This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ting, C.-T. Articles by Yin, F. C. P. Search for Related Content PubMed PubMed Citation Articles by Ting, C.-T. Articles by Yin, F. C. P.

(Hypertension. 1995;25:1326-1332.)
© 1995 American Heart Association, Inc.

Articles

Arterial Hemodynamics in Human Hypertension

Effects of the Calcium Channel Antagonist Nifedipine

Chih-Tai Ting; Jaw-Wen Chen; Mau-Song Chang; Frank C. P. Yin

From the Cardiology Division, Department of Medicine, Veterans General Hospital, Taichung (C.-T.T.); Cardiology Division, Department of Medicine, Veterans General Hospital, Taipei (J.-W.C., M.-S.C.), Taiwan; and Cardiology Division, Department of Medicine, Johns Hopkins Hospital, Baltimore, Md (F.C.P.Y.).

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract Previous studies have shown some distinct hemodynamic alterations in essential hypertension, including increased resistance, wave reflections, and pulse wave velocity and decreased arterial compliance. These abnormalities are completely normalized by nonspecific smooth muscle dilation with nitroprusside but not by combined - and ß-adrenergic blockade or angiotensin-converting enzyme inhibition, suggesting an enhanced smooth muscle tone that cannot be attributed solely to the sympathetic nervous or renin-angiotensin systems. Since hypertensive patients have an enhanced calcium influx–dependent vasoconstriction, we performed the present study to examine the extent to which the dihydropyridine calcium channel antagonist nifedipine could normalize the hemodynamic abnormalities in essential hypertension. An essential hypertensive patient group was compared with a normotensive group similar in age, body size, and proportion of men and women. During diagnostic cardiac catheterization, ascending aortic micromanometer pressures and electromagnetic flows were measured at baseline and after sufficient sublingual nifedipine (mean, 24 mg) to normalize blood pressure. From the pressures and flows, aortic input impedance, wave reflection magnitude, and compliance were computed. In the hypertensive group, the hemodynamic alterations were indistinguishable from those summarized above. Nifedipine produced sufficient vasodilation to completely normalize all of these hemodynamic alterations, including wave reflections. From these results, together with those reported in our previous studies, it is clear that the various classes of antihypertensive agents affect hemodynamics differently. All are capable of decreasing blood pressure to normotensive levels, but only nitroprusside and nifedipine can also completely normalize all the other pulsatile hemodynamic alterations. Thus, these hemodynamic effects of the different classes of antihypertensive agents should be considered in choosing a therapeutic modality.

Key Words: blood pressure • hypertension, essential • antihypertensive agents • calcium channel blockers

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
We and others have shown some distinct hemodynamic abnormalities that accompany human essential hypertension. Compared with normotensive control subjects, hypertensive patients have increased peripheral resistance, pulse wave velocity, and wave reflections^{1 2 3} and decreased arterial compliance.^{4 5 6 7} In an ongoing series of studies, we showed that all of these abnormalities could be completely normalized by nonspecific smooth muscle vasodilation with nitroprusside,² implicating enhanced vascular smooth muscle tone as an etiology for the hemodynamic abnormalities. Short-term intravenous ß-adrenergic blockade alone, however, exacerbated many of the abnormalities.² Adding -blockade to the ß-blockade or producing angiotensin-converting enzyme inhibition with captopril did not completely reverse the abnormalities.^{5 7}

Since abnormally elevated calcium influx–dependent smooth muscle constriction has been implicated in essential hypertension in humans^{8 9 10 11 12} and vascular calcium overload in animals leads to hypertension,^{13 14} it is natural to ask whether calcium channel antagonists are able to completely normalize the hemodynamic alterations. Although calcium channel antagonists are effective antihypertensive agents with well-documented effects on systemic vascular resistance and both large and small arterial compliances,^{15 16 17 18 19 20 21 22} their detailed effects on other aspects of arterial function, particularly on wave reflection properties, have not been carefully documented. Among the commonly available calcium channel blockers, the dihydropyridines typified by nifedipine are more potent inhibitors of vascular contraction than either verapamil or diltiazem.²³ Therefore, in this study we determined whether nifedipine could completely normalize the hemodynamic alterations in a group of essential hypertensive patients. Specifically, during cardiac catheterization, we measured central aortic pressure and flow and calculated the aortic impedance, arterial compliance, and wave reflection during baseline and after sufficient sublingual nifedipine to normalize blood pressure in a group of hypertensive patients with characteristics similar to those in our previous studies. The hemodynamics in these two states were compared with those in an age-matched group of normotensive subjects.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patient Selection
Patient selection, data acquisition, and calculation methods were identical to those previously reported.^{2 5} Briefly, the study population consisted of ethnic Chinese who were undergoing diagnostic cardiac catheterization for chest pain syndrome, evaluation of a systolic murmur, or electrophysiological study for paroxysmal supraventricular tachycardia. The hypertensive group was selected from a population with recently diagnosed hypertension (persistent systolic and diastolic pressures >140 and 90 mm Hg, respectively, both during multiple outpatient examinations and after bed rest in the hospital). All had either not begun antihypertensive treatment or had medications stopped for at least 4 weeks before study. Secondary causes of hypertension were ruled out by the methods previously described.² The results for the normotensive group have been reported previously⁷ and are included for comparison. All subjects gave informed consent for the investigative portion of the study; the study was performed in accordance with institutional guidelines for human research.

Catheterization
All studies were performed after premedication with 5 mg IM chlorpheniramine maleate. Only those patients with no evidence of hemodynamically significant coronary heart disease (<50% narrowing of any major coronary artery), congenital heart disease, or hemodynamically significant valvular heart disease were entered into the study. After completion of the diagnostic portion of the catheterization, high-fidelity micromanometer catheters (model SVPC 684D, Millar Instruments Co) were introduced via a femoral artery sheath into the aorta. These catheters had two micromanometers, one located at the tip and the other 6 cm from the tip of the catheter. In addition, an electromagnetic flow velocity sensor was located at the second pressure sensor. The velocity sensor was connected to a flowmeter (model BL-613, Biotronex Laboratories). The catheter tip was advanced retrograde across the aortic valve to help stabilize the catheter and to keep the sensors in the center of the stream while allowing simultaneous measurement of left ventricular pressure and ascending aortic pressure and flow velocity. After placement across the valve, the catheter was manipulated to obtain an optimal flow velocity signal characterized by a steady diastolic level with maximal systolic amplitude and minimal late systolic negative flow.²⁴ To minimize drift, each catheter was presoaked in saline for at least 2 hours before insertion. After the catheter was withdrawn at the completion of the study, the pressure with the pressure sensor barely submerged in the fluid at atmospheric pressure was used as the zero reference.

The pressure and flow velocity signals during each experimental condition were recorded on analog tape (Hewlett Packard 3968-A) for later off-line analysis. Ascending aortic cross-sectional area during baseline was obtained from two-dimensional echocardiograms. Since previous studies in our laboratory demonstrated that the aortic cross-sectional area did not change by more than 0.2 cm² when blood pressures were altered over a range similar to that encountered in the present study,² the initial aortic area was used throughout the remainder of the study to convert flow velocity to volume flow.

Protocol
Baseline hemodynamics were first recorded. Sublingual nifedipine (Adalat, Bayer) was then administered, 20 mg if diastolic pressure was greater than 105 mm Hg and 10 mg if diastolic pressure was less than 105 mm Hg. Recordings were begun 15 minutes after administration because the maximal effect of nifedipine via the sublingual route occurs after approximately 10 to 20 minutes.^{15 16 17 25 26} At this time, however, if either systolic or diastolic pressure was still above 140/90 mm Hg, another 10 mg was given sublingually and data were recorded after another 15 minutes. The average maximum dose was 24.2 mg (range, 10 to 30 mg). To obtain hemodynamics at the lowest blood pressure, another set of recordings was made after another 15 minutes. The data reported here are those at the time of the lowest blood pressure achieved in each patient.

Calculations and Data Analysis
Calibration, calculation, and data analysis methods were identical to those previously reported.^{2 7} Briefly, analog records were digitized at a rate of 250 Hz with an IBM-compatible personal computer. Pressure and flow signals were resolved into their Fourier harmonics. Only flow harmonics with moduli greater than twice the maximum noise level (obtained from Fourier analysis of the diastolic portion of the signal) were included in the subsequent calculations.²⁴ The input impedance modulus and phase angle for each harmonic above the noise level were calculated as the ratio of the pressure and flow moduli and the difference of the pressure and flow phase angles, respectively. The characteristic impedance (Z_c) was estimated by averaging the suitable impedance moduli for frequencies of 4 Hz and higher.²⁴ Total external power, oscillatory power, the steady power, and the ratio of oscillatory to total power, indicating the efficiency with which the pulsatile energy was converted into forward flow, were also calculated. The frequency of the first zero crossing of the impedance phase angle (f₀), an index of pulse wave velocity, was determined by linear interpolation from the phase angle data. Finally, we decomposed the pressure wave into its forward (P_f) and backward (P_b) components as described previously.^{27 28} The ratio of the backward to forward wave components (P_b/P_f) was used to characterize the degree of arterial wave reflection reaching the aortic root.

We calculated the overall arterial compliance using our previously proposed method,²⁹ which assumes a three-element Windkessel model of the vasculature and explicitly accounts for the pressure dependence of compliance by assuming a specific value for the exponential coefficients of a nonlinear pressure-volume relationship. For the present study we assumed a value of -0.01 for this coefficient for all groups under all conditions. The expression for the compliance (C) at any pressure is³⁰ :

where P_s and P_d are the pressures at end systole and end diastole, respectively; A_s and A_d are the areas under the systolic and diastolic portions of the pressure waveform, respectively; SV is stroke volume; and b is the nonlinear coefficient.

The above hemodynamic parameters were obtained for each beat. In our experience, the coefficients of variation for the directly measured parameters of heart rate, pressure, and flow are approximately 5%, 2%, and 5% to 10%, respectively. For derived parameters the coefficients of variation for resistance and Z_c, power, wave reflection, and compliance are 15% to 20%. Therefore, the data from a minimum of seven (mean, 11.9; range, 7 to 20) acceptable beats were averaged to obtain what we consider to be representative findings for each individual for each condition.

Statistical Analysis
Baseline data for the previously reported normotensive group and this hypertensive group were compared with unpaired t tests. In the hypertensive group the effect of nifedipine was assessed with a paired t test, and the results after the drug were compared with baseline normotensive data with unpaired t tests. Statistical significance was considered to be at a value of P=.05.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The normotensive group was composed of 14 subjects (10 men, 4 women). The data of the normotensive subjects were reported in our recent study.⁷ The hypertensive group consisted of 12 patients with a sex distribution similar to that of the normotensive group (8 men, 4 women). The normotensive and hypertensive groups did not differ significantly in age (32.6±7.4 versus 32.9±7.2 years), height (167.2±9.0 versus 161.1±9.3 cm), body weight (66.7±12.4 versus 64.0±18.7 kg), or aortic cross-sectional areas (6.02±1.36 versus 6.02±1.25 cm²).

The averaged aortic impedance modulus and phase angle spectra for the normotensive and hypertensive groups during baseline conditions and for the hypertensive group after nifedipine are shown in Fig 1. To show the frequency-dependent nature of the impedance and yet account for heart rate variability among the individuals in a group, the data are grouped into 1-Hz frequency intervals. For clarity, only the mean data for each group are shown. During baseline conditions the modulus spectrum of the hypertensive group is shifted so that the lower-frequency (<4 Hz) moduli of the group are elevated above normotensive values. The phase angle spectrum of the hypertensive compared with the normotensive group is shifted such that the frequency of the first zero crossing is higher than in the normotensive group. After nifedipine the low-frequency portion of the modulus spectrum of the hypertensive group is shifted essentially to normal levels, and the phase angle spectrum is shifted so that the difference in the first zero crossing between groups is eliminated. These data indicate that nifedipine effectively normalizes the arterial impedance in hypertension when blood pressure is reduced into the normotensive range.

View larger version (17K): [in this window] [in a new window]   Figure 1. Line graphs show averaged baseline impedance moduli and phase angle spectra for the normotensive group (N, ), hypertensive group (H, ), and hypertensive group after sublingual nifedipine (). Data are grouped in 1-Hz frequency intervals for convenience. Since heart rate differs within each group, different harmonics may be represented in some of the frequency intervals.

Fig 2 illustrates representative ascending aortic pressure waveforms along with their forward and backward components for a normotensive subject and hypertensive patient at baseline and after nifedipine in the hypertensive patient. Compared with the normotensive waveform, there is a late systolic peak pressure indicative of a large reflected wave evident in the hypertensive waveform. The details of this reflected wave in the hypertensive case is more clearly seen in the backward wave component shown in the right lower panel. Not only is the peak backward wave amplitude much larger than in the normotensive case, but there is a very early high "shoulder" that is sustained to the peak. This backward wave is responsible for the late systolic peak in the measured pressure wave. After nifedipine both the late systolic portion and the peak of the reflected wave are greatly attenuated. The result is a pressure waveform without the late systolic peak that more closely resembles that of the normotensive case.

View larger version (21K): [in this window] [in a new window]   Figure 2. Plots show ascending aortic pressure waveforms along with their forward and backward components in a representative normotensive subject (N) and hypertensive patient (H). Comparison of baseline (Base) states shows that there is a much higher backward wave and a prominent late systolic peak in the hypertensive patient, both of which are almost normalized after calcium channel blockade. Nif indicates nifedipine.

The Table summarizes detailed hemodynamic data for the two groups. Comparing the two groups during baseline conditions, the hypertensive patients had higher central aortic systolic, diastolic, and mean pressures; peripheral resistance; total external power; frequency of the first zero crossing of impedance phase angle; and forward pressure wave component and a much higher backward pressure wave component, resulting in a larger wave reflection index. Characteristic impedance did not differ between the two groups. The compliances at systolic, diastolic, and mean blood pressures, as well as that extrapolated to zero pressure, were lower in the hypertensive group. Comparing the compliances at a nearly equivalent pressure, that is, at the mean aortic pressure in the normotensive subjects and diastolic pressure in the hypertensive patients, still revealed a significantly lower compliance in the hypertensive group.

View this table: [in this window] [in a new window]   Table 1. Hemodynamics in Normotensive Subjects and Hypertensive Patients at Baseline and After Nifedipine in Hypertensive Patients

Nifedipine produced a significant hemodynamic effect as evidenced by significant decreases in aortic pressure, resistance, frequency of the first zero crossing of phase angle, forward and backward wave components, and the ratio of the backward to forward wave. In addition, heart rate, total external power, and aortic compliance at all pressures were increased. Comparing these data with the baseline normotensive values revealed no difference in any of the parameters despite the fact that blood pressure was still somewhat higher than in the normotensive group (but within the normotensive range).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The baseline hemodynamic alterations reported herein are indistinguishable from those we previously reported in several similar hypertensive groups.^{2 5 7} Compared with age-matched normotensive subjects, peripheral resistance, pulse wave velocity, and wave reflections are increased and arterial compliance is decreased. Including this group, we have now examined 47 young patients with essential hypertension. The uniformity of findings indicates that these hemodynamic alterations are the hallmark of young human essential hypertension. The complete reversibility of the hemodynamic alterations with certain agents indicates that at this young age, the vascular abnormalities have not yet advanced to an irreversible stage. Our results agree with several previous reports in essential hypertensive patients that calcium channel antagonists normalize peripheral resistance and increase arterial compliance.^{9 15 16 17 19 20 21 22} To our knowledge, however, this is the first study in humans to demonstrate that nifedipine normalizes not only these parameters but also wave reflections. In contrast to our results, one previous study using methods similar to ours reported no significant effect of 10 mg sublingual nifedipine on arterial compliance or pulse wave velocity.¹⁸ Since the nifedipine dose used in that study did not normalize blood pressure, however, those results probably represent an incomplete effect of the drug. Another possible reason for the different results is that their hypertensive group was considerably older than ours (49 versus 33 years). With advancing age, it is not certain that the vascular abnormalities can all be reversed with any particular antihypertensive agent.

There is a late systolic peak in the aortic pressure waveform in the hypertensive patients (Fig 2) that is absent in the normotensive subjects. This elevated systolic peak, combined with decreased arterial compliance, results in higher systolic and pulse pressures, thereby possibly resulting in deleterious effects on the heart and systemic vasculature over the lifetime of the patient. The late systolic peak is caused by the large reflected wave appearing in systole because of a higher pulse wave velocity and/or a more proximal reflecting site. We have shown no difference between hypertensive patients and normotensive subjects, however, in the predominant aortic reflecting site.¹ Since there is no reason to suspect that nifedipine alters the predominant reflecting site, its efficacy most likely can be ascribed to the decreases in both the magnitude of the reflected wave and the pulse wave velocity such that the bulk of the effect of the reflected wave occurs in early diastole rather than late systole.

Since pulse wave velocity is directly related to arterial wall stiffness, which is in turn related to blood pressure, it is not surprising that changes in pulse wave velocity after nifedipine paralleled the blood pressure response. On the other hand, since the dependence of pulse wave velocity on arterial stiffness and size differs from the more complex dependence of characteristic impedance (which also differs from that for compliance) on stiffness and size, one would not necessarily expect these three parameters (pulse wave velocity, characteristic impedance, and compliance) to be affected similarly by hypertension or nifedipine, which was the case.

Although the effect of wave reflections in the central aorta depends on the complex interplay of numerous factors, some studies have shown that the distal descending aorta near the takeoff of the renal arteries is the major site of wave reflections in both normotensive subjects and hypertensive patients.^{1 31} Although we can only speculate at this time, it could be that nifedipine has a prominent action in this region of the aorta. Finally, with regard to compliance, since the arterial compliances in the hypertensive patients are lower than normal even at matched blood pressures, this indicates that unlike pulse wave velocity, the decreased compliance is not a purely passive effect of the elevated blood pressure but rather an intrinsic change in the arterial wall probably related to increased smooth muscle tone. Although our lumped-parameter method of calculating arterial compliance obviates the ability to ascertain where along the vasculature the bulk of the compliance resides, one study in dogs showed that much of the arterial compliance is located in the very proximal aorta.³² Thus, it could be that nifedipine also has a major effect in this portion of the vasculature. While it has long been known that calcium channel blockade lowers peripheral resistance,^{15 16 17 19} our findings of an effect on other regions of the aorta are supported by recent evidence suggesting that calcium channel blockers directly vasodilate the aorta and many arteries in animals,^{33 34} as well as common carotid arteries^{20 21 35 36} and brachial arteries^{19 22} in humans. On the other hand, even though calcium channel blockade appears to have a widespread effect, it has been postulated that there exists some heterogeneity of response of the vascular smooth muscle of different parts of the arterial tree.³⁷ Although our measurement methods cannot directly address these regional effects, the results are compatible with this view.

While essential hypertension is undoubtedly the result of a complex interplay of circulating and tissue neural, hormonal, and endothelial mechanisms affecting the smooth muscle of the vascular wall, the ability of two classes of agents—nonspecific smooth muscle dilators and dihydropyridine calcium channel blockers—to essentially completely normalize the abnormal hemodynamic parameters provides some useful insight even though the specific mechanism or mechanisms for this increased tone remain unclear. Both abnormally high adrenergic tone and vascular tissue angiotensin levels have been postulated as mechanisms underlying essential hypertension.^{38 39 40 41 42} Since neither adrenergic blockade nor angiotensin-converting enzyme inhibition can completely normalize the vascular changes, it appears that factors other than the possible vasoconstriction produced via these two systems may play a more dominant role. Nevertheless, even though nifedipine appears to normalize the hemodynamic alterations, we cannot ascertain the extent to which other, unrelated vasoconstrictive mechanisms may still be extant.

Our results support two alternative mechanisms for the vascular abnormalities in essential hypertension. One mechanism relates to dysfunction of vascular endothelial cells. The important role of the endothelial cells is highlighted by recent reports indicating that there is a defect along the vascular endothelial nitric oxide synthase pathway in essential hypertensive patients.⁴³ Normotensive subjects given a nitric oxide synthase blocker became hypertensive, whereas little change in pressure was observed in hypertensive patients given the blocker. Nitroprusside is effective because it bypasses this pathway. However, it should be pointed out that a recent study does not support an important role of the endothelium in essential hypertension.⁴⁴ A second mechanism relates to an abnormally high calcium influx–dependent smooth muscle vasoconstriction. This possibility is supported by the observations that nifedipine had little or no pressure-lowering effect in normotensive subjects⁸ and that forearm resistance decreased less in normotensive subjects than hypertensive patients given a calcium channel blocker.^{9 10} Other supportive evidence is provided by the observations that an elevated free calcium concentration in platelets in patients with essential hypertension was decreased during long-term therapy with calcium channel blockers^{45 46} and that short-term reduction of blood pressure by sublingual nifedipine was accompanied by a decrease in free intracellular platelet calcium.⁴⁷ Although we cannot distinguish between these two mechanisms, it is likely that both nitroprusside and calcium channel blockade are effective because they act at the final common pathway, namely, the smooth muscle cell. In fact, the actions of these two drugs may not be as distinct as implied above because there is some evidence to suggest not only synergistic actions of calcium channel antagonists and endothelial cell–mediated vasodilation⁴⁸ but also that nitroprusside has some calcium channel antagonistic actions.^{49 50 51}

Some limitations to our study deserve discussion. Our method of estimating total arterial compliance, while having certain advantages over other methods, particularly the ability to account for the pressure dependence of compliance, also has limitations. First, since it is not feasible to measure arterial compliance directly, we can only estimate it using some model of the vasculature. Our method assumes a Windkessel model of the vasculature, which implies no wave reflections. Our other hemodynamic data, however, clearly indicate that excess wave reflections are present in the hypertensive vasculature. Thus, interpretations of the compliance data must be made keeping this model limitation in mind. Second, to account for the pressure dependence requires that one assume a value for the exponential coefficient, b. In this study we assumed a nominal value of -0.01 for both groups at baseline and after nifedipine in the hypertensive patients. We have shown⁴ that severe vasoconstriction will increase b to -0.005, and severe vasodilation will decrease it to -0.015. With the use of identical data, assuming these values of b will yield slightly lower or higher estimates of compliance, respectively. Thus, by selecting the same value for b in all conditions, we have if anything underestimated the differences in compliance between the groups at baseline. In addition, by assuming an unchanged value for b in the hypertensive patients after nifedipine, we are underestimating the increase in compliance due to the vasodilator actions of the drug. In contrast, our method uses the diastolic and total areas under the pressure-time curve. Since these can be affected by heart rate, some of the compliance increases observed with nifedipine could be directly due to the increase in heart rate. However, based on results from our earlier study,⁵² we expect this heart rate effect to be small. Specifically, in that study (see Table 2 in Reference 52⁵² ) we observed a 16% increase in compliance for a doubling of heart rate. Extrapolating those results to the present data, we would expect that the increase in heart rate of 22 beats per minute produced by nifedipine would overestimate by about 15% the observed increase in compliance. This small effect would not alter our major conclusions about the effect of nifedipine on arterial compliance.

Our results and conclusions pertain only to the short-term effects of the drug, which, although probably persisting for hours after sublingual administration,^{25 26} do not necessarily predict the long-term response. However, there are data suggesting that the long-term effects of continued therapy with oral nifedipine are predicted by the short-term response.⁵³ Thus, although there is no reason to suspect that long-term oral administration would produce different results than short-term sublingual administration, this needs to be verified.

Finally, because of the difficulties of identifying suitable subjects for invasive studies such as this, our normotensive data were obtained before we examined this particular hypertensive group. However, because the results from this hypertensive group are indistinguishable from our previous hypertensive groups^{2 4 5 7} and because all the data have been obtained in the same laboratory with essentially the same personnel and techniques over the years, we feel that the comparison between the normotensive subjects and hypertensive patients is statistically valid.

	Acknowledgments

 
This study was supported by grant DOH 83-HR-204 from the Department of Health, the Executive Yuan of the Republic of China.

	Footnotes

 
Reprint requests to Chih-Tai Ting, MD, PhD, Division of Cardiology, Taichung Veterans General Hospital, 160 Section 3, Chung-Kang Rd, Taichung, Taiwan.

Received July 14, 1994; first decision August 23, 1994; accepted February 21, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Ting CT, Chang MS, Wang SP, Chiang BN, Yin FCP. Regional pulse wave velocities in hypertensive and normotensive humans. Cardiovasc Res. 1990;24:865-872.

2. Ting CT, Brin KP, Lin SJ, Wang SP, Chang MS, Chiang BN, Yin FCP. Arterial hemodynamics in human hypertension. J Clin Invest. 1986;78:1462-1471.

3. Merillon JP, Fontenier GJ, Lerallut JF, Jaffrin MY, Motte GA, Genain CP, Gourgon RR. Aortic input impedance in normal man and arterial hypertension: its modification during changes in aortic pressure. Cardiovasc Res. 1982;16:646-656. [Medline] [Order article via Infotrieve]

4. Liu Z, Ting CT, Zhu S, Yin FCP. Aortic compliance in human hypertension. Hypertension. 1989;14:129-136. [Abstract/Free Full Text]

5. Ting CT, Chou CY, Chang MS, Wang SP, Chiang BN, Yin FCP. Arterial hemodynamics in human hypertension: effects of adrenergic blockade. Circulation. 1991;84:1049-1057. [Abstract/Free Full Text]

6. Simon AC, Safar ME, Levenson JA, London GM, Levy BI, Chau NP. An evaluation of large arteries compliance in man. Am J Physiol. 1979;237:H550-H554.

7. Ting CT, Yang TM, Chen JW, Chang MS, Yin FCP. Arterial hemodynamics in human hypertension: effects of angiotensin converting enzyme inhibition. Hypertension. 1993;22:839-846. [Abstract/Free Full Text]

8. Pedersen OL, Christensen NJ, Ramsch KD. Comparison of acute effects of nifedipine in normotensive and hypertensive man. J Cardiovasc Pharmacol. 1980;2:357-366. [Medline] [Order article via Infotrieve]

9. Robinson BF, Dobbs RJ, Bayley S. Response of forearm resistance vessels to verapamil and sodium nitroprusside in normotensive and hypertensive men: evidence for a functional abnormality of vascular smooth muscle in primary hypertension. Clin Sci. 1982;63:33-42. [Medline] [Order article via Infotrieve]

10. Hulthen UL, Bolli P, Amann FW, Kiowski W, Buhler FR. Enhanced vasodilatation in essential hypertension by calcium channel blockade with verapamil. Hypertension. 1982;4(suppl II):II-26-II-31.

11. Cohn JN. Calcium, vascular smooth muscle, and calcium entry blockers in hypertension. Ann Intern Med. 1983;98:806-809.

12. Robinson BF. Altered calcium handling as a cause of primary hypertension. J Hypertens. 1984;2:453-460. [Medline] [Order article via Infotrieve]

13. Fleckenstein A, Frey M, Fleckenstein-Grun G. Antihypertensive and arterial anticalcinotic effects of calcium antagonists. Am J Cardiol. 1986;57:1D-10D. [Medline] [Order article via Infotrieve]

14. Fleckenstein-Grun G, Frey M, Thimm F, Hofgartner W, Fleckenstein A. Calcium overload: an important cellular mechanism in hypertension and arteriosclerosis. Drugs. 1992;44(suppl 1):23-30.

15. Guazzi M, Olivari MT, Polese A, Fiorentini C, Magrini F, Moruzzi P. Nifedipine, a new antihypertensive with rapid action. Clin Pharmacol Ther. 1977;22:528-532. [Medline] [Order article via Infotrieve]

16. Olivari MT, Bartorelli C, Polese A, Fiorentini C, Moruzzi P, Guazzi MD. Treatment of hypertension with nifedipine, a calcium antagonistic agent. Circulation. 1979;59:1056-1062. [Abstract/Free Full Text]

17. Bonaduce D, Ferrara N, Petretta M, Romano E, Postiglione M, Rengo F, Condorelli M. Hemodynamic study of nifedipine administration in hypertensive patients. Am Heart J. 1983;105:865-867. [Medline] [Order article via Infotrieve]

18. Chang KC, Hsieh KS, Kuo TS, Chen HI. Effects of nifedipine on systemic hydraulic vascular load in patients with hypertension. Cardiovasc Res. 1990;24:719-726. [Medline] [Order article via Infotrieve]

19. Levenson JA, Safar ME, Simon AC, Boutier JA, Griener L. Systemic and arterial hemodynamic effects of nifedipine (20 mg) in mild-to-moderate hypertension. Hypertension. 1983;5(suppl V):V-57-V-60.

20. Safar ME, Pannier B, Laurent S, London GM. Calcium-entry blockers and arterial compliance in hypertension. J Cardiovasc Pharmacol. 1989;14(suppl 10):S1-S6.

21. Van Merode T, Van Bortel L, Smeets FAM, Bohm R, Mooij J, Rahn KH, Reneman RS. The effect of verapamil on carotid artery distensibility and cross-sectional compliance in hypertensive patients. J Cardiovasc Pharmacol. 1990;15:109-113. [Medline] [Order article via Infotrieve]

22. Levenson J, Simon AC, Safar ME, Bouthier J, Maarek BC. Large arteries in hypertension: acute effects of a new calcium entry blocker, nitrendipine. J Cardiovasc Pharmacol. 1984;6(suppl 7): S1006-S1010.

23. Ljung B. Vascular selectivity of felodipine. Drugs. 1985;29(suppl 2):46-58.

24. Yin FCP, Guzman PA, Brin KP, Maughan WL, Brinker JA, Traill TA, Weiss JL, Weisfeldt ML. Effect of nitroprusside on hydraulic vascular loads on the right and left ventricle of patients with heart failure. Circulation. 1983;67:1330-1339. [Abstract/Free Full Text]

25. Houston MC. Treatment of hypertensive urgencies and emergencies with nifedipine. Am Heart J. 1986;111:963-969. [Medline] [Order article via Infotrieve]

26. Beer N, Gallegos I, Cohen A, Klein N, Sonnenblick E, Frishman W. Efficacy of sublingual nifedipine in the acute treatment of systemic hypertension. Chest. 1981;79:571-574. [Abstract/Free Full Text]

27. Westerhof N, Sipkema P, Van Den Bos GC, Elzinga G. Forward and backward waves in the arterial system. Cardiovasc Res. 1972;6:648-656. [Medline] [Order article via Infotrieve]

28. Van Den Bos GC, Westerhof N, Randall OS. Pulse wave reflection: can it explain the differences between systemic and pulmonary pressure and flow waves? Circ Res. 1982;51:479-485. [Abstract/Free Full Text]

29. Liu Z, Brin KP, Yin FCP. Estimation of total arterial compliance: an improved method and evaluation of current methods. Am J Physiol. 1986;251:H588-H600. [Abstract/Free Full Text]

30. Yin FCP, Ting CT. Compliance changes in physiological and pathological states. J Hypertens. 1992;10(suppl 6):S31-S33.

31. Latham RD, Westerhof N, Sipkema P, Rubal BJ, Reuderink P, Murgo JP. Regional wave travel and reflections along the human aorta: a study with six simultaneous micromanometric pressures. Circulation. 1985;72:1257-1269. [Abstract/Free Full Text]

32. Campbell KB, Ringo JA, Klavano PA, Robinette JD, Alexander JE. Aortic bulb-aortic orifice hemodynamics in left ventricle-systemic arterial interaction. Am J Physiol. 1985;248:H132-H142.

33. Godfraind T, Miller R, Wibo M. Calcium antagonism and calcium entry blockade. Pharmacol Rev. 1986;38:321-416. [Medline] [Order article via Infotrieve]

34. Yano M, Kumada T, Matsuzaki M, Kohno M, Hiro T, Kohtoku S, Miura T, Katayama K, Ozaki M, Kusukawa R. Effect of diltiazem on aortic pressure-diameter relationship in dogs. Am J Physiol. 1989;256:H1580-H1587. [Abstract/Free Full Text]

35. Thuillez C, Gueret M, Duhaze P, Lhoste F, Kiechel JR, Giudicelli JF. Nicardipine: pharmacokinetics and effects on carotid and brachial blood flows in normal volunteers. Br J Clin Pharmacol. 1984;18:837-847. [Medline] [Order article via Infotrieve]

36. Van Bortel LMAB, Van Merode T, Smeets FAM, Bohm ROB, Reneman RS. Antihypertensive treatment and vessel wall properties of large arteries. Basic Res Cardiol. 1991;86(suppl 1):91-95.

37. Bevan JA, Bevan RD, Hwa JJ, Owen MP, Tayo FM. Calcium regulation in vascular smooth muscle: is there a pattern to its variability within the arterial tree? J Cardiovasc Pharmacol. 1986;8(suppl 8):S71-S75.

38. Philipp T, Distler A, Cordes U. Sympathetic nervous system and blood-pressure control in essential hypertension. Lancet. 1978;2:959-963. [Medline] [Order article via Infotrieve]

39. Buhler FR, Amann FW, Bolli P, Hulthen L, Kiowski W, Landmann R, Burgisser E. Elevated adrenaline and increased alpha-adrenoceptor vasoconstriction in essential hypertension. J Cardiovasc Pharmacol. 1982;4:S134-S138.

40. Berecek KH, Kirk KA, Nagahama S, Oparil S. Sympathetic function in spontaneously hypertensive rats after chronic administration of captopril. Am J Physiol. 1987;252:H796-H806. [Abstract/Free Full Text]

41. Sealey JE, Blumenfeld JD, Bell GM, Pecker MS, Sommers SC, Laragh JH. On the renal basis for essential hypertension: nephron heterogeneity with discordant renin secretion and sodium excretion causing a hypertensive vasoconstriction-volume relationship. J Hypertens. 1988;6:763-777. [Medline] [Order article via Infotrieve]

42. Zimmerman BG. Adrenergic facilitation by angiotensin: does it serve a physiological function? Clin Sci. 1981;60:343-348. [Medline] [Order article via Infotrieve]

43. Panza JA, Casino PR, Kilcoyne CM, Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation. 1993;87:1468-1474. [Abstract/Free Full Text]

44. Cockcroft JR, Chowienczyk PJ, Benjamin N, Ritter JM. Preserved endothelium-dependent vasodilatation in patients with essential hypertension. N Engl J Med. 1994;330:1036-1040. [Abstract/Free Full Text]

45. Erne P, Bolli P, Burgisser E, Buhler FR. Correlation of platelet calcium with blood pressure: effect of antihypertensive therapy. N Engl J Med. 1984;310:1084-1088. [Abstract]

46. Lindner A, Kenny M, Meacham AJ. Effects of a circulating factor in patients with essential hypertension on intracellular free calcium in normal platelets. N Engl J Med. 1987;316:509-513. [Abstract]

47. Lenz T, Haller H, Ludersdorf M, Kribben A, Thiede M, Distler A, Philipp T. Free intracellular calcium in essential hypertension: effects of nifedipine and captopril. J Hypertens. 1985;3(suppl 3):S13-S15.

48. Vanhoutte PM. Vascular endothelium and Ca²⁺ antagonists. J Cardiovasc Pharmacol. 1988;12(suppl 6):S21-S28.

49. Blatter LA, Wier WG. Nitric oxide decreases [Ca²⁺] in vascular smooth muscle by inhibition of the calcium current. Cell Calcium. 1994;15:122-131. [Medline] [Order article via Infotrieve]

50. Magliola L, Jones AW. Sodium nitroprusside alters Ca²⁺ flux components and Ca²⁺-dependent fluxes of K⁺ and Cl^- in rat aorta. J Physiol (Lond). 1990;421:411-424. [Abstract/Free Full Text]

51. Clapp LH, Gurney AM. Modulation of calcium movements by nitroprusside in isolated vascular smooth muscle cells. Pflugers Arch. 1991;418:462-470. [Medline] [Order article via Infotrieve]

52. Yin FCP, Liu Z. Estimating arterial resistance and compliance during transient conditions in humans. Am J Physiol. 1989;257:H190-H197. [Abstract/Free Full Text]

53. Jennings AA, Jee LD, Smith JA, Commerford PJ, Opie LH. Acute effect of nifedipine on blood pressure and left ventricular ejection fraction in severely hypertensive outpatients: predictive effects of acute therapy and prolonged efficacy when added to existing therapy. Am Heart J. 1986;111:557-563. [Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				D. Garcia, P. G. Camici, L.-G. Durand, K. Rajappan, E. Gaillard, O. E. Rimoldi, and P. Pibarot Impairment of coronary flow reserve in aortic stenosis J Appl Physiol, January 1, 2009; 106(1): 113 - 121. [Abstract] [Full Text] [PDF]

				G. F. Mitchell, Y. Lacourciere, J. M. O. Arnold, M. E. Dunlap, P. R. Conlin, and J. L. Izzo Jr Changes in Aortic Stiffness and Augmentation Index After Acute Converting Enzyme or Vasopeptidase Inhibition Hypertension, November 1, 2005; 46(5): 1111 - 1117. [Abstract] [Full Text] [PDF]

				G. F. Mitchell, Y. Lacourciere, J.-P. Ouellet, J. L. Izzo Jr, J. Neutel, L. J. Kerwin, A. J. Block, and M. A. Pfeffer Determinants of Elevated Pulse Pressure in Middle-Aged and Older Subjects With Uncomplicated Systolic Hypertension: The Role of Proximal Aortic Diameter and the Aortic Pressure-Flow Relationship Circulation, September 30, 2003; 108(13): 1592 - 1598. [Abstract] [Full Text] [PDF]

				B. P. Cholley, R. M. Lang, C. E. Korcarz, and S. G. Shroff Smooth muscle relaxation and local hydraulic impedance properties of the aorta J Appl Physiol, June 1, 2001; 90(6): 2427 - 2438. [Abstract] [Full Text] [PDF]

				G. F. Mitchell, L. A. Moye, E. Braunwald, J.-L. Rouleau, V. Bernstein, E. M. Geltman, G. C. Flaker, M. A. Pfeffer, and f. t. S. Investigators Sphygmomanometrically Determined Pulse Pressure Is a Powerful Independent Predictor of Recurrent Events After Myocardial Infarction in Patients With Impaired Left Ventricular Function Circulation, December 16, 1997; 96(12): 4254 - 4260. [Abstract] [Full Text]

				C.-H. Chen, C.-T. Ting, A. Nussbacher, E. Nevo, D. A. Kass, P. Pak, S.-P. Wang, M.-S. Chang, and F. C.P. Yin Validation of Carotid Artery Tonometry as a Means of Estimating Augmentation Index of Ascending Aortic Pressure Hypertension, February 1, 1996; 27(2): 168 - 175. [Abstract] [Full Text]

				C.-T. Ting, C.-H. Chen, M.-S. Chang, and F. C.P. Yin Short- and Long-term Effects of Antihypertensive Drugs on Arterial Reflections, Compliance, and Impedance Hypertension, September 1, 1995; 26(3): 524 - 530. [Abstract] [Full Text]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ting, C.-T. Articles by Yin, F. C. P. Search for Related Content PubMed PubMed Citation Articles by Ting, C.-T. Articles by Yin, F. C. P.