Vasodilator Capacity of Forearm Vessels in Hypertension

Factors determining vascular resistance were examined in 6 normotensive subjects (NT), 5 with established hypertension (EH) and diastolic pressures > 90 mmHg and 7 with borderline hypertension (BH) having pressures intermittently > 140/90 mmHg. Using plethysmography, we measured forearm blood flow (FBF), arterial resistance (FAR) and venous compliance (FVC) before and after autonomic blockade with propranolol 0.2 mg/kg, atropine 0.04 mg/kg and phentolamine 15 mg I.V. Subjects with EH had the highest baseline FBF. MAP was increased 18–22% after atropine and propranolol in all 3 groups. Phentolamine decreased MAP -8.9 ± 2.1% in NT, -6.9 ± 1.2% in BH and -16.5 ± 1.9% in EH (p<0.05). After total blockade, FAR in EH (32.4 ± 4.8 units) was similar to FAR in NT (31.0 ± 3.6 units) whereas that in BH remained high (50.2 ± 3.8 units; p<0.01). Baseline FVC was highest in NT, intermediate in BH and lowest in EH and was not altered by autonomic blockade. Non-gravitational exercise for 6 min during upper arm arterial occlusion after autonomic blockade resulted in a residual FAR of 2.3 ± 0.1 units in NT, 3.8 ± 0.3 units in BH and 4.2 ± 1.7 units in EH (p<0.01) during reactive hyperemia. Increased FAR in our subjects with BH and EH was probably due to structural vascular alterations. The greater increase in FAR and MAP in EH over that observed in BH has a sympathetic nervous system component.     

The possible importance of aldosterone as well as renin in the long-term antihypertensive action of propranolol

In 50 patients with essential hypertension, propranolol produced a significant decrease in blood pressure. The decrease in mean pressure was greatest in patients classified by a renin sodium nomogram as having high renin hypertension. In turn, blood pressure decreased more in patients with normal renin than in those with low renin levels. Indeed, a net increase in diastolic pressure occurred in the low renin subgroup. These findings confirm the value of pretreatment plasma renin measurements for predicting blood pressure responses to propranolol.Over-all, seven of the 50 patients exhibited increases in mean blood pressure during propranolol treatment. Presumably, this occurred because the minimal suppression of renin-angiotensinmediated vasoconstriction in these patients was insufficient to compensate for the unopposed alpha-sympathetic vasoconstriction unmasked by peripheral vascular beta-blockade. Within this group of patients, there was a significant inverse correlation between control renin values and the amplitude of the pressor response.The decrements in plasma renin were slightly greater in patients classified as responders (decrease in mean blood pressure ≥ 10 per cent) than in nonresponders. However, when the propranolol-induced decrements in aldosterone excretion were taken into account, responders to treatment exhibited far greater decreases than non-responders. Thus, higher levels of aldosterone during treatment may operate to oppose the antihypertensive action of propranolol. Ultimately, this dependency of the blood pressure response upon aldosterone levels is at least partly coordinated with propranolol-induced inhibition of renin release, since we found a significant correlation between changes in these hormones during treatment.     

Disparate cardiovascular effects of obesity and arterial hypertension

Since obesity and essential hypertension frequently coexist, a study was designed to analyze some of their cardiovascular effects. Twenty-eight obese patients, half of whom were normotensive and half with established hypertension, were matched for mean arterial pressure with 28 corresponding lean subjects. Systemic and renal hemodynamics, intravascular volume, plasma renin activity, and circulating catecholamine levels were measured. Obese patients had increased cardiac output (p less than 0.001), stroke volume (p less than 0.001), central blood volume (p less than 0.02), plasma and total blood volume (p less than 0.01), and decreased total peripheral resistance (p less than 0.001). In contrast, cardiac output, central blood volume, and stroke volume of hypertensive patients were normal, but they had increased total peripheral (p less than 0.001) and renal vascular resistance (p less than 0.001) and a contracted intravascular volume. Left ventricular stroke work was elevated to a similar level in obesity (p less than 0.001) and hypertension (p less than 0.02), but the increase was caused by an expanded stroke volume in the former and by an increase in systolic pressure in the latter. It is concluded that the disparate effects of obesity and hypertension on total peripheral resistance and intravascular volume counteract and may even offset each other. Thus, obesity may mitigate the effects of chronically elevated total peripheral resistance (and therefore end-organ damage) in essential hypertension. Since both entities affect the heart through different mechanisms, their presence in the same patient results in a double burden to the left ventricle, thereby gently enhancing the long-term risk of congestive failure.     

Pathogenesis of paroxysmal hypertension developing during and after coronary bypass surgery: A study of hemodynamic and humoral factors

A prospective study of hypertension first appearing during and after saphenous vein bypass coronary surgery was performed in 28 patients to examine the incidence, hemodynamics and mechanism of this problem. In 15 patients (54 percent) new hypertension developed (mean arterial pressure greater than 107 mm Hg), characterized by increased peripheral vascular resistance and unchanged cardiac output within 1 hour after surgery. These 15 patients had a longer history of angina of greater severity, but also had relatively well preserved ventricular myocardium. Because plasma renin activity was depressed in patients in the hypertensive group, activation of the renin-angiotensin system was not important in the pathogenesis of this postoperative hypertension. The expected decrease in total peripheral resistance at the onset of cardiopulmonary bypass was observed in all patients, but later during bypass the peripheral resistance increased in all patients in association with a rise in plasma epinephrine levels. Patients who had hypertension postoperatively had a greater increase in arterial pressure and total peripheral resistance during cardiopulmonary bypass than did those with normal postoperative blood pressure. An elevation in plasma epinephrine and norepinephrine concentration, suggesting enhanced sympathoadrenal responsiveness to the challenge of cardiopulmonary bypass, was characteristic of the hypertensive group. This evidence of enhanced sympathetic activity during surgery may be a useful predictor of the development of postoperative hypertension.     

Linear cardiac output in borderline and sustained hypertension

We assessed the relative contributions of raised cardiac output and increased peripheral resistance to elevation and lability of blood pressure in patients with borderline and sustained hypertension. Ninety-five untreated patients were admitted to hospital for assessment. Using Doppler ultrasound, linear cardiac output was measured as minute distance on the day of admission and 24 h later; blood pressure was measured at the same times, enabling calculation of linear resistance (analogous to peripheral vascular resistance). In sustained, but not borderline, hypertension linear resistance was increased at the first measurement (+ 36%, P less than 0.001), but mean minute distance did not differ significantly from normal in either group. Between the first and second measurements in borderline and sustained hypertension there were significant falls of mean blood pressure (-9%, P less than 0.001 and -4%, P less than 0.01). In borderline, but not sustained, hypertension there was an associated fall of linear resistance (-11%, P less than 0.05); in neither group was there a significant change of minute distance. Both elevation and lability of blood pressure in borderline and sustained hypertension are due more to changes of peripheral resistance than to changes of cardiac output.     

Hemodynamic study of 85 patients with borderline hypertension

Hemodynamic changes in supine and upright position (50 ° head-up tilt) and during exercise were studied in 40 normal subjects and 85 patients with borderline hypertension. The latter were classified in 2 groups, according to the level of cardiac index. In group I, with patients in the supine position, cardiac index, stroke index, heart rate and plasma volume were normal, but total peripheral resistance was increased (P < 0.01). During upright tilt, orthostatic decrease of mean arterial pressure (P < 0.05) was observed, and the increase in total peripheral resistance was not greater than in normal subjects. The hemodynamic response to exercise was similar to that of normal subjects. In patients in group II, cardiac index, stroke index and heart rate were increased (P < 0.001), but plasma volume was decreased (P < 0.01) and total peripheral resistance was below normal (P < 0.001). With patients in the upright position, diastolic orthostatic hypertension was observed (P < 0.001) and total peripheral resistance was greater than normal (P < 0.01) despite an abnormal fall of cardiac index (P < 0.05). The hemodynamic response to exercise indicated that total peripheral resistance did not decrease as in normal subjects and in patients of group I (P < 0.001). This study provides evidence that (1) total peripheral resistance is abnormal in patients with borderline hypertension, but only during upright tilt and exercise in patients with high cardiac index, and (2) 2 main disorders seem to be important in the early stage of hypertension: abnormality of blood volume (or blood volume distribution, or both) and impaired neurogenic activity.     

Normal renin uremic hypertension. Study of cardiac hemodynamics, plasma volume, extracellular fluid volume, and the renin angiotensin system.

Studies were undertaken in 33 uremic patients with or without hypertension, 11 normal subjects, and 15 essential hypertensive patients to assess cardiac hemodynamics, plasma volume, extracellular fluid volume, and peripheral renin levels. Cardiac output and intraarterial blood pressure were measured and peripheral vascular resistance index calculated. These studies suggest that uremic hypertension with normal renin values and hypervolemia is hemodynamically sustained by an increase in peripheral resistance rather than by an increased cardiac output. The renin angiotensin system plays a secondary role as compared to overexpansion in the genesis of hypertension in normoreninemic uremic hypertension.     

Abnormal relation of extracellular fluid volume and exchangeable sodium with systemic arterial pressure in early borderline essential hypertension

Interrelations between systemic arterial pressure, extracellular fluid (ECF) volume, exchangeable sodium (Na) and the renin-angiotensin-aldosterone system were studied in 38 young patients with borderline hypertension and in 37 age- and sex-matched control subjects. ECF volume and exchangeable Na were subnormal (not significant) in borderline hypertension. In normal subjects, volume data did not relate to arterial pressure; in contrast, negative correlations were observed between arterial pressure and ECF volume or exchangeable Na in patients with borderline hypertension (in hypertensive women, r greater than or equal to 0.7, p less than 0.01). Plasma renin activity was consistently elevated in borderline hypertension, mainly in the upright posture, and these values were inversely correlated with ECF volume and exchangeable Na. No correlation was observed between arterial pressure and plasma renin activity. These results show that slight elevation of arterial pressure in the early stage of hypertension induces a proportional decrease in ECF volume, suggesting that the phenomenon of pressure-natriuresis is operative in young borderline hypertensive persons. The renin-angiotensin system is activated in these patients, in part to preserve sodium homeostasis.     

Responses of the pressor and depressor regulatory systems to high sodium intake in borderline arterial hypertension]

A total of 25 healthy individuals and 48 borderline hypertensives aged 22-56 years were examined. The healthy subjects having a salt load showed elevated blood histamine concentrations and an unchanged vascular response to histamine, and reduced plasma renin activity. The patients having a salt load displayed high histamine levels, sharply decreased vascular response to histamine, and undepressed plasma renin activity. It is concluded that the pressor mechanisms responsible for controlling vascular tone are more active than the depressor ones during the salt load in patients with borderline hypertension. The humoral response of the patients to a salt load was impaired with elevated plasma cortisol concentrations, which was not followed by sodium retention in the body.     

Hemodynamic characteristics of sodium-sensitive human subjects

Fifty-eight normal subjects and 51 subjects with borderline hypertension underwent microvascular and hemodynamic studies while on an ad libitum diet and during periods of sodium depletion (10 mEq/day) and repletion (200 mEq/day). Hemodynamic measurements included arterial blood pressure, cardiac index, total peripheral resistance, forearm blood flow, vascular resistance, venous compliance, and capillary filtration fraction. Studies of the microcirculation consisted of macrophotography of the bulbar conjunctiva with measurement of anteriolar, venular, and capillary density and diameter. During sodium repletion, cardiac index increased significantly in the normal subjects (2.35 +/- 0.7 vs 2.44 +/- 0.7 L/min/m2; p less than 0.01) and in the borderline hypertensive subjects (2.50 +/- 0.7 vs 2.70 +/- 0.8 L/min/m2; p less than 0.01). However, mean blood pressure rose by more than 5% in only 33 subjects, 13 with normal and 20 with borderline hypertension. When these sodium-sensitive subjects were compared with those whose blood pressure did not rise, the former were found to have significantly higher forearm vascular resistance (32.2 +/- 21 vs 17.9 +/- 12 mm Hg/ml/min/100 g; p less than 0.01), lower forearm blood flow (4.42 +/- 2.7 vs 7.47 +/- 5.0 ml/min/100 g) and lower conjunctival capillary density (3.72 +/- 1.7 vs 5.18 +/- 2.1 [SD] mm/mm2; p less than 0.05). These results indicate that sodium sensitivity in humans is accompanied by elevation of forearm vascular resistance and attenuation of the microcirculation.     

Decrease in blood pressure and increase in total peripheral vascular resistance in supine resting subjects with normotension or essential hypertension

Hemodynamic changes in the supine resting position were investigated in 70 male subjects, consisting of 15 healthy volunteers with normotension (blood pressure of 113 +/- 7/70 +/- 5 mmHg, M +/- SD), 25 patients with borderline essential hypertension (143 +/- 12/90 +/- 6 mmHg) and 30 patients with established essential hypertension (166 +/- 13/108 +/- 6 mmHg). The supine position reduced blood pressure, heart rate, stroke volume and cardiac output (p less than 0.001), but increased total peripheral vascular resistance (p less than 0.001). The decrease in systolic blood pressure (p less than 0.01), stroke volume (p less than 0.05) and cardiac output (p less than 0.05), and the increase in total peripheral vascular resistance (p less than 0.01) were significantly greater in the borderline and established essential hypertensive groups than in the normotensive group. The results demonstrated that the decrease in blood pressure was due to a reduction in both heart rate and stroke volume, and that the decrease in stroke volume and increase in total peripheral vascular resistance seen in the supine position were greater in the hypertensive groups than in the normotensive group. These hyperresponses may contribute to the development and persistence of high blood pressure in patients with essential hypertension.     

Unexpected pressor responses to propranolol in essential hypertension. An interaction between renin, aldosterone and sympathetic activity.

The blood pressure response to propranolol treatment was analyzed retrospectively in 187 patients with benign essential hypertension. In most patients (102 patients, 54 per cent) systolic and/or diastolic blood pressure was decreased by more than 10 per cent (responders). No significant change in blood pressure occurred in 35 per cent (65 patients) of the patients (nonresponders). Surprisingly, in 20 patients (11 per cent) systolic (8 patients) and/or diastolic (14 patients) blood pressure was increased by more than 7 per cent (pressor-responders). All three subgroups received similar amounts of propranolol and irrespective of the effect on the blood pressure, propranolol produced a similar reduction in pulse rates, suggesting similar degree of beta blockade. The three subgroups did not differ in their clinical characteristics, except that the nonresponders were significantly older than the responders. Pretreatment renin values were highest in the responders, somewhat lower in the nonresponders and significantly lower in the pressor-responders. In a representative subset of 66 patients, control and treatment values for plasma renin activity and aldosterone excretion were compared. The responders had the most pronounced decreases in both renin and aldosterone. In striking contrast, no significant changes were observed in the two hormones in those patients whose blood pressure levels rose. Moreover, in the pressor-responders, the drug produced the greatest increases in body weight, reflecting sodium retention. The differences in blood pressure responses observed in different patients may be explained by various interplays between the drug-induced suppression of renin and aldosterone, and the operation of unapposed or reactive alpha sympathetic activity. The latter is presumably active in all patients tending to cause vasoconstriction and hence an increase in peripheral resistance. In the pressor-responders such unopposed alpha-tone combined with the demonstrated lack of renin and aldosterone suppression with attendant fluid retention could work to produce the paradoxical pressor responses. In contrast, in those whose blood pressure levels drop, the drug-induced suppression of renin leads to decreased peripheral resistance despite the unopposed alphatone. The accompanying decrease in aldosterone limits sodium retention and contributes to the fall in blood pressure levels.     

The hemodynamics in young patients with borderline hypertension

Hemodynamics in supine position were studied echocardiographically in 56 young patients with borderline hypertension and 56 age-matched normotensive subjects. In hypertensive patients, the cardiac index (CI) did not increase, but the total peripheral resistance (TPR) increased significantly (p less than 0.005). The hypertensive patients were classified into 2 groups, according to the level of the CI. In patients in group A ("normal" CI), the CI, heart rate and the mean circumferential fiber shortening velocity (mVCF) were normal, but the TPR was increased significantly. In patients in group B ("high" CI), the CI, heart rate and the mVCF increased significantly (hyperkinetic state), but the TPR was normal. Plasma renin activity (PRA) was significantly higher in patients in group B than the normal subjects, but the level of PRA in patients in group A was normal. These findings support the hypothesis that sympathetic nervous activity increases in patients in group B, but not in those in group A. Therefore, this study provides evidence that the TPR is abnormal in patients with borderline hypertension, and an impaired neurogenic activity seems to be important in the early stage of hypertension, as in borderline hypertension associated with a hyperkinetic circulatory state (group B).     

Characteristics of the limb circulation in hypertension

The aim of this study was to investigate the effect of hypertension on the regulation of limb circulation. The study group consisted of 50 patients suffering from hypertension; in 21 cases the peripheral circulation was intact, while 29 patients had peripheral obliterative arterial disease (POAD) (clinical symptoms: intermittent claudication or rest pain). The control group consisted of 67 normotensive patients. In 33 subjects of the control group the peripheral circulation was intact, while 34 patients suffered from POAD (clinical symptoms: intermittent claudication or rest pain). The total limb blood flow (LBF) was measured by using venous isotope dilution technique. In hypertensive patients the limb vascular resistance (LVR) was markedly elevated, but the LBF remained in the normal range. In patients suffering from both hypertension and POAD the LVR was pathologically elevated and the LBF markedly diminished. After acute vasodilator therapy the LBF significantly increased, despite the drop in blood pressure owing to the extensive decrease of the LVR. It appears that in hypertension the elevation of the LVR is the most characteristic change of the limb circulation. The elevation of the arterial blood pressure has no favorable effect on the limb circulation, and the LBF compared with the blood pressure is relatively low.     

Elevated blood viscosity in patients with borderline essential hypertension

In patients with borderline hypertension, total peripheral resistance (TPR) is either elevated or abnormally related to cardiac output. Since blood viscosity is one determinant of TPR, we compared various components of blood viscosity in 25 patients with borderline hypertension and 25 normal subjects. Under all experimental blood flow conditions examined, blood viscosity directly correlated with systolic and diastolic blood pressure (p less than 0.05 or better) and was greater in the hypertensive than in normal subjects. Venous hematocrit and plasma viscosity were higher in the hypertensive patients. These latter rheologic abnormalities accounted for the increased blood viscosity at higher shear rates. At lower shear rates, increased red cell aggregation, primarily mediated by elevated fibrinogen concentration, accounted for the higher blood viscosity in the hypertensive subjects. We conclude that even relatively small elevations in arterial pressure are associated with increased viscous resistance of blood to flow, and that the increased blood viscosity is a consequence of increased hematocrit, plasma viscosity, and red cell aggregation.     

Acute and long-term studies of the mechanisms of action of beta-blocking drugs in lowering blood pressure.

The antihypertensive effect of intravenous (acute) and oral (long-term) beta-adrenergic blockade with propranolol or pindolol was evaluated in 46 male patients with either borderline (group I; 23 patients) or sustained (group II; 23 patients) essential hypertension. Arterial pressure, plasma renin activity and plasma concentration of aldosterone were determined during continuous recumbency overnight every 30 minutes before and after treatment. Patients of group I exhibited a marked variation of their recumbent plasma renin activity with relatively low values before midnight and large increases early in the morning. In contrast, low plasma renin activity values and only minimal fluctuations in renin were observed in patients of group II. Plasma renin activity had a consistent relationship with blood pressure both after acute (r = 0.79) and long-term (r = 0.4) beta-blockade. In four patients of group I, who had high plasma renin activity and had responded to intravenous propranolol, infusion of angiotensin II inhibitor did not lower pressure. In group I following beta-blockade, day-night profiles of renin were similar to those observed in group II before treatment. Thus in this latter subgroup, low renin profiles might reflect reduced beta-adrenergic activity. Acute as well as long-term beta-blockade consistently eliminated the day-night rhythm of plasma renin activity, but it did not change rhythm of plasma concentration of aldosterone. Plasma concentration of aldosterone was lower in group II but appeared to be inappropriately high relative to renin levels. These observations suggest that in hypertensive patients classified according to blood pressure and recumbent plasma renin activity profiles a significant relationship exists between changes in plasma renin activity and arterial pressure responses. Thus, patients with high renin levels respond better to treatment than patients with low renin levels. We conclude that in the patients studied, sympathetic nervous system activity mainly determined renin levels as well as antihypertensive effectiveness of the beta-blocking drugs.     

Comparison of propranolol or hydrochlorothiazide alone for treatment of hypertension. III. Evaluation of the renin-angiotensin system

In this study, the relation between renin activity and therapeutic response to hydrochlorothiazide or propranolol was studied. Patients with a diastolic blood pressure of 95 to 114 mm Hg were treated with propranolol (40 to 320 mg twice daily) or hydrochlorothiazide (25 to 100 mg twice daily). The initial renin profiles were: low, 56 percent (n = 300); normal, 33 percent (n = 174); high, 11 percent (n = 60). A greater incidence of low and fewer high renin profiles (p less than 0.001) were observed in blacks. After furosemide administration (40 mg intravenously), 55 percent of patients (n = 291) had a low renin response and 45 percent (n = 240) had a normal renin response. No correlation between renin profile and renin response was observed, although low renin response and low renin profile occurred more frequently in older patients. Hydrochlorothiazide administration resulted in a greater decrement in diastolic blood pressure (p less than 0.05) in the total group. Irrespective of renin activity, both hydrochlorothiazide and propranolol reduced diastolic blood pressure. When renin profile was considered, no significant variation in response to hydrochlorothiazide therapy was observed, and there was a greater reduction in diastolic blood pressure in the patients with a high renin profile receiving propranolol. In comparing therapeutic response, patients with a low renin profile had a better response to hydrochlorothiazide, and propranolol was more effective in patients with a high renin profile. The anticipated effect of therapy on plasma renin activity was observed. Although these results are consistent with a volume-vasoconstrictor analysis of hypertension, the results of therapy could not have been prejudged from renin profile or responsivity. The slight differences observed do not warrant the expense of renin determinations when a simple determination of therapeutic response is sufficient.     

Vascular reactivity to norepinephrine and hemodynamic parameters in borderline hypertension

Pressor response to norepinephrine, cardiopulmonary blood volume, and hemodynamic parameters were studied in 41 borderline hypertensive patients in comparison with 42 permanent essential hypertensive patients and 28 normal subjects. Borderline hypertensive subjects had a high cardiac index (p < 0.0001), normal total peripheral resistance, and low total blood volume (p < 0.005). The ratio between cardiopulmonary blood volume (CPBV) and total blood volume (TBV) was significantly higher in comparison with normal subjects (p < 0.01) and permanent hypertensive subjects (p < 0.001). The pressor dose of norepinephrine was elevated (p < 0.0001) and was directly correlated with the basal values of the cardiac output (p < 0.005), the cardiopulmonary blood volume (p < 0.001), and the $\text{CPBV}\text{TBV}$ ratio (p < 0.01). None of these results was observed in permanent hypertensive subjects: the only significant result was a negative correlation between the pressor dose of norepinephrine and the basal diastolic arterial pressure (p < 0.0001). This study provides evidence that the cardiac output elevation in borderline hypertensive subjects was related to increased venous return and enhanced sympathetic venous tone.     

Does hyperkinetic circulation constitute a pre-hypertensive stage? A 5-year follow-up of haemodynamics in young men with mild blood pressure elevation

In a previous haemodynamic examination, 44 young men (18-22 years) with blood pressure elevation above the 98th percentile, mean arterial blood pressure (MAP) greater than or equal to 95 +/- 6 mm Hg, showed an increased cardiac index (dye-dilution) and an enhanced resistance at maximal vasodilation of the hand (venous occlusion plethysmography during hyperaemia). This latter finding suggested arteriolar wall hypertrophy. However, the subgroup with the highest cardiac index (greater than or equal to 3.86 1 min-1 x m2) (n = 18) displayed normal vascular resistance at maximal dilation in comparison with the normotensive control group (n = 29). Consequently, functional signs of arteriolar hypertrophy were restricted to individuals with normal or low cardiac index. At the re-investigation 5 years later, a significant reduction in blood pressure was observed in the normotensive control group (MAP: from 88 +/- 7 to 85 +/- 7 mm Hg, P less than 0.05). There was no change in individuals with initially elevated blood pressure. Furthermore, cardiac index fell significantly with time in this latter group. Thus, the blood pressure elevation in the hypertensive group, previously mainly dependent on high blood flow was, 5 years later, more related to an increased total peripheral resistance, (delta total peripheral resistance = 8%). However, no definite evidence indicating development of hypertrophy of the resistance vessels of the hand was observed during the follow-up period. Since the hyperkinetic subgroup did not display a concomitant fall in blood pressure with cardiac output, our results do not support the theory that the hyperkinetic form of borderline hypertension is a temporary phenomenon, explained by the inclusion of anxious individuals afraid of the experimental situation. Hyperkinetic hypertension may be the initial phase of sustained hypertension in a subgroup of the future hypertensive population.