Neuromodulation Device

Abstract

This invention relates to devices, methods and substances for use in the treatment of hypertension and/or elevated blood pressure in a subject.

Claims

1-63. (canceled)

64. A device for stimulating the neural activity of a renal nerve, plexus or neurovascular bundle of a subject for treating hypertension and/or elevated blood pressure, and/or for treating a cardiorespiratory or cardiovascular disorder in a hypertensive subject, and/or for treating a cardiorespiratory or cardiovascular disorder in a subject with elevated blood pressure, the device comprising: one or more electrodes in signaling contact with the renal nerve of the subject; and a controller coupled to the one or more electrodes, the controller configured to control operation of the one or more electrodes to apply a signal in a periodic cycle such that the signal stimulates the neural activity of the renal nerve to produce a physiological response in the subject, wherein the physiological response comprises a decrease in mean arterial blood pressure.

65. A device according to claim 64, wherein the signal comprises an alternating current (AC) waveform of from 0.2 Hz to 20 Hz frequency.

66. A device according to claim 65, wherein the signal comprises a pulse width of 2 ms or less.

67. A device according to claim 66, wherein the signal comprises a pulse width of from 0.4 ms to 2 ms.

68. A device according to claim 65, wherein the signal comprises a current of 1.0 mA to 30 mA.

69. A device according to claim 65, wherein the AC waveform is a sinusoidal waveform.

70. A device according to claim 64, wherein the periodic cycle comprises at least one signal period, wherein the signal is applied during the signal period.

71. A device according to claim 70, wherein the signal is applied continuously during the signal period.

72. A device according to claim 70, wherein the signal is applied in a burst pattern during the signal period, wherein the burst pattern comprises at least one burst in which the signal is on, and at least one rest period in which the signal is off, wherein the rest period begins at the end of a first burst, and ends at the beginning of a subsequent burst.

73. A device according to claim 64, wherein the device further comprises means to detect one or more physiological parameters in the subject, wherein the controller is coupled to said means to detect, and causes said one or more electrodes to apply said signal when the physiological parameter is detected to be meeting or exceeding a predefined threshold value, and further wherein the one or more detected physiological parameters comprise one or more of: mean arterial blood pressure, respiration rate, vascular resistance, hindquarter aortic blood flow, cortical blood flow, diaphragmatic EMG, or air flow.

74. A method of treating hypertension and/or elevated blood pressure in a subject, and/or of treating a cardiorespiratory or cardiovascular disorder in a hypertensive subject, and/or of treating a cardiorespiratory or cardiovascular disorder in a subject with elevated blood pressure, comprising: i. implanting in the subject a device according to claim 64; ii. positioning the one or more electrodes of the device in signaling contact with the renal nerve, plexus or neurovascular bundle of the subject; and iii. activating the apparatus to stimulate neural activity of the renal nerve, plexus or neurovascular bundle in the subject.

75. A method according to claim 74, wherein the signal comprises an alternating current (AC) waveform of from 0.2 to 20 Hz frequency.

76. A method according to claim 75, wherein the signal comprises a pulse width of 2 ms or less.

77. A method according to claim 76, wherein the signal comprises a pulse width of from 0.4 ms to 2 ms.

78. A method according to claim 75, wherein the signal comprises a current of from 1.0 to 30 mA.

79. A method according to claim 75, wherein the AC waveform is a sinusoidal waveform.

80. A method according to claim 74, wherein the signal is applied in a periodic cycle comprising at least one signal period, wherein the signal is applied during the signal period.

81. A method according to claim 80, wherein the signal is applied continuously during the signal period.

82. A method according to claim 80, wherein the signal is applied in a burst pattern during the signal period, wherein the burst pattern comprises at least one burst in which the signal is on, and at least one rest period in which the signal is off, wherein the rest period begins at the end of a first burst, and ends at the beginning of a subsequent burst.

83. A method according to claim 74, further comprising the step of detecting one or more physiological parameters of the subject, wherein the signal is applied only when the detected physiological parameter meets or exceeds a predefined threshold value, wherein the device further comprises one or more detectors configured to detect the one or more physiological parameters, and further wherein the one or more detected physiological parameters comprises at least one of: mean arterial blood pressure, respiration rate, diaphragmatic EMG, hindquarter aortic blood flow, renal cortical blood flow, systemic vascular resistance, cortical vascular resistance, or air flow.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0191] Embodiments of the invention will be described, by way of example, with reference to the following drawings, in which:

[0192] FIG. 1 is a block diagram illustrating elements of a system for performing electrical modulation in the nerve according to the present invention.

[0193] FIG. 2 shows the effect of left renal nerve simulation on mean arterial pressure.

[0194] FIG. 3 shows the effect of left renal nerve stimulation on heart rate.

[0195] FIG. 4 shows the effect of left renal nerve stimulation on aortic (hindquarter) blood flow (ABF).

[0196] FIG. 5 shows the effect of left renal nerve stimulation on aortic (hindquarter) vascular resistance (AVR).

[0197] FIG. 6 shows the effect of left renal nerve stimulation on left renal cortical blood flow (CBF).

[0198] FIG. 7 shows the effect of left renal nerve stimulation on left renal cortical vascular resistance (CVR).

[0199] FIG. 8 shows the effect of left renal nerve stimulation on airway resistance (AR).

[0200] FIG. 9 shows the effect of left renal nerve stimulation on air flow (AF).

[0201] FIG. 10 shows the effect of left renal nerve stimulation on lower airway pressure (LAP).

[0202] FIG. 11 shows the effect of left renal nerve stimulation on upper airway pressure (UAP).

[0203] FIG. 12 shows the effect of left renal nerve stimulation on diaphragmatic EMG.

[0204] FIG. 13 shows the effect of left renal nerve stimulation on respiration rate (RR),

MODES FOR CARRYING OUT THE INVENTION

[0205] Study 1—Assessing the Effect of Renal Nerve Stimulation in Spontaneously Hypertensive Rats

[0206] The inventors set out to test the effect on hypertension of stimulating neural activity in a renal nerve of a spontaneously hypertensive rat (SHR).

[0207] Method

[0208] Male spontaneously hypertensive rats (25-28 weeks of age) were anaesthetized with 50 mg/kg intraperitoneal injection of sodium pentobarbital and maintained with an intravenous infusion of 10 mg/kg/hr sodium pentobarbital into the right femoral vein. Mean arterial blood pressure and heart rate were measured via an intravenous cannula into the right carotid artery, left renal cortical blood flow (CBF) and cortical vascular resistance (CVR), hindquarter aortic blood flow (ABF) and vascular resistance (AVR), upper (UAP) and lower (LAP) airway pressure, airway flow (AF), airway resistance (AR), respiration rate (RR) and diaphragmatic EMG (dEMG). An algorithm that calculates the number of peaks per minute was applied on the integrated diaphragmatic EMG activity to calculate respiratory rate. A bipolar electrode was placed around the left renal nerve and stimulation delivered using a grass stimulator; 5 times (5-6 minutes apart) at 5 Hz, 0.5 ms, 0.5 mA for 30 s and responses were averaged.

[0209] Cardiovascular responses to renal nerve stimulation exhibited reductions in mean arterial blood pressure (FIG. 2), heart rate (FIG. 3), aortic vascular resistance (FIG. 5) and cortical blood flow (FIG. 6). These responses were associated with increases in aortic blood flow (FIG. 4) and cortical vascular resistance (FIG. 7).

[0210] Respiratory responses to renal nerve stimulation exhibited increases in air flow (FIG. 9), respiration rate (FIG. 13) and diaphragmatic EMG (FIG. 12). These were accompanied by a decrease in airway resistance (FIG. 8). Lower airway pressure and upper airway pressure remained unaltered (FIGS. 10 and 11)

[0211] Discussion

[0212] The results show that, under hypertensive conditions, the role of renal nerves is not restricted to modulation of cardiovascular function but also extends to central neuroregulation of respiration and cardiorespiratory function.

[0213] Therefore, stimulation of a renal nerve may be a therapeutic strategy to alleviate hypertension, or symptoms thereof.

REFERENCES

[0214] 1 De Jong et al (2016) Hypertension 67:1211-1217 [0215] 2 Gao et al (2019) Hypertension Research doi.org/10.1038/s41440-019-0237-3 [0216] 3 Katholi et al (2009) Progress in cardiovascular disease 52:243-248 [0217] 4 Esler et al (2010) Lancet 376: 1903-1909 [0218] 5 Krum et al (2009) Lancet 373: 1275-81 [0219] 6 Bhatt et al (2014) New England Journal of Medicine 270: 1390-1401 [0220] 7 Persu et al (2015) Curr Opin Pharmacol 21:48-52 [0221] 8 Shun-Shin et al (2014) BMJ 348:g1937 [0222] [9] Kramer et al., Optogenetic pharmacology for control of native neuronal signaling proteins, 2013; 16(7):816-23.