardiovascular risk factors in a whole population and that such a development is associated with reduced cardiovascular mortality rates.
Subjects with family history of hypertension represent a suitable model to investigate the mechanisms responsible for early cardiovascular structural and functional changes occurring in essential hypertension. In our study we have addressed the factors involved in determining the mild elevation in office blood pressure frequently observed in normotensive subjects with hypertensive parents. In 15 normotensive subjects with both parents hypertensive (FH++) and in 15 normotensive subjects with one parent hypertensive (FH(+)-) we found no evidence of a hyperreactivity to stress as compared to the responses of 15 normotensive subjects with no parental hypertension (FH--). On the contrary FH++ subjects were characterized by a significant although mild increase in their blood pressure values recorded either at rest and in ambulatory conditions over the 24 hours, including night sleep. FH++ and FH(+)- subjects also showed a greater left ventricular mass thickness and a greater minimal forearm vascular resistance than FH-- subjects. Thus, the elevation in blood pressure found in the pre-hypertensive stage in subjects with positive family history for hypertension does not reflect a hyperreactivity to the stress associated with physician's visit but indicates an early and persistent blood pressure elevation. This blood pressure elevation is accompanied by early cardiovascular structural changes which may indicate that these subjects are exposed to a higher risk even before developing overt hypertension.
To clarify the cardiovascular effects of central vasopressin (AVP), a chronic intracerebroventricular (ICV) infusion of AVP was performed in conscious Wistar normotensive rats. Animals were divided into 3 groups: 1) AVP 1 ng/hr (Low), 2) AVP 100 ng/hr (High), and 3) saline (control) ICV infusion. After a 6 day control period, AVP or saline was continuously infused into the lateral cerebroventricle at a rate of 1 microliter/hr using osmotic minipump for 7 days. As a result, a dose-related elevation of AVP concentration in CSF was achieved. Systolic blood pressure in both Low and High AVP infusion was slightly (7-12 mmHg) but significantly higher than that in control. ICV infusion of AVP did not alter urine volume, electrolytes excretion or osmolality, and AVP vascular antagonist injected intravenously failed to affect mean arterial pressure. Furthermore, plasma catecholamines and renin activity did not differ significantly among the groups. Thus, chronic ICV infusion of AVP induced the elevation of blood pressure, which is due to centrally mediated effect of AVP.
In conscious and anaesthetized rats the baroreceptor heart reflex (BHR) was checked before and after i.c.v. application of isotonic or hypertonic (0.6 M; 1.0 M) NaCl solution, artificial cerebrospinal fluid (aCSF) and 1.0 M mannitol solution. The BHR was tested by evaluating the alteration of the inter-beat interval (IBI) in response to an artificial BP rise or drop which had been evoked by i.v. bolus injection of either phenylephrine or sodium nitroprusside. The slope of the correlation function was taken to index the reflex sensitivity. In anaesthetized rats the mean sensitivity of the BHR was 0.6 ms/mm Hg (phenylephrine). l.c.v. administration of isotonic NaCl solution did not change BP, IBI or the BHR sensitivity, whilst i.c.v. infusion of hypertonic NaCl solution increased BP and shortened IBI. The BHR sensitivity was impaired only when 1.0 M NaCl solution was i.c.v. infused by 0.23 ms/mm Hg. In conscious rats the mean sensitivity of the BHR was 1.14 ms/mm Hg (phenylephrine) and 1.35 ms/mm Hg (sodium nitroprusside). In the conscious rats i.c.v. bolus injection of hypertonic NaCl solution increased BP as in anaesthetized rats, however, the IBI was prolonged, whilst 1.0 M mannitol solution and aCSF were without any influence on BP, IBI and BHR. l.c.v. administration of hypertonic NaCl solution reduced the BHR sensitivity by approximately 0.6 ms/mm Hg.
The extent and duration of the blood pressure (BP) lowering effect of 20 mg nitrendipine (NIT) once daily and 40 mg nicardipine slow release (NIC) twice daily were compared in 12 men (aged 39-55 years) with mild essential hypertension according to a randomized, cross over study.Twenty-four-hour non invasive ambulatory BP monitoring (Spacelabs 5200) was performed at the end of a 2-week placebo run-in and after 4 weeks of each active treatment; automatic BP measurements were programmed at 15-min intervals. Both treatments significantly (p<.01) reduced mean 24-hour and daytime systolic (SBP) and diastolic (DBP) BP, but had different effects on daytime BP profiles. NIT decreased SBP and DBP (p<.05) in 5 out of 8 two-hour subperiods (from 8 a.m. to 6 p.m.), followed by a loss of effect; NIC reduced SBP and DBP (p<.05) in 7 out,of 8 two-hour subperiods (from 8 a.m. to 10 p.m.). During the night-time, NIT reduced mean SBP (p<.05) and NIC both mean SBP and DBP values (p<.05; p <.05 vs NIT for SBP). Heart rate was not affected by either treatment.Thus, after short-term treatment in mild essential hypertensives nitrendipine once daily was not as effective as nicardipine slow release twice daily in reducing blood pressure throughout the 24 hours.
The relation between the maximal velocity of red blood cell sodium-lithium countertransport and blood pressure/hypertension has been studied in 2,748 men and women aged 25-74 years who participated in the 1983-85 baseline examination of the Gubbio Population Study, an epidemiologic investigation performed in a hill town of north central Italy.Men had a higher sodium-lithium countertransport velocity than women at all ages, and, in both sexes, a higher velocity was observed at successive ages. Hypertensives of both sexes had a higher sodium-lithium countertransport velocity than normotensive individuals, the difference remaining significant after control for age, body mass index and plasma uric acid concentration. Individuals with high sodium-lithium countertransport velocity had significantly greater prevalence of hypertension in both sexes.The data show the existence of a cross-sectional association between sodium-lithium countertransport velocity and hypertension in general population. Prospective study of the Gubbio population is now in progress to investigate the relation between baseline sodium-lithium countertransport velocity, its change over the years and the incidence of hypertension.
